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• W2152751713 abstract "Studies of the roles of microbial communities in the development of inflammatory bowel disease (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota. More recently, profiling studies of the intestinal microbiome have associated the pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system. Enhanced technologies can increase our understanding of the interactions between the host and its resident microbiota and their respective roles in IBD from both a large-scale pathway view and at the metabolic level. We review important microbiome studies of patients with IBD and describe what we have learned about the mechanisms of intestinal microbiota dysfunction. We describe the recent progress in microbiome research from exploratory 16S-based studies, reporting associations of specific organisms with a disease, to more recent studies that have taken a more nuanced view, addressing the function of the microbiota by metagenomic and metabolomic methods. Finally, we propose study designs and methodologies for future investigations of the microbiome in patients with inflammatory gut and autoimmune diseases in general. Studies of the roles of microbial communities in the development of inflammatory bowel disease (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota. More recently, profiling studies of the intestinal microbiome have associated the pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system. Enhanced technologies can increase our understanding of the interactions between the host and its resident microbiota and their respective roles in IBD from both a large-scale pathway view and at the metabolic level. We review important microbiome studies of patients with IBD and describe what we have learned about the mechanisms of intestinal microbiota dysfunction. We describe the recent progress in microbiome research from exploratory 16S-based studies, reporting associations of specific organisms with a disease, to more recent studies that have taken a more nuanced view, addressing the function of the microbiota by metagenomic and metabolomic methods. Finally, we propose study designs and methodologies for future investigations of the microbiome in patients with inflammatory gut and autoimmune diseases in general. Ramnik J. XavierView Large Image Figure ViewerDownload Hi-res image Download (PPT)Dirk GeversView Large Image Figure ViewerDownload Hi-res image Download (PPT) Over the past decade, inflammatory bowel disease (IBD) has emerged as one of the most studied human conditions linked to the gut microbiota.1Sartor R.B. Microbial influences in inflammatory bowel diseases.Gastroenterology. 2008; 134: 577-594Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar, 2Swidsinski A. Ladhoff A. Pernthaler A. et al.Mucosal flora in inflammatory bowel disease.Gastroenterology. 2002; 122: 44-54Abstract Full Text Full Text PDF PubMed Google Scholar IBD comprises both Crohn's disease (CD) and ulcerative colitis (UC), which together affect more than 3.6 million people.3Loftus Jr., E.V. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences.Gastroenterology. 2004; 126: 1504-1517Abstract Full Text Full Text PDF PubMed Scopus (1126) Google Scholar Large-scale studies of human genetics across a total of 75,000 cases and controls have revealed 163 host susceptibility loci to date.4Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (223) Google Scholar These loci are enriched for pathways that interact with environmental factors to modulate intestinal homeostasis.5Khor B. Gardet A. Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease.Nature. 2011; 474: 307-317Crossref PubMed Scopus (269) Google Scholar The incidence of the disease has been on the rise over the past few decades, further highlighting the role of environmental factors in this disease. IBD was once a very rare disorder and only began to rise dramatically in incidence in the second half of the 20th century in North America and Europe, at times doubling every decade; it has expanded into developing countries in the past 2 decades, although there are more cases of UC than CD in the developing world.6Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar In addition, several twin studies have shown that the concordance rate for IBD between monozygotic twin pairs is significantly less than 50%, with the least concordance in CD.7Halme L. Paavola-Sakki P. Turunen U. et al.Family and twin studies in inflammatory bowel disease.World J Gastroenterol. 