IBD—ulcerative colitis and Crohn's disease—is emerging as a worldwide epidemic. An association between the increased incidence of IBD and environmental factors linked to socioeconomic development has been persistently detected in different parts of the world. The lifestyle in developed countries might impair the natural patterns of microbial colonization of the human gut. The interaction of microbes with mucosal immune compartments in the gut seems to have a major role in priming and regulating immunity. In IBD, mucosal lesions are generated by an excessive or dysregulated immune response against commensal microbes in the gut. In individuals with a genetic susceptibility to IBD, abnormal microbial colonization of the gastrointestinal tract might be the origin of such dysregulation. Developments in gene-sequencing technologies, as well as increased availability of powerful bioinformatic tools, have enabled novel insights into the microbial composition of the human gut microbiota and the effect of microbial communities on human physiology and disease. Studies that used these technologies indicate that dysbiosis (that is, abnormal microbiota composition) and decreased complexity of the gut microbial ecosystem are common features in patients with Crohn's disease or ulcerative colitis. Whether such changes are a cause or a consequence of the disease remains to be elucidated.
Environmental factors are necessary contributors to the pathogenesis of IBD—most individuals with genetic susceptibility do not develop the disease—and are primarily responsible for its growing incidence around the globe
The lifestyle in developed countries can be linked with alterations in the microbial colonization of the human gut
Microbial colonization has an important effect on the instruction and regulation of the immune system
The gut microbiota is an essential factor in driving inflammation and the development of mucosal lesions in IBD; certain microbes exacerbate inflammation, but some others mitigate inflammation
Dysbiosis and decreased complexity of the gut microbial ecosystem are common features in patients with IBD
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White, W. H. On simple ulcerative colitis and other rare intestinal ulcers. Guy's Hosp. Rep. 45, 131–162 (1888).
Crohn, B. B., Ginzburg, L. & Oppenheimer, G. D. Regional ileitis: a pathologic and clinical entity. JAMA 99, 1323–1329 (1932).
Molodecky, N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54 (2012).
Lees, C. W., Barrett, J. C., Parkes, M. & Satsangi, J. New IBD genetics: common pathways with other diseases. Gut 60, 1739–1753 (2011).
Hviid, A., Svanström, H. & Frisch, M. Antibiotic use and inflammatory bowel diseases in childhood. Gut 60, 49–54 (2011).
Bager, P., Simonsen, J., Nielsen, N. M. & Frisch, M. Cesarean section and offspring's risk of inflammatory bowel disease: a national cohort study. Inflamm. Bowel Dis. 18, 857–862 (2012).
Bernstein, C. N. & Shanahan, F. Disorders of a modern lifestyle: reconciling the epidemiology of inflammatory bowel diseases. Gut 57, 1185–1191 (2008).
De Filippo, C. 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 107, 14691–14696 (2010).
Guarner, F. et al. Mechanisms of disease: the hygiene hypothesis revisited. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 275–284 (2006).
Asquith, M. & Powrie, F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. J. Exp. Med. 207, 1573–1577 (2010).
Brandtzaeg, P. Mucosal immunity: induction, dissemination, and effector functions. Scand. J. Immunol. 70, 505–515 (2009).
Sartor, R. B. Microbial influences in inflammatory bowel diseases. Gastroenterology 134, 577–594 (2008).
Guarner, F. What is the role of the enteric commensal flora in IBD? Inflamm. Bowel Dis. 14 (Suppl. 2), S83–S84 (2008).
D'Haens, G. R. et al. Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 114, 262–267 (1998).
Casellas, F. et al. Antiinflammatory effects of enterically coated amoxicillin-clavulanic acid in active ulcerative colitis. Inflamm. Bowel Dis. 4, 1–5 (1998).
Macpherson, A., Khoo, U. Y., Forgacs, I., Philpott-Howard, J. & Bjarnason, I. Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut 38, 365–375 (1996).
Pirzer, U., Schönhaar, A., Fleischer, B., Hermann, E. & Meyer zum Büschenfelde, K. H. Reactivity of infiltrating T lymphocytes with microbial antigens in Crohn's disease. Lancet 338, 1238–1239 (1991).
