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The intestinal microbiota and chronic disorders of the gut


Andrew W. DuPont and Herbert L. DuPont
Abstract | Mucosal surfaces of the gut are colonized by large numbers of heterogeneous bacteria that contribute to intestinal health and disease. In genetically susceptible individuals, a pathogenic community may arise, whereby abnormal gut flora contributes to alterations in the mucosa and local immune system leading to gastrointestinal disease. These diseases include enteric infections, such as Clostridiumdifficile infection, small intestinal bacterial overgrowth, functional gastrointestinal disorders (including IBS), IBD and colorectal cancer. Prebiotics, probiotics and synbiotics (a combination of prebiotics and probiotics) have the capacity to reverse pathologic changes in gut flora and local immunity. Intestinal health and disease need to be thoroughly characterized to understand the interplay between the indigenous microbiota, the immune system and genetic host factors. This Review provides a broad overview of the importance of the intestinal microbiota in chronic disorders of the gut.
DuPont, A. W. & DuPont, H. L. Nat. Rev. Gastroenterol. Hepatol. 8, 523531 (2011); published online 16 August 2011; doi:10.1038/nrgastro.2011.133

Introduction
The human gut supports a dense, diverse and dynamic bacterial ecosystem, which is important to intestinal health. The resident flora of the human gut has been estimated to support between 500 and 1,000 distinct bacterial species, with the total number of bacteria approaching 1014cells and containing 100 times as many genes as the human genome.1 Development of 16S ribosomal RNA (rRNA) gene-sequence-based metagenomic methods has led to major advances in defining the total microbial population of the gut.2 This technique has revealed that two bacterial phyla, the Bacteroidetes and Firmicutes, constitute 90% of the known phylogenetic categories in the healthy gut.3 However, only 20% of the identifiable species detected by 16S rRNA have been success fully cultured. For a long time, it was assumed that gut bacterial strains were inconsequential colonizers of the gut while serving as pathogens when they left the bowel. However, the intestinal microbiota is now considered to have a symbiotic role with the host in maintaining health, and gut bacteria are considered instrumental in the development of chronic gastrointestinal disorders when present in higher than normal concentrations or when present in gut locations expected to support low levels of bacteria. The intestinal microbiota contributes to metabolic activities and is involved in the absorption of nutrients, protection of mucosal surfaces, and the immune structure and function of the gut (Figure1).
Competing interests H. L. DuPont declares associations with the following companies: Intercell; Novartis; Osel Inc.; Salix Pharmaceuticals, Inc.; Santarus. A. W. DuPont declares associations with the following companies: Lexicon Pharmaceuticals; Salix Pharmaceuticals. See the article online for full details of the relationships.

The composition of the microbiota is influenced by host age, environmental and genetic factors, diet, and exposure to chemotherapeutic drugs and probiotics. In addition, antibiotics can substantially alter the gut microbiota, with effects that can be long-term4 (particularly for antibiotic-resistant strains5) and may result in super i nfection with antibiotic-resistant bacteria such as Clostridium difficile or vancomycin-resistant Enterococcus. Computer-assisted definition of gut bacteria could increase our capacity to define the intestinal microbiota in health and disease; this approach will probably be required to understand the importance of the large variations found in the various bacterial groups.6 Quantitative and qualitative alterations to the intestinal microbiota are involved in many disease states, including obesity, atherosclerosis, diabetes, IBD and central nervous system diseases such as autism.7 In this Review, we focus on the importance of the intestinal microbiota in chronic disorders of the gut, whether these are resident bacteria or virulent bacterial strains. This topic combines large bodies of knowledge in the areas of intestinal microbiota, gut immunity and host genetics and deals with how these contribute to the pathogenesis of gastrointestinal disease. We do not feel that a short article can give full justice to this field, but we provide a broad overview. For each of the important areas we have included references to review articles for readers wishing to delve more deeply.

