# Role of commensal and probiotic bacteria in human health: a focus on inflammatory bowel disease

Rebeca Martin Rosique, Sylvie Miquel, Jonathan Ulmer, Noura Kechaou, Philippe Langella, Luis Bermudez Humaran

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## To cite this version:

Rebeca Martin Rosique, Sylvie Miquel, Jonathan Ulmer, Noura Kechaou, Philippe Langella, et al. Role of commensal and probiotic bacteria in human health: a focus on inflammatory bowel disease. Microbial Cell Factories, 2013, 12, 10.1186/1475-2859-12-71. hal-01190516

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# Role of commensal and probiotic bacteria in human health: a focus on inflammatory bowel disease

Rebeca Martín<fnref n="1" />,<fnref n="2" />, Sylvie Miquel<fnref n="1" />,<fnref n="2" />, Jonathan Ulmer<fnref n="1" />,<fnref n="2" />, Noura Kechaou<fnref n="1" />,<fnref n="2" />, Philippe Langella<fnref n="1" />,<fnref n="2" />
and Luis G Bermúdez-Humarán<fnref n="1" />,<fnref n="2" />*

## Abstract

The human gut is one of the most complex ecosystems, composed of 10¹³-10¹⁴ microorganisms which play an important role in human health. In addition, some food products contain live bacteria which transit through our gastrointestinal tract and could exert beneficial effects on our health (known as probiotic effect). Among the numerous proposed health benefits attributed to commensal and probiotic bacteria, their capacity to interact with the host immune system is now well demonstrated. Currently, the use of recombinant lactic acid bacteria to deliver compounds of health interest is gaining importance as an extension of the probiotic concept. This review summarizes some of the recent findings and perspectives in the study of the crosstalk of both commensal and probiotic bacteria with the human host as well as the latest studies in recombinant commensal and probiotic bacteria. Our aim is to highlight the potential roles of recombinant bacteria in this ecosystem.

**Keywords:** Bacteria-host crosstalk, Dysbiosis, Genetically modified microorganisms

## Relationship humans-bacteria: a history of common benefits

The human gastrointestinal tract (GIT) is one of the most complex ecosystems known. Its microbiota consists of a large number of bacteria (10-fold more than the total number of human cells) that shapes many important physiological and metabolic processes as well as the development of the immune system [1,2]. The advances of molecular techniques have shown that the collective adult human GIT microbiota is composed of up to 1000–1150 bacterial species [3,4]. The most frequently found species are Gram-positive bacteria. The predominant species (46-58%) are those with low GC-content and the Clostridium group is the most abundant in this complex ecosystem [4]. Physiological conditions differ widely in the human GIT leading to an individual gut microbiota [5]. Some studies suggest that the faecal microbiota does not necessarily represent the bacteria inside the GIT [6-8]. Additionally, the intestinal lumen microbiota differs

significantly from the one in the mucus layer and near the epithelium due to the poor accessibility of the crypts covered by mucins [9].

Despite its complexity, the faecal microbiota of adult human individuals is unique and highly stable through time [10]. Primocolonizing microorganisms appear in the gut immediately after birth in an organized and lifelong process [11]. During the first year, after the initial establishment of the intestinal microbiota, its composition is relatively simple and varies between individuals [12]. After that, the main dominant groups of the adult microbiota will be conserved between all individuals. These groups are stable in spite of the great number of factors that can affect them [13]. In contrast, at the phylum level, the variation is higher between individuals although people who are related tend to have similar microbiota perhaps due to a shared environment and genetic similarities [13].

This microecosystem, which is a direct consequence of the mutualism between the host and its microbiota, is fundamental for the maintenance of the homeostasis of a healthy individual [5]. Commensal bacteria provide the host with essential nutrients. They metabolize indigestible

<footnote>* Correspondence: luis.bermudez@jouy.inra.fr</footnote>

<footnote n="1">¹INRA, UMR1319 Micalis, F-78350 Jouy-en-Josas, France</footnote>

<footnote n="2">²AgroParisTech, UMR Micalis, F-78350 Jouy-en-Josas, France</footnote>
compounds, defend against colonization of opportunistic pathogens and contribute to the development of the intestinal architecture as well as stimulation of the immune system among others [11]. Conversely, the host provides the bacteria with nutrients and a stable environment [5] (Figure 1). Both host and indigenous microorganisms have then adapted to each other in a particular case of microevolution to maintain the benefits that this mutualism confers [2].