2006; 12: 3668-3672Crossref PubMed Google Scholar IBD is thus a multifaceted disorder in which not only germline genetics and the immune system but also several environmental factors play an important role.8Pillai S. Rethinking mechanisms of autoimmune pathogenesis.J Autoimmun. 2013; 45: 97-103Crossref PubMed Scopus (2) Google Scholar One such factor, the gut microbial community, is gaining increasing attention for its influence on many aspects of health in general9Flint H.J. Scott K.P. Louis P. et al.The role of the gut microbiota in nutrition and health.Nat Rev Gastroenterol Hepatol. 2012; 9: 577-589Crossref PubMed Scopus (51) Google Scholar and IBD in particular (Table 1).Table 1Changes in the Microbiome Linked to IBDMicrobial compositionDecrease in α diversityDecrease in Bacteroides and FirmicutesIncrease in GammaproteobacteriaPresence of E coli, specifically adherent-invasive E coliPresence of FusobacteriumDecrease in Clostridia, Ruminococcaceae, Bifidobacterium, LactobacillusDecrease in F prausnitziiMicrobial functionDecrease in SCFAs, butyrateDecrease in butanoate and propanoate metabolismDecrease in amino acid biosynthesisIncrease in auxotrophyIncrease in amino acid transportIncrease in sulfate transportIncreased oxidative stressIncrease in type II secretion system, secretion of toxins Open table in a new tab The gut microbiota, the largest reservoir of microbes in the body, coexists with its host in variable concentrations throughout the gastrointestinal tract, reaching an upper level in the colon of 1011 or 1012 cells/g of luminal contents.10Dave M. Higgins P.D. Middha S. et al.The human gut microbiome: current knowledge, challenges, and future directions.Transl Res. 2012; 160: 246-257Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar This community performs a range of useful functions for the host, including digesting substrates inaccessible to host enzymes, educating the immune system, and repressing the growth of harmful microorganisms.11O'Hara A.M. Shanahan F. The gut flora as a forgotten organ.EMBO Rep. 2006; 7: 688-693Crossref PubMed Scopus (389) Google Scholar The extensive use of low-resolution surveys of the microbial community structure in the past, as well as renewed efforts using next-generation sequencing for a high-resolution description of composition, function, and ecology,12Qin J. Li R. Raes J. et al.A human gut microbial gene catalogue established by metagenomic sequencing.Nature. 2010; 464: 59-65Crossref PubMed Scopus (1408) Google Scholar, 13Human Microbiome Project ConsortiumStructure, function and diversity of the healthy human microbiome.Nature. 2012; 486: 207-214Crossref PubMed Scopus (425) Google Scholar have improved our overall understanding of the role of the gut microbiota in health, a prerequisite for the study of disease-related dysbiosis. Several factors can intervene with microbial gut community composition, including genetics, diet, age, drug treatment, smoking, and potentially many more (Figure 1).14Blaser M.J. Falkow S. What are the consequences of the disappearing human microbiota?.Nat Rev Microbiol. 2009; 7: 887-894Crossref PubMed Scopus (144) Google Scholar The relative importance of each of these factors is still unclear, but several of them are directly or indirectly linked to the disease state. One of the most important environmental factors affecting microbial composition is dietary preference, which has been shown to determine microbiome composition throughout mammalian evolution.15Ley R.E. Hamady M. Lozupone C. et al.Evolution of mammals and their gut microbes.Science. 2008; 320: 1647-1651Crossref PubMed Scopus (615) Google Scholar Although no specific diet has been shown to directly cause, prevent, or treat IBD, it is important to take interactions between nutrients and microbiota into account when studying the role of the microbiome in disease. Thus far, only limited information on this topic has been gathered in humans, undoubtedly as a result of the challenge of setting up a large-scale controlled diet study. Wu et al have shown that long-term dietary patterns affect the ratios of Bacteroides, Prevotella, and Firmicutes and that short-term changes may not have major influences.16Wu G.D. Chen J. Hoffmann C. et al.Linking long-term dietary patterns with gut microbial enterotypes.Science. 