The intestinal microbiota and immunity


The gut mucosal immune system is the largest lymphoid organ in the body and is recurrently stimulated by antigens from foods, indigenous bacteria and external pathogens that make their way to the small intestine and colon.

University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA (A.W.DuPont, H.L.DuPont). Baylor College of Medicine, Department of Medicine, One Baylor Plaza, Houston, TX77030, USA (H.L.DuPont). Correspondence to: A. W. DuPont andrew.dupont@ uth.tmc.edu

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Key points
The intestinal microbiota consists of heterogeneous and largely nonculturable bacteria that orchestrate homeostasis by communicating with the epithelium and innate and adaptive immune mechanisms of the gut Host immunity is directly involved in the control of the intestinal microbiota and susceptibility to chronic intestinal disease Enteric infection by a high-grade bacterial pathogen can alter susceptibility to IBS by producing chronic intestinal inflammation and a series of events that leads to altered bowel function Certain bacteria in the lumen of the gut can cross the intestinal mucosa, causing systemic infection in a process called translocation In IBD, abnormal gut flora (which may include pathogenic species) and the presence of bacterial antigens with biologic properties produce a pathogenic community, leading to intestinal inflammation Modulation of the intestinal microbiota may be possible through diet or by administration of prebiotics, probiotics, synbiotics, or by fecal transplantation of donor stool from a healthy individual

The intestinal microbiota is involved in the homeostasis and functioning of the local immune system: gut bacteria interact with lymphoid follicles of the gut mucosa, as well as with regulatory and effector Tcells. A balance between the intestinal microbiota and anti microbial peptides is seen in the gut of healthy indivi duals; for example, peptidoglycan from intestinal Gram-negative bacteria seems to communicate with an innate detection system to generate adaptive lymphoid tissue that contributes to a healthy intestinal environment.8 Microbial ligands on commensal flora are recognized by Toll-like receptors (TLRs); activation of TLRs by the gut flora serves to protect the gut from injury.9 Interaction of gut bacteria and TLRs contributes to mucosal homeo stasis and controls local inflammation.10 Further evidence for the importance of the intestinal microbiota in immunity is that animals grown in germ-free environments show delayed onset of cellular and serologic responses and reduced immune responses to gut flora.11,12 In addition, the absence of intestinal microbiota also leads to defects in the systemic immune system with reduced numbers of CD4+ Tcells and systemic antibody levels.13 Although the gut flora generally contributes to a healthy environment, acute and chronic mucosal inflamma tion, which may contribute to the development of IBD,14 can arise as a result of both commensal and pathogenic bacteria that influence the innate and adaptive immune systems. Intestinal microbes can alter host defense mechanisms, leading to the activation of cytokines and the stimulation of adaptive Tcell and Bcell responses. It is not known how the body differentiates between commensal bacteria and pathogenic species that threaten invasion of the mucosa, although the hosts innate intestinal immune system is obviously heavily involved.15 The predominant immunoglobulin in the gut, IgA, which develops against noncommensal organisms is able to neutralize toxins and pathogenic microbes.16

immunity is normally directed to the indigenous gut flora and is protective against the development of mucosal inflammationcrosstalk between mono nuclear cells (including macrophages and dendritic cells), mucosal epithelial cells and gut flora normally prevents local inflammatory changes. These mucosal and immune interactions also have a role in the regulation of the intestinal microbiota. Genome-wide studies are useful for the identification of innate-immunityrelated genes that are important in the development of an inflammatory mucosa. Indigestible food products and their metabolites are used both by gut bacteria and the host. The epithelial layer regulates the passage of nutrients, salt and fluids into the gut and serves as a barrier to microbial invasion. In healthy individuals, the flora and epithelium act together to produce bowel homeostasis. Alterations of the epithelium or in the gut flora can lead to pathologic changes associated with bacterial overgrowth, translocation of bacteria across the mucosa, release of toxic substances, or local inflammation. Presence of a bacterial strain with virulent properties17,18 and adherence to the mucosal surface seem to be critical steps in enteric infection and translocation.19 Gut immune deficiency also facilitates translocation of bacteria, leading to systemic infection.20 The role of the intestinal microbiota in various gastrointestinal diseases is discussed below.

