# Dairy products and inflammation: A review of the clinical evidence

Allessandra Bordoni, Francesca Dansesi, Dominique Dardevet, Didier Dupont, Aida S. Fernandez, Doreen Gille, Claudia Nunes dos Santos, Paula Pinto, Roberta Re, Didier Remond, et al.

► To cite this version:

Allessandra Bordoni, Francesca Dansesi, Dominique Dardevet, Didier Dupont, Aida S. Fernandez, et al. Dairy products and inflammation: A review of the clinical evidence. Critical Reviews in Food Science and Nutrition, 2017, 57 (12), pp.2497-2525. 10.1080/10408398.2014.967385. hal-02629368

HAL Id: hal-02629368

https://hal.inrae.fr/hal-02629368

Submitted on 15 Jan 2024

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Distributed under a Creative Commons Attribution 4.0 International License
# Dairy products and inflammation: A review of the clinical evidence

Allessandra Bordoni, Francesca Dansesi, Dominique Dardevet, Didier Dupont, Aida S. Fernandez, Doreen Gille, Claudia Nunes dos Santos, Paula Pinto, Roberta Re, Didier Remond, et al.

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

Allessandra Bordoni, Francesca Dansesi, Dominique Dardevet, Didier Dupont, Aida S. Fernandez, et al.. Dairy products and inflammation: A review of the clinical evidence. Critical Reviews in Food Science and Nutrition, 2017, 57 (12), pp.2497-2525. 10.1080/10408398.2014.967385. hal-02629368

HAL Id: hal-02629368

https://hal.inrae.fr/hal-02629368v1

Submitted on 15 Jan 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

OPEN ACCESS

# Dairy products and inflammation: A review of the clinical evidence

Alessandra Bordoniª, Francesca Danesiª, Dominique Dardevetb,c, Didier Dupontd, Aida S. Fernandeze, Doreen Gillef, Claudia Nunes dos Santosg,h, Paula Pinto g,i, Roberta Ree, Didier Rémondb,c, Danit R. Shaharj, and Guy Vergèresf

ªDepartment of Agri-Food Sciences and Technologies, University of Bologna, Bologna, Italy; ᵇINRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, France; ᶜClermont Université, Université d'Auvergne, Unité de Nutrition Humaine, Clermont-Ferrand, France; ᶜINRA, Joint Research Unit 1253, Science & Technology of Milk and Egg Products, Rennes, France; ᶜDepartment of Human Nutrition, Leatherhead Food Research, Leatherhead, United Kingdom; ᶜAgroscope, Federal Department of Economic Affairs, Education and Research EAER, Berne, Switzerland; ᶜInstituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Lisbon, Portugal; ᵈInstituto de Biologia Experimental e Tecnológica, Oeiras, Portugal; ᵈEscola Superior Agrária, Inêsituto Politécnico de Santarém, Santarém Portugal; ᵈThe S. Daniel Abraham International Center for Health and Nutrition, Department of Public Health, Ben-Gurion University of the Negev, Beer-Sheva, Israel

**ABSTRACT**

Inflammation is a major biological process regulating the interaction between organisms and the environment, including the diet. Because of the increase in chronic inflammatory diseases, and in light of the immune-regulatory properties of breastfeeding, the ability of dairy products to modulate inflammatory processes in humans is an important but unresolved issue. Here, we report a systematic review of 52 clinical trials investigating inflammatory markers in relation to the consumption of dairy products. An inflammatory score (IS) was defined to quantitatively evaluate this interaction. The IS was significantly positive for the entire data set, indicating an anti-inflammatory activity in humans. When the subjects were stratified according to their health status, the IS was strongly indicative of an anti-inflammatory activity in subjects with metabolic disorders and of a pro-inflammatory activity in subjects allergic to bovine milk. Stratifying the data by product categories associated both low-fat and high-fat products, as well as fermented products, with an anti-inflammatory activity. Remarkably, the literature is characterized by a large gap in knowledge on bioavailability of bioactive nutrients. Future research should thus better combine food and nutritional sciences to adequately follow the fate of these nutrients along the gastrointestinal and metabolic axes.

**KEYWORDS**

Milk; cheese; yoghurt;
immune system; chronic
diseases; obesity; health

**Introduction**

Immunity is a major process among the biological phenomena regulating the interaction of higher organisms with the environment, in particular as it provides a mechanism by which external agents are either rejected (e.g., phagocytosis of pathogens) or internalized (e.g., oral tolerance to ingested food) by the organism. One main expression of the immune system is its ability to mount an inflammatory reaction to these stimuli. If sustained, the inflammatory response may, however, turn against the host's own tissues, leading to a range of chronic inflammatory diseases that have now supplanted infectious diseases worldwide (Hunter and Reddy, 2013). The Global Business Intelligence Research estimated the global inflammatory therapeutics market to reach $85.9 billion in 2017 (Global Business Intelligence Research, 2011).

Most chronic inflammatory diseases (e.g., obesity, diabetes) as well as allergic diseases are strongly influenced by nutrition, the metabolism of food being intimately associated with inflammatory processes (Hotamisligil, 2006). In addition,

postprandial inflammation is part of the normal stress reaction of the cell in response to the ingestion of food (Hernandez-Aguilera et al., 2013). Nutrients thus appear to be able to modulate the inflammatory status of humans and inflammation has consequently emerged as an important research topic in food and nutrition sciences (Calder et al., 2011; Calder et al., 2013; Klop et al., 2012).

Dairy products represent a particularly interesting food type to study in the context of inflammation. From an evolutionary point of view, ancestors of mammalians may have possessed primitive apocrine-like glands in the skin, approximately 310 million years ago, that incorporated elements of the innate immune system in providing protection to the skin and to eggs that were moistened (Oftedal, 2012). Because of its ability to support the development of the immune system of the infant, to inhibit bacterial growth (e.g., lactoferrin) and to deliver anti-oxidative protection (e.g., vitamins or glutathione), the potential of maternal milk to inhibit inflammation in the offspring has

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>
<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

OPEN ACCESS

# Dairy products and inflammation: A review of the clinical evidence

Alessandra Bordoniª, Francesca Danesiª, Dominique Dardevetb,c, Didier Dupontd, Aida S. Fernandeze, Doreen Gillef, Claudia Nunes dos Santosg,h, Paula Pinto g,i, Roberta Ree, Didier Rémondb,c, Danit R. Shaharj, and Guy Vergèresf

ªDepartment of Agri-Food Sciences and Technologies, University of Bologna, Bologna, Italy; ᵇINRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, France; ᶜClermont Université, Université d'Auvergne, Unité de Nutrition Humaine, Clermont-Ferrand, France; ᶜINRA, Joint Research Unit 1253, Science & Technology of Milk and Egg Products, Rennes, France; ᵈDepartment of Human Nutrition, Leatherhead Food Research, Leatherhead, United Kingdom; ᵉAgroscope, Federal Department of Economic Affairs, Education and Research EAER, Berne, Switzerland; ᵈInstituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Lisbon, Portugal; ᵈInstituto de Biologia Experimental e Tecnológica, Oeiras, Portugal; ᵈEscola Superior Agrária, Inêsituto Politécnico de Santarém, Santarém Portugal; ᵈThe S. Daniel Abraham International Center for Health and Nutrition, Department of Public Health, Ben-Gurion University of the Negev, Beer-Sheva, Israel

**ABSTRACT**

Inflammation is a major biological process regulating the interaction between organisms and the environment, including the diet. Because of the increase in chronic inflammatory diseases, and in light of the immune-regulatory properties of breastfeeding, the ability of dairy products to modulate inflammatory processes in humans is an important but unresolved issue. Here, we report a systematic review of 52 clinical trials investigating inflammatory markers in relation to the consumption of dairy products. An inflammatory score (IS) was defined to quantitatively evaluate this interaction. The IS was significantly positive for the entire data set, indicating an anti-inflammatory activity in humans. When the subjects were stratified according to their health status, the IS was strongly indicative of an anti-inflammatory activity in subjects with metabolic disorders and of a pro-inflammatory activity in subjects allergic to bovine milk. Stratifying the data by product categories associated both low-fat and high-fat products, as well as fermented products, with an anti-inflammatory activity. Remarkably, the literature is characterized by a large gap in knowledge on bioavailability of bioactive nutrients. Future research should thus better combine food and nutritional sciences to adequately follow the fate of these nutrients along the gastrointestinal and metabolic axes.

**KEYWORDS**

Milk; cheese; yoghurt;
immune system; chronic
diseases; obesity; health

**Introduction**

Immunity is a major process among the biological phenomena regulating the interaction of higher organisms with the environment, in particular as it provides a mechanism by which external agents are either rejected (e.g., phagocytosis of pathogens) or internalized (e.g., oral tolerance to ingested food) by the organism. One main expression of the immune system is its ability to mount an inflammatory reaction to these stimuli. If sustained, the inflammatory response may, however, turn against the host's own tissues, leading to a range of chronic inflammatory diseases that have now supplanted infectious diseases worldwide (Hunter and Reddy, 2013). The Global Business Intelligence Research estimated the global inflammatory therapeutics market to reach $85.9 billion in 2017 (Global Business Intelligence Research, 2011).

Most chronic inflammatory diseases (e.g., obesity, diabetes) as well as allergic diseases are strongly influenced by nutrition, the metabolism of food being intimately associated with inflammatory processes (Hotamisligil, 2006). In addition,

postprandial inflammation is part of the normal stress reaction of the cell in response to the ingestion of food (Hernandez-Aguilera et al., 2013). Nutrients thus appear to be able to modulate the inflammatory status of humans and inflammation has consequently emerged as an important research topic in food and nutrition sciences (Calder et al., 2011; Calder et al., 2013; Klop et al., 2012).

Dairy products represent a particularly interesting food type to study in the context of inflammation. From an evolutionary point of view, ancestors of mammalians may have possessed primitive apocrine-like glands in the skin, approximately 310 million years ago, that incorporated elements of the innate immune system in providing protection to the skin and to eggs that were moistened (Oftedal, 2012). Because of its ability to support the development of the immune system of the infant, to inhibit bacterial growth (e.g., lactoferrin) and to deliver anti-oxidative protection (e.g., vitamins or glutathione), the potential of maternal milk to inhibit inflammation in the offspring has

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>
<figure><img src="image_7.png" /></figure>

consequently raised interest (Lepage and Van de Perre, 2012). Part of these properties may be maintained when boundaries across species and life cycles are crossed, i.e. in the context of the consumption of dairy products by human adults (Labonte et al., 2013). In addition, the importance of food in modulating the gut microbiota, a key regulator of immunity, has become more evident during the last decade (Kau et al., 2011). Milk is a natural and culturally accepted vector to deliver supplements to the human organism (Ceapa et al., 2013), in particular prebiotic and probiotics that both modulate the microflora and thus influence immune and inflammatory processes. Besides, milk is amenable to a wide range of technological transformations, including its fermentation by lactic acid bacteria to produce fermented dairy products such as yoghurt or cheese whose metabolites may further modulate the ability of milk to influence immune processes in humans (Augustin and Uda-bage, 2007). Milk and dairy products are major food products in human nutrition, amounting to 14% of the caloric intake in developed countries (FAO, 2013b). The Food and Agriculture Organization (FAO) forecasted a world milk production of 784 million tons in 2013 (FAO, 2013a), which amounts to an average of circa 100 L milk per year per human being. An evaluation of the ability of dairy products to modulate inflammatory processes in humans is, thus justified.

Studies addressing the impact of dairy products on inflammatory processes present a contradictory landscape. Indeed, dairy products were reported to be beneficial, inactive, as well as detrimental. For illustration, the ATTICA study reported an inverse relationship between the consumption of dairy products and markers of the metabolic syndrome, including the inflammatory markers associated with this syndrome (Panagiotakos et al., 2010). On the other hand, the relatively high concentrations of saturated fat and dietary antigens in cow milk have raised concern and some scientists claimed that dairy products are a major cause in the development of chronic inflammatory disorders and autoimmune diseases (Melnik, 2009). These opposite statements reflect the wide spectrum of information available in the scientific literature on the relationship between the consumption of dairy products and inflammation. Indeed, many articles have been published on this relationship, but systematic reviews are scarce (Labonte et al., 2013) and incomplete. The association between the consumption of dairy products and inflammation in humans, thus merits clarification for the following reasons: (i) milk and dairy products play qualitatively and quantitatively an important role in human nutrition (Haug et al., 2007); (ii) inflammation, in particular low-grade systemic inflammation, has a significant impact on human health and longevity (Candore et al., 2010); (iii) nutrient metabolism and inflammation are mechanistically closely interconnected (Hotamisligil, 2006; Calder et al., 2011; Klop et al., 2012; Calder et al., 2013; Hernandez-Aguilera et al., 2013).

The property of the foods investigated in human nutritional trials are often poorly documented what renders an objective evaluation of the clinical outcome very difficult. This review aimed to narrow the gap between food science and nutritional

science. The information usually provided by reviews on medical topics (Moher et al., 2009) was thus complemented with product-related information that is usually requested by regulatory authorities to document the functional properties of the food products and nutrients of interest (EFSA Panel on Dietetic Products Nutrition and Allergies, 2011; FDA Office of Nutrition Labeling and Dietary Supplements, 2009).

The specific goals of this review are to:

* Present a structured overview of published original human studies investigating the impact of the consumption of dairy products on inflammatory processes;

* Develop a method to quantitatively evaluate the results extracted from these studies;

* Use this method, in order to evaluate whether pro- or anti-inflammatory properties of dairy products can be concluded from these studies;

* Identify research gaps that should be filled to allow a better evaluation of the anti- or pro-inflammatory properties of specific dairy products in specific human populations.

## Methods

### Literature search strategy

A review was conducted using Medline and Scopus search that includes all original research articles written in English, published since January 1990, on the relationship between inflammatory markers and the consumption of dairy products in humans.

A first Medline search was conducted on February 13, 2013. A search of the Scopus database was also conducted on June 18, 2013 and the entries not identified in Medline were included into the evaluation. Medline and Scopus were searched again on December 10, 2013 to identify and include additional articles published until November 30, 2013. The search strategies were as follows:

* Medline search strategy. (milk OR cheese OR yog\* OR dair\*) AND inflam\* NOT ("breast milk" NOT "human milk") NOT review\*. Filters: Case Reports; Clinical Trial; Clinical Trial, Phase I; Clinical Trial, Phase II; Comparative Study; Controlled Clinical Trial; Multicenter Study; Randomized Controlled Trial; Evaluation Studies; Meta-Analysis; Systematic Reviews; Humans; English;

* Scopus search strategy. (((TITLE-ABS-KEY(milk OR cheese OR yog\* OR dair\*) AND TITLE-ABS-KEY(inflam\*) AND NOT TITLE-ABS-KEY("breast milk" not "human milk")) AND DOCTYPE(ar)) AND (humans)) AND (inflammation) AND (LIMIT-TO(LANGauge, "English")).

### Data collection process

Figure 1 shows the flow diagram with the five phases leading to the quantitative analysis of the 52 clinical studies. Seventy-eight study results were extracted from these clinical studies to measure the impact of dairy products on inflammation in humans.

Phase 1. For phase 1, all studies identified by the search strategy were randomly split into six groups. Each group of studies was distributed to reviewers of one partner institution. Based on title and abstract, only studies that were clearly
<figure><img src="image_8.png" /></figure>

consequently raised interest (Lepage and Van de Perre, 2012). Part of these properties may be maintained when boundaries across species and life cycles are crossed, i.e. in the context of the consumption of dairy products by human adults (Labonte et al., 2013). In addition, the importance of food in modulating the gut microbiota, a key regulator of immunity, has become more evident during the last decade (Kau et al., 2011). Milk is a natural and culturally accepted vector to deliver supplements to the human organism (Ceapa et al., 2013), in particular prebiotic and probiotics that both modulate the microflora and thus influence immune and inflammatory processes. Besides, milk is amenable to a wide range of technological transformations, including its fermentation by lactic acid bacteria to produce fermented dairy products such as yoghurt or cheese whose metabolites may further modulate the ability of milk to influence immune processes in humans (Augustin and Uda-bage, 2007). Milk and dairy products are major food products in human nutrition, amounting to 14% of the caloric intake in developed countries (FAO, 2013b). The Food and Agriculture Organization (FAO) forecasted a world milk production of 784 million tons in 2013 (FAO, 2013a), which amounts to an average of circa 100 L milk per year per human being. An evaluation of the ability of dairy products to modulate inflammatory processes in humans is, thus justified.

Studies addressing the impact of dairy products on inflammatory processes present a contradictory landscape. Indeed, dairy products were reported to be beneficial, inactive, as well as detrimental. For illustration, the ATTICA study reported an inverse relationship between the consumption of dairy products and markers of the metabolic syndrome, including the inflammatory markers associated with this syndrome (Panagiotakos et al., 2010). On the other hand, the relatively high concentrations of saturated fat and dietary antigens in cow milk have raised concern and some scientists claimed that dairy products are a major cause in the development of chronic inflammatory disorders and autoimmune diseases (Melnik, 2009). These opposite statements reflect the wide spectrum of information available in the scientific literature on the relationship between the consumption of dairy products and inflammation. Indeed, many articles have been published on this relationship, but systematic reviews are scarce (Labonte et al., 2013) and incomplete. The association between the consumption of dairy products and inflammation in humans, thus merits clarification for the following reasons: (i) milk and dairy products play qualitatively and quantitatively an important role in human nutrition (Haug et al., 2007); (ii) inflammation, in particular low-grade systemic inflammation, has a significant impact on human health and longevity (Candore et al., 2010); (iii) nutrient metabolism and inflammation are mechanistically closely interconnected (Hotamisligil, 2006; Calder et al., 2011; Klop et al., 2012; Calder et al., 2013; Hernandez-Aguilera et al., 2013).

The property of the foods investigated in human nutritional trials are often poorly documented what renders an objective evaluation of the clinical outcome very difficult. This review aimed to narrow the gap between food science and nutritional

science. The information usually provided by reviews on medical topics (Moher et al., 2009) was thus complemented with product-related information that is usually requested by regulatory authorities to document the functional properties of the food products and nutrients of interest (EFSA Panel on Dietetic Products Nutrition and Allergies, 2011; FDA Office of Nutrition Labeling and Dietary Supplements, 2009).

The specific goals of this review are to:

* Present a structured overview of published original human studies investigating the impact of the consumption of dairy products on inflammatory processes;

* Develop a method to quantitatively evaluate the results extracted from these studies;

* Use this method, in order to evaluate whether pro- or anti-inflammatory properties of dairy products can be concluded from these studies;

* Identify research gaps that should be filled to allow a better evaluation of the anti- or pro-inflammatory properties of specific dairy products in specific human populations.

# Methods

## Literature search strategy

A review was conducted using Medline and Scopus search that includes all original research articles written in English, published since January 1990, on the relationship between inflammatory markers and the consumption of dairy products in humans.

A first Medline search was conducted on February 13, 2013. A search of the Scopus database was also conducted on June 18, 2013 and the entries not identified in Medline were included into the evaluation. Medline and Scopus were searched again on December 10, 2013 to identify and include additional articles published until November 30, 2013. The search strategies were as follows:

* Medline search strategy. (milk OR cheese OR yog* OR dair*) AND inflam* NOT ("breast milk" NOT "human milk") NOT review*. Filters: Case Reports; Clinical Trial; Clinical Trial, Phase I; Clinical Trial, Phase II; Comparative Study; Controlled Clinical Trial; Multicenter Study; Randomized Controlled Trial; Evaluation Studies; Meta-Analysis; Systematic Reviews; Humans; English;

* Scopus search strategy. (((TITLE-ABS-KEY(milk OR cheese OR yog* OR dair*) AND TITLE-ABS-KEY(inflam*) AND NOT TITLE-ABS-KEY("breast milk" not "human milk")) AND DOCTYPE(ar)) AND (humans)) AND (inflammation) AND (LIMIT-TO(LANGUAGES, "English")).

## Data collection process

Figure 1 shows the flow diagram with the five phases leading to the quantitative analysis of the 52 clinical studies. Seventy-eight study results were extracted from these clinical studies to measure the impact of dairy products on inflammation in humans.

Phase 1. For phase 1, all studies identified by the search strategy were randomly split into six groups. Each group of studies was distributed to reviewers of one partner institution. Based on title and abstract, only studies that were clearly
<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /><figcaption>**Figure 1.** Flow diagram of the five phases conducted to establish an IS for the 78 study results extracted from the 52 human studies in which the impact of dairy products on inflammation was investigated.</figcaption></figure>

associated with inflammatory mediators and with the ingestion of dairy products (i.e., milk, cheese, yoghurt, fermented milk, whey products, and other dairy foods) by humans, were kept for phase 2 of the review process. Studies investigating human milk and/or breastfeeding, were excluded. Studies in which dairy products were used as a vector to deliver ingredients such as probiotics, prebiotics or bioactive nutrients such as vitamins or peptides, were excluded. However, studies were included if non-supplemented dairy products were used as control products and if information was available on the impact of these control products on inflammatory markers compared to the baseline values (e.g., comparison before and after treatment). Studies investigating isolated dairy proteins or lipids, were excluded. The information derived from the abstracts and the titles was summarized in tabulated form (see section “Tabulated summary” below) and used for selecting the studies to be evaluated in phase 2 of the review.

**Phase 2.** The studies retained, based on their abstracts, were again randomly split into six groups and each group of studies was distributed to reviewers of one partner institution. The tabulated summary was completed, based on the content of the articles. A workshop took place in Lisbon on June 4–6, 2013 during which the reviewers presented an overview of their evaluation of the studies. Based on these presentations the content and form of the tabulated summary were refined.