**Probiotics: an additional bacterial advantage for humans**

Probiotics are defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” [14]. This concept is based on the observations made by Élie Metchnikoff in 1907 in which the regular consumption of Lactic Acid Bacteria (LAB) in fermented dairy products, such as yogurt, was associated with enhanced health and longevity in many people living in Bulgarian villages [15].

Most probiotics belong to LAB, but new species and genera are being assessed for future use. Some other well-known probiotics are *Bifidobacterium* sp., one strain of the Gram-negative bacterium *Escherichia coli* Nissle 1917 and the yeast *Saccharomyces boulardii* [16].

However, not all microorganisms are beneficial and screenings in order to identify novel candidate probiotics with immunomodulatory properties are frequently performed [17]. In fact, a Dutch trial using a probiotic preparation in patients with acute pancreatitis showed to be harmful [18]. These negative results show how important it is to choose the right protocol (indeed, the main problem with this study was the bad idea to administer massive quantitites of probiotics in very vulnerable patients) and to make a careful selection when using probiotics in humans. Certainly, a supposed beneficial effect of a specific strain cannot be extrapolated to another strain even within to the same species [19,20].

Modulation of host immunity and promotion of host defense are the most commonly supported benefits of

<figure><img src="image_3.png" /><figcaption>**Figure 1** Commensal bacteria cross talk with the host. Commensal bacteria supply the host with essential nutrients and defend the host against opportunistic pathogens. They are involved in the development of the intestinal architecture and immunomodulatory processes. On the other hand, the host provides the bacteria with nutrients and a stable environment.</figcaption></figure>
the consumption of probiotics. For a microorganism to be considered probiotic (i.e. bacteria or yeast), the following criteria need to be fulfilled: i) it should have a clear beneficial effect on the host, ii) it should be non-pathogenic, iii) it should be able to survive transit through the GIT and iv) a large number of viable bacteria must be able to survive prolonged periods (i.e. upon storage) [21].

## What happens if homeostasis is broken?

The term dysbiosis refers to microbial imbalances on or within the body. When homeostasis (balanced microbial ecosystem) is broken, different subdominant opportunistic bacteria can grow leading to a situation of illness. Additionally, when commensal bacteria are depleted, an abnormal health situation can be triggered due to a lack of the benefits these bacteria provide rather than the overgrowth of pathobionts.

### a) Binomial dysbiosis – illness

The term dysbiosis has been related to many different kinds of pathologies although it is not clear whether the imbalance of microbiota is a cause or a consequence of the illness. The clearest correlation between dysbiosis and disease has been found with inflammatory bowel diseases (IBD) where the proportion of Firmicutes, in particular *Faecalibacterium prausnitzii*, was found to be low in patients that exhibited endoscopic recurrence 6 months after surgery [22,23]. IBD, including Crohn's disease (CD) and ulcerative colitis (UC), are characterized by an abnormal activation of the immune system associated with the gut, resulting in a chronic inflammation of the digestive system. However, some other factors also seem to be

involved in IBD such as genetic components [24,25], immunological disorders [26], environmental factors [27,28], pathogens [29,30], and microbiota [10]. Faecal analyses have shown a quantitative and qualitative reduction in the representation of the Firmicutes phylum, mostly the clostridial cluster IV members in CD patients while low numbers of total lactobacilli have been reported in UC members [31,32], although no correlation was found between *F. prausnitzii* abundance and the severity of CD [33]. Even if the composition of the human microbiota is different in each individual, changes in phylogenetic distribution have also been specifically found in obese and diabetic individuals versus normal ones [34,35] (Table 1). The importance of the human microbiota has been demonstrated in the hygiene hypothesis, defined in 1989 by Strachan [36] who postulated that low exposure to infectious agents in early life explains the increased numbers of people suffering from allergies and asthma in developed countries. This hypothesis suggests that a well-balanced human microbiota is a factor that protects from such pathologies [37,38]. Some microbial activities have shown relevance to health and disease. Following this line of thought, the production of short chain fatty acids (SCFA) such as butyrate has been proposed to protect against different illnesses (Table 2).

