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Therapeutic Opportunities in Inflammatory Bowel Disease: Mechanistic Dissection of Host-Microbiome Relationships

2019; Cell Press; Volume: 178; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2019.07.045

1097-4172

Damian R. Plichta, Daniel B. Graham, Sathish Subramanian, Ramnik J. Xavier,

Microscopic Colitis

The current understanding of inflammatory bowel disease (IBD) pathogenesis implicates a complex interaction between host genetics, host immunity, microbiome, and environmental exposures. Mechanisms gleaned from genetics and molecular pathogenesis offer clues to the critical triggers of mucosal inflammation and guide the development of therapeutic interventions. A complex network of interactions between host genetic factors, microbes, and microbial metabolites governs intestinal homeostasis, making classification and mechanistic dissection of involved pathways challenging. In this Review, we discuss these challenges, areas of active translation, and opportunities for development of next-generation therapies. The current understanding of inflammatory bowel disease (IBD) pathogenesis implicates a complex interaction between host genetics, host immunity, microbiome, and environmental exposures. Mechanisms gleaned from genetics and molecular pathogenesis offer clues to the critical triggers of mucosal inflammation and guide the development of therapeutic interventions. A complex network of interactions between host genetic factors, microbes, and microbial metabolites governs intestinal homeostasis, making classification and mechanistic dissection of involved pathways challenging. In this Review, we discuss these challenges, areas of active translation, and opportunities for development of next-generation therapies. Clinical and endoscopic characteristics, such as disease location, distinguish the two major types of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn disease (CD). While UC is restricted to the colon, mucosal inflammation in CD can involve the entire depth of the tissue and is associated with complications such as strictures and fistulas. In some patients, however, IBD cannot be definitively classified as either UC or CD. Treatment regimens overlap for these conditions and include aminosalicylates, corticosteroids, immunomodulators, Janus kinase inhibitors, “biologic” therapies, including monoclonal antibodies to tumor necrosis factor-α (TNF-α), interleukin (IL)-12/23, or integrins to target inflammatory/trafficking pathways. Biologic therapies have increased quality of life and reduced the risk of disease-related complications, including surgery and hospitalization. However, up to 40% of patients do not respond to initial treatment. Among initial responders, 13%–46% lose response over the subsequent year, with estimates varying by therapy, disease subtype, and definition of non-response. In some fistulizing CD cases, fistula recurrence after treatment is as high as 64% (Roda et al., 2016Roda G. Jharap B. Neeraj N. Colombel J.-F. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management.Clin. Transl. Gastroenterol. 2016; 7: e135Crossref PubMed Google Scholar). The lack of treatment response raises two challenges to the advancement of IBD therapy: (1) further need for mechanistic understanding of disease drivers, incorporating features of heterogeneity, host genetics, and the microbiome; and (2) renewed classification systems based on clinical, molecular, and artificial intelligence methods to facilitate prognostication for clinicians to identify therapeutic non-responders and guide proactive treatment algorithms. Our understanding and ability to treat IBD is limited by factors including variable disease onset, genetic and clinical heterogeneity, and pharmacokinetics (Table 1). Many non-responders have adequate circulating levels of the drug, suggesting that rapid drug clearance is not a major contributor to lack of response. Additionally, the complexity of underlying disease mechanisms that impact distinct inflammatory pathways point to an unmet need to develop therapies that target specific pathways, including those that alter intestinal barrier function, tissue metabolism, immunity, fibrosis, and fistulization. While existing IBD therapies target inflammation broadly, utilizing a pathway-focused approach in individual patients may increase the likelihood of success, reduce off-target effects, and result in durable benefits and modification of disease trajectory.Table 1Advancing Therapy in IBDFactors Influencing IBD TherapyClinical ObservationsOpportunities for Discovery and TranslationVariable onset of diseaseinterval between untreated disease/symptoms and treatment associated with treatment failuretriggers for