**Phase 3.** The study results were grouped into five subject categories (see section “Tabulated summary” below) and each group of studies was accordingly redistributed to the reviewers of one partner institution. The studies were re-evaluated to finalize the content of the tabulated summary. Finally, a non-systematic search of the literature was conducted by the reviewers, for each of the five subject categories, to identify human studies that may not have been identified by the previous searches. The form of the complementary search strategy was left to the discretion of the reviewing authors and no additional studies were identified.

**Phase 4.** The tabulated summary of all studies was finally revised by two reviewers from one institution, in order to harmonize its content. In particular, the status of each column in the tabulated summary was changed from the description of one clinical study per column to the description of one study result per column. This

adaptation was motivated by the fact that several studies reported results for more than one dairy product or more than one subject category, each of these study results needing a separate evaluation.

**Phase 5.** A quantitative estimation of the ability of dairy products to modulate inflammation was conducted, for each study result, based on the content of the tabulated summary and on the establishment of the inflammatory score (IS) (see the next two sections).

## Tabulated summary

The tabulated summary was not only defined in broad compliance with the reporting of systematic reviews according to the PRISMA checklist (Moher et al., 2009), but also integrated elements requested by regulatory authorities for the preparation of applications on health claims (EFSA Panel on Dietetic Products Nutrition and Allergies, 2011; FDA Office of Nutrition Labeling and Dietary Supplements, 2009). The tabulated summary contains the following descriptors:

**Reference**—Presents the bibliographic reference of the clinical trial from which each study result was extracted. Studies for which more than one study result was extracted are indicated and the study results are numbered.

**Subject category**—The articles are grouped into five categories based on the clinical status of the subjects enrolled in the selected studies:

* HEALTH, for studies investigating healthy subjects;

* MET, for studies on subjects with metabolic and cardiovascular disorders, including obesity and overweight;

* GIT, for studies enrolling subjects with non-allergic gastrointestinal disorders;

* HYPER, for studies with subjects suffering from food hypersensitivity, in particular allergy to dairy products, but not from lactose intolerance;

* OTHERS, for studies describing subjects with all other disorders, in particular lung disease, joint disease, and infection.

Articles discussing both gastrointestinal disorders and food hypersensitivity are included in the category HYPER.

**Target indication**—Potential health benefit, clinical indication, or safety issue investigated in the study.
<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /><figcaption>**Figure 1.** Flow diagram of the five phases conducted to establish an IS for the 78 study results extracted from the 52 human studies in which the impact of dairy products on inflammation was investigated.</figcaption></figure>

associated with inflammatory mediators and with the ingestion of dairy products (i.e., milk, cheese, yoghurt, fermented milk, whey products, and other dairy foods) by humans, were kept for phase 2 of the review process. Studies investigating human milk and/or breastfeeding, were excluded. Studies in which dairy products were used as a vector to deliver ingredients such as probiotics, prebiotics or bioactive nutrients such as vitamins or peptides, were excluded. However, studies were included if non-supplemented dairy products were used as control products and if information was available on the impact of these control products on inflammatory markers compared to the baseline values (e.g., comparison before and after treatment). Studies investigating isolated dairy proteins or lipids, were excluded. The information derived from the abstracts and the titles was summarized in tabulated form (see section “Tabulated summary” below) and used for selecting the studies to be evaluated in phase 2 of the review.

**Phase 2.** The studies retained, based on their abstracts, were again randomly split into six groups and each group of studies was distributed to reviewers of one partner institution. The tabulated summary was completed, based on the content of the articles. A workshop took place in Lisbon on June 4–6, 2013 during which the reviewers presented an overview of their evaluation of the studies. Based on these presentations the content and form of the tabulated summary were refined.

**Phase 3.** The study results were grouped into five subject categories (see section “Tabulated summary” below) and each group of studies was accordingly redistributed to the reviewers of one partner institution. The studies were re-evaluated to finalize the content of the tabulated summary. Finally, a non-systematic search of the literature was conducted by the reviewers, for each of the five subject categories, to identify human studies that may not have been identified by the previous searches. The form of the complementary search strategy was left to the discretion of the reviewing authors and no additional studies were identified.

**Phase 4.** The tabulated summary of all studies was finally revised by two reviewers from one institution, in order to harmonize its content. In particular, the status of each column in the tabulated summary was changed from the description of one clinical study per column to the description of one study result per column. This

adaptation was motivated by the fact that several studies reported results for more than one dairy product or more than one subject category, each of these study results needing a separate evaluation.

**Phase 5.** A quantitative estimation of the ability of dairy products to modulate inflammation was conducted, for each study result, based on the content of the tabulated summary and on the establishment of the inflammatory score (IS) (see the next two sections).

## Tabulated summary

The tabulated summary was not only defined in broad compliance with the reporting of systematic reviews according to the PRISMA checklist (Moher et al., 2009), but also integrated elements requested by regulatory authorities for the preparation of applications on health claims (EFSA Panel on Dietetic Products Nutrition and Allergies, 2011; FDA Office of Nutrition Labeling and Dietary Supplements, 2009). The tabulated summary contains the following descriptors:

**Reference**—Presents the bibliographic reference of the clinical trial from which each study result was extracted. Studies for which more than one study result was extracted are indicated and the study results are numbered.

**Subject category**—The articles are grouped into five categories based on the clinical status of the subjects enrolled in the selected studies:

* HEALTH, for studies investigating healthy subjects;

* MET, for studies on subjects with metabolic and cardiovascular disorders, including obesity and overweight;

* GIT, for studies enrolling subjects with non-allergic gastrointestinal disorders;

* HYPER, for studies with subjects suffering from food hypersensitivity, in particular allergy to dairy products, but not from lactose intolerance;

* OTHERS, for studies describing subjects with all other disorders, in particular lung disease, joint disease, and infection.

Articles discussing both gastrointestinal disorders and food hypersensitivity are included in the category HYPER.

**Target indication**—Potential health benefit, clinical indication, or safety issue investigated in the study.
**Target population**—Population targeted by the target indication.

**Fat content**—The dairy product investigated is categorized as ‘high-fat’, ‘low-fat’, or, otherwise, “not available (n.a.)”. The classification between high-fat and low-fat dairy products was made based on the information given in the corresponding paper. When the authors did not mention the fat content of the investigated product or when they did not use special terminology such as “fat-reduced, skimmed, semi-skimmed, high-fat, normal-fat,” the study product was classified as “n.a.”.

**Fermentation**—The dairy product investigated is categorized as “fermented,” “non-fermented,” or, otherwise, “n.a.”.

**Test and control products**—Details on the foods used as test or control products (dairy or non-dairy) are reported. Only studies using dairy food products as the test or the control product are considered. For studies with more than one dairy product investigated, each dairy product is reported as a separate study result (one column for each product).

**Test and control subjects**—For each group enrolled in the study as test or control subjects, the number of subjects in the group, their gender (if available), age (including range) and health or disease status is provided (if appropriate). For studies with more than one group of subject investigated, each group is reported as a separate study result (one column for each group).

**Diet**—The composition of the dairy products investigated, its quantity, and the duration of the dairy products consumption during the study period is reported.

**Controlled dairy test**—Studies that are controlled and in which a dairy product is the test product are labeled as “yes,” otherwise as “no”.

**Randomization**—Studies that are randomized are labeled as “randomized,” otherwise either “non-randomized” or “n.a.”.

**Time factor**—The studies are categorized as either “longitudinal” or “cross-sectional”.

**Study results**—The study results are generally expressed by presenting the food products investigated, the inflammatory markers measured, and the direction of the effect. Depending on the study design, seven different types of outcome are presented:

* Outcome 1 [Dairy vs Control], when dairy products are the test products and compared against control products;

* Outcome 2 [Dairy (end time vs baseline)], when dairy products at baseline are compared under fasting conditions over several days (dn vs d0), weeks (wn vs w0), or months (mn vs m0);

* Outcome 3 [Dairy (xh vs 0h)], when dairy products at baseline are compared over several hours in challenge postprandial studies (nh vs 0h);

* Outcome 4 [Dairy (test subjects vs control subjects)], for studies in which the effects of dairy products are compared in two populations of subjects;

* Outcome 5 [Dairy : Correlation], for studies in which the consumption of dairy products is quantitatively correlated to inflammatory markers. If available, adjustments for confounders are indicated;

* Outcome 6 [Dietary pattern 1 vs Dietary pattern 2], for studies in which the relative impact on inflammation of

different dietary patterns containing dairy products is evaluated;

* Outcome 7 [Dietary patterns : Correlation], for studies in which dietary patterns containing dairy products are correlated with inflammatory markers. If available, adjustments for confounders are indicated.

The type of outcome (1-7) is indicated for each study result.

The strength of the effects was expressed by the direction of the statistically significant change in the inflammatory signal (→: no statistically significant effect; ↑: statistically significant increase; ↓: statistically significant decrease) or of the correlations (corr→: no statistically significant correlation; corr↑: statistically significant positive correlation; corr↓: statistically significant negative correlation). The criteria for statistical significance are indicated as reported in each study but are not documented in this review. To avoid bias, care was taken to document all results obtained with the inflammatory markers, including results in which no statistically significant changes were observed. Inflammatory markers are shown in italics in the table if their increase are associated with an anti-inflammatory effect.

**Net change in inflammatory markers**—The inflammatory markers shown in Table 1 were considered for inclusion in this review. This list was extracted from recently published work that compiles a comprehensive list of inflammatory markers reported in nutritional studies (Calder et al., 2013). It offered clear harmonizing criteria for inclusion or exclusion of the IS that were evaluated by each reviewer. The net change in inflammatory markers was calculated for each study result by summing up the changes in all inflammatory results measured. A value of -1 was attributed for each change in inflammatory parameters contributing to a pro-inflammatory status (e.g., an increase in a pro-inflammatory parameter or a decrease in an anti-inflammatory parameter). A value of +1 was attributed for each change in inflammatory parameters contributing to an anti-inflammatory status (e.g., a decrease in a pro-inflammatory parameter or an increase in an anti-inflammatory parameter). A value of 0 was attributed for study results in which the inflammatory markers did not change. None of the 78 study results for which the net change in inflammatory markers was measured provided results in which both anti- and pro-inflammatory changes were observed together.

**Sustainability of effect over time**—This line reports whether sustainability of the inflammatory effect over time was “investigated,” “discussed,” or “not discussed”. A study result investigating and reporting a maintenance of the inflammatory effect after a washout phase of at least one week is labeled “yes”.

**Dose-response**—This line reports whether a dose-response relationship was investigated (yes) or not (no). If yes, a short description is presented.

**Bioavailability data**—Label as “yes” if information is provided on bioavailability of dairy product components, otherwise label as “no”. In cases where bioavailability data was obtained in the study (yes), a short presentation of the information is presented in the table.

**Biological plausibility**—This line presents whether the mechanism of action by which the dairy constituents exert their anti- or pro-inflammatory effects was discussed or
**Target population**—Population targeted by the target indication.

**Fat content**—The dairy product investigated is categorized as ‘high-fat’, ‘low-fat’, or, otherwise, “not available (n.a.)”. The classification between high-fat and low-fat dairy products was made based on the information given in the corresponding paper. When the authors did not mention the fat content of the investigated product or when they did not use special terminology such as “fat-reduced, skimmed, semi-skimmed, high-fat, normal-fat,” the study product was classified as “n.a.”.

**Fermentation**—The dairy product investigated is categorized as “fermented,” “non-fermented,” or, otherwise, “n.a.”.

**Test and control products**—Details on the foods used as test or control products (dairy or non-dairy) are reported. Only studies using dairy food products as the test or the control product are considered. For studies with more than one dairy product investigated, each dairy product is reported as a separate study result (one column for each product).

**Test and control subjects**—For each group enrolled in the study as test or control subjects, the number of subjects in the group, their gender (if available), age (including range) and health or disease status is provided (if appropriate). For studies with more than one group of subject investigated, each group is reported as a separate study result (one column for each group).

**Diet**—The composition of the dairy products investigated, its quantity, and the duration of the dairy products consumption during the study period is reported.

**Controlled dairy test**—Studies that are controlled and in which a dairy product is the test product are labeled as “yes,” otherwise as “no”.

**Randomization**—Studies that are randomized are labeled as “randomized,” otherwise either “non-randomized” or “n.a.”.

**Time factor**—The studies are categorized as either “longitudinal” or “cross-sectional”.

**Study results**—The study results are generally expressed by presenting the food products investigated, the inflammatory markers measured, and the direction of the effect. Depending on the study design, seven different types of outcome are presented:

* Outcome 1 [Dairy vs Control], when dairy products are the test products and compared against control products;

* Outcome 2 [Dairy (end time vs baseline)], when dairy products at baseline are compared under fasting conditions over several days (dn vs d0), weeks (wn vs w0), or months (mn vs m0);

* Outcome 3 [Dairy (xh vs 0h)], when dairy products at baseline are compared over several hours in challenge postprandial studies (nh vs 0h);

* Outcome 4 [Dairy (test subjects vs control subjects)], for studies in which the effects of dairy products are compared in two populations of subjects;

* Outcome 5 [Dairy : Correlation], for studies in which the consumption of dairy products is quantitatively correlated to inflammatory markers. If available, adjustments for confounders are indicated;

* Outcome 6 [Dietary pattern 1 vs Dietary pattern 2], for studies in which the relative impact on inflammation of

different dietary patterns containing dairy products is evaluated;

* Outcome 7 [Dietary patterns : Correlation], for studies in which dietary patterns containing dairy products are correlated with inflammatory markers. If available, adjustments for confounders are indicated.

The type of outcome (1-7) is indicated for each study result.

The strength of the effects was expressed by the direction of the statistically significant change in the inflammatory signal (→: no statistically significant effect; ↑: statistically significant increase; ↓: statistically significant decrease) or of the correlations (corr→: no statistically significant correlation; corr↑: statistically significant positive correlation; corr↓: statistically significant negative correlation). The criteria for statistical significance are indicated as reported in each study but are not documented in this review. To avoid bias, care was taken to document all results obtained with the inflammatory markers, including results in which no statistically significant changes were observed. Inflammatory markers are shown in italics in the table if their increase are associated with an anti-inflammatory effect.

**Net change in inflammatory markers**—The inflammatory markers shown in Table 1 were considered for inclusion in this review. This list was extracted from recently published work that compiles a comprehensive list of inflammatory markers reported in nutritional studies (Calder et al., 2013). It offered clear harmonizing criteria for inclusion or exclusion of the IS that were evaluated by each reviewer. The net change in inflammatory markers was calculated for each study result by summing up the changes in all inflammatory results measured. A value of -1 was attributed for each change in inflammatory parameters contributing to a pro-inflammatory status (e.g., an increase in a pro-inflammatory parameter or a decrease in an anti-inflammatory parameter). A value of +1 was attributed for each change in inflammatory parameters contributing to an anti-inflammatory status (e.g., a decrease in a pro-inflammatory parameter or an increase in an anti-inflammatory parameter). A value of 0 was attributed for study results in which the inflammatory markers did not change. None of the 78 study results for which the net change in inflammatory markers was measured provided results in which both anti- and pro-inflammatory changes were observed together.

**Sustainability of effect over time**—This line reports whether sustainability of the inflammatory effect over time was “investigated,” “discussed,” or “not discussed”. A study result investigating and reporting a maintenance of the inflammatory effect after a washout phase of at least one week is labeled “yes”.

**Dose-response**—This line reports whether a dose-response relationship was investigated (yes) or not (no). If yes, a short description is presented.

**Bioavailability data**—Label as “yes” if information is provided on bioavailability of dairy product components, otherwise label as “no”. In cases where bioavailability data was obtained in the study (yes), a short presentation of the information is presented in the table.

**Biological plausibility**—This line presents whether the mechanism of action by which the dairy constituents exert their anti- or pro-inflammatory effects was discussed or
<figure><img src="image_10.png" /><figcaption>**Table 1.** List of inflammatory mediators selected for the evaluation of the articles<fnref n="1" />.</figcaption></figure>

<table><thead><tr><th>Inflammatory mediator</th><th></th></tr></thead><tbody><tr><td>12-HETE</td><td>LTB4</td></tr><tr><td>15-HETE</td><td>LTB5</td></tr><tr><td>15-HPETE</td><td>LTC4</td></tr><tr><td>2-Arachidonoylglycerol</td><td>Lung function in response to indirect challenge (Allergic asthma)</td></tr><tr><td>5-HETE</td><td>LXA4</td></tr><tr><td>5-HPETE</td><td>Lyso-PA</td></tr><tr><td>a-1-Antichymotrypsin</td><td>Macrophages (total count, tissue infiltration, CD163+, CD68+, S100+)</td></tr><tr><td>a-1-Antitrypsin</td><td>MAPK, activated (Crohn's disease)</td></tr><tr><td>Ab42, increased (Alzheimer's disease)</td><td>MaR1</td></tr><tr><td>Adiponectin, low (obesity, type 2 diabetes)</td><td>MCP-1 (CCL2)</td></tr><tr><td>Anandamide</td><td>Microglia, activated (Alzheimer's disease)</td></tr><tr><td>Antimicrobial antibodies (Crohn's disease)</td><td>MIP-1a (CCL3)</td></tr><tr><td>Antimicrobial peptides</td><td>MIP-2a (CXCL2; GROb; GRO-2)</td></tr><tr><td>Astrocytes, reactive (Alzheimer's disease)</td><td>Monocytes (total count, CD66b, CD11c)</td></tr><tr><td>Autoantibodies</td><td>Neutrophils (total count, tissue infiltration, CD11b)</td></tr><tr><td>B lymphocytes (total count)</td><td>NF-kB (Crohn's disease)</td></tr><tr><td>Basophils, mast cells (total count, tissue infiltration)</td><td>NO (cardiovascular diseases)</td></tr><tr><td>Calprotectin (Crohn's disease)</td><td>Osteopontin (Allergic asthma)</td></tr><tr><td>Complement C3 (C3)</td><td>PAF</td></tr><tr><td>Complement C4 (C4)</td><td>PD1 (NPD1)</td></tr><tr><td>CPN60 (Crohn's disease)</td><td>PGD2</td></tr><tr><td>CRP</td><td>PGD3</td></tr><tr><td>Cysteinyl-LT (Allergic asthma)</td><td>PGE1</td></tr><tr><td>Eicosanoids (Rheumatoid arthritis)</td><td>PGE2</td></tr><tr><td>Eosinophilic cationic protein (Allergic asthma)</td><td>PGE3</td></tr><tr><td>Eosinophils (total count, tissue infiltration, CD11b)</td><td>PGF2α</td></tr><tr><td>Eotaxin (Allergic asthma)</td><td>PGI2</td></tr><tr><td>E-selectin (CD62E)</td><td>PKR (Crohn's disease)</td></tr><tr><td>Fibrinogen</td><td>Plasminogen activator inhibitor-1 (PAI-1)</td></tr><tr><td>GRP78 (Crohn's disease)</td><td>P-selectin (CD62P)</td></tr><tr><td>ICAM-1 (CD54)</td><td>RANTES (CCL5)</td></tr><tr><td>IFN-g</td><td>Rheumatoid factor (Rheumatoid arthritis)</td></tr><tr><td>IgE, total and allergen specific (Allergic diseases)</td><td>RvD1</td></tr><tr><td>IL-10</td><td>RvE1</td></tr><tr><td>IL-12 (IL-12A or p35 or IL-12B or p40 heterodimeric)</td><td>S100 proteins (S100A12, S100A8/A9) (Crohn's disease)</td></tr><tr><td>IL-13 (Allergic asthma)</td><td>Serum amyloid A (SAA)</td></tr><tr><td>IL-17A</td><td>SMAD7 (Crohn's disease)</td></tr><tr><td>IL-18</td><td>Sphingosine-1-phosphate</td></tr><tr><td>IL-1β</td><td>sPLA2</td></tr><tr><td>IL-1ra</td><td>T lymphocytes (total count, tissue infiltration)</td></tr><tr><td>IL-23 (IL-23A or p19 or IL-12B or p40 heterodimeric)</td><td>Tau, total (Alzheimer's disease)</td></tr><tr><td>IL-4 (Allergic asthma)</td><td>TNF-α</td></tr><tr><td>IL-5 (Allergic asthma)</td><td>TNFR (TNFR1 and TNFR2)</td></tr><tr><td>IL-6</td><td>tPA</td></tr><tr><td>IL-8 (CXCL8)</td><td>Tryptase (Allergic asthma)</td></tr><tr><td>Inflammatory gene expression, cytokine expression (Obesity)</td><td>TXA2</td></tr><tr><td>IP-10 (CXCL10)</td><td>VCAM-1 (CD106)</td></tr><tr><td>Leptin</td><td>VEGF (Psoriasis)</td></tr><tr><td>Leucocytes (WBC) (total count, tissue infiltration)</td><td>von Willebrand factor (vWF)</td></tr></tbody></table>

investigated. The mechanism of action is shortly presented.

**Bioactive components**—If discussed or investigated, the components of the dairy products considered as responsible for the anti- or pro-inflammatory effect are shortly presented.

**Clinical evidence**—If available, this line presents the results of clinical endpoints that, if changed, contribute to an upgrading of the overall effect. The list of clinical endpoints includes: non-systemic inflammatory markers (such as, cellular, organ inflammation, joint pain, flare), parameters formally recognized as being associated with the metabolic syndrome including changes in triglycerides, HDL cholesterol, blood pressure, plasma glucose, insulin tolerance, BMI, waist circumference, glucose tolerance, insulin resistance, waist:hip ratio, urinary albumin excretion, albumin:creatinine ratio, markers of oxidative stress known to promote inflammation and other clinical endpoints such as mortality or cardiovascular events.

