The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. The presence of large numbers of symbionts near the epithelial surface of the intestine poses an enormous challenge to the host because it must avoid the activation of harmful inflammatory responses to the microorganisms while preserving its ability to mount robust immune responses to invading pathogens. In patients with inflammatory bowel disease, there is a breakdown of the multiple strategies that the immune system has evolved to promote the separation between symbiotic microorganisms and the intestinal epithelium and the effective killing of penetrant microorganisms, while suppressing the activation of inappropriate T cell responses to resident microorganisms. Understanding the complex interactions between intestinal microorganisms and the host may provide crucial insight into the pathogenesis of inflammatory bowel disease as well as new avenues to prevent and treat the disease.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kaplan, G. G. The global burden of IBD: from 2015 to 2025. Nat. Rev. Gastroenterol. Hepatol. 12, 720–727 (2015).
Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).
Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015).
McGovern, D. P., Kugathasan, S. & Cho, J. H. Genetics of inflammatory bowel diseases. Gastroenterology 149, 1163–1176.e2 (2015).
Pickard, J. M., Zeng, M. Y., Caruso, R. & Nunez, G. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol. Rev. 279, 70–89 (2017).
Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).
Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).
The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).
Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).
Littman, D. R. & Pamer, E. G. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 10, 311–323 (2011).
Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K. & Knight, R. Diversity, stability and resilience of the human gut microbiota. Nature 489, 220–230 (2012).
Honda, K. & Littman, D. R. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759–795 (2012).
Macpherson, A. J., Slack, E., Geuking, M. B. & McCoy, K. D. The mucosal firewalls against commensal intestinal microbes. Semin. Immunopathol. 31, 145–149 (2009).
Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).
Arike, L., Holmen-Larsson, J. & Hansson, G. C. Intestinal Muc2 mucin O-glycosylation is affected by microbiota and regulated by differential expression of glycosyltranferases. Glycobiology 27, 318–328 (2017).
Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).
Johansson, 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. USA 108 (Suppl. 1), 4659–4665 (2011).
McGuckin, M. A., Linden, S. K., Sutton, P. & Florin, T. H. Mucin dynamics and enteric pathogens. Nat. Rev. Microbiol. 9, 265–278 (2011).
Ayabe, T. et al. Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria. Nat. Immunol. 1, 113–118 (2000).
Vaishnava, S., Behrendt, C. L., Ismail, A. S., Eckmann, L. & Hooper, L. V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl Acad. Sci. USA 105, 20858–20863 (2008).
Vaishnava, S. et al. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011).
Caruso, R. et al. A specific gene-microbe interaction drives the development of Crohn’s disease-like colitis in mice. Sci. Immunol. 4, eaaw4341 (2019). This paper shows that a specific pathobiont can accumulate before the development of intestinal inflammation and trigger spontaneous Crohn’s disease-like colitis in genetically susceptible mice.
Sabat, R., Ouyang, W. & Wolk, K. Therapeutic opportunities of the IL-22–IL-22R1 system. Nat. Rev. Drug Discov. 13, 21–38 (2014).
Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).
Qiu, J. et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39, 386–399 (2013).
Pickard, J. M. et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 514, 638–641 (2014).
Goto, Y. et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345, 1254009 (2014).
Pham, T. A. N. et al. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe 16, 504–516 (2014).
Bunker, J. J. & Bendelac, A. IgA responses to microbiota. Immunity 49, 211–224 (2018).
Kubinak, J. L. & Round, J. L. Do antibodies select a healthy microbiota? Nat. Rev. Immunol. 16, 767–774 (2016).
Grootjans, J. et al. Epithelial endoplasmic reticulum stress orchestrates a protective IgA response. Science 363, 993–998 (2019).
Kubinak, J. L. et al. MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe 17, 153–163 (2015).
Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014).
Bunker, J. J. et al. Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A. Immunity 43, 541–553 (2015). This study shows that T cell-independent IgA binds commensal bacteria in the gut but that select species that evade T cell-independent IgA can localize near the intestinal mucosa, where they elicit an alternate T cell-dependent IgA response.