Enteric infections
The healthy intestinal microbiota inhabits the length of the gastrointestinal tract from 1week after birth. It exerts a homeostatic influence on the gut through direct inhibition of other microbes by release of metabolic products, through nutrient depletion, and/or by stimula tion of the innate and adaptive immune responses (Figure1). These homeostatic influences lead to coloniza t ion resistance to nonindigenous strains of bacteria, such as C.difficile, Salmonella spp. and Campylobacter jejuni. However, disruptions of the microbial community predispose people to infection by these enteropathogens. When they become established, these enteropathogens compete for metabolites and influence the composition of the gut flora. C.difficile infection (CDI) occurs when three factors are aligned: alteration of gut flora by antibacterial agents, chemotherapy or PPIs; comorbidity, including advanced age; and exposure to C.difficile vegetative cells and spores.21 Successful treatment of CDI depends upon restoration of the gut flora by withholding the offending antibiotics and by administering probiotics or fecal transplantation from a healthy donor. In CDI the bacterial divisions of Firmicutes and Bacteriodetes are reduced; numbers improve following fecal transplantation.22 A study of the duration of alteration of colonic flora with fecal transplantation demonstrated that microflora from healthy donor samples persisted for the 24weeks of study.23 Prior receipt of antibiotics increases susceptibility to Salmonella infection24,25 and is associated with a prolonged period of infection compared with patients who
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Mechanisms controlling the intestinal microbiota


Mucosal homeostasis is affected by loss of immune reactivity (tolerance) to antigens of the gut flora. Innate
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Intestinal microbiota (5001,000 species with total cell counts of ~1014)

Nutrition and metabolism: fermentation of foods releases antibacterial short-chain fatty acids and other antimicrobial products

Barrier function: colonization of the mucosa and strengthening of the epithelial lining

Crosstalk with immune system

Inhibition of growth of pathogens and abnormal ora

Prevention of growth of pathogens and abnormal ora through utilization of space and nutrients; strengthening of the epithelial barrier by promoting intestinal epithelial cell survival

Enhancement of innate immunity and modulation of in ammation through Toll-like-receptor regulated pathways

Figure 1 | The homeostatic role of the intestinal microbiota.

have not received antibiotics.26 Similarly, one of the risk factors for developing Campylobacter infection is the prior receipt of antibiotics.27,28