**Financing of research**—This line mentions how the study was supported financially and is labeled as either “public”, “private”, “private and public”, or “not presented”.

**Grading criteria**—This line presents the grading criteria used to calculate the IS according to Table 2. The label “None” is attributed a value of 0, indicating a study result in which no net change in inflammatory markers was measured. The label “Anti” is attributed a value of +1, indicating a study result with a positive net change in inflammatory markers. The label “Pro” is attributed a value of -1, indicating a study result with a negative net change in inflammatory markers. For study results with a net change in inflammatory markers different from zero, the labels “Anti” and “Pro” are completed with the numbers 1–11 indicating which one of the quality criteria presented in Table 2 were met. These criteria could be retrieved from the following descriptors in the tabulated summary: (1) “controlled dairy test”, (2) “randomization”, (3) “time factor”, (4) “test

<footnote n="1">¹The markers are listed in alphabetical order. Adapted from (Calder et al., 2013).</footnote>
<figure><img src="image_11.png" /><figcaption>**Table 1.** List of inflammatory mediators selected for the evaluation of the articles<fnref n="1" />.</figcaption></figure>

<table><thead><tr><th>Inflammatory mediator</th><th></th></tr></thead><tbody><tr><td>12-HETE</td><td>LTB4</td></tr><tr><td>15-HETE</td><td>LTB5</td></tr><tr><td>15-HPETE</td><td>LTC4</td></tr><tr><td>2-Arachidonoylglycerol</td><td>Lung function in response to indirect challenge (Allergic asthma)</td></tr><tr><td>5-HETE</td><td>LXA4</td></tr><tr><td>5-HPETE</td><td>Lyso-PA</td></tr><tr><td>a-1-Antichymotrypsin</td><td>Macrophages (total count, tissue infiltration, CD163+, CD68+, S100+)</td></tr><tr><td>a-1-Antitrypsin</td><td>MAPK, activated (Crohn's disease)</td></tr><tr><td>Ab42, increased (Alzheimer's disease)</td><td>MaR1</td></tr><tr><td>Adiponectin, low (obesity, type 2 diabetes)</td><td>MCP-1 (CCL2)</td></tr><tr><td>Anandamide</td><td>Microglia, activated (Alzheimer's disease)</td></tr><tr><td>Antimicrobial antibodies (Crohn's disease)</td><td>MIP-1a (CCL3)</td></tr><tr><td>Antimicrobial peptides</td><td>MIP-2a (CXCL2; GROb; GRO-2)</td></tr><tr><td>Astrocytes, reactive (Alzheimer's disease)</td><td>Monocytes (total count, CD66b, CD11c)</td></tr><tr><td>Autoantibodies</td><td>Neutrophils (total count, tissue infiltration, CD11b)</td></tr><tr><td>B lymphocytes (total count)</td><td>NF-kB (Crohn's disease)</td></tr><tr><td>Basophils, mast cells (total count, tissue infiltration)</td><td>NO (cardiovascular diseases)</td></tr><tr><td>Calprotectin (Crohn's disease)</td><td>Osteopontin (Allergic asthma)</td></tr><tr><td>Complement C3 (C3)</td><td>PAF</td></tr><tr><td>Complement C4 (C4)</td><td>PD1 (NPD1)</td></tr><tr><td>CPN60 (Crohn's disease)</td><td>PGD2</td></tr><tr><td>CRP</td><td>PGD3</td></tr><tr><td>Cysteinyl-LT (Allergic asthma)</td><td>PGE1</td></tr><tr><td>Eicosanoids (Rheumatoid arthritis)</td><td>PGE2</td></tr><tr><td>Eosinophilic cationic protein (Allergic asthma)</td><td>PGE3</td></tr><tr><td>Eosinophils (total count, tissue infiltration, CD11b)</td><td>PGF2a</td></tr><tr><td>Eotaxin (Allergic asthma)</td><td>PGI2</td></tr><tr><td>E-selectin (CD62E)</td><td>PKR (Crohn's disease)</td></tr><tr><td>Fibrinogen</td><td>Plasminogen activator inhibitor-1 (PAI-1)</td></tr><tr><td>GRP78 (Crohn's disease)</td><td>P-selectin (CD62P)</td></tr><tr><td>ICAM-1 (CD54)</td><td>RANTES (CCL5)</td></tr><tr><td>IFN-g</td><td>Rheumatoid factor (Rheumatoid arthritis)</td></tr><tr><td>IgE, total and allergen specific (Allergic diseases)</td><td>RvD1</td></tr><tr><td>IL-10</td><td>RvE1</td></tr><tr><td>IL-12 (IL-12A or p35 or IL-12B or p40 heterodimeric)</td><td>S100 proteins (S100A12, S100A8/A9) (Crohn's disease)</td></tr><tr><td>IL-13 (Allergic asthma)</td><td>Serum amyloid A (SAA)</td></tr><tr><td>IL-17A</td><td>SMAD7 (Crohn's disease)</td></tr><tr><td>IL-18</td><td>Sphingosine-1-phosphate</td></tr><tr><td>IL-1β</td><td>sPLA2</td></tr><tr><td>IL-1ra</td><td>T lymphocytes (total count, tissue infiltration)</td></tr><tr><td>IL-23 (IL-23A or p19 or IL-12B or p40 heterodimeric)</td><td>Tau, total (Alzheimer's disease)</td></tr><tr><td>IL-4 (Allergic asthma)</td><td>TNF-α</td></tr><tr><td>IL-5 (Allergic asthma)</td><td>TNFR (TNFR1 and TNFR2)</td></tr><tr><td>IL-6</td><td>tPA</td></tr><tr><td>IL-8 (CXCL8)</td><td>Tryptase (Allergic asthma)</td></tr><tr><td>Inflammatory gene expression, cytokine expression (Obesity)</td><td>TXA2</td></tr><tr><td>IP-10 (CXCL10)</td><td>VCAM-1 (CD106)</td></tr><tr><td>Leptin</td><td>VEGF (Psoriasis)</td></tr><tr><td>Leucocytes (WBC) (total count, tissue infiltration)</td><td>von Willebrand factor (vWF)</td></tr></tbody></table>

investigated. The mechanism of action is shortly presented.

**Bioactive components**—If discussed or investigated, the components of the dairy products considered as responsible for the anti- or pro-inflammatory effect are shortly presented.

**Clinical evidence**—If available, this line presents the results of clinical endpoints that, if changed, contribute to an upgrading of the overall effect. The list of clinical endpoints includes: non-systemic inflammatory markers (such as, cellular, organ inflammation, joint pain, flare), parameters formally recognized as being associated with the metabolic syndrome including changes in triglycerides, HDL cholesterol, blood pressure, plasma glucose, insulin tolerance, BMI, waist circumference, glucose tolerance, insulin resistance, waist:hip ratio, urinary albumin excretion, albumin:creatinine ratio, markers of oxidative stress known to promote inflammation and other clinical endpoints such as mortality or cardiovascular events.

**Financing of research**—This line mentions how the study was supported financially and is labeled as either “public”, “private”, “private and public”, or “not presented”.

**Grading criteria**—This line presents the grading criteria used to calculate the IS according to Table 2. The label “None” is attributed a value of 0, indicating a study result in which no net change in inflammatory markers was measured. The label “Anti” is attributed a value of +1, indicating a study result with a positive net change in inflammatory markers. The label “Pro” is attributed a value of -1, indicating a study result with a negative net change in inflammatory markers. For study results with a net change in inflammatory markers different from zero, the labels “Anti” and “Pro” are completed with the numbers 1–11 indicating which one of the quality criteria presented in Table 2 were met. These criteria could be retrieved from the following descriptors in the tabulated summary: (1) “controlled dairy test”, (2) “randomization”, (3) “time factor”, (4) “test

<footnote n="1">¹The markers are listed in alphabetical order. Adapted from (Calder et al., 2013).</footnote>
<figure><img src="image_11.png" /><figcaption>**Table 2.** Criteria used to establish the IS to quantitatively evaluate the impact of dairy products on inflammatory processes in humans.</figcaption></figure>

<table><thead><tr><th>Initial grading</th></tr></thead><tbody><tr><td>a Grade 0 for a null net change in inflammatory markers ('None')</td></tr><tr><td>b Grade +1 for a positive net change in inflammatory markers ('Anti')</td></tr><tr><td>c Grade -1 for a negative net change in inflammatory markers ('Pro')</td></tr><tr><td>Cumulative upgrade of IS towards positive (+1) or negative (-1) values</td></tr><tr><td>1 Controlled study (product or subject) with dairy test as a test product</td></tr><tr><td>2 Randomized study</td></tr><tr><td>3 Longitudinal study</td></tr><tr><td>4 The dairy product is not solely measured as part of a dietary pattern</td></tr><tr><td>5 ≥2 inflammatory markers are changed</td></tr><tr><td>6 At least one inflammatory marker is measured in vivo (and not ex vivo)</td></tr><tr><td>7 The change in inflammatory marker is measured over ≥12h, e.g. not postprandially</td></tr><tr><td>8 The effect is still measured after washout period of at least one week</td></tr><tr><td>9 A dose-response is demonstrated with the dairy product</td></tr><tr><td>10 Bioactive molecules or the biological plausibility have been convincingly investigated</td></tr><tr><td>11 A clinical endpoint is changed that can be related to a metabolic dysregulation associated with inflammation</td></tr></tbody></table>

product” or “control product”, (5) “study results” and “net change in inflammatory marker”, (6–7) “study results”, (8) “sustainability of effect over time”, (9) “dose-response”, (10) “biological plausibility” or “bioactive components”, (11) “clinical evidence”.

IS—The IS is the sum of the criteria reported above. Study results in which all criteria are fulfilled could thus theoretically reach an IS of -12 for results indicating a pro-inflammatory activity of dairy products and an IS of +12 for results indicating an anti-inflammatory activity of dairy products. Study results with an initial IS of 0 could not be modified by these criteria and the final IS thus remained 0, independently of the quality of the clinical study.

**Table S1** provides an example of the calculation of the IS for one study result.

## Determination of the IS for groups of study results

A median IS was calculated for the entire data set as well as for the following categories of study results:

* Subjects category (HEALTH, MET, GIT, HYPER);

* Fat content of dairy product (low-fat, high-fat);

* Fermentation status of dairy product (non-fermented, fermented).

Non-parametric statistics were conducted to analyze the data (significance level: *p*<0.05). The two-sided Wilcoxon Signed-Rank test was conducted to identify whether the median IS of the selected categories were statistically different from zero (H0: median IS=0; Ha: median IS≠0). A mean IS>0 indicated an anti-inflammatory effect whereas a pro-inflammatory effect was indicated by a mean IS<0. The Kruskall-Wallis test was conducted to identify difference in the mean IS between different categories of study results.

## Results

Tables 3–5 show the tabulated summary of the 78 study results extracted from the 52 human studies retained for this review. Each table contains 25 descriptors covering a wide range of

study characteristics including, amongst others, a description of the enrolled subjects, the test and control products, the study designs, and the IS (documented in the last line). Table 3 shows the data for study results with a positive IS, i.e., for results indicative of an anti-inflammatory effect of dairy products. Table 4 shows the data for study results with a negative IS, i.e., for results indicative of a pro-inflammatory effect of dairy products. Finally, Table 5 shows the data for study results with an IS=0, i.e., for results with no modulation of inflammatory processes by dairy products.

Figure 2 shows the overall distribution of the data obtained for each of the inflammatory markers listed in Table 1, that were measured at least once in the set of 78 study results reviewed. Out of the 98 inflammatory markers listed in Table 1, 57 markers were investigated at least once (58%). A total of 309 observations were reported with these inflammatory markers, 131 (42%) being accounted for by three cytokines, i.e., CRP (51 observations), IL-6 (44 observations), and TNF-α (36 observations). For each of these cytokines, the number of observations reporting no effect was the highest (CRP: 34 out of 51; IL-6: 26 out of 44; TNF-α: 23 out of 36) followed by the observations reporting an anti-inflammatory effect (CRP: 16 out of 51; IL-6: 15 out of 44; TNF-α: 11 out of 36). The number of these observations reporting a pro-inflammatory effect was the lowest for all three cytokines (CRP: 1 out of 51; IL-6: 3 out of 44; TNF-α: 2 out of 36). The only parameter systematically pointing to the pro-inflammatory state was ‘eosinophil count’ (5 out of 5), a parameter that was exclusively measured in studies investigating subjects with milk allergy and thus categorized in the subject category HYPER.

Taking into account the quality of all studies reviewed in the present article, we have developed a quantitative method that calculates an IS based on the range of eleven criteria listed in Table 2. Figure 3 presents the results of this analysis. Panel A first illustrates the number of study results identified with evidence for an anti-inflammatory activity (32 study results), a pro-inflammatory activity (19 results), or no change in inflammatory activity (27 study results). Panel B shows a distribution of the IS calculated for each of these study results, according to the criteria presented in Table 2. Although both panels in Figure 3 illustrate that the study results are well distributed among all three categories (anti-inflammatory, no effect, pro-inflammatory), the data indicating an anti-inflammatory activity appear to prevail over data pointing to a pro-inflammatory activity. This observation was confirmed by the positive mean IS for the set of 78 study results and the rejection of the null hypothesis for the median IS in the two-sided Wilcoxon Signed-Rank test, indicating an anti-inflammatory activity of dairy products (Table 6).

When the results were stratified according to subject categories, differences in the distribution of the study results appeared between these categories (Figure 4). The group of 37 study results investigating healthy subjects, was characterized by study results covering each of the three possible effects (anti-inflammatory, no effect, pro-inflammatory). On the other hand, the group of 24 study results investigating subjects with metabolic disorders, including healthy obese subjects, was characterized by a lack of data pointing to a pro-inflammatory effect. The groups of study results investigating subjects with
<figure><img src="image_12.png" /><figcaption>**Table 2.** Criteria used to establish the IS to quantitatively evaluate the impact of dairy products on inflammatory processes in humans.</figcaption></figure>

<table><thead><tr><th>Initial grading</th><th></th></tr></thead><tbody><tr><td>a</td><td>Grade 0 for a null net change in inflammatory markers ('None')</td></tr><tr><td>b</td><td>Grade +1 for a positive net change in inflammatory markers ('Anti')</td></tr><tr><td>c</td><td>Grade -1 for a negative net change in inflammatory markers ('Pro')</td></tr><tr><td colspan="2">Cumulative upgrade of IS towards positive (+1) or negative (-1) values</td></tr><tr><td>1</td><td>Controlled study (product or subject) with dairy test as a test product</td></tr><tr><td>2</td><td>Randomized study</td></tr><tr><td>3</td><td>Longitudinal study</td></tr><tr><td>4</td><td>The dairy product is not solely measured as part of a dietary pattern</td></tr><tr><td>5</td><td>≥2 inflammatory markers are changed</td></tr><tr><td>6</td><td>At least one inflammatory marker is measured in vivo (and not ex vivo)</td></tr><tr><td>7</td><td>The change in inflammatory marker is measured over ≥12h, e.g. not postprandially</td></tr><tr><td>8</td><td>The effect is still measured after washout period of at least one week</td></tr><tr><td>9</td><td>A dose-response is demonstrated with the dairy product</td></tr><tr><td>10</td><td>Bioactive molecules or the biological plausibility have been convincingly investigated</td></tr><tr><td>11</td><td>A clinical endpoint is changed that can be related to a metabolic dysregulation associated with inflammation</td></tr></tbody></table>

product” or “control product”, (5) “study results” and “net change in inflammatory marker”, (6–7) “study results”, (8) “sustainability of effect over time”, (9) “dose-response”, (10) “biological plausibility” or “bioactive components”, (11) “clinical evidence”.

IS—The IS is the sum of the criteria reported above. Study results in which all criteria are fulfilled could thus theoretically reach an IS of -12 for results indicating a pro-inflammatory activity of dairy products and an IS of +12 for results indicating an anti-inflammatory activity of dairy products. Study results with an initial IS of 0 could not be modified by these criteria and the final IS thus remained 0, independently of the quality of the clinical study.

**Table S1** provides an example of the calculation of the IS for one study result.

## Determination of the IS for groups of study results

A median IS was calculated for the entire data set as well as for the following categories of study results:

* Subjects category (HEALTH, MET, GIT, HYPER);

* Fat content of dairy product (low-fat, high-fat);

* Fermentation status of dairy product (non-fermented, fermented).

Non-parametric statistics were conducted to analyze the data (significance level: *p*<0.05). The two-sided Wilcoxon Signed-Rank test was conducted to identify whether the median IS of the selected categories were statistically different from zero (H0: median IS=0; Ha: median IS≠0). A mean IS>0 indicated an anti-inflammatory effect whereas a pro-inflammatory effect was indicated by a mean IS<0. The Kruskall-Wallis test was conducted to identify difference in the mean IS between different categories of study results.

## Results

Tables 3–5 show the tabulated summary of the 78 study results extracted from the 52 human studies retained for this review. Each table contains 25 descriptors covering a wide range of

study characteristics including, amongst others, a description of the enrolled subjects, the test and control products, the study designs, and the IS (documented in the last line). Table 3 shows the data for study results with a positive IS, i.e., for results indicative of an anti-inflammatory effect of dairy products. Table 4 shows the data for study results with a negative IS, i.e., for results indicative of a pro-inflammatory effect of dairy products. Finally, Table 5 shows the data for study results with an IS=0, i.e., for results with no modulation of inflammatory processes by dairy products.

Figure 2 shows the overall distribution of the data obtained for each of the inflammatory markers listed in Table 1, that were measured at least once in the set of 78 study results reviewed. Out of the 98 inflammatory markers listed in Table 1, 57 markers were investigated at least once (58%). A total of 309 observations were reported with these inflammatory markers, 131 (42%) being accounted for by three cytokines, i.e., CRP (51 observations), IL-6 (44 observations), and TNF-α (36 observations). For each of these cytokines, the number of observations reporting no effect was the highest (CRP: 34 out of 51; IL-6: 26 out of 44; TNF-α: 23 out of 36) followed by the observations reporting an anti-inflammatory effect (CRP: 16 out of 51; IL-6: 15 out of 44; TNF-α: 11 out of 36). The number of these observations reporting a pro-inflammatory effect was the lowest for all three cytokines (CRP: 1 out of 51; IL-6: 3 out of 44; TNF-α: 2 out of 36). The only parameter systematically pointing to the pro-inflammatory state was ‘eosinophil count’ (5 out of 5), a parameter that was exclusively measured in studies investigating subjects with milk allergy and thus categorized in the subject category HYPER.

Taking into account the quality of all studies reviewed in the present article, we have developed a quantitative method that calculates an IS based on the range of eleven criteria listed in Table 2. Figure 3 presents the results of this analysis. Panel A first illustrates the number of study results identified with evidence for an anti-inflammatory activity (32 study results), a pro-inflammatory activity (19 results), or no change in inflammatory activity (27 study results). Panel B shows a distribution of the IS calculated for each of these study results, according to the criteria presented in Table 2. Although both panels in Figure 3 illustrate that the study results are well distributed among all three categories (anti-inflammatory, no effect, pro-inflammatory), the data indicating an anti-inflammatory activity appear to prevail over data pointing to a pro-inflammatory activity. This observation was confirmed by the positive mean IS for the set of 78 study results and the rejection of the null hypothesis for the median IS in the two-sided Wilcoxon Signed-Rank test, indicating an anti-inflammatory activity of dairy products (Table 6).

