The Gut Microbiota and the Mucosa in IBD Dig Dis 2013;31:278–285 DOI: 10.1159/000354678
The Human Gut Microbiome and Its Dysfunctions Stanislas Mondot a Tomas de Wouters b, c Joël Doré b, c Patricia Lepage b, c Institut Curie, U932, Paris, b INRA, UMR1319-Micalis, and c AgroParisTech, UMR1319-Micalis, Jouy-en-Josas, France
Key Words Microbiota · Gut ecosystem · Resilience · Inflammatory bowel disease
Abstract The human gastrointestinal tract hosts more than 100 trillion bacteria and archaea, which together make up the gut microbiota. The amount of bacteria in the human gut outnumbers human cells by a factor of 10, but some finely tuned mechanisms allow these microorganisms to colonize and survive within the host in a mutual relationship. The human gut microbiota co-evolved with humans to achieve a symbiotic relationship leading to physiological homeostasis. The microbiota provides crucial functions that human cannot exert themselves while the human host provides a nutrientrich environment. Chaotic in the early stages of life, the assembly of the human gut microbiota remains globally stable over time in healthy conditions and absence of perturbation. Following perturbation, such as antibiotic treatment, bacteria will recolonize the niches with a composition and diversity similar to the basal level since the ecosystem is highly resilient. Yet, recurrent perturbations lead to a decrease in resilience capacity of the gut microbiome. Shifts in the bacterial composition and diversity of the human gut microbiota have been associated with intestinal dysfunctions such as inflammatory bowel disease and obesity. More than specific bacteria, a general destructuration of the ecosystem seems
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0278$38.00/0 E-Mail [email protected] www.karger.com/ddi
to be involved in these pathologies. Application of metagenomics to this environment may help in deciphering key functions and correlation networks specifically involved in health maintenance. In term, fecal transplant and synthetic microbiome transplant might be promising therapies for dysbiosis-associated diseases. © 2013 S. Karger AG, Basel
Introduction
Humans are colonized by a multitude of site-specific microbial communities localized on the skin, mucosal surfaces, and in the intestinal tract [1]. A succession of habitats differing drastically in pH, redox potential and transit time defines the nature and degree of colonization along the intestine, which increases steadily along the intestinal tract to reach its highest concentrations in the colon [2]. In the colon, the levels of bacteria are as high as 1011 microorganisms per gram of luminal content, outnumbering the total number of human eukaryotic cells by ten. These microbial communities assure key functions that are necessary for health and well-being of the host including (i) colonic fermentation, (ii) a barrier effect strengthening resistance to colonization by exogenous or
S. Mondot and T. de Wouters contributed equally to this study.
Patricia Lepage INRA, UMR1319-Micalis FR–78350 Jouy-en-Josas (France) E-Mail patricia.lepage @ jouy.inra.fr
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a
Determinants of the Human Gut Microbiota
Colonization at Birth An increasing number of reports points towards an in utero contact of the infant with mother’s fecal bacteria or bacterial components [14–17]. The question of very early versus prenatal colonization however remains a point of debate. Nevertheless, extensive colonization of the intestine starts at birth through the transfer of bacteria from the environment, mainly from the mother to the infant [for review, see 18]. The composition of the intestinal microbiota in this early stage is highly variable [19]. Facultative anaerobic bacteria, especially Escherichia coli and other Enterobacteriaceae have been reported to be the first colonizers of the infant gut where they reduce oxygen thereby establishing the typical strict anaerobic environment in the intestinal lumen during the first days of life. Once the anaerobic gut environment is established, the Human Gut Microbiome and Its Dysfunctions
colonization by strictly anaerobic bacteria such as Clostridium, Bacteroides, Bifidobacteria and occasionally Ruminococcus will start, leading to an increasingly diverse and complex microbial population that can be considered as the typical adult microbiota (high diversity and dominated by Bacteroidetes and Firmicutes) by about 3 years of age [20]. The temporal succession of microbiota establishment is rather well known, while the multiple factors influencing and finally defining the composition are difficult to disentangle. The primordial role of the mother’s microbiota in early colonization is underlined by its high level of similarity at the age of 1 month. Interestingly, this similarity decreases together with the appearance of other environmental exposures [21]. Gestation time, mode of delivery and feeding of the infant are the main extrinsic factors influencing early infant microbiota establishment. Acute prematurity has been linked to increased Staphylococcus colonization [22]. Vaginally born infants show a higher prevalence of Lactobacillus and Prevotella, while infants delivered by cesarean section have increased proportions of Staphylococcus, Corynebacterium and Propionibacterium in their microbiota reflecting exposure to vaginal versus skin microbiota as principal source of bacteria [23]. Diet is a determining factor from early on. Breastfeeding for instance favors the prevalence of Bifidobacteria and Lactobacilli through the specific composition of the mother’s milk. Moreover, increasing reports indicate that breast milk carries its own microbiota containing a multitude of early colonizers of the human intestine such as Staphylococcus, Streptococcus, Propionibacterium, Bifidobacterium, Veillonella, Bacteroides, Clostridium, Enterobacteria and Roseburia [24–27]. However, improvements in infant formulas have led to decreased food-related differences in colonization patterns [2, 15]. Finally, changes in the establishment of gut microbiota have been observed in Western infants, most likely due to improved hygiene and general asepsis in Western countries, resulting in reduced bacterial exposure [2, 15]. This sequential bacterial colonization of the neonatal gut appears to be an important period for the development of a diverse, robust, resilient and functionally efficient microbiota [17]. Functions of the Human Gut Microbiota Predominantly residing in the colon, the intestinal microbiota carries a variety of functions beneficial for its host [28]. A main role is the increase of energy harvest by about 10% from the diet through fermentation of fibers Dig Dis 2013;31:278–285 DOI: 10.1159/000354678