Donaldson, G. P. et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360, 795–800 (2018).
Haas, A. et al. Systemic antibody responses to gut commensal bacteria during chronic HIV-1 infection. Gut 60, 1506–1519 (2011).
Sedman, P. C. et al. The prevalence of gut translocation in humans. Gastroenterology 107, 643–649 (1994).
Zeng, M. Y. et al. Gut microbiota-induced immunoglobulin G controls systemic infection by symbiotic bacteria and pathogens. Immunity 44, 647–658 (2016). This work shows that selective gut symbionts can penetrate the mucosa and disseminate to induce IgG responses, which confer protection against systemic infection by enteric pathogens.
Kelsall, B. Recent progress in understanding the phenotype and function of intestinal dendritic cells and macrophages. Mucosal Immunol. 1, 460–469 (2008).
Smythies, L. E. et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J. Clin. Invest. 115, 66–75 (2005).
Manicassamy, S. et al. Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329, 849–853 (2010).
Franchi, L. et al. NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat. Immunol. 13, 449–456 (2012).
Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004).
Balmer, M. L. et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci. Transl Med. 6, 237ra266 (2014).
Koch, M. A. et al. Maternal IgG and IgA antibodies dampen mucosal T helper cell responses in early life. Cell 165, 827–841 (2016).
Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000).
Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325, 617–620 (2009).
Arabyan, N. et al. Salmonella degrades the host glycocalyx leading to altered infection and glycan remodeling. Sci. Rep. 6, 29525 (2016).
Henderson, I. R., Czeczulin, J., Eslava, C., Noriega, F. & Nataro, J. P. Characterization of Pic, a secreted protease of Shigella flexneri and enteroaggregative Escherichia coli. Infect. Immun. 67, 5587–5596 (1999).
Mantle, M. & Rombough, C. Growth in and breakdown of purified rabbit small intestinal mucin by Yersinia enterocolitica. Infect. Immun. 61, 4131–4138 (1993).
Szabady, R. L., Yanta, J. H., Halladin, D. K., Schofield, M. J. & Welch, R. A. TagA is a secreted protease of Vibrio cholerae that specifically cleaves mucin glycoproteins. Microbiology 157, 516–525 (2011).
Guo, L. et al. Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell 95, 189–198 (1998).
Matamouros, S. & Miller, S. I. S. Typhimurium strategies to resist killing by cationic antimicrobial peptides. Biochim. Biophys. Acta 1848, 3021–3025 (2015).
Boneca, I. G. et al. A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system. Proc. Natl Acad. Sci. USA 104, 997–1002 (2007).
D’Costa, V. M. et al. Salmonella disrupts host endocytic trafficking by SopD2-mediated inhibition of Rab7. Cell Rep. 12, 1508–1518 (2015).
De Souza Santos, M. & Orth, K. The role of the type III secretion system in the intracellular lifestyle of enteric pathogens. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.BAI-0008-2019 (2019).
Franzon, V. L., Arondel, J. & Sansonetti, P. J. Contribution of superoxide dismutase and catalase activities to Shigella flexneri pathogenesis. Infect. Immun. 58, 529–535 (1990).
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).
Johansson, M. E. et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63, 281–291 (2014).
Van Klinken, B. J.-W., Van der Wal, J.-W. G., Einerhand, A., Buller, H. & Dekker, J. Sulphation and secretion of the predominant secretory human colonic mucin MUC2 in ulcerative colitis. Gut 44, 387–393 (1999).
Larsson, J. M. et al. Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation. Inflamm. Bowel Dis. 17, 2299–2307 (2011).
McGovern, D. P. et al. Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn’s disease. Hum. Mol. Genet. 19, 3468–3476 (2010).
Tong, M. et al. Reprograming of gut microbiome energy metabolism by the FUT2 Crohn’s disease risk polymorphism. ISME J. 8, 2193–2206 (2014).
Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411, 603–606 (2001).
Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411, 599–603 (2001).
Ogura, Y. et al. Expression of NOD2 in Paneth cells: a possible link to Crohn’s ileitis. Gut 52, 1591–1597 (2003).
Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005).