When the results were stratified according to subject categories, differences in the distribution of the study results appeared between these categories (Figure 4). The group of 37 study results investigating healthy subjects, was characterized by study results covering each of the three possible effects (anti-inflammatory, no effect, pro-inflammatory). On the other hand, the group of 24 study results investigating subjects with metabolic disorders, including healthy obese subjects, was characterized by a lack of data pointing to a pro-inflammatory effect. The groups of study results investigating subjects with
<table><caption>Table 3. Tabulated summary of the study results with evidence for an anti-inflammatory effect of dairy products.</caption><thead><tr><th>Reference</th><th>(Zemel & Sun, 2008) 1</th><th>(Zemel & Sun, 2008) 2</th><th>(Sugawara et al., 2012)</th><th>(Stancliffe et al., 2011)</th><th>(Zemel et al., 2010)</th><th>(Holmer-Jensen et al., 2011)</th></tr></thead><tbody><tr><td>Subject category</td><td>MET</td><td>MET</td><td>OTHER</td><td>MET</td><td>MET</td><td>MET</td></tr><tr><td>Target indication</td><td>Oxidative stress and inflammation</td><td>Oxidative stress and inflammation</td><td>Chronic obstructive pulmonary disease</td><td>Metabolic syndrome</td><td>Overweight and obesity</td><td>Low-grade inflammation</td></tr><tr><td>Target population</td><td>Obese subjects</td><td>Obese subjects</td><td>Elderly with chronic obstructive pulmonary disease</td><td>Metabolic syndrome subjects</td><td>Overweight and obese subjects</td><td>Obese non-diabetic subjects</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td><td>N.a.</td><td>Low-fat</td><td>N.a.</td></tr><tr><td>Fermentation</td><td>Fermented</td><td>N.a.</td><td>Non-fermented</td><td>N.a.</td><td>Non-fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>Yoghurt</td><td>High dairy diet (milk, yoghurt, hard cheese)</td><td>Nutritional supplement containing whey peptides plus low intensity exercise</td><td>Adequate dairy diet</td><td>Milk smoothies containing 350 mg calcium</td><td>Fat-rich meal supplemented with cod protein, whey isolate, gluten or casein</td></tr><tr><td>Control product</td><td>Sugar-free, calcium-free gelatin dessert</td><td>Low dairy diet</td><td>Normal diet plus low intensity exercise</td><td>Low dairy diet</td><td>Soy smoothies containing 50 mg calcium</td><td>8 F, 3 M / 52±9.4 y / non-diabetic obese</td></tr><tr><td>Test subjects</td><td>13 F, 5 M / 39±10 y / obese</td><td>17 / 42.5±2.6 y / obese</td><td>15 M, 2 F / 77.4±5.2 y / COPD</td><td>10 M, 10 F / 34.4±9.4 y / overweight and obese with metabolic syndrome</td><td>14 M, 6 F / 31±10.3 y / overweight or mildly obese adults</td><td></td></tr><tr><td>Control subjects</td><td>14 F, 2 M / 42±6 y / obese</td><td>17 / 41.3±2.7 y / obese</td><td>14 M, 0 F / 77.1±5.8 y / COPD</td><td>9 M, 11 F / 39.5±10.2 y / overweight and obese with metabolic syndrome</td><td>Adequate dairy (>3.5 servings/d) or low dairy (<0.5 servings/d) / 7, 28, 84 days</td><td>3 smoothies/d / 28 days</td></tr><tr><td>Diet</td><td>3×6 oz yoghurt, including a caloric deficit of 500 kcal/d / 12 weeks</td><td>3 dairy servings / 24 weeks / isocaloric</td><td>2×200 kcal of nutritional supplement plus low intensity exercise / 3 months</td><td>Adequate dairy (>3.5 servings/d) or low dairy (<0.5 servings/d) / 7, 28, 84 days</td><td>Yes</td><td>5'000 KJ fat-rich meal and 45 g protein / single challenge study</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Randomization</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td></tr><tr><td>Study results</td><td><sup>1</sup>Yoghurt (high Ca) vs control (low Ca): CRP ↓; adiponectin ↑</td><td><sup>1</sup>High dairy vs low dairy: CRP ↓; adiponectin ↑</td><td><sup>1</sup>Treatment (whey supplement + exercise) vs control (normal diet + exercise): CRP, IL-6, IL-8, TNF-α ↓</td><td><sup>1</sup>Adequate dairy vs low dairy: TNF-α, MCP-1, IL-6, CRP ↓; adiponectin ↑</td><td><sup>1</sup>Milk vs soy smoothies: IL-6, TNF-α, MCP-1, CRP ↓; adiponectin ↑; IL-15 →</td><td><sup>1</sup>Whey vs cod (4h iAUC postprandial): CCL5/ RANTES, MCP-1 ↓, IL-1ra, IFN-g, adiponectin, eotaxin, IP-10, MIP-1β, VEGF →</td></tr><tr><td>Net change in inflammatory marker</td><td>2</td><td>2</td><td>4</td><td>5</td><td>2</td><td></td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Discussed - Ca signaling, ROS, angiotensin-converting enzyme, fat oxidation, energy utilisation</td><td>Discussed - Ca-signaling, ROS, angiotensin-converting enzyme, fat oxidation, energy utilisation</td><td>Discussed - cytokine production</td><td>Discussed - calcitriol signaling and adiposity-induced inflammatory cytokines</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Investigated - calcium</td><td>Investigated - calcium</td><td>Discussed - whey peptides</td><td>Discussed - calcium, whey protein</td><td>Discussed - ACE inhibitors, bioactive peptides, leucine</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>Yes - yoghurt improves fat loss</td><td>Yes - calcium-rich foods improve fat loss</td><td>Yes - improvement of metabolic and respiratory functions</td><td>Yes - reduction of waist circumference and trunk fat</td><td>Yes - reduction of oxidative stress markers</td><td>Yes - insulinotropic effect of whey proteins</td></tr><tr><td>Financing of research</td><td>Private</td><td>Private</td><td>Not presented</td><td>Private</td><td>Private</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Anti, 1, 2, 3, 4, 5, 6, 7, 10, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 7, 10, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 7, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 7, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 11</td></tr><tr><td>IS</td><td>10</td><td>10</td><td>9</td><td>9</td><td>8</td><td>8</td></tr></tbody></table>

(Continued on next page)

<figure><img src="image_12.png" /></figure>
<table><caption>Table 3. Tabulated summary of the study results with evidence for an anti-inflammatory effect of dairy products.</caption><thead><tr><th>Reference</th><th>(Zemel & Sun, 2008) 1</th><th>(Zemel & Sun, 2008) 2</th><th>(Sugawara et al., 2012)</th><th>(Stancliffe et al., 2011)</th><th>(Zemel et al., 2010)</th><th>(Holmer-Jensen et al., 2011)</th></tr></thead><tbody><tr><td>Subject category</td><td>MET</td><td>MET</td><td>OTHER</td><td>MET</td><td>MET</td><td>MET</td></tr><tr><td>Target indication</td><td>Oxidative stress and inflammation</td><td>Oxidative stress and inflammation</td><td>Chronic obstructive pulmonary disease</td><td>Metabolic syndrome</td><td>Overweight and obesity</td><td>Low-grade inflammation</td></tr><tr><td>Target population</td><td>Obese subjects</td><td>Obese subjects</td><td>Elderly with chronic obstructive pulmonary disease</td><td>Metabolic syndrome subjects</td><td>Overweight and obese subjects</td><td>Obese non-diabetic subjects</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td><td>N.a.</td><td>Low-fat</td><td>N.a.</td></tr><tr><td>Fermentation</td><td>Fermented</td><td>N.a.</td><td>Non-fermented</td><td>N.a.</td><td>Non-fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>Yoghurt</td><td>High dairy diet (milk, yoghurt, hard cheese)</td><td>Nutritional supplement containing whey peptides plus low intensity exercise</td><td>Adequate dairy diet</td><td>Milk smoothies containing 350 mg calcium</td><td>Fat-rich meal supplemented with cod protein, whey isolate, gluten or casein</td></tr><tr><td>Control product</td><td>Sugar-free, calcium-free gelatin dessert</td><td>Low dairy diet</td><td>Normal diet plus low intensity exercise</td><td>Low dairy diet</td><td>Soy smoothies containing 50 mg calcium</td><td>8 F, 3 M / 52±9.4 y / non-diabetic obese</td></tr><tr><td>Test subjects</td><td>13 F, 5 M / 39±10 y / obese</td><td>17 / 42.5±2.6 y / obese</td><td>15 M, 2 F / 77.4±5.2 y / COPD</td><td>10 M, 10 F / 34.4±9.4 y / overweight and obese with metabolic syndrome</td><td>14 M, 6 F / 31±10.3 y / overweight or mildly obese adults</td><td></td></tr><tr><td>Control subjects</td><td>14 F, 2 M / 42±6 y / obese</td><td>17 / 41.3±2.7 y / obese</td><td>14 M, 0 F / 77.1±5.8 y / COPD</td><td>9 M, 11 F / 39.5±10.2 y / overweight and obese with metabolic syndrome</td><td>Adequate dairy (>3.5 servings/d) or low dairy (<0.5 servings/d) / 7, 28, 84 days</td><td>3 smoothies/d / 28 days</td></tr><tr><td>Diet</td><td>3×6 oz yoghurt, including a caloric deficit of 500 kcal/d / 12 weeks</td><td>3 dairy servings / 24 weeks / isocaloric</td><td>2×200 kcal of nutritional supplement plus low intensity exercise / 3 months</td><td>Adequate dairy (>3.5 servings/d) or low dairy (<0.5 servings/d) / 7, 28, 84 days</td><td>Yes</td><td>5'000 KJ fat-rich meal and 45 g protein / single challenge study</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Randomization</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td></tr><tr><td>Study results</td><td><sup>1</sup>Yoghurt (high Ca) vs control (low Ca): CRP ↓; adiponectin ↑</td><td><sup>1</sup>High dairy vs low dairy: CRP ↓; adiponectin ↑</td><td><sup>1</sup>Treatment (whey supplement + exercise) vs control (normal diet + exercise): CRP, IL-6, IL-8, TNF-α ↓</td><td><sup>1</sup>Adequate dairy vs low dairy: TNF-α, MCP-1, IL-6, CRP ↓; adiponectin ↑</td><td><sup>1</sup>Milk vs soy smoothies: IL-6, TNF-α, MCP-1, CRP ↓; adiponectin ↑; IL-15 →</td><td><sup>1</sup>Whey vs cod (4h iAUC postprandial): CCL5/ RANTES, MCP-1 ↓, IL-1ra, IFN-g, adiponectin, eotaxin, IP-10, MIP-1β, VEGF →</td></tr><tr><td>Net change in inflammatory marker</td><td>2</td><td>2</td><td>4</td><td>5</td><td>2</td><td></td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Discussed - Ca signaling, ROS, angiotensin-converting enzyme, fat oxidation, energy utilisation</td><td>Discussed - Ca-signaling, ROS, angiotensin-converting enzyme, fat oxidation, energy utilisation</td><td>Discussed - cytokine production</td><td>Discussed - calcitriol signaling and adiposity-induced inflammatory cytokines</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Investigated - calcium</td><td>Investigated - calcium</td><td>Discussed - whey peptides</td><td>Discussed - calcium, whey protein</td><td>Discussed - ACE inhibitors, bioactive peptides, leucine</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>Yes - yoghurt improves fat loss</td><td>Yes - calcium-rich foods improve fat loss</td><td>Yes - improvement of metabolic and respiratory functions</td><td>Yes - reduction of waist circumference and trunk fat</td><td>Yes - reduction of oxidative stress markers</td><td>Yes - insulinotropic effect of whey proteins</td></tr><tr><td>Financing of research</td><td>Private</td><td>Private</td><td>Not presented</td><td>Private</td><td>Private</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Anti, 1, 2, 3, 4, 5, 6, 7, 10, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 7, 10, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 7, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 7, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 11</td><td>Anti, 1, 2, 3, 4, 5, 6, 11</td></tr><tr><td>IS</td><td>10</td><td>10</td><td>9</td><td>9</td><td>8</td><td>8</td></tr></tbody></table>

(Continued on next page)

<figure><img src="image_13.png" /></figure>
<figure><img src="image_13.png" /><figcaption>Table 3. (Continued)</figcaption></figure>

<table><thead><tr><th>Reference</th><th>(Hunter et al., 2012)</th><th>(de Aguilar-Nascimento et al., 2011)</th><th>(Panagiotakos et al., 2010) 1</th><th>(Panagiotakos et al., 2010) 2</th><th>(Panagiotakos et al., 2010) 3</th><th>(Panagiotakos et al., 2010) 4</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td><td>MET</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Oxidative stress</td><td>Acute ischemic stroke</td><td>Cardiovascular disease</td><td>Cardiovascular disease</td><td>Cardiovascular disease</td><td>Cardiovascular disease</td></tr><tr><td>Target population</td><td>Smokers</td><td>Elderly with acute ischemic stroke fed on enteral formula</td><td>Healthy adults</td><td>Healthy adults</td><td>Healthy adults</td><td>Healthy adults</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>N.a.</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>Non-fermented</td><td>Non-fermented</td><td>Fermented</td><td>Non-fermented</td><td>Non-fermented</td><td>N.a.</td></tr><tr><td>Test product</td><td>Non-supplemented milk</td><td>Enteral feeding formula containing hydrolyzed whey protein</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Control product</td><td>Lemonade</td><td>Enteral formula containing hydrolyzed casein protein</td><td>Low dairy diet (cheese)</td><td>Low dairy diet (full-fat milk)</td><td>Low dairy diet (low fat milk)</td><td>Low dairy diet</td></tr><tr><td>Test subjects</td><td>18 M, 25 F / 30-63 y / healthy smokers</td><td>6 M, 4 F / 67-88 y / acute ischemic stroke</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>1514 M, 1528 F / 25-50 y / healthy</td></tr><tr><td>Control subjects</td><td>—</td><td>3 M, 12 F / 66-90 y / acute ischemic stroke</td><td>456 M, 292 F / 33-53 y / healthy</td><td>456 M, 292 F / 33-53 y / healthy</td><td>456 M, 292 F / 33-53 y / healthy</td><td>456 M, 292 F / 33-53 y / healthy</td></tr><tr><td>Diet</td><td>2 weeks lemonade run-in / 400 mL test product 1.2 or 3 / 6 weeks separated by 4 weeks washout</td><td>Formula / 20 mL/h / 5 days</td><td>Cheese / servings/week: &lt;8; 8-10: 11-14; &gt;14 / frequency of consumption over past year (FFQ)</td><td>Full-fat milk / servings/week: &lt;8; 8-10: 11-14; &gt;14 / frequency of consumption over past year (FFQ)</td><td>Low-fat milk / servings/week: &lt;8; 8-10: 11-14; &gt;14 / frequency of consumption over past year (FFQ)</td><td>Dairy / servings/week: &lt;8; 8-10: 11-14; &gt;14 / frequency of consumption over past year (FFQ)</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Randomization</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Longitudinal</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td><sup>1</sup>Non-supplemented milk vs lemonade; p-selectin, tPA, MCP-1, IL-8, VCAM →; IL-6, IL-1β, TNF-α ↓</td><td><sup>1</sup>Whey formula vs casein formula: CRP →; IL-6 ↓</td><td><sup>2</sup>Feta cheese; corr↓ with CRP, IL-6; corr→ with TNF-α (not adjusted for confounders)</td><td><sup>3</sup>High-fat milk: corr↓ with IL-6, TNF-α; corr→ with CRP (not adjusted for confounders)</td><td><sup>4</sup>Low-fat milk: corr↓ with CRP, IL-6, TNF-α (not adjusted for confounders)</td><td><sup>5</sup>Full-fat dairy: corr↓ with CRP, IL-6, TNF-α (adjusted for confounders)</td></tr><tr><td>Net change in inflammatory marker</td><td>3</td><td>2</td><td>2</td><td>3</td><td>3</td><td>3</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Discussed - anti-inflammatory activities</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Discussed - whey proteins, lactalbumin, lactoferrin</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>N.a.</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Financing of research</td><td>Public</td><td>Private</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td></tr><tr><td>Grading criteria</td><td>Anti, 1, 2, 3, 4, 5, 6, 7</td><td>Anti, 1, 2, 3, 4, 5, 6, 7</td><td>Public Anti, 1, 2, 4, 5, 6, 7, 9</td><td>Public Anti, 1, 2, 4, 5, 6, 7, 9</td><td>Public Anti, 1, 2, 4, 5, 6, 7, 9</td><td>Public Anti, 1, 2, 4, 5, 6, 7, 9</td></tr><tr><td>IS</td><td>8</td><td>8</td><td>8</td><td>8</td><td>8</td><td>8</td></tr></tbody></table>
<figure><img src="image_14.png" /><figcaption>Table 3. (Continued)</figcaption></figure>

<table><thead><tr><th>Reference</th><th>(Hunter et al., 2012)</th><th>(de Aguilar-Nascimento et al., 2011)</th><th>(Panagiotakos et al., 2010) 1</th><th>(Panagiotakos et al., 2010) 2</th><th>(Panagiotakos et al., 2010) 3</th><th>(Panagiotakos et al., 2010) 4</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td><td>MET</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Oxidative stress</td><td>Acute ischemic stroke</td><td>Cardiovascular disease</td><td>Cardiovascular disease</td><td>Cardiovascular disease</td><td>Cardiovascular disease</td></tr><tr><td>Target population</td><td>Smokers</td><td>Elderly with acute ischemic stroke fed on enteral formula</td><td>Healthy adults</td><td>Healthy adults</td><td>Healthy adults</td><td>Healthy adults</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>N.a.</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>Non-fermented</td><td>Non-fermented</td><td>Fermented</td><td>Non-fermented</td><td>Non-fermented</td><td>N.a.</td></tr><tr><td>Test product</td><td>Non-supplemented milk</td><td>Enteral feeding formula containing hydrolyzed whey protein</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Control product</td><td>Lemonade</td><td>Enteral formula containing hydrolyzed casein protein</td><td>Low dairy diet (cheese)</td><td>Low dairy diet (full-fat milk)</td><td>Low dairy diet (low fat milk)</td><td>Low dairy diet</td></tr><tr><td>Test subjects</td><td>18 M, 25 F / 30-63 y / healthy smokers</td><td>6 M, 4 F / 67-88 y / acute ischemic stroke</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>1514 M, 1528 F / 25-50 y / healthy</td></tr><tr><td>Control subjects</td><td>—</td><td>3 M, 12 F / 66-90 y / acute ischemic stroke</td><td>456 M, 292 F / 33-53 y / healthy</td><td>456 M, 292 F / 33-53 y / healthy</td><td>456 M, 292 F / 33-53 y / healthy</td><td>456 M, 292 F / 33-53 y / healthy</td></tr><tr><td>Diet</td><td>2 weeks lemonade run-in / 400 mL test product 1.2 or 3 / 6 weeks separated by 4 weeks washout</td><td>Formula / 20 mL/h / 5 days</td><td>Cheese / servings/week: &lt;8; 8-10: 11-14; &gt;14 / frequency of consumption over past year (FFQ)</td><td>Full-fat milk / servings/week: &lt;8; 8-10: 11-14; &gt;14 / frequency of consumption over past year (FFQ)</td><td>Low-fat milk / servings/week: &lt;8; 8-10: 11-14; &gt;14 / frequency of consumption over past year (FFQ)</td><td>Dairy / servings/week: &lt;8; 8-10: 11-14; &gt;14 / frequency of consumption over past year (FFQ)</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Randomization</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Randomized</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Longitudinal</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td><sup>1</sup>Non-supplemented milk vs lemonade; p-selectin, tPA, MCP-1, IL-8, VCAM →; IL-6, IL-1β, TNF-α ↓</td><td><sup>1</sup>Whey formula vs casein formula: CRP →; IL-6 ↓</td><td><sup>2</sup>Feta cheese; corr↓ with CRP, IL-6; corr→ with TNF-α (not adjusted for confounders)</td><td><sup>3</sup>High-fat milk: corr↓ with IL-6, TNF-α; corr→ with CRP (not adjusted for confounders)</td><td><sup>4</sup>Low-fat milk: corr↓ with CRP, IL-6, TNF-α (not adjusted for confounders)</td><td><sup>5</sup>Full-fat dairy: corr↓ with CRP, IL-6, TNF-α (adjusted for confounders)</td></tr><tr><td>Net change in inflammatory marker</td><td>3</td><td>2</td><td>2</td><td>3</td><td>3</td><td>3</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Discussed - anti-inflammatory activities</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Discussed - whey proteins, lactalbumin, lactoferrin</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>N.a.</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Financing of research</td><td>Public</td><td>Private</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td></tr><tr><td>Grading criteria</td><td>Anti, 1, 2, 3, 4, 5, 6, 7</td><td>Anti, 1, 2, 3, 4, 5, 6, 7</td><td>Public<br>Anti, 1, 2, 4, 5, 6, 7, 9</td><td>Public<br>Anti, 1, 2, 4, 5, 6, 7, 9</td><td>Public<br>Anti, 1, 2, 4, 5, 6, 7, 9</td><td>Public<br>Anti, 1, 2, 4, 5, 6, 7, 9</td></tr><tr><td>IS</td><td>8</td><td>8</td><td>8</td><td>8</td><td>8</td><td>8</td></tr></tbody></table>
<figure><img src="image_14.png" /></figure>

<table><thead><tr><th>Reference</th><th>(Panagiotakos et al., 2010) 5</th><th>(Panagiotakos et al., 2010) 6</th><th>(van Meijl & Mensink, 2010)</th><th>(Sofi et al., 2010) 1</th><th>(Pintus et al., 2013) 1</th><th>(Nestel et al., 2012) 1</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td><td>HEALTH</td><td>MET</td><td>HEALTH</td><td>MET</td><td>MET</td></tr><tr><td>Target indication</td><td>Cardiovascular disease</td><td>Cardiovascular disease</td><td>Metabolic syndrome and cardiovascular disease</td><td>Atherosclerosis</td><td>Hypercholesterolemia</td><td>Systemic inflammation</td></tr><tr><td>Target population</td><td>Healthy adults</td><td>Healthy adults</td><td>Overweight and obese subjects</td><td>Healthy adults</td><td>Mildly hypercholesterolaemic subjects</td><td>Overweight or obese subjects</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>Low-fat</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>N.a.</td><td>Fermented</td><td>N.a.</td><td>Fermented</td><td>Fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>High dairy diet</td><td>Low dairy diet</td><td>Low-fat dairy (milk and yoghurt)</td><td>Pecorino sheep cheese naturally high in CLA</td><td>Sheep cheese naturally enriched with CLA</td><td>Butter</td></tr><tr><td>Control product</td><td>Low dairy diet</td><td>Low dairy diet</td><td>Carbohydrate-rich product</td><td>Commercial cow cheese low in CLA</td><td>Sheep cheese with pill containing 1 g of a palm oil-soybean oil mix</td><td>—</td></tr><tr><td>Test subjects</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>10 M, 25 F / 50±13 y / BMI: 32±4</td><td>4 M, 6 F / 30-65 y / healthy</td><td>19 M, 23 F / 30-60 y / mild hypercholesterolaemia</td><td>13 / 61.6±7.6 y / overweight or obese</td></tr><tr><td>Control subjects</td><td>456 M, 292 F / 33-53 y / healthy</td><td>456 M, 292 F / 33-53 y / healthy</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Diet</td><td>Low-fat dairy / servings/ week: <8; 8-10; 11-14; >14 / frequency of consumption over past year (FFQ)</td><td>Low-fat yoghurt / servings/ week: <8; 8-10; 11-14; >14 / frequency of consumption over past year (FFQ)</td><td>Milk (500 ml/d), yoghurt (150 g/d) / 8 weeks</td><td>Cheese / 200 g/week / 10 weeks</td><td>Naturally enriched sheep cheese or control cheese / 90 g/d / 3 weeks / between 3 weeks washout</td><td>50 g butter / postprandial challenge study</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>No</td></tr><tr><td>Randomization</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Non-randomized</td><td>Randomized</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td></tr><tr><td>Study results</td><td><sup>5</sup>Low-fat yoghurt: corr<sub>L</sub> with TNF-α; corr<sub>R</sub> with CRP, IL-6 (not adjusted for confounders)</td><td><sup>5</sup>Low-fat yoghurt: corr<sub>L</sub> with TNF-α; corr<sub>R</sub> with CRP, IL-6 (not adjusted for confounders)</td><td><sup>1</sup>Low-fat dairy vs carbohydrate-rich meal: s-TNFR-2 ↑, TNF-α, s-TNFR-1, MCP-1, ICAM-1, VCAM-1 →</td><td><sup>1</sup>Pecorino vs control cheese: IL-6, IL-8, TNF-α ↓; IL-10, IL-12 →</td><td><sup>1</sup>Enriched sheep cheese vs control cheese: IL-6 (n = 16), CRP (n = 16), leptin (n = 16), adiponectin (n = 16) →; andanamide ↓</td><td><sup>3</sup>Butter (3h vs 0h): MCP-1, MIP-1α, ICAM-1, VCAM-1 →; IL-6, IL-1β, TNF-α, CRP ↓</td></tr><tr><td>Net change in inflammatory marker</td><td>3</td><td>1</td><td>1</td><td>3</td><td>1</td><td>4</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No</td><td>No</td><td>No</td><td>N.a.</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td><td>Private</td><td>Public</td><td>Public</td><td>Private</td></tr><tr><td>Grading criteria</td><td>Anti, 1, 2, 4, 5, 6, 7, 9</td><td>Anti, 1, 2, 4, 6, 7, 9</td><td>Anti, 1, 2, 3, 4, 6, 7</td><td>Anti, 1, 3, 4, 5, 6, 7</td><td>Anti, 1, 2, 3, 4, 6, 7</td><td>Anti, 2, 3, 4, 5, 6</td></tr><tr><td>IS</td><td>8</td><td>7</td><td>7</td><td>7</td><td>7</td><td>6</td></tr></tbody></table>

