Review Article | Published:

Microbial genes and pathways in inflammatory bowel disease

Abstract

Perturbations in the intestinal microbiome are implicated in inflammatory bowel disease (IBD). Studies of treatment-naive patients have identified microbial taxa associated with disease course and treatment efficacy. To gain a mechanistic understanding of how the microbiome affects gastrointestinal health, we need to move from census to function. Bacteria, including those that adhere to epithelial cells as well as several Clostridium species, can alter differentiation of T helper 17 cells and regulatory T cells. Similarly, microbial products such as short-chain fatty acids and sphingolipids also influence immune responses. Metagenomics and culturomics have identified strains of Ruminococcus gnavus and adherent invasive Escherichia coli that are linked to IBD and gut inflammation. Integrated analysis of multiomics data, including metagenomics, metatranscriptomics and metabolomics, with measurements of host response and culturomics, have great potential in understanding the role of the microbiome in IBD. In this Review, we highlight current knowledge of gut microbial factors linked to IBD pathogenesis and discuss how multiomics data from large-scale population studies in health and disease have been used to identify specific microbial strains, transcriptional changes and metabolic alterations associated with IBD.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Ijssennagger, N. et al. Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon. Proc. Natl Acad. Sci. USA 112, 10038–10043 (2015).

  2. 2.

    Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).

  3. 3.

    Reinhardt, C. et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483, 627–631 (2012).

  4. 4.

    Cho, I. et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621–626 (2012).

  5. 5.

    Lee, W. J. & Hase, K. Gut microbiota-generated metabolites in animal health and disease. Nat. Chem. Biol. 10, 416–424 (2014).

  6. 6.

    Fischbach, M. A. & Segre, J. A. Signaling in host-associated microbial communities. Cell 164, 1288–1300 (2016).

  7. 7.

    Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).

  8. 8.

    Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

  9. 9.

    Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

  10. 10.

    Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).

  11. 11.

    Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

  12. 12.

    Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

  13. 13.

    Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).

  14. 14.

    Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).

  15. 15.

    Fujimura, K. E. et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat. Med. 22, 1187–1191 (2016).

  16. 16.

    Arrieta, M. C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl Med. 7, 307ra152 (2015).

  17. 17.

    Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 842–853 (2016).

  18. 18.

    Zhao, G. et al. Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children. Proc. Natl Acad. Sci. USA 114, E6166–E6175 (2017).

  19. 19.

    Huang, H. et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547, 173–178 (2017).

  20. 20.

    Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605 (2016).

  21. 21.

    Imhann, F. et al. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut 67, 108–119 (2018).

  22. 22.

    Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769–2778 (2018).

  23. 23.

    Zhernakova, A. et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 565–569 (2016).

  24. 24.

    Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).

  25. 25.

    Kronman, M. P., Zaoutis, T. E., Haynes, K., Feng, R. & Coffin, S. E. Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics 130, e794–e803 (2012).

  26. 26.

    Ferrante, M. et al. New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut 56, 1394–1403 (2007).

  27. 27.

    Dotan, I. et al. Antibodies against laminaribioside and chitobioside are novel serologic markers in Crohn’s disease. Gastroenterology 131, 366–378 (2006).

  28. 28.

    Schirmer, M. et al. Compositional and temporal changes in the gut microbiome of pediatric ulcerative colitis patients are linked to disease course. Cell Host Microbe 24, 600–610 (2018).

  29. 29.

    Schaubeck, M. et al. Dysbiotic gut microbiota causes transmissible Crohn’s disease-like ileitis independent of failure in antimicrobial defence. Gut 65, 225–237 (2016).

  30. 30.

    Couturier-Maillard, A. et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123, 700–711 (2013).

  31. 31.

    Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

  32. 32.

    Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007).

  33. 33.

    Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

  34. 34.

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

  35. 35.

    Sellon, R. K. et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66, 5224–5231 (1998).

  36. 36.

    Schultz, M. et al. IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation. Am. J. Physiol. 276, G1461–G1472 (1999).

  37. 37.

