The Influence of Honey-flavored Yogurt on Low-grade Inflammation and Gut Health in Middle to Older Aged Women.
Phase: NA
Conditions: Overweight
Sponsor: University of California, Davis

PROTOCOL TITLE: The influence of honey-flavored yogurt on low-grade inflammation 
and gut health in middle to older aged women. 
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1) Protocol Title 
Title:  The influence of honey-flavored yogurt on low-grade 
inflammation and gut health in middle to older aged women. 
Protocol Version Date: September 25, 2019 
2) Objectives 
 
To assess the influence of four weeks of honey flavored yogurt intake on pro-inflammatory 
CD4+ T Helper (TH)17 cytokines, via Luminex Bead Assay, with a focus on Interleukin (IL)-
23 (primary outcome). The secondary outcomes will be to assess the influence of microbial 
derived metabolites on pro-inflammatory cytokines and oxidative stress. In addition, 
intestinal microbial populations will be determined in order to assess the impact of the 
intervention on this population and metabolism. 
 
3) Background 
 
The goal of the proposed research is to assess the influence of short-term honey intake on 
low-grade inflammation, oxidative stress, and gut microbial-derived metabolites in healthy 
adult women. Honey is a phenolic-rich food that has long been used for beneficial digestive 
health, yet only limited scientific evidence exists that documents this potential health 
benefit, including its effects on measures of immune function and microbial-derived 
metabolites.   
 
Obesity is a risk factor for type 2 diabetes and cardiovascular disease (CVD) with both 
characterized by a low-grade systemic inflammatory phenotype. Inflammation in CVD is 
initiated by endothelial damage, and promoted by a number of cell types, including white 
blood cells and platelets that in themselves produce substantial amounts of lipid mediators, 
cytokines and reactive oxygen species (ROS) that can amplify the immune response. 
Research has focused on the role of adipose tissue dysfunction and insulin resistance in the 
promotion of inflammation, however, recent studies suggest a role for a disturbance in gut 
homeostasis. The gut epithelial barrier and immune system tolerates non-pathogenic 
bacteria, protects against pathogenic subtypes, and absorbs needed nutrients and other 
dietary and intestinal bacterial-derived factors. Diet can significantly influence gut bacterial 
populations within a short period of time. TH17 cytokines, including IL-23, play a role in a 
number of autoimmune diseases including inflammatory bowel disease. In conjunction with 
diet, the gut microbiota produces short chain fatty acids (SCFAs), secondary bile acids 
(BAs), and phytochemical metabolites that influence both local and systemic physiologic 
and immune responses. Therefore, the proposed study will focus on the assessment of the 
influence of short-term daily honey intake on pro-inflammatory Th17 cytokines and the 
influence of known microbial-derived metabolites.  
 
Polyphenols and phenolics from a number of foods have been observed to produce positive 
physiologic effects from circulating metabolites produced after primary small intestinal 
absorption or after bacterial metabolism. A limited number of studies have shown a positive 
influence of an increased intake of certain polyphenolics on the gut microbiome, as well as 
microbial derived metabolites. As genetics, health status, and diet can lend to increased 
variability in the selected biomarkers among individuals, we have included in our research 
plan a metabolomics analysis as a secondary objective.   This approach can potentially 

PROTOCOL TITLE: The influence of honey-flavored yogurt on low-grade inflammation 
and gut health in middle to older aged women. 
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Template Revision: March 19, 2019 
capture phenotypic differences associated with habitual diet that can be related to 
physiological response for which traditional methods of dietary intake and associated 
databases are not sufficiently sensitive to discriminate individual differences in diet and 
metabolism. In addition, individual differences in urolithin metabotype have been observed.  
As urolithins are the microbial metabolites of the tannin ellagitanin, which is found in 
walnuts, strawberries, and some honeys, urolithin metabotype may also allow for further 
discrimination of biomarker response in our study population. 
 