Wilson, C. L. et al. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286, 113–117 (1999).
Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).
Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).
Adolph, T. E. et al. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272–276 (2013).
Siakavellas, S. I. & Bamias, G. Tumor necrosis factor-like cytokine TL1A and its receptors DR3 and DcR3: important new factors in mucosal homeostasis and inflammation. Inflamm. Bowel Dis. 21, 2441–2452 (2015).
Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).
Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 11, 55–62 (2010).
Homer, C. R., Richmond, A. L., Rebert, N. A., Achkar, J. P. & McDonald, C. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology 139, 1630–1641 (2010).
Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).
Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).
Lapaquette, P., Glasser, A. L., Huett, A., Xavier, R. J. & Darfeuille-Michaud, A. Crohn’s disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell. Microbiol. 12, 99–113 (2010).
Brest, P. et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat. Genet. 43, 242–245 (2011).
Kelsen, J. R., Baldassano, R. N., Artis, D. & Sonnenberg, G. F. Maintaining intestinal health: the genetics and immunology of very early onset inflammatory bowel disease. Cell. Mol. Gastroenterol. Hepatol. 1, 462–476 (2015).
Uhlig, H. H. et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147, 990–1007.e3 (2014).
Dhillon, S. S. et al. Variants in nicotinamide adenine dinucleotide phosphate oxidase complex components determine susceptibility to very early onset inflammatory bowel disease. Gastroenterology 147, 680–689.e2 (2014).
Muise, A. M. et al. NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut 61, 1028–1035 (2012).
Schappi, M. G. et al. The nature of colitis in chronic granulomatous disease. J. Pediatr. Gastroenterol. Nutr. 36, 623–631 (2003).
Marciano, B. E. et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics 114, 462–468 (2004).
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015).
Sano, T. et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell 164, 324 (2016).
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).
Yang, Y. et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152–156 (2014).
Ansaldo, E. et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364, 1179–1184 (2019). This paper shows that A. muciniphila-specific T cells differentiate into T follicular helper cells to generate homeostatic IgG1 in gnotobiotic animals but can also adopt multiple T H cell lineages in mice with a complex microbiota.
Weiss, J. M. et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723–1742 (2012).
Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).
Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).
Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).
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).
Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K. & Flavell, R. A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24, 99–146 (2006).
Travis, M. A. et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).
Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).
Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).
Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).
Mottet, C., Uhlig, H. H. & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939–3943 (2003).
Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012).
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).
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).
Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).
Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).
Mucida, D. et al. Retinoic acid can directly promote TGF-β-mediated Foxp3+ Treg cell conversion of naive T cells. Immunity 30, 471–472; author reply 472–473 (2009).
Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Sefik, E. et al. Mucosal immunology. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 349, 993–997 (2015).
Ohnmacht, C. et al. Mucosal immunology. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 349, 989–993 (2015).
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.e4 (2019).
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).
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).
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).
Wlodarska, M. et al. Indoleacrylic acid produced by commensal Peptostreptococcus species suppresses inflammation. Cell Host Microbe 22, 25–37.e6 (2017).
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).
Rutgeerts, P. et al. Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 338, 771–774 (1991).
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).
Thia, K. T. et al. Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn’s disease: a randomized, double-blind, placebo-controlled pilot study. Inflamm. Bowel Dis. 15, 17–24 (2009).
Prantera, C. et al. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology 142, 473–481.e4 (2012).
Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007).
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).
Couturier-Maillard, A. et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123, 700–711 (2013).
Dianda, L. et al. T cell receptor-alpha beta-deficient mice fail to develop colitis in the absence of a microbial environment. Am. J. Pathol. 150, 91–97 (1997).
Taurog, J. D. et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J. Exp. Med. 180, 2359–2364 (1994).
Rath, H. C. et al. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J. Clin. Invest. 98, 945–953 (1996).
Barnes, S. L. et al. Resistin-like molecule β (RELMβ/FIZZ2) is highly expressed in the ileum of SAMP1/YitFc mice and is associated with initiation of ileitis. J. Immunol. 179, 7012–7020 (2007).