    Rath, H. C., Wilson, K. H. & Sartor, R. B. Differential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus or Escherichia coli. Infect. Immun. 67, 2969–2974 (1999).

  38. 38.

    Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

  39. 39.

    Bunker, J. J. & Bendelac, A. IgA responses to microbiota. Immunity 49, 211–224 (2018).

  40. 40.

    Mkaddem, S. B. et al. IgA, IgA receptors, and their anti-inflammatory properties. Curr. Top. Microbiol. Immunol. 382, 221–235 (2014).

  41. 41.

    Moon, C. et al. Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature 521, 90–93 (2015).

  42. 42.

    Mohanan, V. et al. C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions. Science 359, 1161–1166 (2018).

  43. 43.

    Gaudier, E. et al. Butyrate specifically modulates MUC gene expression in intestinal epithelial goblet cells deprived of glucose. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G1168–G1174 (2004).

  44. 44.

    Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

  45. 45.

    Kim, M. H., Kang, S. G., Park, J. H., Yanagisawa, M. & Kim, C. H. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145, 396–406 (2013).

  46. 46.

    Venkatesh, M. et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 41, 296–310 (2014).

  47. 47.

    Wlodarska, M. et al. Indoleacrylic acid produced by commensal Peptostreptococcus species suppresses inflammation. Cell Host Microbe 22, 25–37 (2017). This work identifies a tryptophan derivative produced by gut bacteria that increases mucus production and decreases inflammatory cytokine production.

  48. 48.

    Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

  49. 49.

    Backhed, F. et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 17, 690–703 (2015).

  50. 50.

    Jakobsson, H. E. et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut 63, 559–566 (2014).

  51. 51.

    Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

  52. 52.

    Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012).

  53. 53.

    An, D. et al. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156, 123–133 (2014). This paper shows that sphingolipids produced by intestinal bacteria have a role in colonic iNKT cell homeostasis.

  54. 54.

    Lopez-Serrano, P. et al. Environmental risk factors in inflammatory bowel diseases. Investigating the hygiene hypothesis: a Spanish case–control study. Scand. J. Gastroenterol. 45, 1464–1471 (2010).

  55. 55.

    von Mutius, E. Allergies, infections and the hygiene hypothesis—the epidemiological evidence. Immunobiology 212, 433–439 (2007).

  56. 56.

    Britton, G. J. et al. Microbiotas from humans with inflammatory bowel disease alter the balance of gut Th17 and RORγt+ regulatory T cells and exacerbate colitis in mice. Immunity 50, 212–224 (2019).

  57. 57.

    Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).

  58. 58.

    Mao, K. et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554, 255–259 (2018).

  59. 59.

    Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015).

  60. 60.

    Dobes, J. et al. Gastrointestinal autoimmunity associated with loss of central tolerance to enteric α-defensins. Gastroenterology 149, 139–150 (2015).

  61. 61.

    Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

  62. 62.

    Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

  63. 63.

    Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 15, 382–392 (2014).

  64. 64.

    Sokol, H., Lay, C., Seksik, P. & Tannock, G. W. Analysis of bacterial bowel communities of IBD patients: what has it revealed? Inflamm. Bowel Dis. 14, 858–867 (2008).

  65. 65.

    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).

  66. 66.

    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).

  67. 67.

    Gophna, U., Sommerfeld, K., Gophna, S., Doolittle, W. F. & Veldhuyzen van Zanten, S. J. Differences between tissue-associated intestinal microfloras of patients with Crohn’s disease and ulcerative colitis. J. Clin. Microbiol. 44, 4136–4141 (2006).

  68. 68.

    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).

  69. 69.

    Swidsinski, A., Weber, J., Loening-Baucke, V., Hale, L. P. & Lochs, H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J. Clin. Microbiol. 43, 3380–3389 (2005).

  70. 70.

    Swidsinski, A. et al. Mucosal flora in inflammatory bowel disease. Gastroenterology 122, 44–54 (2002).

  71. 71.

    Kotlowski, R., Bernstein, C. N., Sepehri, S. & Krause, D. O. High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease. Gut 56, 669–675 (2007).