disease-onset at different ages, recurrenceearly stratification of therapy based on baseline clinical and molecular profiling for individualized therapyGenetic heterogeneityGWAS-identified loci, resequencing effortselucidating gene-variant function relationships; genetic risk score developmentDisease progressiondifferent trajectories of diseasefactors determining complications, including recurrence, fibrosis, fistula, stricture, and surgeryInfectious modifiersCMV, C. difficileshared pathways in response to infection/inflammation and off-targetDietary modifiersexclusive enteral nutritionpre-, pro-, and syn-biotic interventions, mechanism of disease modification, interaction with non-dietary therapyDrug deliveryEntyvio integrin therapy versus TNFnanotechnology, gut-on-a-chipDrug turn-overfrequency of administrationmethods to measure drug levels, antibodiesSide effect/off-target effectsimmune suppression, infectious complicationspathway-based discovery Open table in a new tab Current disease classification systems incorporate anatomic distribution, clinical severity, age of onset, and behavior (fibrosing, penetrating). Antibodies toward self, microbial antigens, and other peptides have been proposed as biomarkers of antigen-reactivity with limited clinical utility (Prideaux et al., 2012Prideaux L. De Cruz P. Ng S.C. Kamm M.A. Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm. Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (0) Google Scholar). Classifiers incorporating genetic, microbiome, and clinical parameters to differentiate responders from non-responders to TNF and anti-integrin therapy have been developed (Ananthakrishnan et al., 2017Ananthakrishnan A.N. Luo C. Yajnik V. Khalili H. Garber J.J. Stevens B.W. Cleland T. Xavier R.J. Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases.Cell Host Microbe. 2017; 21: 603-610Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Although promising as a proof-of-concept, such classifiers require further validation for use in routine clinical practice. Given these challenges, this Review proposes specific areas to improve mechanistic understanding and integrate bench and bedside studies to advance therapeutic options. Studies of IBD genetics have identified over 200 loci that explain a modest 8%–13% of disease susceptibility risk variance (Jostins et al., 2012Jostins L. Ripke S. Weersma R.K. Duerr R.H. McGovern D.P. Hui K.Y. Lee J.C. Schumm L.P. Sharma Y. Anderson C.A. et al.International IBD Genetics Consortium (IIBDGC)Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (2381) Google Scholar, de Lange et al., 2017de Lange K.M. Moutsianas L. Lee J.C. Lamb C.A. Luo Y. Kennedy N.A. Jostins L. Rice D.L. Gutierrez-Achury J. Ji S.-G. et al.Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat. Genet. 2017; 49: 256-261Crossref PubMed Scopus (169) Google Scholar, Rivas et al., 2011Rivas M.A. Beaudoin M. Gardet A. Stevens C. Sharma Y. Zhang C.K. Boucher G. Ripke S. Ellinghaus D. Burtt N. et al.National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC)United Kingdom Inflammatory Bowel Disease Genetics ConsortiumInternational Inflammatory Bowel Disease Genetics ConsortiumDeep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.Nat. Genet. 2011; 43: 1066-1073Crossref PubMed Scopus (472) Google Scholar), highlighting the importance of non-genetic modifiers, such as intestinal microbes, that drive the pathological immune response in a genetically susceptible host (Xavier and Podolsky, 2007Xavier R.J. Podolsky D.K. Unravelling the pathogenesis of inflammatory bowel disease.Nature. 2007; 448: 427-434Crossref PubMed Scopus (2581) Google Scholar). Paradoxically, this breakdown in immune tolerance can be driven by seemingly opposing host genetic vulnerabilities. Both hyperinflammatory phenotypes and immunodeficiency phenotypes have been associated with risk of IBD onset. Chronic inflammation resulting from intestinal barrier dysfunction and/or colonization of the epithelial surface can create an intestinal tissue environment that alters colonization niches in the gut. A chronic low-grade inflammatory intestinal milieu can significantly impact the microbiome by selecting against species sensitive to inflammation and promoting blooms of functionally adapted species. Despite the intimate relationship between host and microbiome, identifying confident associations between host genetics (IBD SNPs) and microbiome features remains challenging. The dysbiotic gut microbiome, defined as having a reduced microbial diversity and richness compared to healthy controls, has been extensively characterized in IBD (Lloyd-Price et al., 2019Lloyd-Price J. Arze C. Ananthakrishnan A.N. Schirmer M. Avila-Pacheco J. Poon T.W. Andrews E. Ajami N.J. Bonham K.S. Brislawn C.J. et al.IBDMDB InvestigatorsMulti-omics of the gut microbial ecosystem in inflammatory bowel diseases.Nature. 