(Continued on next page)
<figure><img src="image_15.png" /></figure>

<table><thead><tr><th>Reference</th><th>(Panagiotakos et al., 2010) 5</th><th>(Panagiotakos et al., 2010) 6</th><th>(van Meijl & Mensink, 2010)</th><th>(Sofi et al., 2010) 1</th><th>(Pintus et al., 2013) 1</th><th>(Nestel et al., 2012) 1</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td><td>HEALTH</td><td>MET</td><td>HEALTH</td><td>MET</td><td>MET</td></tr><tr><td>Target indication</td><td>Cardiovascular disease</td><td>Cardiovascular disease</td><td>Metabolic syndrome and cardiovascular disease</td><td>Atherosclerosis</td><td>Hypercholesterolemia</td><td>Systemic inflammation</td></tr><tr><td>Target population</td><td>Healthy adults</td><td>Healthy adults</td><td>Overweight and obese subjects</td><td>Healthy adults</td><td>Mildly hypercholesterolaemic subjects</td><td>Overweight or obese subjects</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>Low-fat</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>N.a.</td><td>Fermented</td><td>N.a.</td><td>Fermented</td><td>Fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>High dairy diet</td><td>Low dairy diet</td><td>Low-fat dairy (milk and yoghurt)</td><td>Pecorino sheep cheese naturally high in CLA</td><td>Sheep cheese naturally enriched with CLA</td><td>Butter</td></tr><tr><td>Control product</td><td>Low dairy diet</td><td>Low dairy diet</td><td>Carbohydrate-rich product</td><td>Commercial cow cheese low in CLA</td><td>Sheep cheese with pill containing 1 g of a palm oil-soybean oil mix</td><td>—</td></tr><tr><td>Test subjects</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>1514 M, 1528 F / 25-50 y / healthy</td><td>10 M, 25 F / 50±13 y / BMI: 32±4</td><td>4 M, 6 F / 30-65 y / healthy</td><td>19 M, 23 F / 30-60 y / mild hypercholesterolaemia</td><td>13 / 61.6±7.6 y / overweight or obese</td></tr><tr><td>Control subjects</td><td>456 M, 292 F / 33-53 y / healthy</td><td>456 M, 292 F / 33-53 y / healthy</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Diet</td><td>Low-fat dairy / servings/ week: <8; 8-10; 11-14; >14 / frequency of consumption over past year (FFQ)</td><td>Low-fat yoghurt / servings/ week: <8; 8-10; 11-14; >14 / frequency of consumption over past year (FFQ)</td><td>Milk (500 ml/d), yoghurt (150 g/d) / 8 weeks</td><td>Cheese / 200 g/week / 10 weeks</td><td>Naturally enriched sheep cheese or control cheese / 90 g/d / 3 weeks / between 3 weeks washout</td><td>50 g butter / postprandial challenge study</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>No</td></tr><tr><td>Randomization</td><td>Randomized</td><td>Randomized</td><td>Randomized</td><td>Non-randomized</td><td>Randomized</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td></tr><tr><td>Study results</td><td><sup>5</sup>Low-fat yoghurt: corr<sub>↓</sub> with TNF-α; corr<sub>→</sub> with CRP, IL-6 (not adjusted for confounders)</td><td><sup>5</sup>Low-fat yoghurt: corr<sub>↓</sub> with TNF-α; corr<sub>→</sub> with CRP, IL-6 (not adjusted for confounders)</td><td><sup>1</sup>Low-fat dairy vs carbohydrate-rich meal: s-TNFR-2 ↑, TNF-α, s-TNFR-1, MCP-1, ICAM-1, VCAM-1 →</td><td><sup>1</sup>Pecorino vs control cheese: IL-6, IL-8, TNF-α ↓; IL-10, IL-12 →</td><td><sup>1</sup>Enriched sheep cheese vs control cheese: IL-6 (n = 16), CRP (n = 16), leptin (n = 16), adiponectin (n = 16) →; andanamide ↓</td><td><sup>3</sup>Butter (3h vs 0h): MCP-1, MIP-1α, ICAM-1, VCAM-1 →; IL-6, IL-1β, TNF-α, CRP ↓</td></tr><tr><td>Net change in inflammatory marker</td><td>3</td><td>1</td><td>1</td><td>3</td><td>1</td><td>4</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No - obesity, hypertension and diabetes mellitus did not correlate with the consumption of dairy products</td><td>No</td><td>No</td><td>No</td><td>N.a.</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td><td>Private</td><td>Public</td><td>Public</td><td>Private</td></tr><tr><td>Grading criteria</td><td>Anti, 1, 2, 4, 5, 6, 7, 9</td><td>Anti, 1, 2, 4, 6, 7, 9</td><td>Anti, 1, 2, 3, 4, 6, 7</td><td>Anti, 1, 3, 4, 5, 6, 7</td><td>Anti, 1, 2, 3, 4, 6, 7</td><td>Anti, 2, 3, 4, 5, 6</td></tr><tr><td>IS</td><td>8</td><td>7</td><td>7</td><td>7</td><td>7</td><td>6</td></tr></tbody></table>

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<table><caption>Table 3. (Continued)</caption><thead><tr><th>Reference</th><th>(Wang et al., 2011) 1</th><th>(Meyer et al., 2011) 1</th><th>(Meyer et al., 2011) 2</th><th>(Jones et al., 2013) 1</th><th>(Romeo et al., 2011)</th><th>(Nestel et al., 2012) 2</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>MET</td><td>HEALTH</td><td>MET</td></tr><tr><td>Target indication</td><td>Obesity and cardiovascular disease</td><td>Coronary heart disease</td><td>Coronary heart disease</td><td>Metabolic syndrome (MS)</td><td>Cardiovascular disease</td><td>Systemic inflammation</td></tr><tr><td>Target population</td><td>Normal-weight and overweight adolescents</td><td>General population</td><td>General population</td><td>Overweight and obese MS participants</td><td>Children</td><td>Overweight or obese subjects</td></tr><tr><td>Fat content</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>Non-fermented</td><td>Non-fermented</td><td>Non-fermented</td><td>N.a.</td><td>Non-fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>Dairy fatty acids</td><td>Inflammatory risk dietary pattern (IRDP), containing butter</td><td>Inflammatory risk dietary pattern (IRDP), containing curd</td><td>High dairy, high calcium diet plus caloric restriction</td><td>Dairy product enriched with nutrients</td><td>Cream</td></tr><tr><td>Control product</td><td>—</td><td>—</td><td>—</td><td>Low dairy, low calcium diet plus caloric restriction</td><td>Milk</td><td>—</td></tr><tr><td>Test subjects</td><td>62 M, 51 F / 14.7±1.2 y / overweight</td><td>981 M / 45-64 y / healthy</td><td>981 M / 45-64 y / healthy</td><td>7 M, 13F / 52.1±1.5 y / obese with MS</td><td>27 M, 26 F / 8-14 y / healthy</td><td>13 / 61.6±7.6 y / overweight or obese</td></tr><tr><td>Control subjects</td><td>—</td><td>—</td><td>—</td><td>7 M, 11F / 50.1±2.7 y / obese with MS</td><td>26 M, 25 F / 8-14 y / healthy</td><td>—</td></tr><tr><td>Diet</td><td>FFQ / measurements of dairy fatty acids</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>3-4 servings low-fat dairy (milk or yoghurt)/d and 350 mg/d Ca supplement or 1 serving of yoghurt/d</td><td>600 mL test or control product per day / 5 months</td><td>115 ml cream / postprandial challenge study</td></tr><tr><td>Controlled dairy test</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>Randomized</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td></tr><tr><td>Study results</td><td><sup>5</sup>Dairy fatty acids: corr↓ with CRP; corr→ with TNF-α (adjusted for confounders)</td><td><sup>7</sup>Pattern including butter: corr↓ with IL-6, CRP, IL-18 (not adjusted for confounders)</td><td><sup>7</sup>Pattern including curd: corr↓ with IL-6, CRP; corr→ with IL-18 (not adjusted for confounders)</td><td><sup>1</sup>High dairy diet and Ca (0.5h) vs low dairy diet (0.5h): IL-6, TNF-α, IL-1β →; MCP-1: ↓</td><td><sup>2</sup>Milk (m5 vs m0): E-selectin, VCAM-1, ICAM-1, WBC count (leukocytes, neutrophils, lymphocytes, eosinophils, monocytes) →; adiponectin ↓</td><td><sup>2</sup>Cream (3h vs 0h): MCP-1, MIP-1a, ICAM-1, IL-6, IL-1β, TNF-α, CRP ↓; VCAM-1 →</td></tr><tr><td>Net change in inflammatory marker</td><td>1</td><td>3</td><td>2</td><td>1</td><td>1</td><td>7</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>No</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>No</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Investigated - odd-numbered dairy fatty acids accumulate in epididymal fat rather than being β-oxidized in liver</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Investigated - dairy fatty acids (15:0, 17:0)</td><td>Yes - inflammatory dietary pattern significantly associated with all-cause mortality, butter contributed negatively to the effect</td><td>Not discussed</td><td>Yes - inflammatory dietary pattern significantly associated with all-cause mortality, curd contributed negatively to the effect</td><td>Not discussed</td><td>N.a.</td></tr><tr><td>Clinical evidence</td><td>Yes - higher levels of dairy fatty acids associated with lower markers of oxidative stress</td><td>Public<br/>Anti, 4, 5, 6, 7, 11</td><td>Public<br/>Anti, 4, 5, 6, 7, 11</td><td>Public<br/>Anti, 4, 5, 6, 7, 11</td><td>Public<br/>Anti, 1, 2, 3, 4, 6</td><td>Private<br/>Anti, 3, 4, 6, 7</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Private</td></tr><tr><td>Grading criteria</td><td>Anti, 4, 6, 7, 10, 11</td><td>Anti, 4, 5, 6, 7, 11</td><td>Anti, 4, 5, 6, 7, 11</td><td>Anti, 4, 5, 6, 7, 11</td><td>Anti, 3, 4, 6, 7</td><td>Private<br/>Anti, 3, 4, 5, 6</td></tr><tr><td>IS</td><td>6</td><td>6</td><td>6</td><td>6</td><td>5</td><td>5</td></tr></tbody></table>
<table><caption>Table 3. (Continued)</caption><thead><tr><th>Reference</th><th>(Wang et al., 2011) 1</th><th>(Meyer et al., 2011) 1</th><th>(Meyer et al., 2011) 2</th><th>(Jones et al., 2013) 1</th><th>(Romeo et al., 2011)</th><th>(Nestel et al., 2012) 2</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>MET</td><td>HEALTH</td><td>MET</td></tr><tr><td>Target indication</td><td>Obesity and cardiovascular disease</td><td>Coronary heart disease</td><td>Coronary heart disease</td><td>Metabolic syndrome (MS)</td><td>Cardiovascular disease</td><td>Systemic inflammation</td></tr><tr><td>Target population</td><td>Normal-weight and overweight adolescents</td><td>General population</td><td>General population</td><td>Overweight and obese MS participants</td><td>Children</td><td>Overweight or obese subjects</td></tr><tr><td>Fat content</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>Non-fermented</td><td>Non-fermented</td><td>Non-fermented</td><td>N.a.</td><td>Non-fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>Dairy fatty acids</td><td>Inflammatory risk dietary pattern (IRDP), containing butter</td><td>Inflammatory risk dietary pattern (IRDP), containing curd</td><td>High dairy, high calcium diet plus caloric restriction</td><td>Dairy product enriched with nutrients</td><td>Cream</td></tr><tr><td>Control product</td><td>—</td><td>—</td><td>—</td><td>Low dairy, low calcium diet plus caloric restriction</td><td>Milk</td><td>—</td></tr><tr><td>Test subjects</td><td>62 M, 51 F / 14.7±1.2 y / overweight</td><td>981 M / 45-64 y / healthy</td><td>981 M / 45-64 y / healthy</td><td>7 M, 13F / 52.1±1.5 y / obese with MS</td><td>27 M, 26 F / 8-14 y / healthy</td><td>13 / 61.6±7.6 y / overweight or obese</td></tr><tr><td>Control subjects</td><td>—</td><td>—</td><td>—</td><td>7 M, 11F / 50.1±2.7 y / obese with MS</td><td>26 M, 25 F / 8-14 y / healthy</td><td>—</td></tr><tr><td>Diet</td><td>FFQ / measurements of dairy fatty acids</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>3-4 servings low-fat dairy (milk or yoghurt)/d and 350 mg/d Ca supplement or 1 serving of yoghurt/d</td><td>600 mL test or control product per day / 5 months</td><td>115 ml cream / postprandial challenge study</td></tr><tr><td>Controlled dairy test</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>Randomized</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td></tr><tr><td>Study results</td><td><sup>5</sup>Dairy fatty acids: corr↓ with CRP; corr→ with TNF-α (adjusted for confounders)</td><td><sup>7</sup>Pattern including butter: corr↓ with IL-6, CRP, IL-18 (not adjusted for confounders)</td><td><sup>7</sup>Pattern including curd: corr↓ with IL-6, CRP; corr→ with IL-18 (not adjusted for confounders)</td><td><sup>1</sup>High dairy diet and Ca (0.5h) vs low dairy diet (0.5h): IL-6, TNF-α, IL-1β →; MCP-1: ↓</td><td><sup>2</sup>Milk (m5 vs m0): E-selectin, VCAM-1, ICAM-1, WBC count (leukocytes, neutrophils, lymphocytes, eosinophils, monocytes) →; adiponectin ↓</td><td><sup>2</sup>Cream (3h vs 0h): MCP-1, MIP-1α, ICAM-1, IL-6, IL-1β, TNF-α, CRP ↓; VCAM-1 →</td></tr><tr><td>Net change in inflammatory marker</td><td>1</td><td>3</td><td>2</td><td>1</td><td>1</td><td>7</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>No</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>No</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Investigated - odd-numbered dairy fatty acids accumulate in epididymal fat rather than being β-oxidized in liver</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Investigated - dairy fatty acids (15:0, 17:0)</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>Yes - higher levels of dairy fatty acids associated with lower markers of oxidative stress</td><td>Yes - inflammatory dietary pattern significantly associated with all-cause mortality, butter contributed negatively to the effect</td><td>Yes - inflammatory dietary pattern significantly associated with all-cause mortality, curd contributed negatively to the effect</td><td>No</td><td>No - no effect on albumin, ferritin, glucose and insulin</td><td>N.a.</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Private</td></tr><tr><td>Grading criteria</td><td>Anti, 4, 6, 7, 10, 11</td><td>Anti, 4, 5, 6, 7, 11</td><td>Anti, 4, 5, 6, 7, 11</td><td>Anti, 1, 2, 3, 4, 6</td><td>Anti, 3, 4, 6, 7</td><td>Anti, 3, 4, 5, 6</td></tr><tr><td>IS</td><td>6</td><td>6</td><td>6</td><td>6</td><td>5</td><td>5</td></tr></tbody></table>
<figure><img src="image_15.png" /></figure>

<table><thead><tr><th>Reference</th><th>(Nestel et al., 2012) 3</th><th>(Meyer et al., 2011) 3</th><th>(Meyer et al., 2011) 4</th><th>(Anderson et al., 2012) 1</th><th>(Esmailzadeh et al., 2007) 1</th><th>(Nettleton et al., 2006) 1</th></tr></thead><tbody><tr><td>Subject category</td><td>MET</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Systemic inflammation</td><td>Coronary heart disease</td><td>Coronary heart disease</td><td>Insulin sensitivity and systemic inflammation</td><td>Systemic inflammation</td><td>Cardiovascular disease</td></tr><tr><td>Target population</td><td>Overweight or obese subjects</td><td>General population</td><td>General population</td><td>General population</td><td>Healthy women</td><td>Healthy adults</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td><td>Low-fat</td><td>Low-fat</td><td>Low-fat</td></tr><tr><td>Fermentation</td><td>N.a.</td><td>Fermented</td><td>Non-fermented</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Test product</td><td>Low-fat dairy</td><td>Inflammatory risk dietary pattern (IRDP), containing cheese</td><td>Inflammatory risk dietary pattern (IRDP), containing condensed milk and cream</td><td>Food cluster including low-fat dairy products</td><td>Dietary patterns including low-fat dairy products</td><td>Dietary patterns low-fat milk and yoghurt</td></tr><tr><td>Control product</td><td>—</td><td>—</td><td>—</td><td>Food cluster high-fat dairy products</td><td>—</td><td>—</td></tr><tr><td>Test subjects</td><td>13 / 61.6±7.6 y / overweight or obese</td><td>981 M / 45-64 y / healthy</td><td>981 M / 45-64 y / healthy</td><td>1751 M and F / 70-79 y / healthy</td><td>486 F / 40-60 y / healthy</td><td>2407 M, 2682 F / 45-84 y / healthy</td></tr><tr><td>Control subjects</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Diet</td><td>400 ml reduced fat milk / postprandial challenge study</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td></tr><tr><td>Controlled dairy test</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td><sup>2</sup>Low-fat dairy (3h vs 0h): MCP-1, MIP-1α, ICAM-1, VCAM-1 →; IL-6, IL-1β, TNF-α, CRP ↓</td><td><sup>7</sup>Pattern including cheese: corr ↓ with IL-6, corr → with CRP, IL-18 (not adjusted for confounders)</td><td><sup>7</sup>Pattern including condensed milk and cream: corr ↓ with CRP, corr → with IL-6, IL-18 (not adjusted for confounders)</td><td><sup>7</sup>Cluster including low-fat dairy vs cluster with high-fat dairy products: IL-6 ↓; TNF-α, CRP →</td><td><sup>7</sup>Pattern including low-fat dairy: corr ↓, with CRP, VCAM-1; corr → with TNF-α, SAA, IL-6, E-selectin, ICAM-1 (after adjustment for confounders)</td><td><sup>7</sup>Pattern including low-fat milk and yoghurt: corr ↓ with CRP, IL-6, ICAM-1; corr → with E-selectin (adjusted for confounders)</td></tr><tr><td>Net change in inflammatory marker</td><td>4</td><td>1</td><td>1</td><td>1</td><td>2</td><td>3</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed - interaction between dietary pattern and PPAR-γ genotype</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Clinical evidence</td><td>N.a.</td><td>Yes - inflammatory dietary pattern significantly associated with all-cause mortality; cheese contributed negatively to the effect</td><td>Yes - inflammatory dietary pattern significantly associated with all-cause mortality, condensed milk and cream contributed negatively to the effect</td><td>Yes - cluster containing low-fat dairy associated with greater insulin sensitivity than cluster with high-fat dairy products</td><td></td><td></td></tr><tr><td>Financing of research</td><td>Private</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Anti, 3, 4, 5, 6</td><td>Anti, 4, 6, 7, 11</td><td>Anti, 4, 6, 7, 11</td><td>Anti, 4, 6, 7, 11</td><td>Anti, 5, 6, 7</td><td>Anti, 5, 6, 7</td></tr><tr><td>IS</td><td>5</td><td>5</td><td>5</td><td>5</td><td>4</td><td>4</td></tr></tbody></table>