### b) Probiotics to restore dysbiosis

As we have seen before, dysbiosis are involved in a great variety of different illnesses. Considering this fact, the administration of beneficial microorganisms to restore the normal ecosystem is a strategy to improve the health status of the patient and/or to prevent a normal healthy individual from acquiring

<table><caption>**Table 1** Some examples of disbiosis found in obesity and diabetes</caption><thead><tr><th>Disease</th><th>Disbiosis</th><th>Model</th><th>Technique</th><th>Sample</th><th>N</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="4">Obesity</td><td>↓ <i>Bacteroidetes</i></td><td rowspan="3">Mice C57BL/6J</td><td>16S RNA sequencing</td><td rowspan="3">Distal intestinal content</td><td>5088 sequences</td><td rowspan="3">[39]</td></tr><tr><td>↑ <i>Firmicutes</i></td><td>16S RNA sequencing</td><td>12</td></tr><tr><td>↑ <i>Firmicutes</i></td><td>Real time PCR</td><td>40</td></tr><tr><td>↑ <i>Bacteroidetes</i></td><td>Humans</td><td>16S RNA sequencing</td><td>Faecal</td><td>154</td><td>[41]</td></tr><tr><td>↑ H2-producing bacterial groups (Prevotellaceae family and certain groups of Firmicutes)</td><td>Humans</td><td>16S RNA sequencing</td><td>Faecal</td><td>9</td><td>[43]</td></tr><tr><td>Type 1 diabetes</td><td>Ratio bacterioidetes/firmicutes altered</td><td>Non obese diabetic mice (NOD)</td><td>16S RNA sequencing</td><td>Faecal</td><td></td><td>[44]</td></tr><tr><td rowspan="4">Type 2 diabetes</td><td>↓ <i>Prevotella</i></td><td rowspan="4">Humans</td><td>16S RNA sequencing</td><td rowspan="4">Real time PCR</td><td>36</td><td rowspan="2">[45]</td></tr><tr><td>↓ <i>Bifidobacterium spp</i></td><td></td><td></td></tr><tr><td>↓ <i>F. prausnitzii</i></td><td>16S RNA sequencing</td><td>28</td></tr><tr><td>↑ <i>Bacteroides</i></td><td>Real time PCR DGGE</td><td></td></tr></tbody></table>
<table><caption>Table 2 Beneficial effects of short chain fatty acids (SCFA)</caption><thead><tr><td>SCFA</td><td>Model</td><td>Effect</td><td>Reference</td></tr></thead><tbody><tr><td rowspan="4">Butyrate</td><td>Tumorigenesis in rat colon and Human colonic cells</td><td>Inhibit the genotoxic activity of nitrosamides and hydrogen peroxide</td><td>[47]</td></tr><tr><td>Human adenocarcinoma R6/C2 and AA/C1 cells and carcionoma PC/JW/F1 cells</td><td>Induce apoptosis</td><td>[48]</td></tr><tr><td>Human intestinal primary epithelial cells (HIPEC), HT-29 and Caco-2 cells</td><td>Immunoregulatory effects</td><td>[49]</td></tr><tr><td>Humans with distal ulcerative colitis</td><td>Improves UC symptoms</td><td>[50]</td></tr><tr><td>Butyrate/acetate/propionate</td><td>Humans with diversion colitis</td><td>Improves the macroscopic and histological signs of inflammation</td><td>[51]</td></tr><tr><td>Propionate</td><td>HT-29 cells</td><td>Anti-proliferative effects</td><td>[52]</td></tr><tr><td>Acetate</td><td>Madin-Darby bovine kidney epithelial cells (MDBK)<br/>E. coli O157:H7 infection</td><td>Protection</td><td>[53]</td></tr></tbody></table>