Dalal, S. R. & Chang, E. B. The microbial basis of inflammatory bowel diseases. J. Clin. Invest. 124, 4190–4196 (2014).
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).
Yilmaz, B. et al. Microbial network disturbances in relapsing refractory Crohn’s disease. Nat. Med. 25, 323–336 (2019). This work shows that, in patients with Crohn’s disease, microbiota networks are related to long-term disease type and severity, the extent and localization of the inflamed segments, and responsiveness to therapy.
Gophna, U., Sommerfeld, K., Gophna, S., Doolittle, W. F. & Veldhuyzen van Zanten, S. J. O. Differences between tissue-associated intestinal microfloras of patients with Crohn’s disease and ulcerative colitis. J. Clin. Microbiol. 44, 4136–4141 (2006).
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.e1 (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).
Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 15, 382–392 (2014).
Franzosa, E. A. et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat. Microbiol. 4, 293–305 (2019). This paper reports metagenomic and metabolomic profiling of cross-sectional stool samples from IBD cohorts to identify associations between intestinal bacteria and metabolites that can predict IBD status.
Ott, S. J. et al. Fungi and inflammatory bowel diseases: alterations of composition and diversity. Scand. J. Gastroenterol. 43, 831–841 (2008).
Li, Q. et al. Dysbiosis of gut fungal microbiota is associated with mucosal inflammation in Crohn’s disease. J. Clin. Gastroenterol. 48, 513–523 (2014).
Sokol, H. et al. Fungal microbiota dysbiosis in IBD. Gut 66, 1039–1048 (2017).
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).
Iliev, I. D. et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 336, 1314–1317 (2012).
McGovern, D. P. et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat. Genet. 42, 332–337 (2010).
Sokol, H. et al. Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 145, 591–601.e3 (2013).
Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).
Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015).
Hughes, E. R. et al. Microbial respiration and formate oxidation as metabolic signatures of inflammation-associated dysbiosis. Cell Host Microbe 21, 208–219 (2017).
Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129 (2007).
Litvak, Y., Byndloss, M. X., Tsolis, R. M. & Baumler, A. J. Dysbiotic proteobacteria expansion: a microbial signature of epithelial dysfunction. Curr. Opin. Microbiol. 39, 1–6 (2017).
Loy, A. et al. Lifestyle and horizontal gene transfer-mediated evolution of Mucispirillum schaedleri, a core member of the murine gut microbiota. mSystems 2, e00171–16 (2017).
Fox, J. G., Ge, Z., Whary, M. T., Erdman, S. E. & Horwitz, B. H. Helicobacter hepaticus infection in mice: models for understanding lower bowel inflammation and cancer. Mucosal Immunol. 4, 22–30 (2011).
Faith, J. J., Ahern, P. P., Ridaura, V. K., Cheng, J. & Gordon, J. I. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci. Transl Med. 6, 220ra211 (2014).
Barnich, N. et al. CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. J. Clin. Invest. 117, 1566–1574 (2007).
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).
Ferrante, M. et al. New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut 56, 1394–1403 (2007).
Benckert, J. et al. The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific. J. Clin. Invest. 121, 1946–1955 (2011).
Pirzer, U., Schonhaar, A., Fleischer, B., Hermann, E. & Meyer zum Buschenfelde, K. H. Reactivity of infiltrating T lymphocytes with microbial antigens in Crohn’s disease. Lancet 338, 1238–1239 (1991).
Duchmann, R. et al. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin. Exp. Immunol. 102, 448–455 (1995).
Duchmann, R. et al. T cell specificity and cross reactivity towards enterobacteria, Bacteroides, Bifidobacterium, and antigens from resident intestinal flora in humans. Gut 44, 812–818 (1999).
Hegazy, A. N. et al. Circulating and tissue-resident CD4+ T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation. Gastroenterology 153, 1320–1337.e16 (2017). This study reports the presence of microbiota-reactive memory CD4 + T cells with a diverse TCR Vβ repertoire in the blood and intestinal mucosa of both patients with IBD and healthy individuals.
Cong, Y. et al. CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease. J. Exp. Med. 187, 855–864 (1998).