(Continued on next page)
<figure><img src="image_16.png" /></figure>

<table><thead><tr><th>Reference</th><th>(Nestel et al., 2012) 3</th><th>(Meyer et al., 2011) 3</th><th>(Meyer et al., 2011) 4</th><th>(Anderson et al., 2012) 1</th><th>(Esmailzadeh et al., 2007) 1</th><th>(Nettleton et al., 2006) 1</th></tr></thead><tbody><tr><td>Subject category</td><td>MET</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Systemic inflammation</td><td>Coronary heart disease</td><td>Coronary heart disease</td><td>Insulin sensitivity and systemic inflammation</td><td>Systemic inflammation</td><td>Cardiovascular disease</td></tr><tr><td>Target population</td><td>Overweight or obese subjects</td><td>General population</td><td>General population</td><td>General population</td><td>Healthy women</td><td>Healthy adults</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td><td>Low-fat</td><td>Low-fat</td><td>Low-fat</td></tr><tr><td>Fermentation</td><td>N.a.</td><td>Fermented</td><td>Non-fermented</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Test product</td><td>Low-fat dairy</td><td>Inflammatory risk dietary pattern (IRDP), containing cheese</td><td>Inflammatory risk dietary pattern (IRDP), containing condensed milk and cream</td><td>Food cluster including low-fat dairy products</td><td>Dietary patterns including low-fat dairy products</td><td>Dietary patterns low-fat milk and yoghurt</td></tr><tr><td>Control product</td><td>—</td><td>—</td><td>—</td><td>Food cluster high-fat dairy products</td><td>—</td><td>—</td></tr><tr><td>Test subjects</td><td>13 / 61.6±7.6 y / overweight or obese</td><td>981 M / 45-64 y / healthy</td><td>981 M / 45-64 y / healthy</td><td>1751 M and F / 70-79 y / healthy</td><td>486 F / 40-60 y / healthy</td><td>2407 M, 2682 F / 45-84 y / healthy</td></tr><tr><td>Control subjects</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Diet</td><td>400 ml reduced fat milk / postprandial challenge study</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td></tr><tr><td>Controlled dairy test</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td><sup>2</sup>Low-fat dairy (3h vs 0h): MCP-1, MIP-1α, ICAM-1, VCAM-1 →; IL-6, IL-1β, TNF-α, CRP ↓</td><td><sup>7</sup>Pattern including cheese: corr ↓ with IL-6, corr → with CRP, IL-18 (not adjusted for confounders)</td><td><sup>7</sup>Pattern including condensed milk and cream: corr ↓ with CRP, corr → with IL-6, IL-18 (not adjusted for confounders)</td><td><sup>7</sup>Cluster including low-fat dairy vs cluster with high-fat dairy products: IL-6 ↓; TNF-α, CRP →</td><td><sup>7</sup>Pattern including low-fat dairy: corr ↓, with CRP, VCAM-1; corr → with TNF-α, SAA, IL-6, E-selectin, ICAM-1 (after adjustment for confounders)</td><td><sup>7</sup>Pattern including low-fat milk and yoghurt: corr ↓ with CRP, IL-6, ICAM-1; corr → with E-selectin (adjusted for confounders)</td></tr><tr><td>Net change in inflammatory marker</td><td>4</td><td>1</td><td>1</td><td>1</td><td>2</td><td>3</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed - interaction between dietary pattern and PPAR-γ genotype</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Clinical evidence</td><td>N.a.</td><td>Yes - inflammatory dietary pattern significantly associated with all-cause mortality; cheese contributed negatively to the effect</td><td>Yes - inflammatory dietary pattern significantly associated with all-cause mortality, condensed milk and cream contributed negatively to the effect</td><td>Yes - cluster containing low-fat dairy associated with greater insulin sensitivity than cluster with high-fat dairy products</td><td></td><td></td></tr><tr><td>Financing of research</td><td>Private</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Anti, 3, 4, 5, 6</td><td>Anti, 4, 6, 7, 11</td><td>Anti, 4, 6, 7, 11</td><td>Anti, 4, 6, 7, 11</td><td>Anti, 5, 6, 7</td><td>Anti, 5, 6, 7</td></tr><tr><td>IS</td><td>5</td><td>5</td><td>5</td><td>5</td><td>4</td><td>4</td></tr></tbody></table>

(Continued on next page)
<figure><img src="image_16.png" /><figcaption>Table 3. (Continued)</figcaption></figure>

<table><thead><tr><th>Reference</th><th>(Dawczynski et al., 2013)</th><th>(Hlebowicz et al., 2011)</th></tr></thead><tbody><tr><td>Subject category</td><td>MET</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Hypertriacylglyceridemia and CVD</td><td>Cardiovascular disease</td></tr><tr><td>Target population</td><td>Adults with hypertriacylglyceridemia and risk of CVD</td><td>General population</td></tr><tr><td>Fat content</td><td>High-fat</td><td>Low-fat</td></tr><tr><td>Fermentation</td><td>Fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>Two yoghurts differently enriched with fat (fish oil)</td><td>Dietary pattern including low-fat milk</td></tr><tr><td>Control product</td><td>Yoghurt</td><td>Dietary pattern including high-fat dairy products (cheese, whole milk, butter)</td></tr><tr><td>Test subjects</td><td>1) 17 / 61.6±11.9 y / hypertriacylglyceridemia<br>2) 16 / 61.8±7.1 y / hypertriacylglyceridemia<br>14 / 58.2±7.4 y / hypertriacylglyceridemia<br>125 g control or test product / 10 weeks</td><td>2040 M, 2959 F / 45-68 y / healthy</td></tr><tr><td>Control subjects</td><td></td><td>—</td></tr><tr><td>Diet</td><td></td><td>Diet assessment (FFQ) / 13 y of follow-up for CVD events</td></tr><tr><td>Controlled dairy test</td><td>No</td><td>Yes</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td><sup>2</sup>Yoghurt (w10 vs w0): CRP, IFN-γ (T-cells ex vivo) →; TNF-α (T-cells ex vivo) ↓</td><td><sup>6</sup>Low-fat milk pattern vs high-fat dairy pattern: WBC ↓; CRP →</td></tr><tr><td>Net change in inflammatory marker</td><td>1</td><td>1</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>N.a.</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Discussed - PUFA</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>No - cardiovascular risk factors not changed after 10 weeks</td><td>No discussed</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Anti, 3, 4, 7</td><td>Anti, 1, 6, 7</td></tr><tr><td>IS</td><td>4</td><td>4</td></tr></tbody></table>
<figure><img src="image_17.png" /><figcaption>Table 3. (Continued)</figcaption></figure>

<table><thead><tr><th>Reference</th><th>(Dawczynski et al., 2013)</th><th>(Hlebowicz et al., 2011)</th></tr></thead><tbody><tr><td>Subject category</td><td>MET</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Hypertriacylglyceridemia and CVD</td><td>Cardiovascular disease</td></tr><tr><td>Target population</td><td>Adults with hypertriacylglyceridemia and risk of CVD</td><td>General population</td></tr><tr><td>Fat content</td><td>High-fat</td><td>Low-fat</td></tr><tr><td>Fermentation</td><td>Fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>Two yoghurts differently enriched with fat (fish oil)</td><td>Dietary pattern including low-fat milk</td></tr><tr><td>Control product</td><td>Yoghurt</td><td>Dietary pattern including high-fat dairy products (cheese, whole milk, butter)</td></tr><tr><td>Test subjects</td><td>1) 17 / 61.6±11.9 y / hypertriacylglyceridemia<br>2) 16 / 61.8±7.1 y / hypertriacylglyceridemia<br>14 / 58.2±7.4 y / hypertriacylglyceridemia<br>125 g control or test product / 10 weeks</td><td>2040 M, 2959 F / 45-68 y / healthy</td></tr><tr><td>Control subjects</td><td></td><td>—</td></tr><tr><td>Diet</td><td></td><td>Diet assessment (FFQ) / 13 y of follow-up for CVD events</td></tr><tr><td>Controlled dairy test</td><td>No</td><td>Yes</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td><sup>2</sup>Yoghurt (w10 vs w0): CRP, IFN-γ (T-cells ex vivo) →; TNF-α (T-cells ex vivo) ↓</td><td><sup>6</sup>Low-fat milk pattern vs high-fat dairy pattern: WBC ↓; CRP →</td></tr><tr><td>Net change in inflammatory marker</td><td>1</td><td>1</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>N.a.</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Discussed - PUFA</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>No - cardiovascular risk factors not changed after 10 weeks</td><td>No discussed</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Anti, 3, 4, 7</td><td>Anti, 1, 6, 7</td></tr><tr><td>IS</td><td>4</td><td>4</td></tr></tbody></table>
<figure><img src="image_17.png" /></figure>

gastrointestinal disorders (8 study results) and of subjects with allergy to dairy products (6 study results) lacked study results indicative of an anti-inflammatory effect.

These observations were statistically confirmed by compar-
ing the distribution of the IS for the groups of study results
investigating healthy subjects and subjects with metabolic dis-
orders (Table 6). Both mean IS were positive and the null
hypothesis for the median IS in the two-sided Wilcoxon
Signed-Rank test was rejected, pointing to an anti-inflamma-
tory activity of dairy products in these two subject categories.
The mean IS of the MET subject category were higher than for
the HEALTH subject category, but the Kruskal-Wallis test did
not point to a statistically significant difference in the median
IS between both subject categories. The mean IS for the GIT
subject category was negative, but the Wilcoxon Signed-Rank
test on the median IS did not point to a statistically significant
effect. However, the mean IS for the HYPER subject category
was negative and the null hypothesis for the median IS in the
two-sided Wilcoxon Signed-Rank test was rejected, indicating a
pro-inflammatory effect of dairy products in subjects allergic to
dairy products. Finally, a group of studies in which the subjects
could not be attributed to any of the above categories, had a
median IS that was statistically not different from zero.

In order to investigate the impact of dairy product process-
ing, in particular fat processing and fermentation on the IS, the
study results were stratified according to the fat content and
fermentation status of the dairy products investigated.

Thirty-five study results with high-fat dairy products and 20
study results with low-fat products were reported (Figure 5). In
contrast to the high-fat products, none of the study results with
low-fat products indicated a pro-inflammatory activity. The
mean IS of the low-fat product category was, indeed, lower
than for the high-fat product category but the Kruskal-Wallis
test on the median IS did not demonstrate this difference to
reach statistical significance (p=0.083). However, the mean IS
of each product category was positive and the null hypothesis
for the median IS in the two-sided Wilcoxon Signed-Rank test
was rejected, indicating an anti-inflammatory activity for both
low-fat and high-fat dairy products (Table 6).

Thirty-three study results could be identified in which non-
fermented dairy products were investigated, whereas 16 study
results were reported with fermented products (Figure 6). The
mean IS of both the non-fermented and fermented product cat-
egory were positive, but the two-sided Wilcoxon Signed-Rank
test on the median IS only indicated a significant anti-inflam-
matory activity for the fermented product category (Table 6).

In an attempt to identify the bioactive nutrients potentially
modulating inflammation, and to complement the human data
with preclinical data, we conducted a non-systematic and
non-quantitative evaluation of the literature available on the
inflammatory properties of dairy products in animal models
(unpublished data). Most of these studies reported an anti-
inflammatory effect; however, due to the different animal mod-
els and protocols used in the selected articles, it was not possi-
ble to compare results and to perform an analysis as we did for
human studies. It was anyway clear that the importance of
identifying the molecule(s) responsible for the effect, and its
mechanism of action, is poorly considered in animal studies,
too.

Discussion

Pro- and ant-inflammatory properties of dairy products

Overall, the IS of the entire data set composed of 78 study
results, extracted from 52 human studies indicates that the con-
sumption of dairy products is associated with anti-inflamma-
tory properties in humans. We qualify this association as weak,
although significant, because the IS has a low magnitude that is
indicative of a low level of confidence in the effect estimate.

By stratifying the study results according to the health status
of the enrolled subjects, we identified a pro-inflammatory activ-
ity of dairy products in subjects with milk allergy. This result is
mechanistically expected, as hypersensitive reactions can obvi-
ously be linked to the pro-inflammatory state (Savilahti and
Westerholm-Ormio, 2004). We therefore conclude that the IS
is an adequate tool to evaluate the impact of food and dietary
patterns on inflammation.

A systematic review recently assessed eight randomized con-
trolled nutritional intervention studies, which have investigated
the impact of dairy product consumption on biomarkers of
inflammation in overweight and obese adults (Labonte et al.,
2013). The authors concluded that the consumption of dairy
products did not exert adverse effects on biomarkers of inflam-
mation in these subjects, and that limitations among these
studies did not allow for the differentiation between a beneficial
or neutral impact of dairy products on inflammation. In our
review, stratifying the data according to the health status of the
subjects, allowed us to identify 24 study results in the MET sub-
ject category. The IS of this data set indicates an anti-inflamma-
tory property of dairy products in subjects with metabolic
disorders. Noteworthy, the significantly positive IS was also
indicative of an anti-inflammatory effect of dairy products in
the HEALTH group. We found, however, a trend towards a
higher IS in the MET group, compared to the HEALTH group
suggesting a stronger evidence for an anti-inflammatory activ-
ity of dairy products in the former subject category. This find-
ing is illustrated by the identification of ten studies reporting a
pro-inflammatory activity of dairy products in the HEALTH
group, whereas the MET group is the only category in which
none of the studies reported a pro-inflammatory activity of
dairy products. The specific reactivity of the MET group may
be linked mechanistically to the inflammatory nature of obesity.
Obesity is associated with a low-grade systemic chronic inflam-
matory state, characterized by the abnormal production of
inflammatory cytokines (Guri and Bassaganya-Riera, 2011;
Schwander et al., 2014). As low-grade systemic inflammation
links obesity to metabolic pathologies, including insulin resis-
tance, cardiovascular diseases, or type-2 diabetes, targeting obe-
sity-related inflammatory components may be a useful
preventive strategy. Low-grade chronic inflammation is modu-
lated by nutrients such as fatty acids, glucose, bioactive plant
compounds, vitamins and minerals, which either enhance or
alleviate the inflammatory state (Hirai et al., 2010). In this con-
text, as obese subjects are characterized by low-grade systemic
inflammation, the MET group may be more prone to the anti-
inflammatory action of dairy products than metabolically
healthy subjects.

Stratifying the data according to categories of dairy prod-
ucts, revealed an anti-inflammatory activity for both low-fat
<figure><img src="image_18.png" /></figure>

gastrointestinal disorders (8 study results) and of subjects with allergy to dairy products (6 study results) lacked study results indicative of an anti-inflammatory effect.

These observations were statistically confirmed by compar-
ing the distribution of the IS for the groups of study results
investigating healthy subjects and subjects with metabolic dis-
orders (Table 6). Both mean IS were positive and the null
hypothesis for the median IS in the two-sided Wilcoxon
Signed-Rank test was rejected, pointing to an anti-inflamma-
tory activity of dairy products in these two subject categories.
The mean IS of the MET subject category were higher than for
the HEALTH subject category, but the Kruskal-Wallis test did
not point to a statistically significant difference in the median
IS between both subject categories. The mean IS for the GIT
subject category was negative, but the Wilcoxon Signed-Rank
test on the median IS did not point to a statistically significant
effect. However, the mean IS for the HYPER subject category
was negative and the null hypothesis for the median IS in the
two-sided Wilcoxon Signed-Rank test was rejected, indicating a
pro-inflammatory effect of dairy products in subjects allergic to
dairy products. Finally, a group of studies in which the subjects
could not be attributed to any of the above categories, had a
median IS that was statistically not different from zero.

In order to investigate the impact of dairy product process-
ing, in particular fat processing and fermentation on the IS, the
study results were stratified according to the fat content and
fermentation status of the dairy products investigated.

Thirty-five study results with high-fat dairy products and 20
study results with low-fat products were reported (Figure 5). In
contrast to the high-fat products, none of the study results with
low-fat products indicated a pro-inflammatory activity. The
mean IS of the low-fat product category was, indeed, lower
than for the high-fat product category but the Kruskal-Wallis
test on the median IS did not demonstrate this difference to
reach statistical significance (p=0.083). However, the mean IS
of each product category was positive and the null hypothesis
for the median IS in the two-sided Wilcoxon Signed-Rank test
was rejected, indicating an anti-inflammatory activity for both
low-fat and high-fat dairy products (Table 6).

Thirty-three study results could be identified in which non-
fermented dairy products were investigated, whereas 16 study
results were reported with fermented products (Figure 6). The
mean IS of both the non-fermented and fermented product cat-
egory were positive, but the two-sided Wilcoxon Signed-Rank
test on the median IS only indicated a significant anti-inflam-
matory activity for the fermented product category (Table 6).

In an attempt to identify the bioactive nutrients potentially
modulating inflammation, and to complement the human data
with preclinical data, we conducted a non-systematic and
non-quantitative evaluation of the literature available on the
inflammatory properties of dairy products in animal models
(unpublished data). Most of these studies reported an anti-
inflammatory effect; however, due to the different animal mod-
els and protocols used in the selected articles, it was not possi-
ble to compare results and to perform an analysis as we did for
human studies. It was anyway clear that the importance of
identifying the molecule(s) responsible for the effect, and its
mechanism of action, is poorly considered in animal studies,
too.

Discussion

Pro- and ant-inflammatory properties of dairy products

Overall, the IS of the entire data set composed of 78 study
results, extracted from 52 human studies indicates that the con-
sumption of dairy products is associated with anti-inflamma-
tory properties in humans. We qualify this association as weak,
although significant, because the IS has a low magnitude that is
indicative of a low level of confidence in the effect estimate.

By stratifying the study results according to the health status
of the enrolled subjects, we identified a pro-inflammatory activ-
ity of dairy products in subjects with milk allergy. This result is
mechanistically expected, as hypersensitive reactions can obvi-
ously be linked to the pro-inflammatory state (Savilahti and
Westerholm-Ormio, 2004). We therefore conclude that the IS
is an adequate tool to evaluate the impact of food and dietary
patterns on inflammation.

A systematic review recently assessed eight randomized con-
trolled nutritional intervention studies, which have investigated
the impact of dairy product consumption on biomarkers of
inflammation in overweight and obese adults (Labonte et al.,
2013). The authors concluded that the consumption of dairy
products did not exert adverse effects on biomarkers of inflam-
mation in these subjects, and that limitations among these
studies did not allow for the differentiation between a beneficial
or neutral impact of dairy products on inflammation. In our
review, stratifying the data according to the health status of the
subjects, allowed us to identify 24 study results in the MET sub-
ject category. The IS of this data set indicates an anti-inflamma-
tory property of dairy products in subjects with metabolic
disorders. Noteworthy, the significantly positive IS was also
indicative of an anti-inflammatory effect of dairy products in
the HEALTH group. We found, however, a trend towards a
higher IS in the MET group, compared to the HEALTH group
suggesting a stronger evidence for an anti-inflammatory activ-
ity of dairy products in the former subject category. This find-
ing is illustrated by the identification of ten studies reporting a
pro-inflammatory activity of dairy products in the HEALTH
group, whereas the MET group is the only category in which
none of the studies reported a pro-inflammatory activity of
dairy products. The specific reactivity of the MET group may
be linked mechanistically to the inflammatory nature of obesity.
Obesity is associated with a low-grade systemic chronic inflam-
matory state, characterized by the abnormal production of
inflammatory cytokines (Guri and Bassaganya-Riera, 2011;
Schwander et al., 2014). As low-grade systemic inflammation
links obesity to metabolic pathologies, including insulin resis-
tance, cardiovascular diseases, or type-2 diabetes, targeting obe-
sity-related inflammatory components may be a useful
preventive strategy. Low-grade chronic inflammation is modu-
lated by nutrients such as fatty acids, glucose, bioactive plant
compounds, vitamins and minerals, which either enhance or
alleviate the inflammatory state (Hirai et al., 2010). In this con-
text, as obese subjects are characterized by low-grade systemic
inflammation, the MET group may be more prone to the anti-
inflammatory action of dairy products than metabolically
healthy subjects.