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opportunistic pathogens [3], and (iii) maturation of the intestinal epithelium and immune system [4]. Any dysbiosis (i.e. a disequilibrium of the ecosystem) could therefore lead to diseases [5, 6]. Indeed, several pathologies, such as inflammatory bowel diseases (IBD), irritable bowel syndrome, and allergic diseases, have been associated with alterations in the composition of the gut microbiota as compared with healthy subjects [7, 8]. The composition of gut microbial communities was first described by culture-based studies, which estimated that 400–500 different species can colonize the adult human gut [9]. The use of culture-independent approaches, mostly based on the analysis of 16S rRNA gene marker, has revealed a far more complex intestinal microbial community than previously described. The proportion of cultivable bacteria in the human gut ranged from 15 to 85% depending on the study [10], with more than 1,200 characterized bacterial species [11]. Four major phyla constitute this ecosystem: the Firmicutes and Bacteroidetes being the most abundant, and to a lesser extent Actinobacteria and Proteobacteria. The adult fecal microbiota composition is specific to each individual even though a universal microbial core which contains 66 molecular species, conserved over 50% of a population, has been described [12]. In absence of perturbations (antibiotics, pathogens, etc.) the individual dominant gut microbiota is relatively stable over time [13]. In the field of microbial ecology, the development of high-throughput sequencing technologies is currently leading to a constantly improved understanding of complex ecosystems.
Factors Modulating the Adult Microbiota Despite the phylum level similarities of the intestinal microbiota, the species level composition is highly variable between subjects. This high variability is explained by the differential inoculation through the environment but also by genetic predisposition of the host as well as long-term nutritional behavior of the individuals. The different possible microbiota compositions for each individual can be seen as a stability landscape in which there are multiple alternative equilibria [38]. The 280
Dig Dis 2013;31:278–285 DOI: 10.1159/000354678
stability of one of these equilibria is maintained by the trophic structure of the ecosystem as well as the physicochemical conditions the host offers to its microbiota. If one of these two conditions is disturbed in a major way, the introduced disequilibrium will not return to its original state but find an alternative equilibrium. Probability of such permanent changes increases with the strength of the disturbance and the low stability (i.e. resilience) of the actual ecosystem [1]. The most prominent impact is the frequent use of antibiotics. By selectively diminishing specific bacterial populations, antibiotics may aid subdominant populations to become dominant colonizers. In the same way by selectively feeding specific subgroups, their thrive can be favored [39]. Host physiological and genetic factors can modulate the composition of the intestinal microbiota in multiple ways. Besides the effect of long-term alimentary habits [40], the transit time, secretion of bile acids, the degree of the innate immune reaction and the integrity of intestinal anaerobic environment are known to impact the human microbiota [41].
Importance of Diversity and Structure of the Ecosystem to Ensure Beneficial Effect
The human gut microbiota has developed mainly commensalistic relationships with its associated host. This pacific crosstalk is the result of a long-term evolutionary process implicating a strict microorganism selection by the host which ensures homeostasis within the intestine [42, 43]. A clear result of this co-evolution is the establishment of both meticulous microbiota composition and structure. In the past, numerous studies have highlighted the importance of preserving the gut microbiota integrity, notably in cases of diverse disorders such as IBD or obesity [44, 45]. A large amount of data has been obtained on the human gut microbiota and its implication in human health. Studies that define the host-microbiota relationship as mutualistic have accumulated [46]. In its normal state (eubiosis) the human gut microbiota is dominated by four phyla. The overlap between individuals, however, is narrowed at the species level of microbiota composition. Still, a set of 66 bacterial species mainly belonging to Firmicutes phylum and characterized by a high prevalence within the human population (≥50%) and a high abundance (≥35.8%) have been identified [12]. Metagenomic studies and notably Qin et al. [47] confirmed this result by depicting a similar core microbiota composed of 75 bacterial species. This study also Mondot /de Wouters /Doré /Lepage
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[2]. In order to degrade these polymers resistant to degradation by human enzymes into monosaccharides, the intestinal microbiome produces a large panel of carbohydrate active enzymes (CAZymes). Short-chain fatty acids (mainly butyrate, propionate, acetate) resulting from this fermentation are the main carbon source for the colonic epithelium and thus induce a proper maturation and regeneration of the colonic epithelium [29–31]. Shortchain fatty acids, however, are not exclusively used as an energy source. They modulate pH, are ligands to different receptors (GRP41 and GRP43) and play an important role in osmotic regulation, gut motility, energy metabolism and transcriptional regulation [32, 33]. Numerous other bacterial metabolites have been identified to have ligand binding or epigenetic properties such as polyunsaturated fatty acids, folic acid, riboflavin and microorganism-associated molecular patterns [34, 35]. The gut microbiota is also crucial for the development of a proper immune system since bacterial colonization is a prerequisite for immunoglobulin A production in the intestinal lumen [36]. Besides its beneficial effect, this dense population of microorganisms in the intestine represents a constant threat for the host. In order to control the microbial populations, the intestinal epithelium and its covering mucus layer represent an important and tightly regulated barrier. The innate immune response controls bacterial growth near the intestinal epithelium by the secretion of immunoglobulin A and antimicrobial peptides, such as defensins, in response to microbial-associated molecular patterns and other bacterial metabolites. This multitude of interdependent factors that contribute to the overall well-being of the host is surprisingly stable over time. The key to this stability is thought to be the diversity and high degree of redundancy of the ecosystem [37]. However, modern lifestyle seems to favor a shift in the microbial composition thereby breaking this delicate balance and leading to chronic disequilibrium referred to as dysbiosis.