2011; 334: 105-108Crossref PubMed Scopus (391) Google Scholar In addition, Zimmer et al have studied the impact of a strict vegan or vegetarian diet on the microbiota17Zimmer J. Lange B. Frick J.S. et al.A vegan or vegetarian diet substantially alters the human colonic faecal microbiota.Eur J Clin Nutr. 2012; 66: 53-60Crossref PubMed Scopus (15) Google Scholar and found a significant reduction in Bacteroides species, Bifidobacterium species, and the Enterobacteriaceae, whereas total bacterial load remained unaltered. Since the Enterobacteriaceae are among the taxa that are consistently found to be increased in patients with IBD (see the following text), it would be of value to include both short-term and long-term dietary patterns in future studies of the role of the microbiome in IBD. Given the complexity of dietary effects, including such information will likely only be feasible in a large cohort study.18Moschen A.R. Wieser V. Tilg H. Dietary factors: major regulators of the gut's microbiota.Gut Liver. 2012; 6: 411-416Crossref PubMed Scopus (6) Google Scholar There is an age-related variation in the distribution of IBD phenotypes, with 3 distinct stages of onset. A peak age of onset is typically 15 to 30 years of age, with late-onset cases occurring closer to 60 years of age and early onset occurring at younger than 10 years of age. Noticeably, the latter group has had a significant increase in incidence over the past decade.19Martin-de-Carpi J. Rodriguez A. Ramos E. et al.Increasing incidence of pediatric inflammatory bowel disease in Spain (1996-2009): the SPIRIT Registry.Inflamm Bowel Dis. 2013; 19: 73-80Crossref PubMed Scopus (11) Google Scholar These stages correspond to phases in which the gut microbiota alters its diversity and stability.20Spor A. Koren O. Ley R. Unravelling the effects of the environment and host genotype on the gut microbiome.Nat Rev Microbiol. 2011; 9: 279-290Crossref PubMed Scopus (143) Google Scholar Early life is marked by a microbiome of low complexity and low stability, one that is more volatile, is affected by the birth route, and fluctuates with events such as changes in diet (switch from breastfeeding to solid foods), illness, and puberty.21Dominguez-Bello M.G. Blaser M.J. Ley R.E. et al.Development of the human gastrointestinal microbiota and insights from high-throughput sequencing.Gastroenterology. 2011; 140: 1713-1719Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar It takes until adulthood for the microbial assemblage to reach maximal stability and complexity, with improved resilience toward perturbations.22Lozupone C.A. Stombaugh J.I. Gordon J.I. et al.Diversity, stability and resilience of the human gut microbiota.Nature. 2012; 489: 220-230Crossref PubMed Scopus (132) Google Scholar However, decreased stability has been observed in elderly subjects (60 years of age or older).23Claesson M.J. Cusack S. O'Sullivan O. et al.Composition, variability, and temporal stability of the intestinal microbiota of the elderly.Proc Natl Acad Sci U S A. 2011; 108: 4586-4591Crossref PubMed Scopus (162) Google Scholar Given these different characteristics of the microbiome at the 3 distinct stages of disease onset, a different role for the microbiome in disease initiation and progression should be considered. A potential link between genetics and the microbiome has long been suspected. The first identified CD susceptibility gene was NOD2,24Ogura Y. Bonen D.K. Inohara N. et al.A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.Nature. 2001; 411: 603-606Crossref PubMed Scopus (3022) Google Scholar which stimulates an immune reaction on recognizing muramyl dipeptide, a cell wall peptidoglycan constituent of gram-positive and gram-negative bacteria. NOD2 is expressed in Paneth cells, which are located predominantly in the terminal ileum at the base of intestinal crypts, and produce antimicrobial defensins.25Stappenbeck T.S. Hooper L.V. Gordon J.I. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells.Proc Natl Acad Sci U S A. 2002; 99: 15451-15455Crossref PubMed Scopus (375) Google Scholar Therefore, it may not be surprising that mutations in NOD2 can have significant effects on the composition of the microbial milieu. Indeed, patients with IBD carrying NOD2 mutations have increased numbers of mucosa-adherent bacteria2Swidsinski A. Ladhoff A. Pernthaler A. et al.Mucosal flora in inflammatory bowel disease.Gastroenterology. 2002; 122: 44-54Abstract Full Text Full Text PDF PubMed Google Scholar and decreased transcription of the anti-inflammatory cytokine interleukin 10.26Philpott D.J. Girardin S.E. Crohn's disease-associated Nod2 mutants reduce IL10 transcription.Nat Immunol. 2009; 10: 455-457Crossref PubMed Scopus (9) Google Scholar Patients with IBD carrying NOD2 and ATG16L1, an IBD susceptibility gene involved in autophagy, risk alleles have significant alterations in the structure of their gut microbiota, including decreased levels of Faecalibacterium and increased levels of Escherichia.27Frank D.N. Robertson C.E. Hamm C.M. et al.Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.Inflamm Bowel Dis. 2011; 17: 179-184Crossref PubMed Scopus (97) Google Scholar Subjects homozygous for loss-of-function alleles for FUT2 are “nonsecretors” who do not express ABO antigen on the gastrointestinal mucosa and bodily secretions. Nonsecretors are at increased risk for CD28McGovern D.P. Jones M.R. Taylor K.D. et al.Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease.Hum Mol Genet. 2010; 19: 3468-3476Crossref PubMed Scopus (54) Google Scholar and exhibit substantial alterations in the mucosa-associated microbiota.29Rausch P. Rehman A. Kunzel S. et al.Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype.Proc Natl Acad Sci U S A. 2011; 108: 19030-19035Crossref PubMed Scopus (34) Google Scholar Host genetics may thus play a strong role in the establishment and shaping of the gut microbiota; indeed, monozygotic twins share more similar microbiomes than nontwin siblings.30Turnbaugh P.J. Hamady M. Yatsunenko T. et al.A core gut microbiome in obese and lean twins.Nature. 2009; 457: 480-484Crossref PubMed Scopus (1272) Google Scholar In regard to the skin, a recent study in patients with primary immunodeficiency showed a bidirectional dialogue between the microbiome and the host immune system. The skin of patients with primary immunodeficiency has an altered population composition compared with immunocompetent subjects, which in turn results in increased susceptibility to infection by altering the immune response toward pathogens.31Smeekens S.P. Huttenhower C. Riza A. et al.Skin microbiome imbalance in patients with STAT1/STAT3 defects impairs innate host defense responses.J Innate Immun. 2013 Jun 22; ([Epub ahead of print])PubMed Google Scholar Although there are currently no genome-wide studies examining the interactions between common human genetic variation and the composition of the microbial ecosystem, such a study could be of great value.5Khor B. Gardet A. Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease.Nature. 2011; 474: 307-317Crossref PubMed Scopus (269) Google Scholar Many IBD susceptibility loci suggest an impaired response to microbes in disease, but the causality of this relationship is unclear. The pathogenesis of IBD may result from a dysregulation of the mucosal immune system driving a pathogenic immune response against the commensal gut flora.32Strober W. Fuss I. Mannon P. The fundamental basis of inflammatory bowel disease.J Clin Invest. 2007; 117: 514-521Crossref PubMed Scopus (519) Google Scholar Some studies have shown that the gut microbiota is an essential factor in driving inflammation in IBD1Sartor R.B. Microbial influences in inflammatory bowel diseases.Gastroenterology. 2008; 134: 577-594Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar; indeed, short-term treatment with enterically coated antibiotics dramatically reduces intestinal inflammation33Casellas F. Borruel N. Papo M. et al.Antiinflammatory effects of enterically coated amoxicillin-clavulanic acid in active ulcerative colitis.Inflamm Bowel Dis. 1998; 4: 1-5Crossref PubMed Google Scholar and has been shown to have some efficacy in IBD and particularly in pouchitis.34Sartor R.B. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics.Gastroenterology. 2004; 126: 1620-1633Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar Specifically, rifaximin has shown efficacy in recent trials in CD.35Rietdijk S.T. D'Haens G.R. Recent developments in the treatment of inflammatory bowel disease.J Dig Dis. 2013; 14: 282-287Crossref PubMed Scopus (3) Google Scholar Additionally, patients with IBD show mucosal secretion of immunoglobulin G antibodies36Macpherson A. Khoo U.Y. Forgacs I. et al.Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria.Gut. 1996; 38: 365-375Crossref PubMed Google Scholar and mucosal T-cell responses against commensal microbiota.37Pirzer U. Schonhaar A. Fleischer B. et al.Reactivity of infiltrating T lymphocytes with microbial antigens in Crohn's disease.Lancet. 1991; 338: 1238-1239Abstract PubMed Scopus (85) Google Scholar The dramatic improvements in DNA sequencing technology and analysis over the past decade have set the stage for investigations of the IBD microbiome. Many studies have found structural imbalances, or dysbioses, that occur in IBD since the initial report,38Frank D.N. St Amand A.L. Feldman R.A. et al.Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases.Proc Natl Acad Sci U S A. 2007; 104: 13780-13785Crossref PubMed Scopus (788) Google Scholar and a broad pattern has begun to emerge that includes a reduction in biodiversity, a decreased representation of several taxa within the Firmicutes phylum, and an increase in the Gammaproteobacteria.27Frank D.N. Robertson C.E. Hamm C.M. et al.Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases.Inflamm Bowel Dis. 2011; 17: 179-184Crossref PubMed Scopus (97) Google Scholar, 39Morgan X.C. Tickle T.L. Sokol H. et al.Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment.Genome Biol. 2012; 13: R79Crossref PubMed Scopus (54) Google Scholar Many studies consistently report a decrease in biodiversity, known as α diversity or species richness in ecological terms, which is a measure of the total number of species in a community. There is reduced α diversity in the fecal microbiome in patients with CD compared with healthy controls,40Manichanh C. Rigottier-Gois L. Bonnaud E. et al.Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach.Gut. 2006; 55: 205-211Crossref PubMed Scopus (450) Google Scholar which was also found in pairs of monozygotic twins discordant for CD.41Dicksved J. Halfvarson J. Rosenquist M. et al.Molecular analysis of the gut microbiota of identical twins with Crohn's disease.ISME J. 2008; 2: 716-727Crossref PubMed Scopus (104) Google Scholar This decreased diversity has been attributed to reduced diversity specifically within the Firmicutes phylum42Kang S. Denman S.E. Morrison M. et al.Dysbiosis of fecal microbiota in Crohn's disease patients as revealed by a custom phylogenetic microarray.Inflamm Bowel Dis. 2010; 16: 2034-2042Crossref PubMed Scopus (62) Google Scholar and has also been associated with temporal instability in the dominant taxa in both UC and CD.43Martinez C. Antolin M. Santos J. et al.Unstable composition of the fecal microbiota in ulcerative colitis during clinical remission.Am J Gastroenterol. 2008; 103: 643-648Crossref PubMed Scopus (39) Google Scholar There is reduced diversity in inflamed versus noninflamed tissues even within the same patient, and patients with CD have lower overall bacterial loads at inflamed regions.44Sepehri S. Kotlowski R. Bernstein C.N. et al.Microbial diversity of inflamed and noninflamed gut biopsy tissues in inflammatory bowel disease.Inflamm Bowel Dis. 2007; 13: 675-683Crossref PubMed Scopus (59) Google Scholar The largest IBD-related microbiome study to date is on new-onset CD in a multicenter pediatric cohort.45Gevers D. Kugathasan S. Denson L.A. et al.The treatment-naïve microbiome in new-onset Crohn's disease.Cell Host Microbe. 2014; 15: 382-392Abstract Full Text Full Text PDF PubMed Google Scholar This study analyzed more than 1000 treatment-naïve samples, which were collected from multiple concurrent gastrointestinal locations, from patients representing the variety of disease phenotypes with respect to location, severity, and behavior. In addition to a detailed characterization of the specific organisms either lost or associated with disease, this study indicates that assessing the rectal mucosa–associated microbiome offers unique potential for convenient and early diagnosis of CD. Other nonbacterial members of the microbiota, namely the fungi, viruses, archaea, and phage, may have a significant role in gastrointestinal disease46Hunter P. The secret garden's gardeners. Research increasingly appreciates the crucial role of gut viruses for human health and disease.EMBO Rep. 2013; 14: 683-685Crossref PubMed Google Scholar; however, the vast majority of recent studies of the microbiota are based on 16S sequencing, thus largely ignoring these groups of organisms. For example, norovirus infection, in the context of an intact gut microflora and mutated Atg16l1, is required for the development of CD in a mouse model.47Cadwell K. Patel K.K. Maloney N.S. et al.Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine.Cell. 2010; 141: 1135-1145Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar A number of studies note a relationship between fungi and IBD,48Trojanowska D. Zwolinska-Wcislo M. Tokarczyk M. et al.The role of Candida in inflammatory bowel disease. Estimation of transmission of C. albicans fungi in gastrointestinal tract based on genetic affinity between strains.Med Sci Monit. 2010; 16: CR451-CR457PubMed Google Scholar including an overall increase in fungal diversity in UC and CD.49Ott S.J. Kuhbacher T. Musfeldt M. et al.Fungi and inflammatory bowel diseases: alterations of composition and diversity.Scand J Gastroenterol. 2008; 43: 831-841Crossref PubMed Scopus (50) Google Scholar The relationship between these organisms and IBD will no doubt be explored in more detail in the coming years, because microbiome studies will increasingly be performed by unbiased shotgun sequencing. Specific taxonomic shifts have been reported in IBD (Table 1). The Enterobacteriaceae are increased in relative abundance both in patients with IBD and in mouse models.50Lupp C. Robertson M.L. Wickham M.E. et al.Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae.Cell Host Microbe. 2007; 2: 119-129Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar Escherichia coli, particularly adherent-invasive E coli strains, have been isolated from ileal CD (iCD) biopsy specimens in culture-based studies51Darfeuille-Michaud A. Boudeau J. Bulois P. et al.High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease.Gastroenterology. 2004; 127: 412-421Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar and are enriched in patients with UC.52Sokol H. Lepage P. Seksik P. et al.Temperature gradient gel electrophoresis of fecal 16S rRNA reveals active Escherichia coli in the microbiota of patients with ulcerative colitis.J Clin Microbiol. 2006; 44: 3172-3177Crossref PubMed Scopus (46) Google Scholar This enrichment is more pronounced in mucosal samples than in fecal samples.53Chassaing B. Darfeuille-Michaud A. The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases.Gastroenterology. 2011; 140: 1720-1728Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar The increase in Enterobacteriaceae may indicate the preference of this clade for an inflammatory environment. In fact, treatment with mesalamine, an anti-inflammatory drug used in patients with IBD, decreases intestinal inflammation and is associated with a decrease in Escherichia/Shigella.39Morgan X.C. Tickle T.L. Sokol H. et al.Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment.Genome Biol. 2012; 13: R79Crossref PubMed Scopus (54) Google Scholar, 54Benjamin J.L. Hedin C.R. Koutsoumpas A. et al.Smokers with active Crohn's disease have a clinically relevant dysbiosis of the gastrointestinal microbiota.Inflamm Bowel Dis. 2012; 18: 1092-1100Crossref PubMed Scopus (10) Google Scholar In addition to trends seen in the lumen, a number of studies have observed a shift in microbes that are attached to the intestinal mucus layer. The small intestine has a single mucus layer, whereas the colon has 2 mucus layers: a firmly attached inner mucus layer that is essentially sterile and an outer mucus layer of variable thickness.55Johansson M.E. Larsson J.M. Hansson G.C. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions.Proc Natl Acad Sci U S A. 2011; 108: 4659-6465Crossref PubMed Scopus (126) Google Scholar The mucus layer consists of mucins, trefoil peptides, and secretory immunoglobulin A.56Cario E. Microbiota and innate immunity in intestinal inflammation and neoplasia.Curr Opin Gastroenterol. 2013; 29: 85-91Crossref PubMed Scopus (5) Google Scholar Although host-microbiota interactions are bidirectional, direct contact with the epithelium is limited by the mucus and the production of antimicrobial factors such as defensins and RegIII-γ.57Shanahan F. The colonic microbiota in health and disease.Curr Opin Gastroenterol. 2013; 29: 49-54Crossref PubMed Scopus (8) Google Scholar, 58Vaishnava S. Yamamoto M. Severson K.M. et al.The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine.Science. 2011; 334: 255-258Crossref PubMed Scopus (151) Google Scholar, 59Hooper L.V. Littman D.R. Macpherson A.J. Interactions between the microbiota and the immune system.Science. 2012; 336: 1268-1273Crossref PubMed Scopus (242) Google Scholar As long as the mucus layer is relatively healthy and intact, microbes will attach to the mucus and generally do not have direct access to epithelial cells. There is a greater overall density of attached bacteria on the colonic mucus layer in patients with UC compared with healthy controls.2Swidsinski A. Ladhoff A. Pernthaler A. et al.Mucosal flora in inflammatory bowel disease.Gastroenterology. 2002; 122: 44-54Abstract Full Text Full Text PDF PubMed Google Scholar The adherent-invasive E coli pathovar, in particular, is at higher abundance in mucosal biopsy specimens from patients with CD compared with healthy subjects and particularly high in ileal specimens.60Martinez-Medina M. Aldeguer X. Lopez-Siles M. et al.Molecular diversity of Escherichia coli in the human gut: new ecological evidence supporting the role of adherent-invasive E. coli (AIEC) in Crohn's disease.Inflamm Bowel Dis. 2009; 15: 872-882Crossref PubMed Scopus (83) Google Scholar Adherent-invasive E coli invades epithelial cells and can replicate within macrophages61Glasser" @default.
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• W2152751713 date "2014-05-01" @default.
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• W2152751713 title "The Microbiome in Inflammatory Bowel Disease: Current Status and the Future Ahead" @default.
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