dysbiosis in the future. Currently, there is evidence of the use of probiotics as therapeutics against traveler's diarrhea, irritable bowel syndrome (IBS), IBD, lactose intolerance, peptic ulcers, allergy and autoimmune disorders among others [55-60]. For instance, it has been suggested that colonization of the GIT with Bifidobacteria properly shapes gut microbiota, induces oral tolerance and decreases the frequency of allergic disorders [61]. For lactobacilli, a clinical study demonstrates that perinatal administration of a probiotic strain of *Lactobacillus rhamnosus* GG (LGG) reduces the development of atopic eczema in children [61-64]. This effect may be due to the anti-inflammatory properties of this probiotic bacterium. Consumption of LGG by children with atopic dermatitis has been reported to enhance the production of the anti-inflammatory cytokine IL-10 [65]. Other studies have demonstrated that oral administration of *L. casei* Shirota strain to mice inhibited specific IgE production [66] while Abrahamsson et al. [67] have observed in a double-blind, randomized, placebo-controlled trial that infants treated with *L. reuteri* ATCC 55730 strain had less IgE-associated eczema. As mentioned above, when the equilibrium of the microbiota is disturbed, the bacterial ecosystem is thought to contribute to several intestinal diseases such as IBD. In fact, gut microbiota metabolize nutrients, produce vitamins and degrade toxic products (such as: carcinogens, food additives, bile salts, and cholesterol, among others) [68,69], where the importance and interest in modulate microbiota with probiotic products. Results from animal models and human clinical trials have confirmed various therapeutic effects of selected strains of probiotics in IBD [56,70]. For instance, *L. casei* BL23 strain has shown anti-inflammatory effects in a murine DSS-induced colitis model [71] and some other probiotic

strains (eg. VSL#3, LGG, BIFICO, *E. coli* Nissle) have shown effects in human patients with pouchitis, UC and CD [72]. Additionally, the modulatory effect of *Lactobacillus acidophilus* in intestinal pain due to the induction of opioid and cannabinoid receptors has been reported in rats [73]. This fact highlights the use of probiotics in other intestinal disorders such as such as IBS, characterized by chronic abdominal pain, discomfort, bloating and alteration of bowel habits. In this sense, in the last years, many studies confirm the overall positive results of probiotics in human IBS patients using different bacteria such as: *Lactobacillus* spp., *Bifidobacterium* and *Streptococcus* among others [74].

From this perspective, the use of probiotics has been expanded in the last few years, with a great number of probiotic products in our supermarkets and pharmacies. However, the knowledge of their mechanisms of action remains largely unknown.

## New prospects of commensal and probiotic bacteria: genetically modified microorganisms

a) Strategies to deliver therapeutic molecules. Since probiotic therapy is mainly focused on restoring the normal balance of the intestinal ecosystem, we can deduce that the use of commensal bacteria as probiotics is the natural way to get rid of dysbiosis within the GIT. Furthermore, they represent potential live delivery vectors for target compounds (Figure 2). The use of live delivery vectors, such as food-grade LAB, at the mucosal level has been widely described before [75-79]. They are based on the use of recombinant bacteria producing the heterologous molecule of interest *in vivo* and their use is mainly related to vaccines. This is due to the fact that genetically engineered bacteria or viruses (used as carriers) producing
<figure><img src="image_4.png" /><figcaption>**Figure 2** Extension of the commensals-probiotics hypothesis. The development of a genetically modified commensal (or probiotic) could reach all the beneficial properties found in a commensal bacterium joint to the probiotic effects due to the ability to deliver molecules to the gastrointestinal tract (GIT).</figcaption></figure>

heterologous antigens can increase the immunogenicity of otherwise weakly immunogenic antigens. In addition, such live bacterial vectors have the additional advantage (compared to viruses) of having a genome able to harbor many heterologous genes, in contrast to viruses where the capacity to encapsulate foreign DNA is limited. This research field comes from exploring novel effective strategies to deliver therapeutic molecules to the mucosal tissues in order to avoid degradation and promote uptake of the antigen *in situ* (ie. in the GIT), and stimulate adaptive immune responses rather than the tolerogenic immune responses that are observed in feeding studies with soluble antigens [80]. Besides the enhancement of the potency and specificity of mucosal delivery of therapeutic molecules, the use of mucosal routes reduces potential side effects observed in systemic ones.