Dysfunctions in Inflammatory Bowel Diseases
IBD are chronic relapsing disorders composed by two major diseases, Crohn’s disease (CD) and ulcerative colitis (UC). Recent decades have provided a body of evidence dealing with the involvement of the gut microbiota in the etiopathology of IBD. Overall, IBD patients’ microbiota is mostly characterized by a loss of bacterial diversity at both the phylogenetic and functional levels. The IBD-associated microbiota is dysbiotic and characterized by a reverse Firmicutes/Bacteroidetes ratio [51, 52] associated with an increase in Proteobacteria [53, 54]. Differential levels for particular bacterial species, as compared to healthy individuals’ microbiota, have been reported for both UC and CD microbiota. CD is characterized by decreased proportions of bacteria belonging to the human gut core microbiota. Notably, a lower amount of Faecalibacterium prausnitzii and members of the Clostridium clusters IV (C. leptum group) and XIV (C. coccoides group) have been reported [55–57]. Conversely, increased levels of Enterobacteriaceae, specific strains of E. coli (AIEC) and some Ruminococcus species have been identified [54, 57–60]. UC is characterized by a decreased relative proportion of Clostridium cluster XIV [56] and a higher number of E. coli and/or sulfate-reducing bacteria [56, 61].
Human Gut Microbiome and Its Dysfunctions
The IBD microbiota activity also seems to be impaired and meta-Omics studies highlighted mainly a loss of essential functionalities. Qin et al. [47] described a CD microbiome harboring 25% fewer genes than individuals not suffering from IBD and metaproteomics investigation of IBD-associated microbiota reported a decreased number of bacterial proteins [62]. CD metabolome has been characterized by reduced levels of butyrate, acetate, methylamine, trimethylamine and elevated quantity of amino acids [63]. Jansson et al. [64] highlighted a defective metabolism for amino acids, fatty acids, bile acids and arachidonic acid. UC metabolome has been characterized by increased amounts of taurine and cadaverine [65]. Studies integrating IBD host specificities combined with their microbiota composition have provided new insights into the host-microbiota crosstalk. Lepage et al. [44] linked bacterial genus abundance to host transcriptomic patterns and observed a loss of host-microbiota interaction in the IBD context. A study focused on the ‘secretor’ genotype (FUT2 gene) demonstrated substantial differences in bacterial community composition, diversity, and structure, and several bacterial species displayed a disease-bygenotype association [66]. Also, NOD2 composite genotype and ATG16L1 genotype were significantly associated with shifts in microbial compositions that affect the relative frequencies of Faecalibacterium and Escherichia taxa [67]. Attempts to describe the IBD microbiome structure have been recently undertaken and it seems that changes affect the interactions of the microbiota with the gut environment. These changes are mostly due to a modification of peripheral functionalities rather than the core metabolic one. Finally, the IBD microbiome’s structure displayed a reduced network-wide modularity [68]. Results obtained from studies investigating the IBDassociated microbiota have depicted a deeply altered microbiome. Causes and consequences of such modifications are still being investigated in order to establish further biological links between IBD microbiome and the diseases’ etiopathology.
Dysfunctions in Obesity
Numerous studies linked obesity to an altered gut microbiome. This was associated to the energy harvested from the diet as well as energy storage in the host [69]. Mouse and human display a similar obesity-associated gut microbiota composition. As for IBD-associated microbiota, the Firmicutes/Bacteroidetes ratio is affected and an increase of Firmicutes, specifically the Mollicutes Dig Dis 2013;31:278–285 DOI: 10.1159/000354678
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provided insights into the functional capabilities of the gut microbiome and described a shared microbiome composed of 536,112 ± 12,167 prevalent genes. Defined as our other genome, the gut microbiome complements the human genome by synthesizing health-related molecules. Recently, a new concept has arisen and the notion of ‘enterotypes’ to describe general population groups based on their microbiome has been introduced [48]. Enterotypes are mainly explained by the abundance of three prevalent bacterial genera: Bacteroides, Ruminococcus and Prevotella. Originally, enterotypes had not been linked to host health status or human habits, but a recent study identified a positive correlation between enterotypes and long-term dietary habits [49]. Diversity is also key driver of the ecosystem’s fitness. It ensures high redundancy in bacterial functions even though microbial composition differs [50]. Complex interactions and correlation networks between microorganisms at the different intestinal niches need to be further addressed to be able to apprehend the structural impact of the ecosystem on human health.