  72. 72.

    Mylonaki, M., Rayment, N. B., Rampton, D. S., Hudspith, B. N. & Brostoff, J. Molecular characterization of rectal mucosa-associated bacterial flora in inflammatory bowel disease. Inflamm. Bowel Dis. 11, 481–487 (2005).

  73. 73.

    Conte, M. P. et al. Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease. Gut 55, 1760–1767 (2006).

  74. 74.

    Schultsz, C., Van Den Berg, F. M., Ten Kate, F. W., Tytgat, G. N. & Dankert, J. The intestinal mucus layer from patients with inflammatory bowel disease harbors high numbers of bacteria compared with controls. Gastroenterology 117, 1089–1097 (1999).

  75. 75.

    Prindiville, T., Cantrell, M. & Wilson, K. H. Ribosomal DNA sequence analysis of mucosa-associated bacteria in Crohn’s disease. Inflamm. Bowel Dis. 10, 824–833 (2004).

  76. 76.

    Yilmaz, B. et al. Microbial network disturbances in relapsing refractory Crohn’s disease. Nat. Med. 25, 323–336 (2019).

  77. 77.

    Morgan, X. C. et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 13, R79 (2012).

  78. 78.

    Vich Vila, A. et al. Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome. Sci. Transl Med. 10, eaap8914 (2018).

  79. 79.

    Franzosa, E. A. et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat. Microbiol. 4, 293–305 (2019). This work pairs metagenomic and metabolomic data from a cross-sectional IBD cohort to identify associations between gut bacteria and metabolites that are predictive of IBD status.

  80. 80.

    Lewis, J. D. et al. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn’s disease. Cell Host Microbe 18, 489–500 (2015). This study shows that microbial dysbiosis results from independent effects of inflammation, diet and antibiotics and is an important factor in the context of enteral nutrition and anti-TNF treatment in paediatric patients with CD.

  81. 81.

    Hall, A. B. et al. A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med. 9, 103 (2017).

  82. 82.

    The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

  83. 83.

    Lloyd-Price, J. et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569, 655–662 (2019)

  84. 84.

    Sundin, J. et al. Fecal chromogranins and secretogranins are linked to the fecal and mucosal intestinal bacterial composition of IBS patients and healthy subjects. Sci. Rep. 8, 16821 (2018).

  85. 85.

    Konstantinidis, K. T., Rossello-Mora, R. & Amann, R. Uncultivated microbes in need of their own taxonomy. ISME J. 11, 2399–2406 (2017).

  86. 86.

    Martinez-Medina, M. & Garcia-Gil, L. J. Escherichia coli in chronic inflammatory bowel diseases: an update on adherent invasive Escherichia coli pathogenicity. World J. Gastrointest. Pathophysiol. 5, 213–227 (2014).

  87. 87.

    Elhenawy, W., Tsai, C. N. & Coombes, B. K. Host-specific adaptive diversification of Crohn’s disease-associated adherent-invasive Escherichia coli. Cell Host Microbe 25, 301–312 (2019).

  88. 88.

    Palmela, C. et al. Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut 67, 574–587 (2018).

  89. 89.

    Atarashi, K. et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science 358, 359–365 (2017). This study links specific strains of oral Klebsiella species that are increased in IBD with T H 1 cell induction and inflammation.

  90. 90.

    Rashid, T., Ebringer, A. & Wilson, C. The role of Klebsiella in Crohn’s disease with a potential for the use of antimicrobial measures. Int. J. Rheumatol. 2013, 610393 (2013).

  91. 91.

    Garrett, W. S. et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292–300 (2010).

  92. 92.

    Carvalho, F. A. et al. Crohn’s disease adherent-invasive Escherichia coli colonize and induce strong gut inflammation in transgenic mice expressing human CEACAM. J. Exp. Med. 206, 2179–2189 (2009).

  93. 93.

    Lopez-Siles, M., Duncan, S. H., Garcia-Gil, L. J. & Martinez-Medina, M. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics. ISME J. 11, 841–852 (2017).