Finally, we have  observed that the intake of phenolic-rich honey can increase plasma 
antioxidant activity within hours of intake. While intriguing, regulatory agencies now  
prefer outcomes of oxidative stress of known physiological relevance and mechanism.  
Therefore, in order to capture the impact of honey intake on ROS production, we will 
measure NADPH oxidase (NOX2), uric acid (UA) and total nitrate/nitrite and related nitric 
oxide (NO) metabolites (RSNO). These measures were selected based on their contribution 
to oxidative stress, physiologic function, and disease pathology, and they are influenced by 
the diet and microbiome.  
 
 
4) Inclusion and Exclusion Criteria 
 
Prior to enrollment, all volunteers that meet the initial inclusion and exclusion criteria 
based on a telephone interview will be asked to participate in a clinical screening visit.  
This screening visit will assess the individual’s overall health, and whether the individual 
meets the inclusion and exclusion criteria for the study. Participants will arrive in the 
morning to the Department of Nutrition’s Ragle Human Nutrition Research Center. The 
participants will provide their written consent, after which time their weight and height 
are measured. The subjects will undergo an office blood pressure measurement. After 
completion of the blood pressure measurement, a fasting blood sample (30mL ~ 2 Tbsp.) 
will be collected. This will conclude the screening visit. The blood sample will be sent to 
the UC Davis Medical Center Pathology Lab used for the measurement of a complete 
blood cell count, plasma lipids and a comprehensive metabolic panel. 
 
We seek to enroll individuals that are overweight, not obese, with no self-reported 
disease. As hormonal changes throughout the menstrual cycle can potentially influence 
the outcome measures we will only enroll women who are postmenopausal with an 
absence of a period for at least 2 years. To further limit potential variability, we will also 
exclude those individuals who are on prescription medications, supplement use, and/or 
consume a high plant based diet. 
 
Inclusion and Exclusion Criteria 
 
Inclusion: 
• 
Postmenopausal female: 45-65 years 
• 
Women: lack of menses for at least two years. 
• 
Subject is willing and able to comply with the study protocols. 
• 
Subject is willing to participate in all study procedures 

PROTOCOL TITLE: The influence of honey-flavored yogurt on low-grade inflammation 
and gut health in middle to older aged women. 
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• 
BMI 25.0 – 30.0 kg/m2 
 
 
 
 
Exclusion: 
• 
BMI ≥ 31 kg/m2 
• 
Food allergies 
• 
Self-reported use of daily anticoagulation agents including aspirin, 
NSAIDs 
• 
Vegan, Vegetarians, food faddists or those consuming a non-traditional 
diet 
• 
Use of concentrated food supplements/powders and extracts 
• 
Fruit consumption > 2 cups/day  
• 
Vegetable consumption >3  cups/day  
• 
Self-reported restriction of physical activity due to a chronic health 
condition 
• 
Self-reported chronic/routine high intensity exercise 
• 
Self-reported diabetes 
• 
Blood pressure ≥ 140/90 mm Hg 
• 
Self-reported renal or liver disease 
• 
Self-reported heart disease, which includes cardiovascular events and 
stroke 
• 
Abnormal Metabolic or CBC panels (laboratory values outside the 
reference range) if determined to be clinically significant by the study 
physician. 
• 
Self-reported cancer within past 5 years 
• 
Self-reported malabsorption 
• 
Currently taking prescription drugs or supplements. 
• 
Supplement use  other than a general formula of vitamins and minerals 
that meet the RDA 
• 
Not willing to stop any supplement use, including herbal, plant or 
botanical, fish oil, oil supplements a month prior to study enrollment. 
• 
Indications of substance or alcohol abuse within the last 3 years 
• 
Cannabis use 
• 
Screening LDL ≥ 190 mg/dl for those who have 0-1 major risk factors 
apart from LDL cholesterol (i.e. family history of premature coronary 
artery disease (male first degree relative < 55 years; CHD in female first 
degree relative < 65 years), cigarette  smoker, HDL-C ≤ 40 mg/dL]. (using 
NCEP calculator http://cvdrisk.nhlbi.nih.gov/calculator.asp) 
• 
Screening LDL ≥ 160 mg/dl for those who have 2 major risk factors apart 
from LDL cholesterol [i.e. family history of premature coronary artery 
disease (male first degree relative < 55 years; CHD in female first degree 
relative < 65 years), cigarette smoker, HDL-C ≤ 40 mg/dL]. 
 