In principle, two types of bacterial vectors can be
used to deliver compounds at the mucosal level:
attnuated pathogens and non-pathogenic bacteria.
Gram-positive commensal or food-grade bacteria
constitute attractive good alternatives to pathogenic
bacteria [79,81]. Particularly, the food-grade LAB are
attractive candidates because they have been used
for centuries in the fermentation and preservation of
food, and are considered to be safe organisms with a
GRAS (Generally Recognized As Safe) status. One

major advantage of LAB as delivery vectors for
vaccines purposes is their potential to elicit both
antigen-specific immune responses at mucosal
surfaces and effective systemic immune responses.
Indeed, some studies have successfully shown that
candidate LAB vaccines elicited antigen-specific IgA
responses in feces, saliva or bronchoalveolar and
intestinal lavage fluids, as well as antigen-specific
IgA-secreting cells in the lungs and mesenteric
lymph nodes [82-94].

These studies with encouraging results confirm the
potential use of LAB as live vectors for mucosal
immunization and/or therapy. In this context, the
model LAB species, *Lactococcus lactis*, has been
used for the heterologous expression of therapeutic
proteins such as: antigens, cytokines and enzymes.
Thus, the resulting recombinant lactococci strains
have been successfully tested for their prophylactic
and therapeutic effects in many animal models
such as: Human Papillomavirus type-16
(HPV-16)-induced tumors in mice [83,88], bovine
β-lactoglobulin (BLG)-allergic reaction in mice
[95,96] and body weight and food consumption in
obese mice [85,97].

b) Use of recombinant LAB and commensals in IBD.
Modulation of the mucosal immune system has
been demonstrated in IBD. The currently
used therapies to treat IBD are based on
anti-inflammatory drugs combined with
immunosuppressives [98]. Immunomodulatory
molecules have been efficient in the control of
inflammation and in the remission of the episodes of
the illness. The use of LAB to prevent and treat
colitis was performed with a recombinant L. lactis
strain producing and delivering IL-10, an
anti-inflammatory cytokine, in situ in different
mouse models [99]. Daily mucosal administration of
recombinant L. lactis secreting IL-10 led to a 50%
decrease of the colitis induced by the administration
of dextran sodium sulfate (DSS) in mice. This
beneficial effect was dependent on the in situ
secretion of IL-10 by the live lactococci. The
rationale in using recombinant L. lactis for a local
delivery of IL-10 in IBD is due to the large number
of scientific studies proving that the topical
treatment with this cytokine has clinic benefits [100]
although systemic IL-10 administration in Crohn's
disease patients has been associated with
considerable side effects which are partly due
to the fact that systemic IL-10 induces the pro-
inflammatory cytokine IFN-γ [101-103]. To address
the safety issues in using genetically modified
organisms in humans, the gene encoding the L.
lactis thymidylate synthase (thyA) was replaced by
the gene of the human IL-10 (hIL-10) to generate
one L. lactis strain auxotrophic for thymidine or
thymine [104]. The viability and contention of this
strain was validated in vivo in a swine model [104].
Additionally, a small Phase I clinical study in
patients with CD using the thyA-/hIL-10+ strain
was recently conducted. This study not only showed
that the contention strategy is effective, but also that
the mucosal expression of IL-10 by L. lactis is
feasible in humans [105]. However, a phase IIA trial
was performed which revealed that, although safety,
tolerability, environmental containment and
assessment of biomarkers associated with the strains
have been achieved, no statistically significant
difference has been found versus placebo in terms of
beneficial effects (press release published in 2009).
Due to these results, the necessity to optimize the
LAB delivery strategy (new strains, different
expression systems and different nature of the
delivered molecules) is a requirement to reach a
clear demonstration of their efficacy in human
clinical trials, leading to their better acceptance
[76-78,106-109]. The delivery of immunosuppressive
cytokines by other bacteria has also been tested. The
probiotic potential of IL-10-expressing E. coli Nissle
1917 has been outlined in a mouse model of IBD
[110]. The use of LAB to produce Trefoil Factors
(TFF) at the mucosal level to treat IBD has also