Toward Ecosystem Restoration
The repeatedly demonstrated role of the intestinal microbiota in different pathologies has led to increasing efforts to shape the composition of the intestinal microbiota as a means of prevention or therapy. Probiotics – i.e. the administration of living microbial strains with beneficial effects on the host – proved to be efficient for preven282
Dig Dis 2013;31:278–285 DOI: 10.1159/000354678
tion of moderate intestinal conditions [75, 76]. Probiotics are largely thought to act through the modulation of the gut microbiota equilibrium and its functionality. Although the efficacy of probiotics is sometimes debatable, they offer great potential benefits to health and are safe for human use, and the interest of an early supplementation has been suggested [67], even in preterm infants [5]. However, these effects are strain-specific and further work is still required to confirm their health benefits. Prebiotics are non-digestible substrates leading to specific changes in the composition and activity of beneficial gut microbiota [63]. They are mainly oligosaccharides, e.g. fructooligosaccharides (FOS) and galactooligosaccharides (GOS). Administration of such prebiotics has been shown to selectively stimulate Bifidobacteria and Lactobacilli to a lesser extent. Mixing pre- and probiotic, namely a symbiotic, can thus have synergic effects and increase the effectiveness of probiotics [63]. The concept of selectively increasing Bifidobacteria and Lactobacilli however seems to narrow. Dysfunctionality of the intestinal microbiota is generally accepted to be linked to an overall reduction in diversity of the ecosystem. Therefore, more recent approaches aim at reconstituting a higher degree of diversity. The administration of prebiotics can indeed lead to an ecological shift if it addresses keystone species of the ecosystem. Due to the resilience feature of the intestinal microbiota, most successful efforts to permanently change or restore microbial composition are either long-term nutritional interventions or linked to a severe disturbance of the ecosystem such as antibiotic treatment or intestinal infections. The transplantation of the total microbiota from one individual to another has effectively been used for decades as therapy for recurrent Clostridium difficile infections [77, 78]. The complex nature of intestinal microbiota composition however only justifies such an intervention after a rigorous risk assessment. On an experimental scale, Vrieze et al. [79] demonstrated that therapy through fecal transplant is also efficient to increase insulin sensitivity in individuals with metabolic syndrome. These successes raise the question of fecal transplantation therapies using synthetic microbiomes. Resilience of the human gut microbiota implies repeated transplantation at several weeks of interval to maintain the donor populations in the receiver gut. Strategies disturbing the resilience capacity of the human gut microbiota (i.e. via repeated antibiotic challenges) or selecting bacteria that are non-individual specific (i.e. bacteria from the phylogenetic core) as transplant synthetic microbiome might overcome this issue. Mondot /de Wouters /Doré /Lepage
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class, has repeatedly been reported [45, 70, 71]. Further evidence demonstrating the importance of the microbiome came from transfer studies from obese mice donors to germ-free lean ones. Such microbiota transfer promoted greater increases in fat deposition than transplants from lean donors [71, 72]. Indeed, obese microbiomes show increased functional capacity to harvest energy from diet. Noteworthy, enrichment in genes involved in carbohydrate, lipid, and amino acid metabolism was identified in obese microbiome. Obesity has further been linked to an aberrant hostmicrobiome crosstalk. Suppression of a circulating lipoprotein lipase inhibitor, the angiopoietin-like protein 4 (Angptl4), was shown to be involved in microbiota-induced deposition of triglycerides in adipocytes. Another study linked the regulation of host energy balance to the G-protein-coupled receptors 41 (GPR41) whose activity is shown to be dependent on the gut microbiota’s metabolic activity [73]. In extreme cases of obesity requiring a Roux-en-Y gastric bypass surgery, the human gut microbiota changes dramatically following surgery. Obese patients receiving this medication displayed, presurgically, a microbiota depleted of bacteria belonging to the Bacteroides/Prevotella group (Bacteroidetes phylum), and this was negatively and positively correlated with corpulence caloric and food intake, respectively. Furthermore, an increased level of E. coli 3 months after surgery was inversely correlated to fat mass and leptin levels. Moreover, reduced proportions of lactic acid bacteria including Lactobacillus/Leuconostoc/Pediococcus group and Bifidobacterium have been observed [74]. Changes in gut microbiota composition could therefore account for the drastic weight loss observed in Roux-en-Y gastric bypass surgery that cannot solely be explained by reduced nutrient absorption. Altogether, these results provide evidence of an impaired gut microbiota associated with obesity. Microbiome variations affect both the composition and the functionality of the obese gut environment and lead to a deregulation of the host-microbiota crosstalk.
Conclusion
The human gut microbiota and its associated bacterial gene reservoir is a key component of intestinal homeostasis. New technologies recently highlighted important and diverse functions of this bacterial consortium, which is currently leading to improvements in therapeutic application, for instance with the development of fecal transplantation to treat or ameliorate IBD and metabolic disorders, or with the development of diagnostic and prognostic markers. Yet the structure of this individual
ecosystem itself, its degree of resilience and a high diversity seem to be crucial for proper health benefits of every individual and thus need to be further assessed, mostly at mucosal surfaces where this microbiome is in constant interaction with its host.
Disclosure Statement The authors have no conflicts of interest to disclose.