(using NCEP calculator http://cvdrisk.nhlbi.nih.gov/calculator.asp); 
• 
Screening LDL ≥ 130 mg/dl for those who have 2 major risk factors apart 
from LDL cholesterol [i.e. family history of premature coronary artery 

P R O T O C O L TI T L E: T he i nfl ue nce of h o ne y-fla v ore d y o g urt o n l o w- gra de i nfla m mati o n 
a n d g ut healt h i n mi d dle t o ol der a ge d w o me n. 
Pa ge 4 of 1 0  
 
H R P- 5 0 3 -P T O T O C O L T E M P L A T E - Ge neral 
 
 
Te m plate Re visi o n: Marc h 1 9, 2 0 1 9  
disease ( male first de gree relati ve < 5 5 years; C H D i n fe male first de gree 
relati ve < 6 5 years), ci garette s m o ker, H D L-C ≤ 4 0 m g/ d L], a n d a 
Fra mi n g ha m 1 0- year Ris k Sc ore 1 0- 2 0 % ( usi n g N C E P calc ulat or 
htt p://c v dris k. n hl bi. ni h. g o v/calc ulat or.as p). 
•  
C urre nt e nr ollee i n a cli nical researc h st u d y.  
 
 T he f oll o wi n g s pecial p o p ulati o ns will be e xcl u de d: 
•  I n di vi d uals w h o are n ot yet a d ults (i nfa nts, c hil dre n, tee na gers) 
•  Pre g na nt w o me n 
•  Pris o ners 
 
5)  St u d y Ti meli nes  
 
We e x pect t hat it will ta ke a p pr o xi matel y 3 years t o recr uit, e nr oll a n d c o m plete t he 
st u d y, as well as, t o c o m plete t he data a nal ysis.  T he scree ni n g da y visit will ta ke 
a p pr o xi matel y 1 h o ur t o c o m plete t he c o nse nti n g pr ocess, a nt hr o p o me tric meas ures, 
c o m plete t he healt h a n d dietar y q uesti o n naire a n d t he bl o o d dra w. Partici pa nts eli gi ble 
f or e nr oll me nt will be as ke d t o partici pate i n a 1 2 wee k st u d y t hat i ncl u des a pre-visit, 
pl us 4 st u d y da y visits, wit h eac h visit lasti n g a b o ut 2 h o urs. T he y will als o be as ke d t o 
arri ve at t he facilit y after 2 wee ks of t heir assi g ne d y o g urt i nta ke i n or der t o pic k u p 
y o g urt f or a n a d diti o nal 2 wee ks of i nta ke. T his visit s h o ul d ta ke n o l o n ger t ha n 3 0 
mi n utes P artici pa nts will be as ke d t o c o m plete dail y c o m plia nce l o gs t hat will d oc u me nt 
pr o d uct i nta ke, a n d 3 da y f o o d rec or ds d uri n g t he last t w o wee ks of eac h st u d y p hase 
 
6)  St u d y E n d p oi nts  
 
T he o bjecti ve will be t o assess t he i nfl ue nce of f o ur wee ks of h o ne y fla v ore d y o g urt 
i nta ke o n pr o-i nfla m mat or y C D 4 + T Hel per ( T H) 1 7 c yt o ki nes, via L u mi ne x Bea d Assa y, 
wit h a f oc us o n I nterle u ki n (I L)- 2 3. C yt o ki nes i ncl u de d i n t he pa nel are: Il- 1 b, I L - 4, I L- 6, 
I L- 1 0, I L- 1 7a, I L- 2 1, I L- 2 2, I L- 2 3, I L- 3 1, I L- 3 3, I F N, T N F, IL- 1 7f. 
 