Small intestinal bacterial overgrowth


Small intestinal bacterial overgrowth (SIBO) is defined as an abnormal number and/or type of bacteria growing in the small intestine. Bacterial growth is normally sparse in the small intestine owing to the effects of gastric acid on ingested microorganisms, efficient upper gut motility that limits substrate time and subsequent growth of bacteria, the bacteriostatic properties of pancreatic and biliary secretions, and the presence of the ileocecal valve. SIBO can arise in situations in which anatomic alterations of the gut influence normal motility patterns, such as bowel obstruction or gastrectomy, scleroderma, radiation enteropathy, small bowel diverticulosis, diabetic visceral neuropathy and blind loop syndrome as a result of surgery. SIBO can also occur in patients with IBS, cirrhosis and liver failure, celiac disease, Crohns disease and nonalcoholic steatohepatitis. SIBO is accompanied by maldigestion and malabsorption. Levels of disaccharidases may be reduced secondary to injury of the enterocyte brush-border in patients with SIBO.29 Patients typically complain of bloating, abdominal discomfort or pain, and diarrhea. Jejunal cultures, including cultures from unwashed small bowel biopsy specimens, that show 105 bacteria per ml are considered the gold standard for diagnosis of SIBO by many researchers.30,31 Given the length of the small bowel and regional potential of SIBO, sampling only a proximal region may lack sensitivity for making a diagnosis. Measuring levels of breath hydrogen and methane after the administration of lactulose or glucose represents an important screening test despite the occurrence of false-positive results related to rapid orocecal transit of lactulose, or false-negative results owing to rapid absorption of glucose in the proximal jejunum in some patients.32 In humans, hydrogen and methane are produced exclusively by intestinal bacteria, either by colonic bacteria or by small bowel bacteria in the case of SIBO. Although measuring breath hydrogen levels is accepted as a diagnostic tool by many who study SIBO, more studies are needed to determine the significance of breath methane levels.33 Some researchers in the field suggest that there is no gold standard for diagnosing SIBO. These researchers suggest that clinical illness (for
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example, abdominal bloating), response to antimicrobial treatment, and small intestinal bacterial count are the best methods to assess and diagnose SIBO.34 A high frequency of SIBO is reported in patients with cirrhosis,3538 which is related to delayed intestinal transit times39 and decreased numbers of small intestinal bacteriostatic conjugated bile acids.37,40 SIBO leads to a further decrease in conjugated bile acids by causing deconjugation of bile acids, which are rapidly absorbed by nonionic diffusion.41,42 Increased small intestinal permeability associated with portal hypertension and bacterial overgrowth probably explains the bacterial translocation that occurs in patients with cirrhosis.4345