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32 Flint HJ, Scott KP, Louis P, Duncan SH: The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 2012; 9:577–589. 33 Ge H, Li X, Weiszmann J, Wang P, Baribault H, Chen J-L, et al: Activation of G-proteincoupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma-free fatty acids. Endocrinology 2008; 149: 4519–4526. 34 Leblanc JG, Milani C, De Giori GS, Sesma F, Van Sinderen D, Ventura M: Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr Opin Biotechnol 2013; 24: 160–168. 35 Druart C, Neyrinck AM, Dewulf EM, De Backer FC, Possemiers S, Van de Wiele T, et al: Implication of fermentable carbohydrates targeting the gut microbiota on conjugated linoleic acid production in high-fat-fed mice. Br J Nutr 2013, E-pub ahead of print. 36 Macpherson AJ, Geuking MB, McCoy KD: Immunoglobulin A: a bridge between innate and adaptive immunity. Curr Opin Gastroenterol 2011;27:529–533. 37 Tschöp MH, Hugenholtz P, Karp CL: Getting to the core of the gut microbiome. Nat Biotechnol 2009;27:344–346. 38 Shade A, Peter H, Allison SD, Baho DL, Berga M, Bürgmann H, et al: Fundamentals of microbial community resistance and resilience. Front Microbiol 2012;3:417. 39 Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, et al: Selective increases of Bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 2007;50:2374–2383. 40 De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, et al: Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010;107:14691–14696. 41 Rigottier-Gois L: Dysbiosis in inflammatory bowel diseases: the oxygen hypothesis. ISME J 2013;7:1256–1261. 42 Ley RE, Hamady M, Lozupone C, Turnbaugh PJ, Ramey RR, Bircher JS, et al: Evolution of mammals and their gut microbes. Science 2008;777:1647–1651. 43 Ley RE, Peterson DA, Gordon JI: Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006;124: 837–848. 44 Lepage P, Häsler R, Spehlmann ME, Rehman A, Zvirbliene A, Begun A, et al: Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 2011;141:227–236. 45 Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al: A core gut microbiome in obese and lean twins. Nature 2009;457:480–484.
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The Human Gut Microbiome and Its Dysfunctions Stanislas Mondot a Tomas de Wouters b, c Joël Doré b, c Patricia Lepage b, c Institut Curie, U932, Paris, b INRA, UMR1319-Micalis, and c AgroParisTech, UMR1319-Micalis, Jouy-en-Josas, France
Key Words Microbiota · Gut ecosystem · Resilience · Inflammatory bowel disease
Abstract The human gastrointestinal tract hosts more than 100 trillion bacteria and archaea, which together make up the gut microbiota. The amount of bacteria in the human gut outnumbers human cells by a factor of 10, but some finely tuned mechanisms allow these microorganisms to colonize and survive within the host in a mutual relationship. The human gut microbiota co-evolved with humans to achieve a symbiotic relationship leading to physiological homeostasis. The microbiota provides crucial functions that human cannot exert themselves while the human host provides a nutrientrich environment. Chaotic in the early stages of life, the assembly of the human gut microbiota remains globally stable over time in healthy conditions and absence of perturbation. Following perturbation, such as antibiotic treatment, bacteria will recolonize the niches with a composition and diversity similar to the basal level since the ecosystem is highly resilient. Yet, recurrent perturbations lead to a decrease in resilience capacity of the gut microbiome. Shifts in the bacterial composition and diversity of the human gut microbiota have been associated with intestinal dysfunctions such as inflammatory bowel disease and obesity. More than specific bacteria, a general destructuration of the ecosystem seems
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0278$38.00/0 E-Mail [email protected] www.karger.com/ddi
to be involved in these pathologies. Application of metagenomics to this environment may help in deciphering key functions and correlation networks specifically involved in health maintenance. In term, fecal transplant and synthetic microbiome transplant might be promising therapies for dysbiosis-associated diseases. © 2013 S. Karger AG, Basel
Introduction
Humans are colonized by a multitude of site-specific microbial communities localized on the skin, mucosal surfaces, and in the intestinal tract [1]. A succession of habitats differing drastically in pH, redox potential and transit time defines the nature and degree of colonization along the intestine, which increases steadily along the intestinal tract to reach its highest concentrations in the colon [2]. In the colon, the levels of bacteria are as high as 1011 microorganisms per gram of luminal content, outnumbering the total number of human eukaryotic cells by ten. These microbial communities assure key functions that are necessary for health and well-being of the host including (i) colonic fermentation, (ii) a barrier effect strengthening resistance to colonization by exogenous or
S. Mondot and T. de Wouters contributed equally to this study.
Patricia Lepage INRA, UMR1319-Micalis FR–78350 Jouy-en-Josas (France) E-Mail patricia.lepage @ jouy.inra.fr
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a
Determinants of the Human Gut Microbiota
Colonization at Birth An increasing number of reports points towards an in utero contact of the infant with mother’s fecal bacteria or bacterial components [14–17]. The question of very early versus prenatal colonization however remains a point of debate. Nevertheless, extensive colonization of the intestine starts at birth through the transfer of bacteria from the environment, mainly from the mother to the infant [for review, see 18]. The composition of the intestinal microbiota in this early stage is highly variable [19]. Facultative anaerobic bacteria, especially Escherichia coli and other Enterobacteriaceae have been reported to be the first colonizers of the infant gut where they reduce oxygen thereby establishing the typical strict anaerobic environment in the intestinal lumen during the first days of life. Once the anaerobic gut environment is established, the Human Gut Microbiome and Its Dysfunctions
colonization by strictly anaerobic bacteria such as Clostridium, Bacteroides, Bifidobacteria and occasionally Ruminococcus will start, leading to an increasingly diverse and complex microbial population that can be considered as the typical adult microbiota (high diversity and dominated by Bacteroidetes and Firmicutes) by about 3 years of age [20]. The temporal succession of microbiota establishment is rather well known, while the multiple factors influencing and finally defining the composition are difficult to disentangle. The primordial role of the mother’s microbiota in early colonization is underlined by its high level of similarity at the age of 1 month. Interestingly, this similarity decreases together with the appearance of other environmental exposures [21]. Gestation time, mode of delivery and feeding of the infant are the main extrinsic factors influencing early infant microbiota establishment. Acute prematurity has been linked to increased Staphylococcus colonization [22]. Vaginally born infants show a higher prevalence of Lactobacillus and Prevotella, while infants delivered by cesarean section have increased proportions of Staphylococcus, Corynebacterium and Propionibacterium in their microbiota reflecting exposure to vaginal versus skin microbiota as principal source of bacteria [23]. Diet is a determining factor from early on. Breastfeeding for instance favors the prevalence of Bifidobacteria and Lactobacilli through the specific composition of the mother’s milk. Moreover, increasing reports indicate that breast milk carries its own microbiota containing a multitude of early colonizers of the human intestine such as Staphylococcus, Streptococcus, Propionibacterium, Bifidobacterium, Veillonella, Bacteroides, Clostridium, Enterobacteria and Roseburia [24–27]. However, improvements in infant formulas have led to decreased food-related differences in colonization patterns [2, 15]. Finally, changes in the establishment of gut microbiota have been observed in Western infants, most likely due to improved hygiene and general asepsis in Western countries, resulting in reduced bacterial exposure [2, 15]. This sequential bacterial colonization of the neonatal gut appears to be an important period for the development of a diverse, robust, resilient and functionally efficient microbiota [17]. Functions of the Human Gut Microbiota Predominantly residing in the colon, the intestinal microbiota carries a variety of functions beneficial for its host [28]. A main role is the increase of energy harvest by about 10% from the diet through fermentation of fibers Dig Dis 2013;31:278–285 DOI: 10.1159/000354678