  94. 94.

    Franzosa, E. A. et al. Relating the metatranscriptome and metagenome of the human gut. Proc. Natl Acad. Sci. USA 111, E2329–E2338 (2014).

  95. 95.

    Schirmer, M. et al. Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat. Microbiol. 3, 337–346 (2018). This work demonstrates that metatranscriptomic profiling can reveal species-specific biases in transcriptional activity of gut bacteria, including IBD-specific microbial characteristics, providing new insight into the potential mechanisms of host–microbial dysbiosis in disease.

  96. 96.

    Korem, T. et al. Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples. Science 349, 1101–1106 (2015).

  97. 97.

    Thorburn, A. N., Macia, L. & Mackay, C. R. Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity 40, 833–842 (2014).

  98. 98.

    Donia, M. S. & Fischbach, M. A. Human microbiota. Small molecules from the human microbiota. Science 349, 1254766 (2015).

  99. 99.

    Ursell, L. K. et al. The intestinal metabolome: an intersection between microbiota and host. Gastroenterology 146, 1470–1476 (2014).

  100. 100.

    Levy, M. et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163, 1428–1443 (2015).

  101. 101.

    Jacobs, J. P. et al. A disease-associated microbial and metabolomics state in relatives of pediatric inflammatory bowel disease patients. Cell. Mol. Gastroenterol. Hepatol. 2, 750–766 (2016).

  102. 102.

    Kolho, K. L., Pessia, A., Jaakkola, T., de Vos, W. M. & Velagapudi, V. Faecal and serum metabolomics in paediatric inflammatory bowel disease. J. Crohns Colitis 11, 321–334 (2017).

  103. 103.

    Scoville, E. A. et al. Alterations in lipid, amino acid, and energy metabolism distinguish Crohn’s disease from ulcerative colitis and control subjects by serum metabolomic profiling. Metabolomics 14, 17 (2018).

  104. 104.

    Jansson, J. et al. Metabolomics reveals metabolic biomarkers of Crohn’s disease. PLOS ONE 4, e6386 (2009).

  105. 105.

    Mitsuyama, K. et al. Antibody markers in the diagnosis of inflammatory bowel disease. World J. Gastroenterol. 22, 1304–1310 (2016).

  106. 106.

    Sokol, H. et al. Fungal microbiota dysbiosis in IBD. Gut 66, 1039–1048 (2017).

  107. 107.

    Leonardi, I. et al. CX3CR1+ mononuclear phagocytes control immunity to intestinal fungi. Science 359, 232–236 (2018).

  108. 108.

    Chiaro, T. R. et al. A member of the gut mycobiota modulates host purine metabolism exacerbating colitis in mice. Sci. Transl Med. 9, eaaf9044 (2017).

  109. 109.

    Limon, J. J. et al. Malassezia is associated with Crohn’s disease and exacerbates colitis in mouse models. Cell Host Microbe 25, 377–388 (2019).

  110. 110.

    Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).

  111. 111.

    McGovern, D. P. et al. Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn’s disease. Hum. Mol. Genet. 19, 3468–3476 (2010).

  112. 112.

    Wilen, C. B. et al. Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science 360, 204–208 (2018).

  113. 113.

    Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015).

  114. 114.

    Lopetuso, L. R., Ianiro, G., Scaldaferri, F., Cammarota, G. & Gasbarrini, A. Gut virome and inflammatory bowel disease. Inflamm. Bowel Dis. 22, 1708–1712 (2016).

  115. 115.

    Ananthakrishnan, A. N. et al. Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe 21, 603–610 (2017).

  116. 116.

    Kolho, K. L. et al. Fecal microbiota in pediatric inflammatory bowel disease and its relation to inflammation. Am. J. Gastroenterol. 110, 921–930 (2015).

  117. 117.

    Doherty, M. K. et al. Fecal microbiota signatures are associated with response to ustekinumab therapy among Crohn’s disease patients. mBio 9, e02120–17 (2018).

  118. 118.

    Shaw, K. A. et al. Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease. Genome Med. 8, 75 (2016).