been studied. TFF are a class of nonmitogenic
peptides that play important roles in the protection
and repair of the intestinal epithelium [111]. These
peptides are known because of their strong
protective effects and for repairing the mucosa after
damage. For this reason, they are interesting
molecules to potentially treat IBD. However, when
they are administered by an oral route, they adhere
to the gut mucosa and are absorbed at the intestinal
level. Interestingly, intragastric administration of
recombinant L. lactis secreting TFF leads to the
expression of the active peptides in the colon and
prevents and repairs the damage due to the acute
colitis induced by DSS [112]. Another strategy to
treat colitis was also based on the use of
recombinant L. lactis secreting the LcrV antigen, an
anti-inflammatory protein produced by Yersinia
pseudotuberculosis to escape the immune response
of the host. The therapeutic and protective potential
of this strain was evaluated using two colitis murine
models: DSS and trinitrobenzene sulfonic acid
(TNBS) [113]. Still, another strategy to treat IBD is
the use of antioxidant enzymes. It is well established
that GIT inflammation is associated with an influx
of neutrophils and macrophages and with the
production of inflammatory mediators such as:
proteases, cytokines and reactive oxygen species
(ROS) [114]. ROS include the superoxide radical
(O₂⁻), hydrogen peroxide (H₂O₂), and the hydroxyl
radical (·OH). Their reactivity toward lipids, proteins
and DNA causes both cytotoxic and mutagenic
cellular damages [115]. To detoxify ROS, cells have
evolved protective mechanisms via antioxidant
enzymes such as superoxide dismutases (SOD) and
catalases (CAT) which degrade O₂⁻ and H₂O₂
respectively, and thus prevent the formation of·OH
[116]. In this context, different studies have shown
that recombinant strains of Lactobacillus spp.
expressing either SOD or CAT can reduce
inflammation in mouse models [71,117-119]. In
some cases, the anti-inflammatory mechanism of
these recombinant strains has been elucidated and
linked to the inhibition of neutrophil recruitment
[117]. The mucosal expression of elafin, a natural
protease inhibitor expressed in healthy intestinal
mucosa, is diminished in patients with IBD.
Recently, LAB secreting elafin have been tested in
chronic and acute colitis models and the inflamed
epithelium was protected from increased intestinal
permeability and from the release of cytokines and
chemokines by LAB secreting elafin [120].
In addition to these recombinant probiotic strains,
mutants in specific genes encoding potential
probiotic functions (mucal adhesion factors,
resistance to acid, specific cell wall components,
etc.) have been engineered to compare their
biological effects with that of their wild-type
counterparts. In 2005, Grangette et al. [121] has
provided an illustration of this approach by
constructing a mutant of *Lactobacillus plantarum*
impaired in its capacity to incorporate D-alanine in
teichoic acids (Dlt⁻ mutant) [121]. Strikingly, when
tested *in vivo*, the Dlt⁻ mutant proved to be more
protective in a mouse model of colitis than the wild-
type strain. Furthermore, the use of lipoteichoic acid
(LTA)-deficient *L. acidophilus* in *in vitro* analysis
enhances IL-10 production by dendritic cells and
macrophages and downregulates IL-12 and TNF-α
[122]. This strain is also able to significantly protect
dextran sulfate sodium and CD4⁺CD45RB⁺high

T cell-induced colitis in mice [123] and to normalize
innate and adaptative pathogenic immune responses
in established colonic polyps causing cancer
regression [124]. However, no protective effects have
been found in LTA-induced pro-inflammatory
signals and subsequent colitis [125]. Altogether, with
the possibility to express different factors such as
ScFv antibodies, host targeting molecules and
immunomodulators in LAB, more applications and
progress towards studies in humans should be
performed in a next future.