Functional gastrointestinal disorders


Functional gastrointestinal disorders (FGIDs), including IBS, are among the most common chronic diseases seen in the general public; IBS is reported in 1020% of the general population.46 By definition, FGIDs cannot be explained by biochemical or anatomic alterations of the gut. However, as research progresses it is likely that many of the entities currently considered to be FGIDs will be classified on the basis of a defined pathophysiology. Evidence is accumulating to suggest that FGIDs are caused by a variety of host, microbial and environmental factors that interact to result in low-grade mucosal inflammation. In the case of postinfectious IBS, this sequence of events is initiated following enteric infection by a high-grade enteropathogen. Published studies have shown that patients with IBS have definable alterations of fecal flora compared with healthy persons (Figure2), with variations seen in the subgroups of patients with diarrhea-predominant or constipation-predominant disease.4749 The high counts of Veillonella and Lactobacillus found in patients with IBS are associated with increased levels of short-chain fatty acids, including acetic and propionic acids, which seem to contribute to clinical symptoms.50 The gut flora of the colon of patients with IBS interacts directly, or through products of metabolism, with the intestinal epithelium to maintain a state of mucosal immune activation that is mediated by TLRs, which are part of the innate immune system.51 Thus, elevated cytokine levels and TLR activity contribute to the low-grade inflammation seen in patients with IBS. 51 One way in which the intestinal microbiota modulates the innate and adaptive immune mechanisms of the gut in patients with IBS may be
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related to host immune response to bacterial flagellin, which is a structural component of bacterial flagellae.52 Intestinal microbes also have a role in the pathogenesis of postinfectious IBS, which character istically develops following a bacterial infection in genetically susceptible persons.53 In patients with IBS, the intestinal microbiota influences sensor, motor and immune systems of the gut that interact with higher brain centers; this interaction is the so-called gutbrain axis.54 Despite its limitations, as discussed above, the lactulose breath test has been used to diagnose SIBO in patients with IBS. 5557 A meta-analysis of 11 pooled studies showed that results from breath testing were more often abnormal among patients with IBS than controls (OR 4.46, 95% CI 1.6911.80).58 However, culture of smallintestinal aspirate showed SIBO to be present in 4% of patients with IBS, which was the same prevalence as seen in IBS-negative controls.59 Indirect evidence for the importance of intestinal bacteria in the development of IBS is that the nonabsorbable antimicrobial agent, rifaximin, has been shown to favorably affect the course of nonconstipation forms of the disease,60 although it may be that rifaximin has direct anti-inflammatory effects on epithelial cells.61 Further evidence suggests that the gut flora is at least partially related to the delayed gastric, small bowel and total gut propulsive motility seen in patients with IBS. For example, the phaseIII migrating motor complex (MMC), which serves to cleanse the small intestine of debris approximately every 90min in the fasting state,62 has been shown to be reduced in frequency in the presence of SIBO.63 The phaseIII MMC has also been shown to be reduced in number and duration in patients with IBS and SIBO diagnosed by lactulose breath testing; normaliza tion of breath testing after the administration of antibiotics was associated with an improvement in the number of phaseIII MMCs.64 The gas produced by bacteria anywhere in the gut 65 or in the small bowel (owing to SIBO)66 can cause gas-related symptoms in IBS, including bloating and abdominal distension. Limited study of the microbiota in patients with IBS suggests that they have alterations in the proportions of commensal bacteria, but more research is needed on this topic.67 Third, diversion of intestinal contents improves disease inflammation in patients with Crohns disease, with relapse occurring after restoration of the fecal stream.73 Fourth, patients with Crohns disease may demonstrate the presence of systemic antibodies against microbial antigens.74 The gut flora seems to communicate with the hosts epithelial cells and intestinal immune factors thus contributing to the development of inflamma tion75through a variety of ways, including secretion of quorum-sensing molecules or through direct damage to the epithelium through definable virulence properties of the bacteria. Bacterial DNA can be an immuno modulatory component of healthy gut flora or can lead to persistent inflammation of the intestine. It is likely that the mucosal-associated bacterial flora is more important than the luminal flora in IBD.7678 Patients with IBD lose normal tolerance to commensal intestinal flora; an inappropriate immune response develops, which leads to alterations of the intestinal epithelial barrier and alteration of normal gut immunity. Antibodies directed against components of indigenous gut flora have been identified in both ulcerative colitis and Crohns disease. For example, patients with IBD, especially Crohns disease, have been shown to have antibodies against microbial antigens including Saccharomyces cerevisiae (ASCA), Escherichia coli outer membrane porin C (OmpC) and Pseudomonas fluorescens I2 sequence, and patients with high levels of reactivity to microbial antigens have a high frequency of strictures, intestinal perforations and small bowel surgery.74,79 Bacterial protein flagellin has been implicated in the development of intestinal inflammation in Crohns disease through an effect on TLR5 activation.80 In addition, gut bacteria can bind to the mucosa by microbial polysaccharides and polynucleotides, which are also recognized by TLRs, thus contributing to the inflammatory response. Abnormal flora is not able to block these immune mediatorsincluding TLRs and the transcription factor nuclear factor B (NFB)that contribute to the inflammatory response in IBD.81 Mucosal bacterial concentration has been shown to be abnormally increased in IBD, with concentrations corre lating with severity of disease but not degree of gut inflammation.78 Microbial-derived proteolytic degradation of the extracellular matrix may also contribute to the pathogenesis of IBD.82 Successful antibacterial therapy in Crohns disease may be the result of changes in the flora, with inhibition of deleterious metabolites improving local inflammation.83 rRNA sequence analysis of mucosal samples from patients with Crohns disease and ulcerative colitis84 has provided evidence that mucosal invasion by gut bacteria occurs in IBD. In one study, members of the Firmicutes phylum were nearly absent in Crohns disease but were present in controls and in patients with ulcerative colitis.85 Other studies have shown a reduction in counts of both Bacteroidetes and Firmicutes in patients with ulcerative colitis and Crohns disease. 84,86 Patients with Crohns disease characteristically show presence of genera within Proteobacteria (especially Escherichia).87,88
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IBD
In individuals who are genetically susceptible to IBD, the normally harmonious relationship between gut bacteria and the intestinal mucosa is altered, which contributes to the inflammatory process (Figure3). The fecal microbiota in patients with IBD is different to that seen in healthy individuals;68 in patients with IBD there seems to be a reduction in the diversity of fecal microbiota, with an increase in the number of mucosally-adherent bacteria.69,70 Indirect evidence contributes to the hypothesis that the intestinal microbiota is important in the pathogenesis of IBD. First, in several different animal models it has been shown that intestinal inflammation does not develop in a germ-free environment.71 Second, experimental colitis can be successfully treated with anti bacterial agents.72
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Host predisposed to IBS (for example, genetic makeup or psychological disturbance)