Stratifying the data according to categories of dairy prod-
ucts, revealed an anti-inflammatory activity for both low-fat
<figure><img src="image_18.png" /><figcaption>Table 4. Tabulated summary of the study results with evidence for a pro-inflammatory effect of dairy products.</figcaption></figure>

<table><thead><tr><th>Reference</th><th>(Iacono et al., 1998)</th><th>(Kristjansson et al., 2007)</th><th>(Rebholz et al., 2013)</th><th>(Henderson et al., 2012)</th><th>(Ufsemer et al., 2012)</th><th>(Kagalwalla et al., 2011)</th></tr></thead><tbody><tr><td>Subject category</td><td>HYPER</td><td>GIT</td><td>HEALTH</td><td>HYPER</td><td>HEALTH</td><td>HYPER</td></tr><tr><td>Target indication</td><td>Chronic constipation</td><td>Coeliac disease</td><td>Cardiovascular disease risk</td><td>Food allergy</td><td>General health</td><td>Food allergy</td></tr><tr><td>Target population</td><td>Children with chronic constipation</td><td>Subjects with coeliac disease</td><td>Healthy adults</td><td>Subjects with food allergies</td><td>General population</td><td>Children with eosinophilic esophagitis</td></tr><tr><td>Fat content</td><td>High-fat</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Fermentation</td><td>Non-fermented</td><td>Non-fermented</td><td>Non-fermented</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Test product</td><td>Milk</td><td>Milk powder, purified bovine casein and b-lactalbumin</td><td>Milk protein supplement</td><td>SFED (six food elimination diet): milk, soy, wheat, egg, peanuts/tree nuts, seafood</td><td>Spray-dried pasteurised fermented milk products with inactivated B. xylanisolvens</td><td>SFED (six food elimination diet): cow's milk, soy, wheat, egg, peanuts/tree nuts, seafood</td></tr><tr><td>Control product</td><td>Soy milk</td><td>—</td><td>Carbohydrate placebo</td><td>—</td><td>Milk powder</td><td>—</td></tr><tr><td>Test subjects</td><td>29 M, 36 F / 34.6±17.1 mo / constipation and perianal lesions with pain on defecation</td><td>6 M, 14 F / 25-68 y / coeliac disease</td><td>34 F, 68 M / 46 y / healthy</td><td>98 / ≤ 21 y / eosinophilic esophagitis</td><td>47 M, 43 F / 18-65 y / healthy</td><td>25 M, 11 F / 7.6±4.3 y / eosinophilic esophagitis</td></tr><tr><td>Control subjects</td><td>—</td><td>10 M, 5 F / 19-58 y / healthy</td><td>Milk protein or placebo / 40 g/d / 2 weeks intervention separated by 3 weeks washout</td><td>—</td><td>12 M, 16 F / 18-65 y / healthy</td><td>—</td></tr><tr><td>Diet</td><td>470±135 mL/d Milk and 450± 120 mL/d soy milk / 15 days</td><td>Single rectal challenge with wheat gluten, dried cow's milk powder in NaCl, α-lactalbumin and casein</td><td>Yes</td><td>SFED / 4 months</td><td>2 weeks depletion / 1 serving/d / 6 weeks intervention / 2 weeks recovery</td><td>SFED / ≥ 6 weeks / reintroduction of foods</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Randomized</td><td>Randomized</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Randomization</td><td>Randomized</td><td>Randomized</td><td>Longitudinal</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td></tr><tr><td>Study results</td><td><sup>1</sup>Milk vs soy milk: IgE, infiltration of inflammatory cells in rectal mucosa ↑; CRP →</td><td><sup>4</sup>Milk (coeliac vs healthy): Myeloperoxidase (MPO), NO ↑; Eosinophil cationic protein (ECP) →</td><td><sup>1</sup>Milk protein vs carbohydrate: CRP, IL-6, TNF-α, VCAM-1, ICAM-1, leptin, adiponectin →; E-selectin ↑</td><td><sup>6</sup>SFED (m4 vs baseline): eosinophilic esophagitis (eosinophil count) ↓</td><td><sup>2</sup>Milk powder (w3, w6, w8 vs w0): ex vivo phagocytotic activity of granulocytes (w3), ex vivo NK cell activities (w3, w6), TNF-α (w8) ↑; all other conditions including CRP, WBC and, lymphocyte counts →</td><td><sup>6</sup>SFED (≥w6 vs baseline): eosinophilic esophagitis (eosinophil count) ↓</td></tr><tr><td>Net change in inflammatory marker</td><td>-2</td><td>-2</td><td>-1</td><td>-1</td><td>-3</td><td>-1</td></tr><tr><td>Sustainability of effect over time</td><td>N.a.</td><td>Not discussed</td><td>Not discussed</td><td>N.a.</td><td>No</td><td>N.a.</td></tr><tr><td>Dose-response Bioavailability data</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Discussed - innate immune response to milk protein, and casein</td><td>Not discussed</td><td>Investigated - re-occurrence eosinophilic esophagitis after milk reintroduction</td><td>Not discussed</td><td>Investigated - re-occurrence eosinophilic esophagitis after milk reintroduction</td></tr><tr><td>Clinical evidence</td><td>Yes - anal lesions tended to disappear after removal of milk and introduction of soy milk</td><td>N.a.</td><td>No - cardiovascular risk factors do not change significantly</td><td>Yes - SFED reduces endoscopic and histopathologic features of eosinophilic esophagitis</td><td>No - control milk powder did not modify liver enzyme values</td><td>Yes - reduction endoscopic and histopathologic features of eosinophilic esophagitis</td></tr><tr><td>Financing of research</td><td>Not presented</td><td>Private and Public</td><td>Public</td><td>Private</td><td>Private</td><td>Private and Public</td></tr><tr><td>Grading criteria</td><td>Pro, 1, 2, 3, 4, 5, 6, 7, 11</td><td>Pro, 1, 2, 3, 4, 5, 6, 7, 10</td><td>Pro, 1, 2, 3, 4, 6, 7</td><td>Pro, 3, 6, 7, 10, 11</td><td>Pro, 3, 4, 5, 6, 7</td><td>Pro, 3, 6, 7, 10, 11</td></tr><tr><td>IS</td><td>-9</td><td>-9</td><td>-7</td><td>-6</td><td>-6</td><td>-6</td></tr></tbody></table>
<figure><img src="image_19.png" /><figcaption>Table 4. Tabulated summary of the study results with evidence for a pro-inflammatory effect of dairy products.</figcaption></figure>

<table><thead><tr><th>Reference</th><th>(Iacono et al., 1998)</th><th>(Kristjansson et al., 2007)</th><th>(Rebholz et al., 2013)</th><th>(Henderson et al., 2012)</th><th>(Ufsemer et al., 2012)</th><th>(Kagalwalla et al., 2011)</th></tr></thead><tbody><tr><td>Subject category</td><td>HYPER</td><td>GIT</td><td>HEALTH</td><td>HYPER</td><td>HEALTH</td><td>HYPER</td></tr><tr><td>Target indication</td><td>Chronic constipation</td><td>Coeliac disease</td><td>Cardiovascular disease risk</td><td>Food allergy</td><td>General health</td><td>Food allergy</td></tr><tr><td>Target population</td><td>Children with chronic constipation</td><td>Subjects with coeliac disease</td><td>Healthy adults</td><td>Subjects with food allergies</td><td>General population</td><td>Children with eosinophilic esophagitis</td></tr><tr><td>Fat content</td><td>High-fat</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Fermentation</td><td>Non-fermented</td><td>Non-fermented</td><td>Non-fermented</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Test product</td><td>Milk</td><td>Milk powder, purified bovine casein and b-lactalbumin</td><td>Milk protein supplement</td><td>SFED (six food elimination diet): milk, soy, wheat, egg, peanuts/tree nuts, seafood</td><td>Spray-dried pasteurised fermented milk products with inactivated B. xylanisolvens</td><td>SFED (six food elimination diet): cow's milk, soy, wheat, egg, peanuts/tree nuts, seafood</td></tr><tr><td>Control product</td><td>Soy milk</td><td>—</td><td>Carbohydrate placebo</td><td>—</td><td>Milk powder</td><td>—</td></tr><tr><td>Test subjects</td><td>29 M, 36 F / 34.6±17.1 mo / constipation and perianal lesions with pain on defecation</td><td>6 M, 14 F / 25-68 y / coeliac disease</td><td>34 F, 68 M / 46 y / healthy</td><td>98 / ≤ 21 y / eosinophilic esophagitis</td><td>47 M, 43 F / 18-65 y / healthy</td><td>25 M, 11 F / 7.6±4.3 y / eosinophilic esophagitis</td></tr><tr><td>Control subjects</td><td>—</td><td>10 M, 5 F / 19-58 y / healthy</td><td>Milk protein or placebo / 40 g/d / 2 weeks intervention separated by 3 weeks washout</td><td>—</td><td>12 M, 16 F / 18-65 y / healthy</td><td>—</td></tr><tr><td>Diet</td><td>470±135 mL/d Milk and 450± 120 mL/d soy milk / 15 days</td><td>Single rectal challenge with wheat gluten, dried cow's milk powder in NaCl, α-lactalbumin and casein</td><td>Yes</td><td>SFED / 4 months</td><td>2 weeks depletion / 1 serving/d / 6 weeks intervention / 2 weeks recovery</td><td>SFED / ≥ 6 weeks / reintroduction of foods</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Randomized</td><td>Randomized</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Randomization</td><td>Randomized</td><td>Randomized</td><td>Longitudinal</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td></tr><tr><td>Study results</td><td><sup>1</sup>Milk vs soy milk: IgE, infiltration of inflammatory cells in rectal mucosa ↑; CRP →</td><td><sup>4</sup>Milk (coeliac vs healthy): Myeloperoxidase (MPO), NO ↑; Eosinophil cationic protein (ECP) →</td><td><sup>1</sup>Milk protein vs carbohydrate: CRP, IL-6, TNF-α, VCAM-1, ICAM-1, leptin, adiponectin →; E-selectin ↑</td><td><sup>5</sup>SFED (m4 vs baseline): eosinophilic esophagitis (eosinophil count) ↓</td><td><sup>2</sup>Milk powder (w3, w6, w8 vs w0): ex vivo phagocytotic activity of granulocytes (w3), ex vivo NK cell activities (w3, w6), TNF-α (w8) ↑; all other conditions including CRP, WBC and, lymphocyte counts →</td><td><sup>6</sup>SFED (≥w6 vs baseline): eosinophilic esophagitis (eosinophil count) ↓</td></tr><tr><td>Net change in inflammatory marker</td><td>-2</td><td>-2</td><td>-1</td><td>-1</td><td>-3</td><td>-1</td></tr><tr><td>Sustainability of effect over time</td><td>N.a.</td><td>Not discussed</td><td>Not discussed</td><td>N.a.</td><td>No</td><td>N.a.</td></tr><tr><td>Dose-response Bioavailability data</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Discussed - innate immune response to milk protein, and casein</td><td>Not discussed</td><td>Investigated - re-occurrence eosinophilic esophagitis after milk reintroduction</td><td>Not discussed</td><td>Investigated - re-occurrence eosinophilic esophagitis after milk reintroduction</td></tr><tr><td>Clinical evidence</td><td>Yes - anal lesions tended to disappear after removal of milk and introduction of soy milk</td><td>N.a.</td><td>No - cardiovascular risk factors do not change significantly</td><td>Yes - SFED reduces endoscopic and histopathologic features of eosinophilic esophagitis</td><td>No - control milk powder did not modify liver enzyme values</td><td>Discussed - milk antigens (peptides)</td></tr><tr><td>Financing of research</td><td>Not presented</td><td>Private and Public</td><td>Public</td><td>Private</td><td>Private</td><td>Private and Public</td></tr><tr><td>Grading criteria IS</td><td>Pro, 1, 2, 3, 4, 5, 6, 7, 11</td><td>Pro, 1, 2, 3, 4, 5, 6, 7, 10</td><td>Pro, 1, 2, 3, 4, 6, 7</td><td>Pro, 3, 6, 7, 10, 11</td><td>Pro, 3, 4, 5, 6, 7</td><td>Yes - reduction endoscopic and histopathologic features of eosinophilic esophagitis</td></tr></tbody></table>
<figure><img src="image_19.png" /></figure>

<table><thead><tr><th>Reference</th><th>(Spergel et al., 2005)</th><th>(Gonsalves et al., 2012)</th><th>(Kagalwalla et al., 2012)</th><th>(Deopurkar et al., 2010)</th><th>(Jyonouchi et al., 2002)</th><th>(Meyer et al., 2007)</th></tr></thead><tbody><tr><td>Subject category</td><td>HYPER</td><td>HYPER</td><td>GIT</td><td>HEALTH</td><td>GIT</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Food allergy</td><td>Food allergy</td><td>Eosinophilic esophageal inflammation</td><td>Postprandial oxidative stress and inflammation</td><td>Gastrointestinal symptoms</td><td>Systemic immunity</td></tr><tr><td>Target population</td><td>Subjects allergic to milk and patients with eosinophilic esophagitis</td><td>Adults with eosinophilic esophagitis</td><td>Children with eosinophilic esophageal inflammation</td><td>General population</td><td>Children with autism spectrum disorder</td><td>Healthy subjects</td></tr><tr><td>Fat content</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>High-fat</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Fermentation</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>Non-fermented</td><td>Non-fermented</td><td>Fermented</td></tr><tr><td>Test product</td><td>Elimination diet excluding milk</td><td>SFED (six food elimination diet): Milk milk, soy, wheat, egg, peanuts/tree nuts, seafood</td><td>Milk</td><td>Cream</td><td>Milk protein</td><td>Probiotic yoghurt</td></tr><tr><td>Control product</td><td>—</td><td>—</td><td>—</td><td>Water</td><td>—</td><td>Conventional yoghurt</td></tr><tr><td>Test subjects</td><td>100 M, 46 F / 6.50±4.50 y / eosinophilic esophagitis</td><td>25 M, 25 F / 19-76 y / eosinophilic esophagitis</td><td>12 M, 5 F / 5.5±3.2 y / eosinophilic esophagitis</td><td>48 / 25-47 y / healthy</td><td>59 M, 13 F / 1-17 y / autism spectrum disorder (ASD)<br>17 M, 7 F / 0.5-13 y / dietary protein intolerance (DPI)</td><td>33 F / 22-29 y / healthy</td></tr><tr><td>Control subjects</td><td>—</td><td>—</td><td>—</td><td>—</td><td>12 M, 3 F / 1-16 y / healthy<br>18 M, 8 F / 0.5-2 y / healthy siblings</td><td>—</td></tr><tr><td>Diet</td><td>Elimination diet milk / 4-8 weeks</td><td>SFED / 6 weeks / reintroduction by addition of one food group every 2 weeks</td><td>Milk elimination / 6 weeks</td><td>33 g cream or 300 mL / postprandial challenge study</td><td>Ex vivo activation of (PBMCS) by dietary allergens (e.g milk protein)</td><td>100 g/d conventional or probiotic yoghurt / 2 weeks / 200 g/d yoghurt / 2 weeks</td></tr><tr><td>Control dairy test</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>Non-randomized</td><td>Non-randomized</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Cross-sectional</td><td>Longitudinal</td></tr><tr><td>Study results</td><td>²Milk elimination diet (w4-8 vs baseline): eosinophilic esophagitis ↓</td><td>⁶SDEF (w6 vs baseline): eosinophilic esophagitis ↑</td><td>²Milk elimination (w6 vs w0): TNF-α↑ at 1h and 3h; → at 5h; IL-1β↑ → at 1h, ↑ at 3h and 5h; IL-6: → at 1h, 3h and 5h; NF-κB↑ at 3h</td><td>³Cream (1h, 3h and 5 h vs 0h): TNF-α↑ at 1h and 3h; → at 5h; IL-1β↑ → at 1h, ↑ at 3h and 5h; IL-6: → at 1h, 3h and 5h; NF-κB↑ at 3h</td><td>⁴Milk protein (ex vivo: ASD and DPI PBMCs vs control PBMCs): TNF-α, IFN-g ↑, IL-5 →</td><td>²Conventional yoghurt (w2 or w4 vs w0) (ex vivo blood culture): TNF-α, IL-1β, ↑; IFN-g, IL-10, IL-6 →</td></tr><tr><td>Net change in inflammatory marker</td><td>-1</td><td>-1</td><td>-1</td><td>-3</td><td>-2</td><td>-2</td></tr><tr><td>Sustainability of effect over time</td><td>N.a.</td><td>N.a.</td><td>Not discussed</td><td>Not discussed</td><td>Discussed</td><td>No</td></tr><tr><td>Dose-response Bioavailability data</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Biological plausibility</td><td>Investigated - re-occurrence of milk leads to re-occurrence eosinophilic esophagitis</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Discussed - milk, egg, soy and beef</td><td>Discussed - milk and wheat</td><td>Not discussed</td><td>Discussed - LPS and TLR-4 signaling, SOCS3 and TLR-4 expression</td><td>Discussed - macrophage activation, aberrant innate immune responses against LPS</td><td>Discussed - Th1 promoting activity of lactic acid bacteria</td></tr><tr><td>Clinical evidence</td><td>Yes - decrease of symptoms of eosinophilic esophagitis and esophageal inflammation</td><td>Yes - reduction of endoscopic and histopathologic features of eosinophilic esophagitis</td><td>Yes - histological remission after 6 weeks milk elimination diet</td><td>Not increase free fatty acids, triglycerises, VLDL, and endotoxin, no effect on total cholesterol</td><td>Investigated - β-lactoglobulin, casein, α-lactalbumin</td><td>Not discussed</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Private and public</td></tr><tr><td>Grading criteria</td><td>Pro, 3, 6, 7, 10, 11</td><td>Pro, 3, 6, 7, 10, 11</td><td>Pro, 3, 6, 7, 11</td><td>Pro, 1, 3, 4, 5, 6</td><td>Pro, 1, 4, 5, 7, 10</td><td>Pro, 3, 4, 5, 7</td></tr><tr><td>IS</td><td>-6</td><td>-6</td><td>-5</td><td>-6</td><td>-6</td><td>-5</td></tr></tbody></table>

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<figure><img src="image_20.png" /></figure>

<table><thead><tr><th>Reference</th><th>(Spergel et al., 2005)</th><th>(Gonsalves et al., 2012)</th><th>(Kagalwalla et al., 2012)</th><th>(Deopurkar et al., 2010)</th><th>(Jyonouchi et al., 2002)</th><th>(Meyer et al., 2007)</th></tr></thead><tbody><tr><td>Subject category</td><td>HYPER</td><td>HYPER</td><td>GIT</td><td>HEALTH</td><td>GIT</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Food allergy</td><td>Food allergy</td><td>Eosinophilic esophageal inflammation</td><td>Postprandial oxidative stress and inflammation</td><td>Gastrointestinal symptoms</td><td>Systemic immunity</td></tr><tr><td>Target population</td><td>Subjects allergic to milk and patients with eosinophilic esophagitis</td><td>Adults with eosinophilic esophagitis</td><td>Children with eosinophilic esophageal inflammation</td><td>General population</td><td>Children with autism spectrum disorder</td><td>Healthy subjects</td></tr><tr><td>Fat content</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>High-fat</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Fermentation</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>Non-fermented</td><td>Non-fermented</td><td>Fermented</td></tr><tr><td>Test product</td><td>Elimination diet excluding milk</td><td>SFED (six food elimination diet): Milk milk, soy, wheat, egg, peanuts/tree nuts, seafood</td><td>Milk</td><td>Cream</td><td>Milk protein</td><td>Probiotic yoghurt</td></tr><tr><td>Control product</td><td>—</td><td>—</td><td>—</td><td>Water</td><td>—</td><td>Conventional yoghurt</td></tr><tr><td>Test subjects</td><td>100 M, 46 F / 6.50±4.50 y / eosinophilic esophagitis</td><td>25 M, 25 F / 19-76 y / eosinophilic esophagitis</td><td>12 M, 5 F / 5.5±3.2 y / eosinophilic esophagitis</td><td>48 / 25-47 y / healthy</td><td>59 M, 13 F / 1-17 y / autism spectrum disorder (ASD) 17 M, 7 F / 0.5-13 y / dietary protein intolerance (DPI)</td><td>33 F / 22-29 y / healthy</td></tr><tr><td>Control subjects</td><td>—</td><td>—</td><td>—</td><td>—</td><td>12 M, 3 F / 1-16 y / healthy 18 M, 8 F / 0.5-2 y / healthy siblings Ex vivo activation of (PBMCS) by dietary allergens (e.g milk protein)</td><td>—</td></tr><tr><td>Diet</td><td>Elimination diet milk / 4-8 weeks SFED / 6 weeks / reintroduction by addition of one food group every 2 weeks</td><td>Milk elimination / 6 weeks</td><td>33 g cream or 300 mL / postprandial challenge study</td><td>—</td><td>—</td><td>100 g/d conventional or probiotic yoghurt / 2 weeks / 2 weeks washout / 200 g/d yoghurt / 2 weeks</td></tr><tr><td>Control dairy test</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>Non-randomized</td><td>Non-randomized</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Cross-sectional</td><td>Longitudinal</td></tr><tr><td>Study results</td><td>²Milk elimination diet (w4-8 vs baseline): eosinophilic esophagitis ↓</td><td>⁶SDEF (w6 vs baseline): eosinophilic esophagitis ↑</td><td>²Milk elimination (w6 vs w0): TNF-α↑ at 1h and 3h; → at 5h; IL-1β↑ → at 1h, ↑ at 3h and 5h; IL-6: → at 1h, 3h and 5h; NF-κB↑ at 3h</td><td>³Cream (1h, 3h and 5 h vs 0h): TNF-α↑ at 1h and 3h; → at 5h; IL-1β↑ → at 1h, ↑ at 3h and 5h; IL-6: → at 1h, 3h and 5h; NF-κB↑ at 3h</td><td>⁴Milk protein (ex vivo: ASD and DPI PBMCs vs control PBMCs): TNF-α, IFN-g ↑, IL-5 →</td><td>²Conventional yoghurt (w2 or w4 vs w0) (ex vivo blood culture): TNF-α, IL-1β, ↑; IFN-g, IL-10, IL-6 →</td></tr><tr><td>Net change in inflammatory marker</td><td>-1</td><td>-1</td><td>-1</td><td>-3</td><td>-2</td><td>-2</td></tr><tr><td>Sustainability of effect over time</td><td>N.a.</td><td>N.a.</td><td>Not discussed</td><td>Not discussed</td><td>Discussed</td><td>No</td></tr><tr><td>Dose-response Bioavailability data</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Biological plausibility</td><td>Investigated - re-occurrence of milk leads to re-occurrence eosinophilic esophagitis</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Discussed - milk, egg, soy and beef</td><td>Discussed - milk and wheat</td><td>Discussed - saturated fats</td><td>Discussed - LPS and TLR-4 signaling, SOCS3 and TLR-4 expression</td><td>Discussed - macrophage activation, aberrant innate immune responses against LPS</td><td>Discussed - Th1 promoting activity of lactic acid bacteria</td></tr><tr><td>Clinical evidence</td><td>Yes - decrease of symptoms of eosinophilic esophagitis and esophageal inflammation</td><td>Yes - reduction of endoscopic and histopathologic features of eosinophilic esophagitis</td><td>Yes - histological remission after 6 weeks milk elimination diet</td><td>Yes - increase free fatty acids, triglycerises, VLDL, and endotoxin, no effect on total cholesterol</td><td>Investigated - β-lactoglobulin, casein, α-lactalbumin</td><td>Not discussed</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Private and public</td></tr><tr><td>Grading criteria</td><td>Pro, 3, 6, 7, 10, 11</td><td>Pro, 3, 6, 7, 10, 11</td><td>Pro, 3, 6, 7, 11</td><td>Pro, 1, 3, 4, 5, 6</td><td>Pro, 1, 4, 5, 7, 10</td><td>Pro, 3, 4, 5, 7</td></tr><tr><td>IS</td><td>-6</td><td>-6</td><td>-5</td><td>-6</td><td>-6</td><td>-5</td></tr></tbody></table>