2019; 569: 655-662Crossref PubMed Scopus (58) Google Scholar, Vich Vila et al., 2018Vich Vila A. Imhann F. Collij V. Jankipersadsing S.A. Gurry T. Mujagic Z. Kurilshikov A. Bonder M.J. Jiang X. Tigchelaar E.F. et al.Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome.Sci. Transl. Med. 2018; 10: eaap8914Crossref PubMed Google Scholar) and reviewed in detail (Schirmer et al., 2019Schirmer M. Garner A. Vlamakis H. Xavier R.J. Microbial genes and pathways in inflammatory bowel disease.Nat. Rev. Microbiol. 2019; 17: 497-511Crossref PubMed Scopus (13) Google Scholar). The reduced richness does not necessarily simplify the task of finding links to host genetics. Inter-personal microbiome variation remains high in IBD, with many species occurring rarely in the general population due to diet, use of medication, or ecological interactions. In addition, the different physiological functions and geography of the GI tract creates ecological niches that select for distinct microbial communities, which are additionally stratified by their mucosal or lumenal location (Zmora et al., 2018Zmora N. Zilberman-Schapira G. Suez J. Mor U. Dori-Bachash M. Bashiardes S. Kotler E. Zur M. Regev-Lehavi D. Brik R.B.-Z. et al.Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.Cell. 2018; 174: 1388-1405Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). Several studies identified links between genetic variants and gut microbes. For example, NOD2 variants are associated with abundance of Faecalibacterium prausnitzii, genus Roseburia, and family Enterobacteriaceae (Aschard et al., 2019Aschard H. Laville V. Tchetgen E.T. Knights D. Imhann F. Seksik P. Zaitlen N. Silverberg M.S. Cosnes J. Weersma R.K. et al.Genetic effects on the commensal microbiota in inflammatory bowel disease patients.PLoS Genet. 2019; 15: e1008018Crossref PubMed Scopus (4) Google Scholar, Knights et al., 2014Knights D. Silverberg M.S. Weersma R.K. Gevers D. Dijkstra G. Huang H. Tyler A.D. van Sommeren S. Imhann F. Stempak J.M. et al.Complex host genetics influence the microbiome in inflammatory bowel disease.Genome Med. 2014; 6: 107Crossref PubMed Scopus (157) Google Scholar). NOD2 is a host intracellular sensor of bacterial infection that recognizes the prokaryotic cell wall component muramyl dipeptide (MDP) and elicits a proinflammatory cytokine response in phagocytes (Girardin et al., 2003Girardin S.E. Boneca I.G. Viala J. Chamaillard M. Labigne A. Thomas G. Philpott D.J. Sansonetti P.J. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection.J. Biol. Chem. 2003; 278: 8869-8872Crossref PubMed Scopus (1669) Google Scholar). The ubiquity of MDP across microbiome taxa/phyla, however, likely precludes identification of functional associations. In fact, NOD2 variants associate with taxa that are also observed in microbiome case-control studies in non-IBD diseases such as liver cirrhosis (Qin et al., 2014Qin N. Yang F. Li A. Prifti E. Chen Y. Shao L. Guo J. Le Chatelier E. Yao J. Wu L. et al.Alterations of the human gut microbiome in liver cirrhosis.Nature. 2014; 513: 59-64Crossref PubMed Scopus (624) Google Scholar), suggesting that NOD2-associated dysregulation of microbial sensing broadly contributes to dysbiosis. This example underscores the complexity of IBD genetics and microbiome diversity and highlights challenges in identifying functional host-microbiome connections. Current challenges highlight the need for new computational approaches to associate microbiome traits with host genetics. For example, the fungal mycobiome, often overlooked in IBD studies, can be functionally distinguished from the bacterial microbiome based on the mechanisms by which the host innate immune system recognizes microbial ligands. CARD9 is an essential adaptor protein required for nuclear factor κB (NF-κB) activation downstream of fungal ligand-sensing receptors such as Dectin-1. Consistent with its role in antifungal immunity, a common CARD9 missense variant (S12N) was associated with intestinal colonization by a commensal fungus Malassezia restricta in CD (Limon et al., 2019Limon J.J. Tang J. Li D. Wolf A.J. Michelsen K.S. Funari V. Gargus M. Nguyen C. Sharma P. Maymi V.I. et al.Malassezia Is Associated with Crohn’s Disease and Exacerbates Colitis in Mouse Models.Cell Host Microbe. 2019; 25: 377-388Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). Furthermore, CARD9 has been linked to circulating antibodies against M. restricta, indicating that breakdown of innate immunity translates into durable adaptive immunity in CD patients (Limon et al., 2019Limon J.J. Tang J. Li D. Wolf A.J. Michelsen K.S. Funari V. Gargus M. Nguyen C. Sharma P. Maymi V.I. et al.Malassezia Is Associated with Crohn’s Disease and Exacerbates Colitis in Mouse Models.Cell Host Microbe. 