The next step in this field seems to choose new
delivery bacteria. As mentioned above, *L. lactis* is the
most widely used LAB in the production of
heterologous proteins and is considered as the model
LAB and live delivery vector model [75]. Despite all
the advantages mentioned above, this bacterium has a
short survival time (~24 hours) in the human GIT
leading thus to a reduced time of action. In contrast,
other probiotic bacteria which could be natural
colonizers of the GIT, could combine their intrinsic
probiotic effects to the probiotic effects conferred by
the heterologous delivered protein. The most
achieved project in this field is the one based on the
use of the commensal *Bacteroides ovatus* [126]
Indeed, Hamady et al. [127] chose this bacterium for
the *in vivo* delivery of proteins for its ability to
colonize the colon and its xylan utilisation properties.
They were able to develop a xylan-regulated delivery
of i) human keratynocyte growth factor-2 to the
inflamed colon [128] and ii) the human TGF-b1 to
treat colitis in mice [129]. These promising results
confirm the potential of the use of recombinant
commensal for *in vivo* delivery.

**Conclusions and future research**

We can conclude that current probiotic research en-
courages the search and characterization of gut bacteria

as a model for finding new natural or engineered pro-
biotic strains to be used to restore the normal balance of
the human gut ecosystem.

The fact that commensal and probiotic bacteria inter-
act with the host immune system is now well accepted
and illustrated by *in vitro* and *in vivo* experiments.
However, the current knowledge of the molecular mecha-
nisms involved in this cross-talk remain poorly under-
stood. Although some mechanisms and active compounds
have been identified in a few commensal or probiotic
strains [130], and taking into account that the human GIT
is composed of 10¹³-10¹⁴ microorganisms, it is necessary
to explore profoundly this research area and in particular
to elucidate the exact role of bacterial compounds in
homeostasis and immune response.

As for the use of genetically modified commensal and
probiotic bacteria in humans, it is certain that most of
the studies being done are Proof-of-Concept. However,
although some researchers have claimed that genetically
modified probiotics should be banned [131], the data
obtained in the phase I clinical trial with the recom-
binant strain of *L. lactis* secreting IL-10 (see above in
the text) showed that the containment strategy (ie. re-
lease of such genetically modified organisms into na-
ture) used to construct the strain [104] was not only
safe and effective but also that mucosal delivery of IL-
10 by a genetically modified LAB is feasible in humans
[105].

In conclusion, it is clear that the analysis of the impact
of commensals and probiotics on the host immune sys-
tem has entered a new and fascinating phase of research.
This new area offers us new knowledge that can be
exploited to develop new approaches to modulate host
immunity for protection against infectious diseases or
for immunotherapy.

**Abbreviations**

BLG: β-lactoglobulin; CAT: Catalases; CD: Crohn's disease; DSS: Dextran sodium sulfate; GIT: Gastrointestinal tract; GMO: Genetically modified organisms; GRAS: Generally recognized as safe; HPV-16: Human Papillomavirus type-16; IBD: Inflammatory bowel disease; IBS: Irritable bowel syndrome; LAB: Lactic acid bacteria; LGG: *Lactobacillus rhamnosus* GG; ROS: Reactive oxygen species; SCFA: Short chain fatty acids; SOD: Superoxide dismutases; TFF: Treefoil factors; TNBS: Trinitrobenzene sulfonic acid; UC: Ulcerative colitis.

**Competing interests**

The authors declare that they have no competing interests.

**Authors' contribution**

RM and LBH wrote the main text, figures and tables. SM, NK, JU, PL corrected and helped to draft the manuscript. All authors have read and approved the final manuscript.

**Acknowledgements**

RM and SM receive a salary from FParis collaborative project selected and supported by the Vitagora Competitive Cluster and funded by the French FUI (Fond Unique Interministériel; FUI: n°F1010012D), the FEDER (Fonds Européen de Développement Régional; Bourgogne: 34606), the Burgundy Region, the Conseil Général 21 and the Grand Dijon.
Received: 14 May 2013 Accepted: 18 July 2013

Published: 23 July 2013

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doi:10.1186/1475-2859-12-71

Cite this article as: Martín *et al*. Role of commensal and probiotic bacteria in human health: a focus on inflammatory bowel disease. *Microbial Cell Factories* 2013 **12**:71.

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