Abnormal fecal ora

Delayed gastric, small bowel and total gut propulsive motility

Postinfectious IBS (following infection with a high-grade enteropathogen)

Low-grade in ammation of the gut: mucosal immune activation involving TLRs and release of cytokines without downregulation

Stimulation of the gutbrain axis: abdominal pain and discomfort related to visceral hypersensitivity; change in bowel function; bloating and other gas-related symptoms from gas trapping in the gastrointestinal tract or SIBO; and anxiety and/or depression

Figure 2 | Pathogenesis of IBS and postinfectious IBS.

In addition, patients with IBD characteristically have a decrease in beneficial carbohydrate-utilizing bacteria, such as Bifidobacterium and Lactobacillus spp. and a decrease in Fecalibacterium prausnitzii. Adherent-invasive E.coli (AIEC) strains have been shown to disrupt the integrity of the mucosal epi thelial barrier of the ileum and induce a chronic immune response, perhaps by targeting Peyers patches, 89 and may have an important early role in the development of Crohns disease.90 Strains of E.coli may be important in ulcerative colitis as well as Crohns disease. Although it seems that F.prausnitzii has no etiologic role in IBD,91 it has been postulated that the ratio of F.prausnitzii to E.coli could be used to evaluate individuals susceptible to IBD or at risk of recurrence of Crohns disease.79 In a twin study, the sibling with Crohns disease had a reduced concentration of F.prausnitzii and increased abundance of E.coli compared with the healthy twin.92 It has been known for several decades that some patients with IBD have high titers of antibodies to E.coli O antigens. One study demonstrated differences between E.coli adhesion in ileal and colonic or rectal areas in patients with IBD, while in one study genomic differences between strains of E.coli isolated from patients with Crohns disease and ulcerative colitis were seen.93 The phylogenetic group of E.coli provides clues as to how intestinal flora contributes to the development of IBD.94 A recent study provided evidence of unique bacterial species in patients with Crohns disease,86 which could provide a diagnostic tool if verified. For nearly half a century there have been data to link enteric infection by Mycobacterium avium paratuberculosis (MAP) with Crohns disease.95 MAP is found in common foods and may be a secondarily infecting organism. The importance of MAP in IBD is still being studied and debated.96 However, MAP is unlikely to be involved in most cases of Crohns disease but may explain a small percentage of illness. Patients with IBD are more susceptible to CDI, which can trigger disease flares and contribute to mucosal inflammation. CDI should be considered in patients with worsening IBD. Other enteric pathogens are being explored for a role in exacerbations of IBD, including Campylobacter spp., Salmonella spp., noroviruses and cytomegalovirus. These pathogenic microbes are more likely to encourage the onset of pre-existent subclinical disease or to worsen
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existing mild disease rather than to cause the disease processes denovo. Host factors in the development of IBD include altered mucosal physiology. Increased intestinal permeability has been demonstrated in patients with Crohns disease.97 Overgrowth of mucosal bacteria may inhibit immune reactivity and mucosal immunity.98 Alteration of the gut mucus layer may affect the replication and attachment of intestinal bacteria that influence gut function and immune status.99 The formation of a bacterial biofilm may influence colonization and mucosal effects. Patients with IBD were shown to have twice the concentration of mucosal Bacteroides fragilis biofilm compared with controls, the concentration of which was modified by antimicrobial therapy.100 Genetic factors that influence gut flora and mucosal immunity are also clearly involved in the development of IBD.101 The reduced occurrence of IBD in countries with reduced hygiene levels (Africa and southern Asia) raises the possibility that early exposure to pathogenic microbes conditions the gut to better handle microbial insults later in life. Indirect evidence supporting this hypothesis is seen in neonatal IBD-prone mice, in which exposure to antigens of commensal flora leads to reductions in intestinal inflammation.102 In addition, oral hygiene practices alter the oral flora and can lead to imbalances of gut flora.103 Chassaing and Darfeuille-Michaud review the interactions between commensal microbiota and enteric pathogens in IBD,79 whilst Matricon etal. provide a detailed discussion of the immunopathogenesis of IBD.104