  119. 119.

    Halmos, E. P. & Gibson, P. R. Dietary management of IBD—insights and advice. Nat. Rev. Gastroenterol. Hepatol. 12, 133–146 (2015).

  120. 120.

    Narula, N. et al. Enteral nutritional therapy for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev. 4, CD000542 (2018).

  121. 121.

    Dziechciarz, P., Horvath, A., Shamir, R. & Szajewska, H. Meta-analysis: enteral nutrition in active Crohn’s disease in children. Aliment. Pharmacol. Ther. 26, 795–806 (2007).

  122. 122.

    Albenberg, L. G. & Wu, G. D. Diet and the intestinal microbiome: associations, functions, and implications for health and disease. Gastroenterology 146, 1564–1572 (2014).

  123. 123.

    Lee, D. et al. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology 148, 1087–1106 (2015).

  124. 124.

    Ananthakrishnan, A. N. et al. A prospective study of long-term intake of dietary fiber and risk of Crohn’s disease and ulcerative colitis. Gastroenterology 145, 970–977 (2013).

  125. 125.

    Llewellyn, S. R. et al. Interactions between diet and the intestinal microbiota alter intestinal permeability and colitis severity in mice. Gastroenterology 154, 1037–1046 (2018).

  126. 126.

    Albenberg, L. et al. A diet low in red and processed meat does not reduce rate of Crohn’s disease flares. Gastroenterology https://doi.org/10.1053/j.gastro.2019.03.015 (2019).

  127. 127.

    Paramsothy, S. et al. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J. Crohns Colitis 11, 1180–1199 (2017).

  128. 128.

    Levy, A. N. & Allegretti, J. R. Insights into the role of fecal microbiota transplantation for the treatment of inflammatory bowel disease. Therap. Adv. Gastroenterol. 12, 1756284819836893 (2019).

  129. 129.

    Smillie, C. S. et al. Strain tracking reveals the determinants of bacterial engraftment in the human gut following fecal microbiota transplantation. Cell Host Microbe 23, 229–240 (2018).

  130. 130.

    Vermeire, S. et al. Donor species richness determines faecal microbiota transplantation success in inflammatory bowel disease. J. Crohns Colitis 10, 387–394 (2016).

  131. 131.

    Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014). This study pioneered the use of IgA coating to identify inflammatory members of the IBD gut microbiota.

  132. 132.

    Larmonier, C. B., Shehab, K. W., Ghishan, F. K. & Kiela, P. R. T. Lymphocyte dynamics in inflammatory bowel diseases: role of the microbiome. Biomed. Res. Int. 2015, 504638 (2015).

  133. 133.

    Ni, J. et al. A role for bacterial urease in gut dysbiosis and Crohn’s disease. Sci. Transl Med. 9, eaah6888 (2017).

  134. 134.

    Winter, S. E. et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013).

  135. 135.

    Zhu, W. et al. Precision editing of the gut microbiota ameliorates colitis. Nature 553, 208–211 (2018). This paper shows that tungstate treatment inhibits molybdenum-cofactor-dependent microbial respiratory pathways in the mammalian gut and prevents the dysbiotic expansion of Enterobacteriaceae during gut inflammation.

  136. 136.

    Kugathasan, S. et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet 389, 1710–1718 (2017).

  137. 137.

    Hyams, J. S. et al. Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. Lancet 393, 1708–1720 (2019).

  138. 138.

    Tanoue, T. et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565, 600–605 (2019).

  139. 139.

    Podolsky, D. K. Inflammatory bowel disease. N. Engl. J. Med. 347, 417–429 (2002).

  140. 140.

    Hering, N. A., Fromm, M. & Schulzke, J. D. Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics. J. Physiol. 590, 1035–1044 (2012).

  141. 141.

    Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010).

  142. 142.

    VanDussen, K. L. et al. Genetic variants synthesize to produce Paneth cell phenotypes that define subtypes of Crohn’s disease. Gastroenterology 146, 200–209 (2014).

  143. 143.