(Continued on next page)
<table><caption>Table 4. (Continued)</caption><thead><tr><th>Reference</th><th>(Unknown, 1994) 1</th><th>(Anderson et al., 2012) 2</th><th>(Nettleton et al., 2006) 2</th><th>(Vazquez-Agell et al., 2013)</th><th>(Hlebowicz et al., 2011) 2</th><th>(Esmailzadeh et al., 2007) 2</th></tr></thead><tbody><tr><td>Subject category</td><td>GIT</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Ulcerative colitis</td><td>Insulin sensitivity and systemic inflammation</td><td>Cardiovascular disease</td><td>Systemic inflammation</td><td>Cardiovascular disease</td><td>Systemic inflammation</td></tr><tr><td>Target population</td><td>General population</td><td>General population</td><td>Healthy adults</td><td>Healthy adults</td><td>General population</td><td>Healthy women</td></tr><tr><td>Fat content</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>N.a.</td><td>N.a.</td><td>Fermented</td><td>Non-fermented</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Test product</td><td>Dietary patterns including 'Western food' (includes butter, cheese)</td><td>Food cluster including high-fat dairy products</td><td>Dietary patterns including cheese</td><td>Cocoa powder with milk or water</td><td>Dietary pattern: 'Milk fat' including cheese, whole milk, butter</td><td>Dietary patterns including high-fat dairy products</td></tr><tr><td>Control product</td><td>—</td><td>Food cluster including low-fat dairy products</td><td>—</td><td>Whole milk</td><td>Dietary patterns: 'Many foods and drinks' and 'Low-fat and high-fibre' including low-fat milk</td><td>—</td></tr><tr><td>Test subjects</td><td>56 M, 45 F / 10-42 y / ulcerative colitis</td><td>1751 / 70-79 y / healthy</td><td>2407 M, 2682 F / 45-84 y / healthy</td><td>9 F, 9 M / 19-49 y / healthy</td><td>2040 M, 2959 F / 45-68 y / healthy</td><td>486 F / 40-60 y / healthy</td></tr><tr><td>Control subjects</td><td>79 M, 64 F / 10-42 y / other diseases</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Diet</td><td>Food frequency questionnaire (FFQ)</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>Washout / 40 g cocoa in 250 mL whole milk or 40 g cocoa in 250 mL water or 250 mL whole milk</td><td>Diet assessment (FFQ) / 13 y follow-up for CVD events</td><td>Diet assessment (FFQ)</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td><td>Yes</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td>⁴Western food (butter, cheese) (ulcerative colitis patients vs control subjects): ulcerative colitis ↑</td><td>⁶Cluster including high-fat dairy products vs cluster including low-fat dairy): IL-6 ↑; TNF-α, CRP →</td><td>⁵'Pattern including cheese: corr↑ with CRP, IL-6; corr→ with ICAM-1, E-selectin (adjusted for confounders)</td><td>³Whole milk (6h vs 0h): NF-kB activation in PBMC ↑; ICAM-1, VCAM-1, E-selectin →</td><td>⁶'Milk fat' pattern vs 'Many food and drinks' ⁷'Pattern including high-fat dairy products: corr↑ with IL-6, SAA; corr→ with CRP, TNF-α, E-selectin, ICAM-1, VCAM-1 (after adjustment for confounders)</td><td>⁸'Pattern including high-fat dairy products: corr↑ with IL-6, SAA; corr→ with CRP, TNF-α, E-selectin, ICAM-1, VCAM-1 (after adjustment for confounders)</td></tr><tr><td>Net change in inflammatory marker</td><td>-1</td><td>-1</td><td>-2</td><td>-1</td><td>-1</td><td>-2</td></tr><tr><td>Sustainability of effect over time</td><td>N.a.</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>N.a.</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>Yes - FFQ with consumption from 'none or hardly' to 'almost daily'</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Discussed - no interaction between dietary pattern and PPAR-γ genotype</td><td>Not discussed</td><td>Discussed - postprandial NF-kB activation after high-fat meal</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>No</td><td>Yes - cluster containing low-fat dairy associated with greater insulin sensitivity than cluster with high-fat dairy products</td><td>N.a.</td><td>No</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Pro, 1, 6, 7, 9</td><td>Pro, 1, 6, 7, 11</td><td>Pro, 5, 6, 7</td><td>Pro, 3, 4, 6</td><td>Pro, 1, 6, 7</td><td>Pro, 5, 6, 7</td></tr><tr><td>IS</td><td>-5</td><td>-5</td><td>-4</td><td>-4</td><td>-4</td><td>-4</td></tr></tbody></table>

<figure><img src="image_20.png" /></figure>
<table><caption>Table 4. (Continued)</caption><thead><tr><th>Reference</th><th>(Unknown, 1994) 1</th><th>(Anderson et al., 2012) 2</th><th>(Nettleton et al., 2006) 2</th><th>(Vazquez-Agell et al., 2013)</th><th>(Hlebowicz et al., 2011) 2</th><th>(Esmailzadeh et al., 2007) 2</th></tr></thead><tbody><tr><td>Subject category</td><td>GIT</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Ulcerative colitis</td><td>Insulin sensitivity and systemic inflammation</td><td>Cardiovascular disease</td><td>Systemic inflammation</td><td>Cardiovascular disease</td><td>Systemic inflammation</td></tr><tr><td>Target population</td><td>General population</td><td>General population</td><td>Healthy adults</td><td>Healthy adults</td><td>General population</td><td>Healthy women</td></tr><tr><td>Fat content</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>N.a.</td><td>N.a.</td><td>Fermented</td><td>Non-fermented</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Test product</td><td>Dietary patterns including 'Western food' (includes butter, cheese)</td><td>Food cluster including high-fat dairy products</td><td>Dietary patterns including cheese</td><td>Cocoa powder with milk or water</td><td>Dietary pattern: 'Milk fat' including cheese, whole milk, butter</td><td>Dietary patterns including high-fat dairy products</td></tr><tr><td>Control product</td><td>—</td><td>Food cluster including low-fat dairy products</td><td>—</td><td>Whole milk</td><td>Dietary patterns: 'Many foods and drinks' and 'Low-fat and high-fibre' including low-fat milk</td><td>—</td></tr><tr><td>Test subjects</td><td>56 M, 45 F / 10-42 y / ulcerative colitis</td><td>1751 / 70-79 y / healthy</td><td>2407 M, 2682 F / 45-84 y / healthy</td><td>9 F, 9 M / 19-49 y / healthy</td><td>2040 M, 2959 F / 45-68 y / healthy</td><td>486 F / 40-60 y / healthy</td></tr><tr><td>Control subjects</td><td>79 M, 64 F / 10-42 y / other diseases</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Diet</td><td>Food frequency questionnaire (FFQ)</td><td>Diet assessment (FFQ)</td><td>Diet assessment (FFQ)</td><td>Washout / 40 g cocoa in 250 mL whole milk or 40 g cocoa in 250 mL water or 250 mL whole milk</td><td>Diet assessment (FFQ) / 13 y follow-up for CVD events</td><td>Diet assessment (FFQ)</td></tr><tr><td>Controlled dairy test</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td><td>Yes</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td>⁴Western food (butter, cheese) (ulcerative colitis patients vs control subjects): ulcerative colitis ↑</td><td>⁶Cluster including high-fat dairy products vs cluster including low-fat dairy): IL-6 ↑; TNF-α, CRP →</td><td>⁵'Pattern including cheese: corr↑ with CRP, IL-6; corr→ with ICAM-1, E-selectin (adjusted for confounders)</td><td>³Whole milk (6h vs 0h): NF-kB activation in PBMC ↑; ICAM-1, VCAM-1, E-selectin →</td><td>⁶'Milk fat' pattern vs 'Many food and drinks' ⁷'Pattern including high-fat dairy products: corr↑ with IL-6, SAA; corr→ with CRP, TNF-α, E-selectin, ICAM-1, VCAM-1 (after adjustment for confounders)</td><td>⁸'Pattern including high-fat dairy products: corr↑ with IL-6, SAA; corr→ with CRP, TNF-α, E-selectin, ICAM-1, VCAM-1 (after adjustment for confounders)</td></tr><tr><td>Net change in inflammatory marker</td><td>-1</td><td>-1</td><td>-2</td><td>-1</td><td>-1</td><td>-2</td></tr><tr><td>Sustainability of effect over time</td><td>N.a.</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>N.a.</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>Yes - FFQ with consumption from 'none or hardly' to 'almost daily'</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Discussed - no interaction between dietary pattern and PPAR-γ genotype</td><td>Not discussed</td><td>Discussed - postprandial NF-kB activation after high-fat meal</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>No</td><td>Yes - cluster containing low-fat dairy associated with greater insulin sensitivity than cluster with high-fat dairy products</td><td>N.a.</td><td>No</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Financing of research</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Pro, 1, 6, 7, 9</td><td>Pro, 1, 6, 7, 11</td><td>Pro, 5, 6, 7</td><td>Pro, 3, 4, 6</td><td>Pro, 1, 6, 7</td><td>Pro, 5, 6, 7</td></tr><tr><td>IS</td><td>-5</td><td>-5</td><td>-4</td><td>-4</td><td>-4</td><td>-4</td></tr></tbody></table>

<figure><img src="image_21.png" /></figure>
<figure><img src="image_21.png" /></figure>

<table><thead><tr><th>Reference</th><th>(Nettleton et al., 2006) 3</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Cardiovascular disease</td></tr><tr><td>Target population</td><td>Healthy adults</td></tr><tr><td>Fat content</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>N.a.</td></tr><tr><td>Test product</td><td>Dietary pattern including cheese, whole milk and yoghurt</td></tr><tr><td>Control product</td><td></td></tr><tr><td>Test subjects</td><td>2407 M, 2682 F / 45-84 y / healthy</td></tr><tr><td>Control subjects</td><td>—</td></tr><tr><td>Diet</td><td>Diet assessment (FFQ)</td></tr><tr><td>Controlled dairy</td><td>No</td></tr><tr><td>test</td><td></td></tr><tr><td>Randomization</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td><sup>7</sup>Pattern including cheese, whole milk, and yoghurt: corr↑ with ICAM-1; corr→ with CRP, IL-6. E-selectin (adjusted for confounders)</td></tr><tr><td>Net change in inflammatory marker</td><td>-1</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td></tr><tr><td>Dose-response Bioavailability data</td><td>No</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>N.a.</td></tr><tr><td>Financing of research</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Pro, 6, 7</td></tr><tr><td>IS</td><td>-3</td></tr></tbody></table>
<figure><img src="image_22.png" /></figure>

<table><thead><tr><th>Reference</th><th>(Nettleton et al., 2006) 3</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td></tr><tr><td>Target indication</td><td>Cardiovascular disease</td></tr><tr><td>Target population</td><td>Healthy adults</td></tr><tr><td>Fat content</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>N.a.</td></tr><tr><td>Test product</td><td>Dietary pattern including cheese, whole milk and yoghurt</td></tr><tr><td>Control product</td><td></td></tr><tr><td>Test subjects</td><td>2407 M, 2682 F / 45-84 y / healthy</td></tr><tr><td>Control subjects</td><td>—</td></tr><tr><td>Diet</td><td>Diet assessment (FFQ)</td></tr><tr><td>Controlled dairy</td><td>No</td></tr><tr><td>test</td><td></td></tr><tr><td>Randomization</td><td>N.a.</td></tr><tr><td>Time factor</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td><sup>7</sup>Pattern including cheese, whole milk, and yoghurt: corr↑ with ICAM-1; corr→ with CRP, IL-6. E-selectin (adjusted for confounders)</td></tr><tr><td>Net change in inflammatory marker</td><td>-1</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td></tr><tr><td>Dose-response</td><td>No</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>N.a.</td></tr><tr><td>Financing of research</td><td>Public</td></tr><tr><td>Grading criteria</td><td>Pro, 6, 7</td></tr><tr><td>IS</td><td>-3</td></tr></tbody></table>
<figure><img src="image_22.png" /><figcaption>Table 5. Tabulated summary of the study results with no evidence for an inflammatory modulation of dairy products.</figcaption></figure>

<table><thead><tr><th>Reference</th><th>(Beavers et al., 2009)</th><th>(Monagas et al., 2009)</th><th>(Dawczynski et al., 2009)</th><th>(Raff et al., 2008)</th><th>(Lee et al., 2007)</th><th>(Unknown, 1994) 2</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td><td>MET</td><td>OTHER</td><td>HEALTH</td><td>MET</td><td>GIT</td></tr><tr><td>Target indication</td><td>Systemic inflammation and oxidative stress</td><td>Cardiovascular disease</td><td>Rheumatoid arthritis (RA)</td><td>Cardiovascular disease and diabetes</td><td>Mild hypertension</td><td>Ulcerative colitis</td></tr><tr><td>Target population</td><td>Postmenopausal healthy women</td><td>Patients at high risk of cardiovascular disease</td><td>Adults with RA</td><td>Healthy subjects</td><td>Mildly hypertensive subjects</td><td>General population</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td><td>Low-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>Non-fermented</td><td>Non-fermented</td><td>Fermented</td><td>Non-fermented</td><td>Non-fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>Soy milk</td><td>Skim milk with cocoa powder</td><td>n-3 supplemented dairy (yoghurt, cheese, butter)</td><td>CLA-enriched butter</td><td>Skim milk + whey peptides powder</td><td>Milk</td></tr><tr><td>Control product</td><td>Low-fat milk</td><td>Skim milk</td><td>Conventional dairy products (yoghurt, cheese and butter)</td><td>Butter with low CLA</td><td>Skim milk</td><td>—</td></tr><tr><td>Test subjects</td><td>16 F / 53.88±3.65 y / healthy</td><td>45 / ≥55 y / cardiovascular disease</td><td>37 F, 2 M / 57.9±10.8 y / RA</td><td>18 M / 27-35 y / healthy</td><td>14 M, 13 F / 55.3±10.4 y / mild hypertension</td><td>56 M, 45 F / 10-42 y / ulcerative colitis</td></tr><tr><td>Control subjects</td><td>15 F / 55.00±3.12 y / healthy</td><td>—</td><td>—</td><td>20 M / 19-33 y / healthy</td><td>16 M, 10 F / 47.8±11.6 y / mild hypertension</td><td>79 M, 64 F / 10-42 y / other diseases</td></tr><tr><td>Diet</td><td>3 servings/d low-fat milk or soy milk / 28 days</td><td>500 mL/d milk or milk + 40 g/d cocoa powder / 4 weeks</td><td>200 g yoghurt, 30 g cheese and 20-30 g butter daily / 3 months for test and 3 month control products / washout 8 weeks</td><td>CLA enriched butter (4.6 g/d CLA) or control butter (0.3 g/d CLA) / 5 weeks</td><td>125 mL/d / 12 weeks</td><td>Food frequency questionnaire (FFQ)</td></tr><tr><td>Controlled dairy test</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>N.a.</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td>Longitudinal</td><td>2Skim milk (4w vs w0): P-selectin, E-selectin, ICAM-1, VCAM-1, MCP-1, IL-6, CRP, T-lymphocyte adhesion markers, monocyte adhesion markers</td><td>2Control dairy (w12 vs w0): CRP, lymphocytes, monocytes, granulocytes →</td><td>2Control butter (w5 vs w0): CRP, PAI-1 →</td><td>2Skim milk (w12 vs w0): IL-6, CRP, PAI-1, leucocyte number →</td><td>4Milk consumption (ulcerative colitis patients vs control subjects): ulcerative colitis →</td></tr><tr><td>Net change in inflammatory marker</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>N.a.</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes - FFQ with consumption from 'none or hardly' to 'almost daily'</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>No - no effect on oxidative stress markers</td><td>Yes - BMI and weight decreased, blood pressure and heart rate unchanged</td><td>No - no changes in joint inflammation</td><td>Yes - FVIIc, HOMA-R increased</td><td>Yes - blood pressure significantly No reduced, metabolic variables unchanged</td><td>Public</td></tr><tr><td>Financing of research</td><td>Private and public</td><td>Public</td><td>Private and public</td><td>Public</td><td>Public</td><td>Public</td></tr><tr><td>Grading criteria</td><td>None</td><td>None</td><td>None</td><td>None</td><td>None</td><td>None</td></tr><tr><td>IS</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr></tbody></table>
<figure><img src="image_23.png" /><figcaption>Table 5. Tabulated summary of the study results with no evidence for an inflammatory modulation of dairy products.</figcaption></figure>

<table><thead><tr><th>Reference</th><th>(Beavers et al., 2009)</th><th>(Monagas et al., 2009)</th><th>(Dawczynski et al., 2009)</th><th>(Raff et al., 2008)</th><th>(Lee et al., 2007)</th><th>(Unknown, 1994) 2</th></tr></thead><tbody><tr><td>Subject category</td><td>HEALTH</td><td>MET</td><td>OTHER</td><td>HEALTH</td><td>MET</td><td>GIT</td></tr><tr><td>Target indication</td><td>Systemic inflammation and oxidative stress</td><td>Cardiovascular disease</td><td>Rheumatoid arthritis (RA)</td><td>Cardiovascular disease and diabetes</td><td>Mild hypertension</td><td>Ulcerative colitis</td></tr><tr><td>Target population</td><td>Postmenopausal healthy women</td><td>Patients at high risk of cardiovascular disease</td><td>Adults with RA</td><td>Healthy subjects</td><td>Mildly hypertensive subjects</td><td>General population</td></tr><tr><td>Fat content</td><td>Low-fat</td><td>Low-fat</td><td>High-fat</td><td>High-fat</td><td>Low-fat</td><td>High-fat</td></tr><tr><td>Fermentation</td><td>Non-fermented</td><td>Non-fermented</td><td>Fermented</td><td>Non-fermented</td><td>Non-fermented</td><td>Non-fermented</td></tr><tr><td>Test product</td><td>Soy milk</td><td>Skim milk with cocoa powder</td><td>n-3 supplemented dairy (yoghurt, cheese, butter)</td><td>CLA-enriched butter</td><td>Skim milk + whey peptides powder</td><td>Milk</td></tr><tr><td>Control product</td><td>Low-fat milk</td><td>Skim milk</td><td>Conventional dairy products (yoghurt, cheese and butter)</td><td>Butter with low CLA</td><td>Skim milk</td><td>—</td></tr><tr><td>Test subjects</td><td>16 F / 53.88±3.65 y / healthy</td><td>45 / ≥55 y / cardiovascular disease</td><td>37 F, 2 M / 57.9±10.8 y / RA</td><td>18 M / 27-35 y / healthy</td><td>14 M, 13 F / 55.3±10.4 y / mild hypertension</td><td>56 M, 45 F / 10-42 y / ulcerative colitis</td></tr><tr><td>Control subjects</td><td>15 F / 55.00±3.12 y / healthy</td><td>—</td><td>—</td><td>20 M / 19-33 y / healthy</td><td>16 M, 10 F / 47.8±11.6 y / mild hypertension</td><td>79 M, 64 F / 10-42 y / other diseases</td></tr><tr><td>Diet</td><td>3 servings/d low-fat milk or soy milk / 28 days</td><td>500 mL/d milk or milk + 40 g/d cocoa powder / 4 weeks</td><td>200 g yoghurt, 30 g cheese and 20-30 g butter daily / 3 months for test and 3 month control products / washout 8 weeks</td><td>CLA enriched butter (4.6 g/d CLA) or control butter (0.3 g/d CLA) / 5 weeks</td><td>125 mL/d / 12 weeks</td><td>Food frequency questionnaire (FFQ)</td></tr><tr><td>Controlled dairy test</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Randomization</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td><td>N.a.</td></tr><tr><td>Time factor</td><td>N.a.</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Longitudinal</td><td>Cross-sectional</td></tr><tr><td>Study results</td><td>Longitudinal</td><td>2Skim milk (4w vs w0): P-selectin, E-selectin, ICAM-1, VCAM-1, MCP-1, IL-6, CRP, T-lymphocyte adhesion markers, monocyte adhesion markers</td><td>2Control dairy (w12 vs w0): CRP, lymphocytes, monocytes, granulocytes →</td><td>2Control butter (w5 vs w0): CRP, PAI-1 →</td><td>2Skim milk (w12 vs w0): IL-6, CRP, PAI-1, leucocyte number →</td><td>4Milk consumption (ulcerative colitis patients vs control subjects): ulcerative colitis →</td></tr><tr><td>Net change in inflammatory marker</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Sustainability of effect over time</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>N.a.</td></tr><tr><td>Dose-response</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes - FFQ with consumption from 'none or hardly' to 'almost daily'</td></tr><tr><td>Bioavailability data</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Biological plausibility</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Bioactive components</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td><td>Not discussed</td></tr><tr><td>Clinical evidence</td><td>No - no effect on oxidative stress markers</td><td>Yes - BMI and weight decreased, blood pressure and heart rate unchanged</td><td>No - no changes in joint inflammation</td><td>Yes - FVIIc, HOMA-R increased</td><td>Yes - blood pressure significantly No reduced, metabolic variables unchanged</td><td>Public</td></tr><tr><td>Financing of research</td><td>Private and public</td><td>Public</td><td>Private and public</td><td>Public</td><td>Public</td><td>Public</td></tr><tr><td>Grading criteria</td><td>None</td><td>None</td><td>None</td><td>None</td><td>None</td><td>None</td></tr><tr><td>IS</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr></tbody></table>