Colorectal cancer
An important relationship has been established between the intestinal microbiota and potential effects on the immune system and colorectal cancer.105 High concentrations of bacteria in colonic biopsy specimens have been detected in 90% of patients with colorectal cancers and 93% of patients with colonic adenomas compared to 0% in asymptomatic controls. 106 Bacterial or viral enteric infections may also have a role in gastrointestinal cancers.107 Persistent immune dysregulation brought on by pathologic flora can contribute to inflammation and neoplastic changes of the mucosa. Increased carcinogen production has been associated with intestinal anaerobic bacteria and can be lowered with Lactobacillus probiotic
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Host with genetic predisposition to the development of IBD

Abnormal intestinal microbiota develops, with decrease in bene cial ora such as Bidobacterium, Lactobacillus spp. and Fecalibacterium prausnitzii

Mucosal-associated ora disrupts epithelial cell barrier causing local intolerance (hypersensitivity) to antigens of normal ora (including bacterial protein agellin, which activates TLR5 in Crohns disease)

Metabolites of normal gut ora unavailable to block release of NFB and cytokines

Adherent-invasive Escherichia coli in ileum of patients with Crohns disease, and bio lm from Bacteroides in all patients with IBD, further disrupts the integrity of epithelial cell barrier

Dysregulation of the mucosal adaptive and innate immune response Other microbes, such as Mycobacterium paratuberculosis (Crohn's disease), Campylobacter, C. difcile and noroviruses, may have a role in selected cases of IBD

Chronic in ammation in all patients; granulomata, abscesses and stulas in patients with Crohns disease

Figure 3 | The role of intestinal microbiota and enteric pathogens in the pathogenesis of IBD. Abbreviations: SIBO, small intestinal bacterial overgrowth; TLR, Toll-like receptor.

supplementation.108 Diet has a major influence on gut flora,109 and the release of products of bacterial metab olism by specific floral groups has unique immuno stimulatory and immunomodulatory activity that can perturb cell growth, favoring the development of colon cancer.110 Bacteria are also able to bio-transform primary bile acids to secondary bile salts, which have been found to have carcinogenic effects that contribute to the develop ment of colon cancer.111 Thus, the intestinal microbiota seems to contribute to the development of colorectal cancer by inducing chronic inflammation and generating reactive metabolites and carcinogens.112 It has been postulated that studying the fecal microbiota could provide an early detection method for colorectal cancer.113 A review by Zhang etal. on the topic of the microbiota and colorectal cancer is recommended.113