Iqbal, N. et al. T helper 1 and T helper 2 cells are pathogenic in an antigen-specific model of colitis. J. Exp. Med. 195, 71–84 (2002).
Kullberg, M. C. et al. Induction of colitis by a CD4+ T cell clone specific for a bacterial epitope. Proc. Natl Acad. Sci. USA 100, 15830–15835 (2003).
Lodes, M. J. et al. Bacterial flagellin is a dominant antigen in Crohn disease. J. Clin. Invest. 113, 1296–1306 (2004).
Kim, S. C. et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology 128, 891–906 (2005).
Kullberg, M. C. et al. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism. Infect. Immun. 66, 5157–5166 (1998).
Xu, M. et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554, 373–377 (2018).
Chai, J. N. et al. Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation. Sci. Immunol. 2, aal5068 (2017). References 169 and 170 show that Helicobacter species drive inducible T reg cell differentiation in the colon during homeostasis but the same bacteria also induce pathobiont-specific colitic CD4 + T H cells in the absence of T reg cells.
Chiaranunt, P., Tometich, J. T., Ji, J. & Hand, T. W. T cell proliferation and colitis are initiated by defined intestinal microbes. J. Immunol. 201, 243–250 (2018).
Hand, T. W. et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science 337, 1553–1556 (2012).
Cong, Y., Feng, T., Fujihashi, K., Schoeb, T. R. & Elson, C. O. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc. Natl Acad. Sci. USA 106, 19256–19261 (2009).
Josefowicz, S. Z., Lu, L. F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012).
Liu, Z. et al. Immune homeostasis enforced by co-localized effector and regulatory T cells. Nature 528, 225–230 (2015).
van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013).
Paramsothy, S. et al. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J. Crohns Colitis 11, 1180–1199 (2017).
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).
Rossen, N. G. et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 149, 110–118.e4 (2015).
Suskind, D. L. et al. Fecal microbial transplant effect on clinical outcomes and fecal microbiome in active Crohn’s disease. Inflamm. Bowel Dis. 21, 556–563 (2015).
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).
Ledder, O. & Turner, D. Antibiotics in IBD: still a role in the biological era? Inflamm. Bowel Dis. 24, 1676–1688 (2018).
Khan, K. J. et al. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am. J. Gastroenterol. 106, 661–673 (2011).
Wang, S. L., Wang, Z. R. & Yang, C. Q. Meta-analysis of broad-spectrum antibiotic therapy in patients with active inflammatory bowel disease. Exp. Ther. Med. 4, 1051–1056 (2012).
Ford, A. C. et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am. J. Gastroenterol. 109, 1547–1561 (2014).
Kruis, W. et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 53, 1617–1623 (2004).
Sassone-Corsi, M. et al. Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature 540, 280–283 (2016).
Kristensen, N. B. et al. Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials. Genome Med. 8, 52 (2016).
Mills, J. P., Rao, K. & Young, V. B. Probiotics for prevention of Clostridium difficile infection. Curr. Opin. Gastroenterol. 34, 3–10 (2018).
Steidler, L. et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289, 1352–1355 (2000).
Braat, H. et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin. Gastroenterol. Hepatol. 4, 754–759 (2006).
Liu, S., Li, Y., Deng, B. & Xu, Z. Recombinant Lactococcus lactis expressing porcine insulin-like growth factor I ameliorates DSS-induced colitis in mice. BMC Biotechnol. 16, 25 (2016).
Shigemori, S. et al. Oral delivery of Lactococcus lactis that secretes bioactive heme oxygenase-1 alleviates development of acute colitis in mice. Microb. Cell Fact. 14, 189 (2015).
Bermudez-Humaran, L. G. et al. Serine protease inhibitors protect better than IL-10 and TGF-β anti-inflammatory cytokines against mouse colitis when delivered by recombinant lactococci. Microb. Cell Fact. 14, 26 (2015).
Wang, X., Wong, K., Ouyang, W. & Rutz, S. Targeting IL-10 family cytokines for the treatment of human diseases. Cold Spring Harb. Perspect. Biol. 11, a028548 (2019).