2019; 25: 377-388Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). Similar to the impact of fungi on immunity, host genetic variation interacts with viral encounters to modulate intestinal homeostasis. For example, the IBD risk gene Atg16l1 functionally interacts with viral sensing pathways mediated by cGAS-STING to regulate intestinal inflammation in an IL-22-dependent manner (Aden et al., 2018Aden K. Tran F. Ito G. Sheibani-Tezerji R. Lipinski S. Kuiper J.W. Tschurtschenthaler M. Saveljeva S. Bhattacharyya J. Häsler R. et al.ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING.J. Exp. Med. 2018; 215: 2868-2886Crossref PubMed Scopus (22) Google Scholar). Atg16l1 hypomorphic mice with dextran sodium sulfate-induced epithelial injury exhibit Paneth cell granule morphology abnormalities and exacerbated colitis when infected with a murine norovirus (MNV CR6) (Cadwell et al., 2010Cadwell K. Patel K.K. Maloney N.S. Liu T.-C. Ng A.C.Y. Storer C.E. Head R.D. Xavier R. Stappenbeck T.S. Virgin H.W. 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 (587) Google Scholar). These examples underscore the role of non-bacterial microbiome constituents in host immunity. Further unraveling these interactions will require cohort expansion and stool sample biobanking, followed by microbiome typing of bacteria as well as fungi, small eukaryotes, and vira in patients with genotypes of interest. In IBD genetics, risk variants implicate a core set of functionally related pathways that represent vulnerabilities to intestinal inflammation (Momozawa et al., 2018Momozawa Y. Dmitrieva J. Théâtre E. Deffontaine V. Rahmouni S. Charloteaux B. Crins F. Docampo E. Elansary M. Gori A.-S. et al.International IBD Genetics ConsortiumIBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.Nat. Commun. 2018; 9: 2427Crossref PubMed Scopus (5) Google Scholar). They encompass four broad overlapping categories: (1) microbial sensors and innate cytokine pathways, (2) antibacterial effector mechanisms (oxidative burst, autophagy), (3) antigen presentation and adaptive cytokine pathways, and (4) epithelial barrier function. For example, NOD2 and CARD9 variants alter NF-κB signaling, increasing inflammatory cytokine production across microbial sensing pathways. According to this pathway-level perspective, functional connections between host and microbiome are best approached by searching for associations between host-pathway genetic risk scores and microbe-pathway metagenomic annotations (Figure 1). In essence, this strategy condenses a multitude of host genetic risk factors into functionally related pathway scores and parses many metagenomes into functionally related gene classes, thereby allowing for discovery of pathway-level associations between host genetic factors and the microbiome. This approach addresses inter-personal genetic heterogeneity, which introduces diverse vulnerabilities for microbiome dysbiosis. Encapsulating these genetic variants into separate scores or mutation loads for the major groups of IBD pathways could account for the molecular programs implicated in UC and CD and facilitate identification of common and rare variants in the same genes (Christodoulou et al., 2013Christodoulou K. Wiskin A.E. Gibson J. Tapper W. Willis C. Afzal N.A. Upstill-Goddard R. Holloway J.W. Simpson M.A. Beattie R.M. et al.Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes.Gut. 2013; 62: 977-984Crossref PubMed Scopus (74) Google Scholar). Furthermore, it would reduce the multiple testing burden when analyzing associations between IBD genetics and environmental modifiers such as the gut microbiome. Coding variants associated with early onset IBD, including rare XIAP variants that diminish NOD2 signaling or mutations in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex subunit genes, suggest functional interactions between the innate immune system and the microbiome (Amininejad et al., 2018Amininejad L. Charloteaux B. Theatre E. Liefferinckx C. Dmitrieva J. Hayard P. Muls V. Maisin J.-M. Schapira M. Ghislain J.-M. et al.International IBD Genetics ConsortiumAnalysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn’s Disease.Gastroenterology. 2018; 154: 2165-2177Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, Denson et al., 2018Denson L.A. Jurickova I. Karns R. Shaw K.A. Cutler D.J. Okou D.T. Dodd A. Quinn K. Mondal K. Aronow B.J. et al.Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients With Crohn’s Disease.Gastroenterology. 