Modulating the intestinal microbiota


The specific diet of a person can markedly influence the resident flora of their intestine.109 A study of infants in five European countries showed differences in the microbiota before and after weaning. In addition, geographic differences were associated with differences in the microbiota.114 The type of meat consumed and the cooking method (fried, baked or boiled) also has an effect on the colonic flora.115 Using diet to alter the gut flora is a largely unexplored method that may have potential to improve digestive and gastrointestinal health. Other ways to favorably alter the intestinal microbiota in order to prevent and treat gastrointestinal disease are through the use of prebiotics, probiotics and synbiotics. These agents can favorably influence microbial interactions with the immune system and the gut epithelium. Prebiotics are nondigestible food ingredients, often oligosaccharides (such as inulin, fructo-oligosaccharides, galacto-oligosaccharides, isomalto-oligosaccharides and soya-oligosaccharides, pyrodextrins and lactulose) that are found naturally in many high-fiber foods, including certain fruits, vegetables and grains. Prebiotics stimulate the growth and activity of carbohydrate-utilizing
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bacteria, including Bifidobacteria and lactic acid bacteria, which results in the release of organic acids.116 These acids produce an antibacterial environment (which resembles the intestinal environment seen in breast-fed infants) that inhibits enteropathogens. In addition, prebiotics have a role in intestinal immunity by modulating immune parameters in the gut-associated lymphoid tissue (GALT) and secondary lymphoid tissues117 through the release of organic acids or by components of the bacterial cell wall or cytoplasm interacting with immune cells.118 Prebiotics seem to have their major effects in the flora-rich colon rather than the small bowel. Probiotics are viable microorganisms that proliferate in the gut and exert positive health effects. Examples of species of probiotics that are currently in use or under evaluation are: Lactobacillus rhamnosus , L.reuteri , L.acidophilus , L. bulgaricus , Bifidobacterium infantis, Saccaromyces boulardii, Enterococcus faecium, the Nissle strain of Escherichia coli and Clostridium butyricum. The specific probiotic strain employed is important. These ordinarily nonpathogenic yeast or bacteria have the capacity to decrease pathogen attachment and prevent subsequent invasion of the mucosa by blocking binding sites and by upregulating antimicrobial substances in the gut. In addition, probiotics can modify epithelial function and enhance intestinal immunity by inhibition of cyto k ines and NFB. 119 Rectal administration of Lactobacillus casei DG was shown to modify the mucosal microbiota and reduce inflammatory products in the gut of patients with ulcerative colitis.120 Probiotics have been shown to prevent enteric infection by high-grade pathogens, success fully treat antibiotic-associated diarrhea, and reduce putrefactive bacteria and their metabolites potentially associated with malignant alteration in the gut. 121,122 Prebiotics and probiotics have been successfully used in patients with IBD in an attempt to favorably affect gut flora.123 The term synbiotics refers to food supplements that contain a combination of prebiotics and probiotics that act synergistically.
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Fecal transplantation has become an effective treatment for refractory or recurrent CDI.124 Future studies in this area should be directed toward elucidation of the metagenomic alterations in CDI to better understand how fecal transplantation works in order to improve treatment of the disease. microbial species to gastrointestinal health and to the pathogenesis of disease, and characterizing the interaction of the gut flora with the intestinal immune response, host genetics and mucosal physiology is also necessary. Modulation of the gut flora and prevention of enteric infection with diet, prebiotics, probiotics and drugs may ultimately provide the means to develop optimal gastrointestinal health in disease-prone individuals. In addition, studying anaerobic bacteria associated with mucosal biofilms that exist on the surface of the gut 125 could help to define future targets for therapy.
Review criteria
PubMed was searched using the terms gut microbiota and health, gut microbiota and immunity, gastrointestinal flora, bacteria and inflammatory bowel disease, intestinal microbiome, bacterial overgrowth, functional bowel disease and irritable bowel syndrome for articles published since 2000. We emphasized recent publications. Our intent was to provide a general review of a very broad topic rather than an in-depth analysis.

Conclusions
The intestine supports the growth of large numbers of primarily nonculturable bacteria. The intestinal microbiota can contribute to a healthy microbial community, with bacteria optimally communicating with the intestinal epithelium and the local innate and adaptive immune system. However, alterations to the gut flora can lead to a pathogenic microbial community in genetically susceptible hosts that causes persistent local inflammation, changes in epithelial function and chronic disease such as IBS, IBD or colorectal cancer. Altering the gut flora by antibiotics can also lead to superinfection with high-grade pathogens such as C.difficile. Studies are needed to measure the diversity, function and resistance to antibiotics of the intestinal microbiota. Research aimed at determining the contribution of each
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