Borruel, N. et al. Increased mucosal tumour necrosis factor α production in Crohn's disease can be downregulated ex vivo by probiotic bacteria. Gut 51, 659–664 (2002).
Carol, M. et al. Modulation of apoptosis in intestinal lymphocytes by a probiotic bacteria in Crohn's disease. J. Leukoc. Biol. 79, 917–922 (2006).
Llopis, M. et al. Lactobacillus casei downregulates commensals' inflammatory signals in Crohn's disease mucosa. Inflamm. Bowel Dis. 15, 275–283 (2009).
Pender, S. L. Do metalloproteinases contribute to tissue destruction or remodeling in the inflamed gut? Inflamm. Bowel Dis. 14 (Suppl. 2), S136–S137 (2008).
Borruel, N. et al. Effects of nonpathogenic bacteria on cytokine secretion by human intestinal mucosa. Am. J. Gastroenterol. 98, 865–870 (2003).
Hart, A. L. et al. Modulation of human dendritic cell phenotype and function by probiotic bacteria. Gut 53, 1602–1609 (2004).
Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731–16736 (2008).
Marwaha, A. K., Leung, N. J., McMurchy, A. N. & Levings, M. K. TH17 cells in autoimmunity and immunodeficiency: protective or pathogenic? Front. Immunol. 3, 129 (2012).
Rook, G. A. Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology 126, 3–11 (2009).
Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).
Kelly, D. et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA. Nat. Immunol. 5, 104–112 (2004).
Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).
Strober, W., Fuss, I. & Mannon, P. The fundamental basis of inflammatory bowel disease. J. Clin. Invest. 117, 514–521 (2007).
Handelsman, J., Rondon, M. R., Brady, S. F., Clardy, J. & Goodman, R. M. Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. Chem. Biol. 5, R245–R249 (1998).
Fox, G. E., Magrum, L. J., Balch, W. E., Wolfe, R. S. & Woese, C. R. Classification of methanogenic bacteria by 16S ribosomal RNA characterization. Proc. Natl Acad. Sci. USA 74, 4537–4541 (1977).
Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006).
Rodrigue, S. et al. Whole genome amplification and de novo assembly of single bacterial cells. PLoS ONE 4, e6864 (2009).
The NIH Common Fund Office of Strategic Coordination. Human Microbiome Project [online], (2012).
Nelson, K. E. et al. A catalog of reference genomes from the human microbiome. Science 328, 994–999 (2010).
Proctor, L. M. The Human Microbiome Project in 2011 and beyond. Cell Host Microbe 10, 287–291 (2011).
DeSantis, T. Z. et al. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl. Environ. Microbiol. 72, 5069–5072 (2006).
Pruesse, E. et al. SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB. Nucleic Acids Res. 35, 7188–7196 (2007).
Cole, J. R. et al. The Ribosomal Database Project: improved alignments and new tools for rRNA analysis. Nucleic Acids Res. 37, D141–D145 (2009).
Costello, E. K. et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694–1697 (2009).
Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
MetaHIT. Metagenomics of the Human Gastrointestinal Tract [online], (2012).
Gosalbes, M. J. et al. Metatranscriptomic approach to analyze the functional human gut microbiota. PLoS ONE 6, e17447 (2011).
Frank, D. N. & Pace, N. R. Gastrointestinal microbiology enters the metagenomics era. Curr. Opin. Gastroenterol. 24, 4–10 (2008).
Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).
Caporaso, J. G. et al. Moving pictures of the human microbiome. Genome Biol. 12, R50 (2011).
Lepage, P. et al. Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD. Inflamm. Bowel Dis. 11, 473–480 (2005).
Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).
Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).
Ott, S. J. et al. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut 53, 685–693 (2004).
Mai, V., Braden, C. R., Heckendorf, J., Pironis, B. & Hirshon, J. M. Monitoring of stool microbiota in subjects with diarrhea indicates distortions in composition. J. Clin. Microbiol. 44, 4550–4552 (2006).