S ec on dar y o utc o mes will be t o assess t he i n fl ue nce of micr o bial deri ve d meta b olites o n 
pr o-i nfla m mat or y c yt o ki nes a n d o xi dati ve stress. I n a d diti o n, i ntesti nal micr o bial 

PROTOCOL TITLE: The influence of honey-flavored yogurt on low-grade inflammation 
and gut health in middle to older aged women. 
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Template Revision: March 19, 2019 
populations will be determined in order to assess the impact of the intervention on this 
population and metabolism. 
The outcomes will be as follows: 
Gut Microbial Derived Metabolites: 
• Plasma secondary bile acids (BAs)  
• Fecal short chain fatty acids (SCFAs)  
• Conjugated and unconjugated urolithins and other ellagitannin-derived plasma 
metabolites  
Oxidative Stress: 
• Plasma soluble NADPH oxidase (NOX2) 
• Plasma Uric Acid (UA) 
• Plasma total Nitrate/Nitrite and Nitric Oxide related metabolites (RSNO) 
Microbiome/Metabolism: 
• Serum and Urine Metabolomics 
• Fecal microbiome 
 
7) Procedures Involved 
Experimental Approach: 
A randomized, double-blind, crossover dietary intervention trial will test the 
effects of 4 weeks of daily honey-flavored yogurt intake on markers of 
inflammation (Th17 cytokines) and oxidative stress (NOX2, UA, RSNO) and 
associative changes with microbial derived metabolites (SCFAs, BAs, 
ellgaitanins), metabolism and the fecal microbiome.  
Study Design: 
Twenty overweight (25-30 kg/m2) women 45-65 years of age will be enrolled 
into a 12 week dietary intervention trial. The study design will be a 2-arm 
crossover, with each arm 4 weeks in length.  A 4 week washout period will be in 
between the two ars.  blinded and controlled crossover study design. Prior to 
study enrollment, potential volunteers will be initially screened for eligibility 
using a telephone scree, then prescreened with a fasting blood sample (30mL ~ 2 
Tbsp.), and a health interview. The blood samples will be sent to the UC Davis 
Medical Center Pathology Lab for a comprehensive metabolic and lipid panels 
and complete blood counts. 
Those qualified for enrollment will be randomized to consume 2 morning 
servings of a 0.6 cup (150g) of plain yogurt with : A) cane sugar added in an 
isocaloric level as the honey or, B) 1 tbsp of phenolic-rich honey for 4 weeks. A 
one-month washout between periods will be used.  The participants will be 
instructed to consume one yogurt in replacement of or as part of breakfast, and as 
a late morning snack.  They will also be instructed to not add any additional items 
to the yogurt.  Therefore, each study participant will consume 2 tbsp. of honey a 
day for four weeks, which is a realistic amount typically consumed by honey 
users. They will be provided two weeks worth of yogurt, which they will be 
instructed to keep frozen until 1-2 days prior to intake, which at that time they can 

PROTOCOL TITLE: The influence of honey-flavored yogurt on low-grade inflammation 
and gut health in middle to older aged women. 
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store in the refrigerator.  After the first two weeks of intake they will be asked to 
arrive to the Ragle center in order to pick up an additional two weeks of yogurt. 
 One week prior to each study visit, the participants will be asked to refrain from 
the intake of non-steroidal anti-inflammatory medications, and from using mouth 
wash as these can affect the microbiome and inflammatory markers. 
Study volunteers will be asked to participate in 4 study visits each scheduled 
before yogurt intake and after 4 weeks of daily yogurt intake.   
For each study visit: 
The study participants will be asked to collect a stool sample with the kit provided 
at home 24-48 hours prior to each study visit. They will also be asked to collect a 
“first” morning urine prior to their arrival to the facility. 
Collection procedures will be performed at the same time of the day to minimize 
circadian effects. Anthropometric measures will be collected, and blood pressure 
will be measured after a 15 minute resting period (3 measurements taken 5 
minutes apart). A fasted (12 hour no food or beverage, except water) blood 
sample (50 mL, ~3.5 tbsp) will be collected for the biochemical measurements, 
and a spot urine will be collected for metabolomics 
Plasma and blood will be sent to the UC Davis Medical Center Pathology Lab for 
a comprehensive metabolic and lipid panels and complete blood counts. 
Dietary intakes will be assessed during each dietary phase with three-day food 
records. Compliance will be assessed through the use of a daily intake log, and 
return of used and return of unused packaging.  
Potential gastrointestinal symptoms and bowel changes will be assessed via a 
daily log and a weekly questionnaire. 
Test Yogurts: 
The honey will be provided from commercial producers from the National Honey 
Board, and will be one of the following: alfalfa, clover, orange blossom or 
buckwhet. The final selected honey will have the highest total polyphenolic 
content. Plain yogurt and sugar will be purchased through a grocery or restaurant 
supply. Plain Greek non-fat yogurt (for example Chobani) that provides S. 
Thermophilus, L. Bulgarious, L. Acidophilus, Bifidus and L. Casei as a culture 
will be selected. The test yogurt will include 1 tablespoon per serving of the 
selected honey and will provide 149 total calories and 13g of protein. The control 
yogurt will be isocalorically matched, and sweetened with 17g of cane sugar 
(such as “C&H” brand), a commonly used commercial sweetener in yogurts. The 
yogurts will be portioned out into individual serving sizes and stored frozen. The 
participants will be instructed to thaw their daily portions 2-3 days prior to intake 
in the refrigerator. The yogurts will be mixed and packaged at the Ragle Human 
Nutrition Center’s commercial kitchen facility. The formulated yogurts will be 
kept frozen until they are distributed  