Zhu, W. et al. Precision editing of the gut microbiota ameliorates colitis. Nature 553, 208–211 (2018).
Lee, D. et al. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology 148, 1087–1106 (2015).
Lee, D. et al. Comparative effectiveness of nutritional and biological therapy in North American children with active Crohn’s disease. Inflamm. Bowel Dis. 21, 1786–1793 (2015).
Borrelli, O. et al. Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn’s disease: a randomized controlled open-label trial. Clin. Gastroenterol. Hepatol. 4, 744–753 (2006).
Grover, Z., Muir, R. & Lewindon, P. Exclusive enteral nutrition induces early clinical, mucosal and transmural remission in paediatric Crohn’s disease. J. Gastroenterol. 49, 638–645 (2014).
Lewis, J. D. et al. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn’s disease. Cell Host Microbe 22, 247 (2017).
Llewellyn, S. R. et al. Interactions between diet and the intestinal microbiota alter intestinal permeability and colitis severity in mice. Gastroenterology 154, 1037–1046.e2 (2018).
Anderson, C. A. et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 43, 246–252 (2011).
Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).
Bouma, G. & Strober, W. The immunological and genetic basis of inflammatory bowel disease. Nat. Rev. Immunol. 3, 521–533 (2003).
Baumgart, D. C. & Sandborn, W. J. Crohn’s disease. Lancet 380, 1590–1605 (2012).
The authors apologize to colleagues whose work was not cited or was cited through other review articles because of space limitations. The authors thank G. Chen for critical review of the manuscript. Work in G.N.’s laboratory is supported by US National Institutes of Health grants. R.C. is supported by a Career Developments Award from the Crohn’s and Colitis Foundation. B.C.L. is supported by a Canadian Institutes of Health Research (CIHR) Fellowship.
The authors declare no competing interests.
Peer review information
Nature Reviews Immunology thanks J. Faith, J. Round and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Microorganisms that, under normal circumstances, live as non-harmful symbionts but can induce pathology under certain conditions, usually involving environmental and/or genetic alterations.
- Crypts of Lieberkühn
Invaginations of the small intestine that contain epithelial stem cells and Paneth cells.
- Oxidative burst
The rapid production of reactive oxygen species by phagocytes that can directly kill bacteria.
- Segmented filamentous bacteria
(SFB). A species of Clostridium-related bacteria that primarily inhabits the terminal ileum of mice and promotes T helper 17 cell development.
- Endoplasmic reticulum stress
A consequence of dysregulated protein processing in the endoplasmic reticulum that initiates unfolded protein response pathways; unresolved endoplasmic reticulum stress is associated with inflammatory bowel disease.
- Unfolded protein response
(UPR). A group of intracellular signal transduction pathways that facilitates the folding, processing, export and degradation of proteins derived from the endoplasmic reticulum during stressed conditions.
- Very early-onset IBD
A form of inflammatory bowel disease (IBD) diagnosed when symptoms manifest before the age of 6 years; it presents with a severe disease course, extensive colonic involvement, poor response to therapy and the frequent need for abdominal surgery.
- Faecal stream diversion
A diverting terminal ileostomy constructed proximally to an ileocolonic anastomosis, thereby excluding the neoterminal ileum, the anastomosis and the colon from the faecal intestinal transit.
- Tbx21 −/−Rag2 −/− mice
Immunocompromised mice that have no adaptive immune cells and only innate immune cells with a deficiency in T-box transcription factor 21 (TBX21).
- 16S ribosomal RNA gene sequencing
A DNA amplification technology for the study of a gene conserved among bacteria that is used for species identification and taxonomic classification of bacteria.
- Adherent and invasive Escherichia coli
E. coli strains that can adhere to and invade intestinal epithelial cells.
- Faecal microbiota transplantation
(FMT). The transfer of the intestinal microbial community from a healthy individual to a patient through infusion of stool, typically by endoscopy.
About this article
Cite this article
Caruso, R., Lo, B.C. & Núñez, G. Host–microbiota interactions in inflammatory bowel disease. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-019-0268-7