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Abstract
Human biology can only be fully assessed by combining an
analysis of both the host and its surrounding environment.
As a part of the environment, the human gastrointestinal
tract hosts more than 100 trillion bacteria making up the gut
microbiota. The human host provides a nutrient-rich environment while the microbiota provides indispensable functions that humans cannot exert themselves. Shifts in the bacterial makeup of the human gut microbiota have been associated with disorders such as inflammatory bowel disease
(IBD), irritable bowel syndrome and obesity. However, since
most bacteria inhabiting our gut are not cultivable to date,
until recently little was known about their individual functions. Metagenomics, i.e. the analysis of the collective genomes present in a defined ecosystem, gives insight into
these specific functions. The first extensive catalogue of the
intestinal metagenome outnumbers the size of the human
genome by a factor of 150. Recently, 3 distinct types of gut
composition within the human population have been highlighted. These so-called enterotypes are characterized by
the dominant genera (Bacteroides, Prevotella and Ruminococcus) and their co-occurring phylogenetic groups. In accordance with the previously described impact of nutritional
behavior (diet, probiotics and prebiotics) on specific bacte-
The gastrointestinal tract is a highly complex ecosystem and its homeostasis requires a finely balanced regulation and cross-talk between host cells, the resident microbiota and the immediate environment. The human
gastrointestinal tract hosts more than 100 trillion bacteria which together make up most of the gut microbiota.
The average total number of bacterial species is estimated
to be 1,000 per individual [1, 2]. The restricted number of
phyla represented in the gastrointestinal tract compared
to other ecosystems (4 main phyla out of 50 existing phyla) suggests a tight coevolutionary history between the
host and its microbiota [3, 4]. Indeed, the human gut microbiota can be considered as a further organ within the
human organism [5] that coevolved with its host in order
to achieve a symbiotic relationship contributing to physiological homeostasis [6]. The intricate interplay established between the host and the gut microbiota is mandatory to maintain a balanced environment within the gut
Patricia Lepage
INRA, MICALIS-UMR1319
Domaine de Vilvert
FR78352 Jouy-en-Josas (France)
E-Mail patricia.lepage@jouy.inra.fr
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Key Words
Microbiota Crohns disease Ulcerative colitis Nutrition
Enterotypes
Homeostasis
of mucosal
immunity
Health
Disease
Intestine
as a gate
keeper
Homeostasis
of nutrient
metabolism
Energy
homeostasis
ENVIRONMENT
DIET
HOST
(fig.1). The human host provides a nutrient-rich environment while the microbiota provides indispensable functions that the human physiology lacks, such as the production of some vitamins, the digestion of complex polysaccharides [7] and the shaping of the immunological
environment [8, 9]. Indeed, commensal bacteria influence the normal development and function of the mucosal immune system, such as the induction of IgA production, mucin production and the tightening of the epithelial barrier. Through the production of short-chain fatty
acids, mainly acetate, propionate and butyrate, resident
bacteria positively influence intestinal epithelial cell proliferation and differentiation, and also mediate various
metabolic effects [10]. Production of short-chain fatty acids by commensal bacteria is achieved through the fermentation of carbohydrates and fibers and is directly correlated with the ingested amount, availability to bacteria
and microbiota composition.
Even though bacteria in the human gut outnumber
human cells by a factor of 10 [11, 12], some finely tuned
mechanisms allow these microorganisms to colonize and
survive within the host in a commensalistic relationship
[13]. This tolerance phenomenon is facilitated through
the physical separation of bacteria and host cells via the
mucus layer, but also through modifications of antigenic
moieties of microbiota components to reduce their immunogenic properties and by direct modulation of localized host immune responses [1416].
34
Shifts in bacterial composition of the human gut microbiota have been associated with health disturbances
such as inflammatory bowel disease (IBD), irritable bowel syndrome and obesity [1725]. More than 10 years ago,
the concept of dysbiosis or unbalanced composition of
the intestinal microbiota was introduced in the IBD research field [26]. Although the impressive list of documented microbial alterations in IBD patients was recently reviewed [27], the original question remains if dysbiosis is just a secondary phenomenon in IBD or truly
causal [28]. Dysbiosis has been highlighted at the general
community level with a decreased amount of bacteria belonging to the Firmicutes phylum and increased levels of
Proteobacteria in the microbiota of IBD patients. A key
element in gut homeostasis is the diversity of the ecosystem. High species richness for a given ecosystem indicates a high level of redundancy in its functions which
further denotes the ability of the ecosystem to best withstand natural disturbances. Hence, ageing and a high
BMI are associated with decreased microbial diversity in
the gut [29]. In Crohns disease (CD) also, decreased diversity of the microbiota was noticed in the distal part of
the intestine and this was significant within the Firmicutes phylum [23, 30]. The Clostridium leptum group
of the Firmicutes was the most impacted with a specific
species, i.e. Faecalibacterium prausnitzii that proved to be
consistently less represented in the gut of CD patients.
This specific bacterium also demonstrated an anti-inflammatory effect in vitro and in animal models [31, 32].