PROTOCOL TITLE: The influence of honey-flavored yogurt on low-grade inflammation 
and gut health in middle to older aged women. 
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8) Data and/or Specimen Management and Confidentiality 
I understand that the UC Davis Health Electronic Health Record 
(EMR/EPIC) also contains the clinical data for Marshall Medical 
Center (MMC). I understand that MMC patient data cannot be accessed 
for research purposes and that I must take the necessary steps to ensure 
that MMC data is not accessed, used, or disclosed for UC Davis Health 
research purposes. 
 
Statistical Analysis: IL-23 is considered a key regulator of the inflammatory 
TH17 response 7, therefore, the response of IL-23 to 4 weeks of honey intake will 
be the primary outcome measure. The study is powered using data from our 
previous study in overweight or obese children and 4-week dietary changes in IL-
23, using a mean difference of 28.9 pg/mL with a SD of 30 pg/mL, an n =18 will 
be needed for an α =0.05 at 80% power. We will enroll 20 participants in order to 
account for potential attrition, which typically has been less than 10% in our 
recent clinical studies among postmenopausal women.  Statistical testing will be 
conducted by Repeated Measures Two-way ANOVA with Tukey’s post hoc 
testing, using treatment and time as factors. Confirmation of potential period 
effects will be analyzed, as well as, comparing the baseline after washout to the 
“pre-testing” period sampling that will occur on an individual’s baseline diet prior 
to treatment assignment. Multivariate analysis will be conducted to assess 
relationships between the changes in cytokine response to circulating markers, 
and bacterial taxa with honey intake. Multiple comparison adjustments will 
follow the False Discovery Rate correction. 
All data derived from this study will be identified through an alpha numerical 
code. The code will be associated with the individual’s name and contact 
information in an enrollment log kept as separate file stored on a password 
protected departmental servers. Only the clinical coordinator and research staff 
that are responsible for the daily conduct of the research study will access this 
information. 
The enrollment log will contain the subject’s name, contact information, 
enrollment details and study identifier that will be kept in a file and folder that is 
separate from study data. The enrollment log satisfies IRB requirements for 
subject enrollment data, and only enables the study coordinator with study flow, 
by linking study folders for the current study day with the correct subject 
identifier. This enrollment log will be saved and maintained on a server in the 
Department of Nutrition.  All departmental servers are housed in a secure server 
room with an alarm system and restricted access (physical access to the drives is 
restricted and only designed study coordinators can access the server drive in 
question).  No identifiable human subject data will be accessed on any mobile 
devices (USB flash drives, laptops, cell phones, etc). If any de-identified data is 
stored on a mobile device, such as a laptop, it would be encrypted, as all 
departmental laptop hard drives are encrypted with bitlocker.  