    Adolph, T. E. et al. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272–276 (2013).

  144. 144.

    Surawicz, C. M., Haggitt, R. C., Husseman, M. & McFarland, L. V. Mucosal biopsy diagnosis of colitis: acute self-limited colitis and idiopathic inflammatory bowel disease. Gastroenterology 107, 755–763 (1994).

  145. 145.

    Van der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).

  146. 146.

    McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345–349 (2012).

  147. 147.

    Desai, D., Faubion, W. A. & Sandborn, W. J. Review article: biological activity markers in inflammatory bowel disease. Aliment. Pharmacol. Ther. 25, 247–255 (2007).

  148. 148.

    Francescone, R., Hou, V. & Grivennikov, S. I. Cytokines, IBD, and colitis-associated cancer. Inflamm. Bowel Dis. 21, 409–418 (2015).

  149. 149.

    Fernando, M. R., Saxena, A., Reyes, J. L. & McKay, D. M. Butyrate enhances antibacterial effects while suppressing other features of alternative activation in IL-4-induced macrophages. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G822–G831 (2016).

  150. 150.

    Wikoff, W. R. et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl Acad. Sci. USA 106, 3698–3703 (2009).

  151. 151.

    Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

  152. 152.

    Williams, B. B. et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 16, 495–503 (2014).

  153. 153.

    Devlin, A. S. & Fischbach, M. A. A biosynthetic pathway for a prominent class of microbiota-derived bile acids. Nat. Chem. Biol. 11, 685–690 (2015).

  154. 154.

    Cao, W. et al. The xenobiotic transporter Mdr1 enforces T cell homeostasis in the presence of intestinal bile acids. Immunity 47, 1182–1196 (2017).

  155. 155.

    Fischbach, M. A. & Sonnenburg, J. L. Eating for two: how metabolism establishes interspecies interactions in the gut. Cell Host Microbe 10, 336–347 (2011).

  156. 156.

    Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

  157. 157.

    Serena, C. et al. Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota. ISME J. 12, 1642–1657 (2018).

  158. 158.

    Ferreyra, J. A. et al. Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host Microbe 16, 770–777 (2014).

  159. 159.

    De Vadder, F. et al. Microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis. Cell Metab. 24, 151–157 (2016).

  160. 160.

    Abdel Hadi, L., Di Vito, C. & Riboni, L. Fostering inflammatory bowel disease: sphingolipid strategies to join forces. Mediators Inflamm. 2016, 3827684 (2016).

  161. 161.

    Segata, N. GraPhlAn. Bitbucket https://bitbucket.org/nsegata/graphlan/wiki/Home (2018).

  162. 162.

    Vaughn, B. P. et al. Increased intestinal microbial diversity following fecal microbiota transplant for active Crohn’s disease. Inflamm. Bowel Dis. 22, 2182–2190 (2016).

Download references

Acknowledgements

The authors thank T. Reimels for editorial assistance and for help with figure design. R.J.X. received funding from the US National Institutes of Health (P30 DK043351 and R01 AT009708), the Crohn’s and Colitis Foundation of America, and the Center for Microbiome Informatics and Therapeutics at MIT.

Reviewer information

Nature Reviews Microbiology thanks J. Faith, C. Manichanh, and other anonymous reviewer(s), for their contribution to the peer review of this work.

Author information

M.S., A.G., H.V., and R.J.X. conceived and wrote the article. All authors substantially contributed to discussion of content and reviewed/edited the manuscript before submission. M.S. generated Fig. 2.

Correspondence to Melanie Schirmer or Hera Vlamakis or Ramnik J. Xavier.

Ethics declarations

Competing interests

R.J.X. is a consultant to Nestle and Novartis. All other authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related Links

Inflammatory Bowel Disease Multi’omics Database. https://ibdmdb.org/

Supplementary information

Supplementary Information

Glossary

Microbiota

The collection of microorganisms in a particular environment.

Microbiome

The genes, genomes and products of the microbiota.

Barrier function

Epithelial cell–cell junctions plus the mucosal layer that permit nutrients and prevent luminal contents from accessing the rest of the body.