Noor, S. O. et al. Ulcerative colitis and irritable bowel patients exhibit distinct abnormalities of the gut microbiota. BMC Gastroenterol. 12, 134 (2010).
Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007).
Willing, B. P. et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139, 1844–1854 (2010).
Lepage, P. et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 141, 227–236 (2011).
Martínez, C. et al. Unstable composition of the fecal microbiota in ulcerative colitis during clinical remission. Am. J. Gastroenterol. 103, 643–648 (2008).
Rowan, F. et al. Desulfovibrio bacterial species are increased in ulcerative colitis. Dis. Colon Rectum 53, 1530–1536 (2010).
Roediger, W. E., Moore, J. & Babidge, W. Colonic sulfide in pathogenesis and treatment of ulcerative colitis. Dig. Dis. Sci. 42, 1571–1579 (1997).
Pitcher, M. C., Beatty, E. R. & Cummings, J. H. The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis. Gut 46, 64–72 (2000).
Swidsinski, A. et al. Mucosal flora in inflammatory bowel disease. Gastroenterology 122, 44–54 (2002).
Ohkusa, T. et al. Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody. J. Gastroenterol. Hepatol. 17, 849–853 (2002).
Ohkusa, T. et al. Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis. Gut 52, 79–83 (2003).
Strauss, J. et al. Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm. Bowel Dis. 17, 1971–1978 (2011).
Sokol, H., Lepage, P., Seksik, P., Doré, J. & Marteau, P. Temperature gradient gel electrophoresis of fecal 16S rRNA reveals active Escherichia coli in the microbiota of patients with ulcerative colitis. J. Clin. Microbiol. 44, 3172–3177 (2006).
Chassaing, B. & Darfeuille-Michaud, A. The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140, 1720–1728 (2011).
Sokol, H. et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm. Bowel Dis. 15, 1183–1189 (2009).
Varela, E. et al. Colonization by Faecalibacterium prausnitzii and maintenance of clinical remission in patients with ulcerative colitis. Gastroenterology 140, S-47 (2011).
Selby, W. et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology 132, 2313–2319 (2007).
Manichanh, C. et al. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55, 205–211 (2006).
Dicksved, J. et al. Molecular analysis of the gut microbiota of identical twins with Crohn's disease. ISME J. 2, 716–727 (2008).
Kang, S. et al. Dysbiosis of fecal microbiota in Crohn's disease patients as revealed by a custom phylogenetic microarray. Inflamm. Bowel Dis. 16, 2034–2042 (2010).
Scanlan, P. D., Shanahan, F., O'Mahony, C. & Marchesi, J. R. Culture-independent analyses of temporal variation of the dominant fecal microbiota and targeted bacterial subgroups in Crohn's disease. J. Clin. Microbiol. 44, 3980–3988 (2006).
Darfeuille-Michaud, A. et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. Gastroenterology 127, 412–421 (2004).
Martinez-Medina, 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. 15, 872–882 (2009).
Chassaing, B. et al. Crohn disease-associated adherent-invasive E. coli bacteria target mouse and human Peyer's patches via long polar fimbriae. J. Clin. Invest. 121, 966–975 (2011).
Shen, B. Acute and chronic pouchitis-pathogenesis, diagnosis and treatment. Nat. Rev. Gastroenterol. Hepatol. 9, 323–333 (2012).
McLaughlin, S. D. et al. The bacteriology of pouchitis: a molecular phylogenetic analysis using 16S rRNA gene cloning and sequencing. Ann. Surg. 252, 90–98 (2010).
The authors received funding from the European Commission Seventh Framework Programme (MetaHIT, grant agreement HEALTH-F4-2007-201052), and Fondo de Investigaciones Sanitarias (FIS PI10/00902, Ministerio de Ciencia e Innovacion, Spain). CIBEREHD is funded by the Instituto de Salud Carlos III (Madrid, Spain).
The authors declare no competing financial interests.
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Manichanh, C., Borruel, N., Casellas, F. et al. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol 9, 599–608 (2012). https://doi.org/10.1038/nrgastro.2012.152
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