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and gut health in middle to older aged women. 
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All study folders are identified by the study participant code, and all contents 
within the folders will only contain this code.  This will include all source 
documents.  A source document will be maintained for each study visit, to include 
the screening.  The source document serves as a check for the adherence of study 
procedures including, and checks for the proper conduct of the consenting process 
during the screening visit.  
All questionnaires and consent forms will be kept in a locked cabinet in a 
departmental office that is accessible only to the study researchers. All samples, 
including those sent out for outside analysis (for example, lipid analysis at 
UCDMC) will have only a numerical identifier, and date/time. 
All data resulting from the sample analysis will also be kept in a spreadsheet 
associated with the numerical identifier that will be saved and maintained on the 
Department of Nutrition server, in a drop-box that is accessible only to study 
researchers; it will be ID and password protected. Department servers are 
maintained in a highly secured facility due to the proprietary nature of some UC 
Davis, Department of Nutrition research. 
 
9) Data and/or Specimen Banking 
Plasma/serum samples will be stored coded for up to 5 years at -80oC freezer in 
a secured laboratory at the Department of Nutrition. After the 5 year period the 
samples will be destroyed. Data will be continued to be maintained indefinitely 
in the Department of Nutrition as described above. Only those individuals 
involved in the analyses will have direct access to the samples.  Upon 
appropriate IRB approval, and subjects’ permission, de-identified samples and 
data may be shared with outside researchers or analytical core facilities. These 
outside researchers will not have access to any identifiable subject information. 
De-identified samples will be provided to investigators that specialize in the 
measurement of the Th17 cytokines, microbiome and metabolomics, and the 
Department of Pathology. 
10) Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
Participants will be monitored for intolerance/adverse reaction to yogurt or honey intake 
throughout the study period by direct questioning by study staff. They will also be 
monitored for adverse effects of phlebotomy during the blood draws. 
 
 
11) Withdrawal of Subjects 
 
In the event that volunteers withdraw from the research, they will receive prorated 
compensation for whatever portion of the study they have completed. If the investigators 
determine that a volunteer no longer meets the eligibility criteria, they will be withdrawn 

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and gut health in middle to older aged women. 
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from the research study.  Blood samples from time points that occurred prior to 
withdrawal will still be analyzed, and will not be destroyed. 
 
In case of the incidence of any serious adverse effects. We will consult with the volunteer 
as to their symptoms, and if necessary, withdraw them from the study. Any serious 
adverse event as well as other unanticipated problems will be reported to the IRB within 
five days of the investigator becoming aware of such an event. 
 
 
12) Risks to Subjects 
 
Risks and side effects related to consumption of the yogurts may include a change in 
bowel sensation or function.  This might include abdominal fullness/bloating, abdominal 
gurgling, increased gas leading to increased pressure, or gas expulsion.  More extreme 
changes like cramping, diarrhea or constipation may occur. 
 
Other risks include those associated with venipuncture, which may include potential 
discomfort, bruising, dizziness, and rarely, infection. We have rarely encountered 
instances in which subjects reported serious discomfort, and therefore, we assess the 
likelihood and seriousness of this risk to be small. 
 
13) Potential Benefits to Subjects 
 
No direct benefits to the individual participants are anticipated. 
 
14) Sharing of Results with Subjects 
 
The participants will receive copies of their clinical laboratory reports, which will give 
them general information regarding their overall health status. 
 
15) Prior Approvals 
 
No prior approvals needed. 
 
16) Provisions to Protect the Privacy Interests of Subjects 
 
During the telephone screening process the individuals will be informed that they do not 
need to answer any questions that they feel uncomfortable answering.  Additional health 
or dietary habit information will be obtained during the clinical screening visit, via 
written questionnaire that will not include the person’s name in order for them to answer 
in private. Situations where private health information will be obtained, such as weight 

PROTOCOL TITLE: The influence of honey-flavored yogurt on low-grade inflammation 
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or blood pressure measurement will be conducted in a private area, away from the view 
or hearing of others. 
 
17) Economic Burden to Subjects 
 
Participation in this study will not be an economic burden. 
 
18) Review Requirements 
        Are there any contractual obligations or other considerations that 
require IRB review of this research, or review at intervals other 
than those required by the Common Rule or FDA? If yes, check 
box: 
 
 Yes 
 
X No