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opportunistic pathogens [3], and (iii) maturation of the intestinal epithelium and immune system [4]. Any dysbiosis (i.e. a disequilibrium of the ecosystem) could therefore lead to diseases [5, 6]. Indeed, several pathologies, such as inflammatory bowel diseases (IBD), irritable bowel syndrome, and allergic diseases, have been associated with alterations in the composition of the gut microbiota as compared with healthy subjects [7, 8]. The composition of gut microbial communities was first described by culture-based studies, which estimated that 400–500 different species can colonize the adult human gut [9]. The use of culture-independent approaches, mostly based on the analysis of 16S rRNA gene marker, has revealed a far more complex intestinal microbial community than previously described. The proportion of cultivable bacteria in the human gut ranged from 15 to 85% depending on the study [10], with more than 1,200 characterized bacterial species [11]. Four major phyla constitute this ecosystem: the Firmicutes and Bacteroidetes being the most abundant, and to a lesser extent Actinobacteria and Proteobacteria. The adult fecal microbiota composition is specific to each individual even though a universal microbial core which contains 66 molecular species, conserved over 50% of a population, has been described [12]. In absence of perturbations (antibiotics, pathogens, etc.) the individual dominant gut microbiota is relatively stable over time [13]. In the field of microbial ecology, the development of high-throughput sequencing technologies is currently leading to a constantly improved understanding of complex ecosystems.
Factors Modulating the Adult Microbiota Despite the phylum level similarities of the intestinal microbiota, the species level composition is highly variable between subjects. This high variability is explained by the differential inoculation through the environment but also by genetic predisposition of the host as well as long-term nutritional behavior of the individuals. The different possible microbiota compositions for each individual can be seen as a stability landscape in which there are multiple alternative equilibria [38]. The 280
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stability of one of these equilibria is maintained by the trophic structure of the ecosystem as well as the physicochemical conditions the host offers to its microbiota. If one of these two conditions is disturbed in a major way, the introduced disequilibrium will not return to its original state but find an alternative equilibrium. Probability of such permanent changes increases with the strength of the disturbance and the low stability (i.e. resilience) of the actual ecosystem [1]. The most prominent impact is the frequent use of antibiotics. By selectively diminishing specific bacterial populations, antibiotics may aid subdominant populations to become dominant colonizers. In the same way by selectively feeding specific subgroups, their thrive can be favored [39]. Host physiological and genetic factors can modulate the composition of the intestinal microbiota in multiple ways. Besides the effect of long-term alimentary habits [40], the transit time, secretion of bile acids, the degree of the innate immune reaction and the integrity of intestinal anaerobic environment are known to impact the human microbiota [41].
Importance of Diversity and Structure of the Ecosystem to Ensure Beneficial Effect
The human gut microbiota has developed mainly commensalistic relationships with its associated host. This pacific crosstalk is the result of a long-term evolutionary process implicating a strict microorganism selection by the host which ensures homeostasis within the intestine [42, 43]. A clear result of this co-evolution is the establishment of both meticulous microbiota composition and structure. In the past, numerous studies have highlighted the importance of preserving the gut microbiota integrity, notably in cases of diverse disorders such as IBD or obesity [44, 45]. A large amount of data has been obtained on the human gut microbiota and its implication in human health. Studies that define the host-microbiota relationship as mutualistic have accumulated [46]. In its normal state (eubiosis) the human gut microbiota is dominated by four phyla. The overlap between individuals, however, is narrowed at the species level of microbiota composition. Still, a set of 66 bacterial species mainly belonging to Firmicutes phylum and characterized by a high prevalence within the human population (≥50%) and a high abundance (≥35.8%) have been identified [12]. Metagenomic studies and notably Qin et al. [47] confirmed this result by depicting a similar core microbiota composed of 75 bacterial species. This study also Mondot /de Wouters /Doré /Lepage
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[2]. In order to degrade these polymers resistant to degradation by human enzymes into monosaccharides, the intestinal microbiome produces a large panel of carbohydrate active enzymes (CAZymes). Short-chain fatty acids (mainly butyrate, propionate, acetate) resulting from this fermentation are the main carbon source for the colonic epithelium and thus induce a proper maturation and regeneration of the colonic epithelium [29–31]. Shortchain fatty acids, however, are not exclusively used as an energy source. They modulate pH, are ligands to different receptors (GRP41 and GRP43) and play an important role in osmotic regulation, gut motility, energy metabolism and transcriptional regulation [32, 33]. Numerous other bacterial metabolites have been identified to have ligand binding or epigenetic properties such as polyunsaturated fatty acids, folic acid, riboflavin and microorganism-associated molecular patterns [34, 35]. The gut microbiota is also crucial for the development of a proper immune system since bacterial colonization is a prerequisite for immunoglobulin A production in the intestinal lumen [36]. Besides its beneficial effect, this dense population of microorganisms in the intestine represents a constant threat for the host. In order to control the microbial populations, the intestinal epithelium and its covering mucus layer represent an important and tightly regulated barrier. The innate immune response controls bacterial growth near the intestinal epithelium by the secretion of immunoglobulin A and antimicrobial peptides, such as defensins, in response to microbial-associated molecular patterns and other bacterial metabolites. This multitude of interdependent factors that contribute to the overall well-being of the host is surprisingly stable over time. The key to this stability is thought to be the diversity and high degree of redundancy of the ecosystem [37]. However, modern lifestyle seems to favor a shift in the microbial composition thereby breaking this delicate balance and leading to chronic disequilibrium referred to as dysbiosis.