Glycaemic response

The glycaemic response to food describes its effect on blood glucose levels after consumption.

Non-caseating granulomas

Granulomas are clusters of immune cells that form during infection, inflammation or in the presence of a foreign substance to prevent a systemic spread. The absence of necrosis is a defining feature of non-caseating granulomas. In Crohn’s disease, non-caseating granulomas are formed during inflammation without an obvious infectious trigger.

Hygiene hypothesis

According to the hygiene hypothesis, a lack of early childhood microbial exposure affects the development of the immune system. This has been ascribed to the increase of allergic and autoimmune diseases in Western countries.

Mannan

A mannose polymer and component of fungal and plant cell walls.

Atypical perinuclear anti-neutrophil cytoplasmic antibody

Anti-neutrophil cytoplasmic antibodies are classified based on staining patterns. Cytoplasmic anti-neutrophil cytoplasmic antibody (ANCA) refers to staining of the entire cytoplasm, and perinuclear ANCA refers to staining of the area around the nucleus. Perinuclear ANCAs have been implicated in inflammatory bowel disease; however, their target antigens are unknown and they are therefore described as atypical perinuclear ANCA.

Laminaribioside

A glucose disaccharide building block of laminarin and a component of the cell walls of fungi and algae.

Chitobioside

A building block of the N-acetylglucosamine-based glycan chitin and a component of the cell walls of microorganisms.

Mannobioside

A disaccharide of mannose.

Colectomy

A surgical procedure removing all or part of the colon.

Strains

The classical microbiological definition of strain is a single bacterial isolate. In the context of metagenomic data, it refers to a combination of single-nucleotide polymorphisms that are computationally predicted to be linked and originating from an individual strain genome.

Metatranscriptome

All of the RNA in an environment.

Culturomics

The process of using classical microbiological techniques to culture and identify unknown bacteria that inhabit a given environment.

Indole metabolites

Indole metabolites derive from microbial metabolism of tryptophan and can be recognized by several host receptors that regulate host–microbial homeostasis.

Metagenomes

All the genetic material present in an environment, consisting of the genomes of numerous organisms.

RORγt+ Treg cells

Regulatory T cells that express the transcription factor RORγt, a nuclear hormone receptor and critical regulator of antimicrobial immunity.

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy

An autoimmune disease characterized by destruction of endocrine tissues, chronic mucocutaneous candidiasis and ectodermal disorders.

16S ribosomal RNA (rRNA) gene

A gene conserved among bacteria often used for taxonomic classification.

Keystone taxa

Species with high connectivity in microbial networks (built based on statistical associations), suggesting that they are a key component of the ecosystem and their removal would result in drastic changes to the microbial ecosystem.

Anti-tumour necrosis factor therapy

Drugs that target tumour necrosis factor to decrease inflammation are often used to treat autoimmune diseases and inflammatory bowel disease.

Irritable bowel syndrome

A chronic condition, which affects the large intestine and causes abdominal pain, cramping and shifts in bowel movement patterns. In contrast to inflammatory bowel disease, irritable bowel syndrome is not associated with mucosal inflammation, ulcers or other damage to the bowel.

Chromogranins and secretogranins

A family of water-soluble acidic glycoproteins that are mainly produced by endocrine cells, such as the enteroendocrine cells of the gut. Also known as granins, they are precursors of biologically active peptides involved in inflammation.

Metabolome

All of the metabolites in an environment.

Probiotic

An organism or multiple organisms that confer beneficial effects to the host.

Postbiotic

A bacterial metabolic product that mediates benefits to the host.

Prebiotic

A certain food or food component that confers a beneficial effect by providing a competitive advantage to beneficial commensal bacteria capable of metabolizing these substrates or by augmenting the production of metabolic products that result from their fermentation.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1: Inflammatory bowel disease and the microbiota.
Fig. 2: Phylogenetic tree of bacterial species associated with inflammatory bowel disease.
Fig. 3: Microbiome-based therapies for inflammatory bowel disease.