In fecal samples of CD patients, depleted bacterial species
related mostly to Firmicutes phylum (C. leptum group,
Subdoligranulum sp., Ruminococcus bromii, R. albus, Oscillibacter valericigenes, F. prausnitzii and Eubacterium
rectale), Bacteroidetes phylum (Prevotella distasonis, Bacteroides vulgatus and Alistipes putredinis) and to a lesser
extent Actinobacteria (Bifidobacterium bifidum still
controversial) while species from the Proteobacteria phylum (Escherichia coli, Proteus vulgaris, Acinetobacter junii and Klebsiella pneumoniae), Enterococcus faecium,
Streptococcus sp. were overrepresented in CD patients [1,
17, 3335]. It is noteworthy that species showing increased
proportions in feces of patients with CD are for the large
part facultative anaerobes and opportunistic pathogens.
The microbiota during active ileal inflammatory disease
might hence be adapted to a high redox potential probably linked to a loss of epithelial barrier integrity [17]. At a
mucosal level, similar changes are regularly observed.
deWouters/Dor/Lepage
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Resistance to infections
No intestinal disorders
Healthy ageing
MICROBIOTA
Gastrointestinal infections
Asthma/atopy
Obesity
Metabolic syndrome
Cancer
Rheumatoid arthritis
Crohn disease
Ulcerative colitis
early as the 1960s, a high consumption of simple carbohydrates was linked with CD development [42]. Further
analyses specified that the key factor was the industrial
way of preparing and refining sugars. Even though a simple carbohydrate-rich diet may modulate the microbial
populations in the gut toward a Bacteroidetes-enriched
microbiota, deciphering the impact of raw versus refined
sugars has still to be performed in a more accurate way.
While dietary fibers are known to have a beneficial
impact on general gastrointestinal comfort and protective effects against cancer and metabolic diseases [43, 44],
their role in IBD remains vague. Fibers, via their fermentation end-products (short-chain fatty acids), show clear
anti-inflammatory properties, but are also capable of reducing intestinal permeability [45]. The fact that patients
avoid a high-fiber diet in case of diarrhea might account
in a large part for the conflicting results observed on fiber-rich food and IBD.
A clearer association can be seen with protein intake
since UC patients have a higher relapse risk when consuming lots of meat, protein and alcohol [46, 47]. An increased incidence of CD and UC in Japan has also been
associated with the increased consumption of animal and
milk proteins [48, 49]. Finally, as critically highlighted by
Chapman-Kiddell and colleagues [41], assessing the direct link between food intake and IBD remains very challenging and there is a definite need for more rigorous research that may need to focus on aspects of the whole diet
prior to development of the disease.
From birth, the environment shapes our gut microbiota and epithelium. Our first nutrients, i.e. breast milk or
formula milk, strongly impact the gut microbiota composition [50]. As a consequence an adequate substitute for
breast milk remains a great challenge in infant feeding,
and industries have kept adapting formulas in order to
make these as close as possible to mothers milk. After
weaning, the diversification of diet is associated with an
important diversification of bacterial species in our gut
microbiota. With the exception of the impact of targeted
foods and nutrients, such as prebiotics, the impact of diet
in this crucial stage of gut microbiota development has
been only sparsely studied. Attention has mainly been
paid to probiotic bacteria such as lactobacilli and bifidobacteria. As strong producers of short-chain fatty acids
through fiber degradation, they have been linked to numerous beneficial effects such as the strengthening of the
Dig Dis 2012;30(suppl 3):3339
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36
Alterations in diet composition result in both quantitative and qualitative changes in the supply of substrates
to the large intestinal microbiota. The impact that dietary
changes have upon microbial metabolism occurs through
several interrelated mechanisms [67]. Modulating the
microbiota towards a more beneficial pattern can hence
be set as a strategic therapeutic target through diet modifications as observed in other pathologies such as obesity and metabolic disorders (Clement and colleagues,
pers. comm.). In these contexts, the microbiota re-equildeWouters/Dor/Lepage
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Conclusion
However, it is now admitted that the intestinal microbiota of all individuals can be stratified into at least 3
enterotypes. These enterotypes are linked to the predominance of a single genus together with its associated
phylogenetic network, and might represent different ecological solutions for the human intestinal tract. Even
though it is not linked to specific pathologies, enterotype
distribution is significantly associated with specific dietary habits. Diet can specifically influence the species
composition of the intestinal microbiota.
Since the diversity of the intestinal microbiota is a crucial marker for health or eubiosis of the intestine and
therefore the entire human organism, it may be beneficial
to improve its development and maintenance. There are
numerous intrinsic and environmental factors that can
influence microbial diversity in the gastrointestinal tract.
The most striking, and probably one of the most important, is still the nutrients ingested by the host. In addition,
both bacterial metabolism and bacterial competition are
strongly influenced by the gut environment, i.e. local
conditions of pH, oxygen and hydrogen, metabolite concentration and gut transit time. The gut environment is
also determined by host secretions and secondary bacterial metabolites, such as antimicrobials and quorumsensing molecules. If we therefore want to use modifications of intestinal microbiota composition as a therapeutic or preventive strategy in the treatment of IBD,
long-term dietary interventions or recommendations are
going to most likely play a crucial role.
Disclosure Statement
The authors declare no conflict of interest.
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