Dysfunctions in Inflammatory Bowel Diseases
IBD are chronic relapsing disorders composed by two major diseases, Crohn’s disease (CD) and ulcerative colitis (UC). Recent decades have provided a body of evidence dealing with the involvement of the gut microbiota in the etiopathology of IBD. Overall, IBD patients’ microbiota is mostly characterized by a loss of bacterial diversity at both the phylogenetic and functional levels. The IBD-associated microbiota is dysbiotic and characterized by a reverse Firmicutes/Bacteroidetes ratio [51, 52] associated with an increase in Proteobacteria [53, 54]. Differential levels for particular bacterial species, as compared to healthy individuals’ microbiota, have been reported for both UC and CD microbiota. CD is characterized by decreased proportions of bacteria belonging to the human gut core microbiota. Notably, a lower amount of Faecalibacterium prausnitzii and members of the Clostridium clusters IV (C. leptum group) and XIV (C. coccoides group) have been reported [55–57]. Conversely, increased levels of Enterobacteriaceae, specific strains of E. coli (AIEC) and some Ruminococcus species have been identified [54, 57–60]. UC is characterized by a decreased relative proportion of Clostridium cluster XIV [56] and a higher number of E. coli and/or sulfate-reducing bacteria [56, 61].
Human Gut Microbiome and Its Dysfunctions
The IBD microbiota activity also seems to be impaired and meta-Omics studies highlighted mainly a loss of essential functionalities. Qin et al. [47] described a CD microbiome harboring 25% fewer genes than individuals not suffering from IBD and metaproteomics investigation of IBD-associated microbiota reported a decreased number of bacterial proteins [62]. CD metabolome has been characterized by reduced levels of butyrate, acetate, methylamine, trimethylamine and elevated quantity of amino acids [63]. Jansson et al. [64] highlighted a defective metabolism for amino acids, fatty acids, bile acids and arachidonic acid. UC metabolome has been characterized by increased amounts of taurine and cadaverine [65]. Studies integrating IBD host specificities combined with their microbiota composition have provided new insights into the host-microbiota crosstalk. Lepage et al. [44] linked bacterial genus abundance to host transcriptomic patterns and observed a loss of host-microbiota interaction in the IBD context. A study focused on the ‘secretor’ genotype (FUT2 gene) demonstrated substantial differences in bacterial community composition, diversity, and structure, and several bacterial species displayed a disease-bygenotype association [66]. Also, NOD2 composite genotype and ATG16L1 genotype were significantly associated with shifts in microbial compositions that affect the relative frequencies of Faecalibacterium and Escherichia taxa [67]. Attempts to describe the IBD microbiome structure have been recently undertaken and it seems that changes affect the interactions of the microbiota with the gut environment. These changes are mostly due to a modification of peripheral functionalities rather than the core metabolic one. Finally, the IBD microbiome’s structure displayed a reduced network-wide modularity [68]. Results obtained from studies investigating the IBDassociated microbiota have depicted a deeply altered microbiome. Causes and consequences of such modifications are still being investigated in order to establish further biological links between IBD microbiome and the diseases’ etiopathology.
Dysfunctions in Obesity
Numerous studies linked obesity to an altered gut microbiome. This was associated to the energy harvested from the diet as well as energy storage in the host [69]. Mouse and human display a similar obesity-associated gut microbiota composition. As for IBD-associated microbiota, the Firmicutes/Bacteroidetes ratio is affected and an increase of Firmicutes, specifically the Mollicutes Dig Dis 2013;31:278–285 DOI: 10.1159/000354678
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provided insights into the functional capabilities of the gut microbiome and described a shared microbiome composed of 536,112 ± 12,167 prevalent genes. Defined as our other genome, the gut microbiome complements the human genome by synthesizing health-related molecules. Recently, a new concept has arisen and the notion of ‘enterotypes’ to describe general population groups based on their microbiome has been introduced [48]. Enterotypes are mainly explained by the abundance of three prevalent bacterial genera: Bacteroides, Ruminococcus and Prevotella. Originally, enterotypes had not been linked to host health status or human habits, but a recent study identified a positive correlation between enterotypes and long-term dietary habits [49]. Diversity is also key driver of the ecosystem’s fitness. It ensures high redundancy in bacterial functions even though microbial composition differs [50]. Complex interactions and correlation networks between microorganisms at the different intestinal niches need to be further addressed to be able to apprehend the structural impact of the ecosystem on human health.
Toward Ecosystem Restoration
The repeatedly demonstrated role of the intestinal microbiota in different pathologies has led to increasing efforts to shape the composition of the intestinal microbiota as a means of prevention or therapy. Probiotics – i.e. the administration of living microbial strains with beneficial effects on the host – proved to be efficient for preven282
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tion of moderate intestinal conditions [75, 76]. Probiotics are largely thought to act through the modulation of the gut microbiota equilibrium and its functionality. Although the efficacy of probiotics is sometimes debatable, they offer great potential benefits to health and are safe for human use, and the interest of an early supplementation has been suggested [67], even in preterm infants [5]. However, these effects are strain-specific and further work is still required to confirm their health benefits. Prebiotics are non-digestible substrates leading to specific changes in the composition and activity of beneficial gut microbiota [63]. They are mainly oligosaccharides, e.g. fructooligosaccharides (FOS) and galactooligosaccharides (GOS). Administration of such prebiotics has been shown to selectively stimulate Bifidobacteria and Lactobacilli to a lesser extent. Mixing pre- and probiotic, namely a symbiotic, can thus have synergic effects and increase the effectiveness of probiotics [63]. The concept of selectively increasing Bifidobacteria and Lactobacilli however seems to narrow. Dysfunctionality of the intestinal microbiota is generally accepted to be linked to an overall reduction in diversity of the ecosystem. Therefore, more recent approaches aim at reconstituting a higher degree of diversity. The administration of prebiotics can indeed lead to an ecological shift if it addresses keystone species of the ecosystem. Due to the resilience feature of the intestinal microbiota, most successful efforts to permanently change or restore microbial composition are either long-term nutritional interventions or linked to a severe disturbance of the ecosystem such as antibiotic treatment or intestinal infections. The transplantation of the total microbiota from one individual to another has effectively been used for decades as therapy for recurrent Clostridium difficile infections [77, 78]. The complex nature of intestinal microbiota composition however only justifies such an intervention after a rigorous risk assessment. On an experimental scale, Vrieze et al. [79] demonstrated that therapy through fecal transplant is also efficient to increase insulin sensitivity in individuals with metabolic syndrome. These successes raise the question of fecal transplantation therapies using synthetic microbiomes. Resilience of the human gut microbiota implies repeated transplantation at several weeks of interval to maintain the donor populations in the receiver gut. Strategies disturbing the resilience capacity of the human gut microbiota (i.e. via repeated antibiotic challenges) or selecting bacteria that are non-individual specific (i.e. bacteria from the phylogenetic core) as transplant synthetic microbiome might overcome this issue. Mondot /de Wouters /Doré /Lepage
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class, has repeatedly been reported [45, 70, 71]. Further evidence demonstrating the importance of the microbiome came from transfer studies from obese mice donors to germ-free lean ones. Such microbiota transfer promoted greater increases in fat deposition than transplants from lean donors [71, 72]. Indeed, obese microbiomes show increased functional capacity to harvest energy from diet. Noteworthy, enrichment in genes involved in carbohydrate, lipid, and amino acid metabolism was identified in obese microbiome. Obesity has further been linked to an aberrant hostmicrobiome crosstalk. Suppression of a circulating lipoprotein lipase inhibitor, the angiopoietin-like protein 4 (Angptl4), was shown to be involved in microbiota-induced deposition of triglycerides in adipocytes. Another study linked the regulation of host energy balance to the G-protein-coupled receptors 41 (GPR41) whose activity is shown to be dependent on the gut microbiota’s metabolic activity [73]. In extreme cases of obesity requiring a Roux-en-Y gastric bypass surgery, the human gut microbiota changes dramatically following surgery. Obese patients receiving this medication displayed, presurgically, a microbiota depleted of bacteria belonging to the Bacteroides/Prevotella group (Bacteroidetes phylum), and this was negatively and positively correlated with corpulence caloric and food intake, respectively. Furthermore, an increased level of E. coli 3 months after surgery was inversely correlated to fat mass and leptin levels. Moreover, reduced proportions of lactic acid bacteria including Lactobacillus/Leuconostoc/Pediococcus group and Bifidobacterium have been observed [74]. Changes in gut microbiota composition could therefore account for the drastic weight loss observed in Roux-en-Y gastric bypass surgery that cannot solely be explained by reduced nutrient absorption. Altogether, these results provide evidence of an impaired gut microbiota associated with obesity. Microbiome variations affect both the composition and the functionality of the obese gut environment and lead to a deregulation of the host-microbiota crosstalk.
Conclusion
The human gut microbiota and its associated bacterial gene reservoir is a key component of intestinal homeostasis. New technologies recently highlighted important and diverse functions of this bacterial consortium, which is currently leading to improvements in therapeutic application, for instance with the development of fecal transplantation to treat or ameliorate IBD and metabolic disorders, or with the development of diagnostic and prognostic markers. Yet the structure of this individual
ecosystem itself, its degree of resilience and a high diversity seem to be crucial for proper health benefits of every individual and thus need to be further assessed, mostly at mucosal surfaces where this microbiome is in constant interaction with its host.
Disclosure Statement The authors have no conflicts of interest to disclose.
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