2018; 154: 2097-2110Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). For example, the NADPH oxidase complex (CYBB, CYBBA, NCF1, NCF2, NCF4) is highly expressed in phagocytes, providing innate defense against microbial infection by producing toxic reactive oxygen intermediates (ROIs). Loss-of-function mutations in NADPH oxidase subunits result in chronic granulomatous disease (CGD), a severe primary immunodeficiency associated with recurrent bacterial and fungal infections. CGD patients are susceptible to infection with catalase-positive bacteria (Muise et al., 2012Muise A.M. Xu W. Guo C.-H. Walters T.D. Wolters V.M. Fattouh R. Lam G.Y. Hu P. Murchie R. Sherlock M. et al.NEOPICSNADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2.Gut. 2012; 61: 1028-1035Crossref PubMed Scopus (100) Google Scholar), suggesting that in IBD, hypomorphic alleles of NADPH oxidase subunits may alter host immunity to allow catalase-positive gut commensals to occupy a permissive niche. This rationale suggests a possible relationship between host genotypes and abundance of microbiome genes mitigating ROI toxicity (e.g., catalase, superoxide dismutase, thioredoxin). Thus, carriers of IBD risk variants in NCF4 may have higher incidences of colonization by various facultative anaerobes in the Enterobacteriaceae family that can tolerate oxygen levels found in intestinal tissue but are normally susceptible to killing by phagocyte-derived ROI. In summary, condensing functionally related host genetic variables and microbiome traits could facilitate discovery and strengthening of associations between human genetics and the gut microbiome (Rothschild et al., 2018Rothschild D. Weissbrod O. Barkan E. Kurilshikov A. Korem T. Zeevi D. Costea P.I. Godneva A. Kalka I.N. Bar N. et al.Environment dominates over host genetics in shaping human gut microbiota.Nature. 2018; 555: 210-215Crossref PubMed Scopus (362) Google Scholar), particularly within the context of immune functions discussed in detail in the following sections. Among the most robust genetic associations linking host immunity with microbial infection and/or autoimmunity are variants within the human leukocyte antigen (HLA) locus. Population-level HLA gene variation is concentrated within the peptide-binding groove of class I and class II major histocompatibility complexes (MHC). Variants alter MHC binding specificity and profoundly impact the spectrum of antigenic peptides presented to T cells. How HLA impacts commensal antigen presentation to T cells in IBD and how commensal-specific T cells impact intestinal pathology remains unclear. MHC class I and II (HLA) allele associations have been reported for CD (15 alleles) and UC (16 alleles, mostly class II), while fine variant mapping detected signal heterogeneity for clinical IBD phenotypes (Goyette et al., 2015Goyette P. Boucher G. Mallon D. Ellinghaus E. Jostins L. Huang H. Ripke S. Gusareva E.S. Annese V. Hauser S.L. et al.International Inflammatory Bowel Disease Genetics ConsortiumAustralia and New Zealand IBDGCBelgium IBD Genetics ConsortiumItalian Group for IBD Genetic ConsortiumNIDDK Inflammatory Bowel Disease Genetics ConsortiumUnited Kingdom IBDGCWellcome Trust Case Control ConsortiumQuebec IBD Genetics ConsortiumHigh-density mapping of the MHC identifies a shared role for HLA-DRB1∗01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.Nat. Genet. 2015; 47: 172-179Crossref PubMed Scopus (127) Google Scholar). DRB1∗01:03 is a strong MHC II risk allele for IBD with colonic involvement, while DRB1∗07:01 in CD associates with non-colonic inflammation (Goyette et al., 2015Goyette P. Boucher G. Mallon D. Ellinghaus E. Jostins L. Huang H. Ripke S. Gusareva E.S. Annese V. Hauser S.L. et al.International Inflammatory Bowel Disease Genetics ConsortiumAustralia and New Zealand IBDGCBelgium IBD Genetics ConsortiumItalian Group for IBD Genetic ConsortiumNIDDK Inflammatory Bowel Disease Genetics ConsortiumUnited Kingdom IBDGCWellcome Trust Case Control ConsortiumQuebec IBD Genetics ConsortiumHigh-density mapping of the MHC identifies a shared role for HLA-DRB1∗01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.Nat. Genet. 2015; 47: 172-179Crossref PubMed Scopus (127) Google Scholar). Sequence preferences for HLA binding are established for many alleles, however, it remains unclear how the T cell pool is shaped by HLA-associated peptidomes during thymic selection and in the periphery. The host immune system maintains tolerance to diverse immunogenic antigens produced by commensals. In this regard, the microbiome can be considered a host “self” tissue that is uniquely immune-privileged. The intestinal lumen is not constitutively occupied by immune cells and is not directly surveilled by mechanisms of cellular immunity but is subject to protection by mechanisms of humoral immunity (Bunker et al., 2017Bunker J.J. Erickson S.A. Flynn T.M. Henry C. Koval J.C. Meisel M. Jabri B. Antonopoulos D.A. Wilson P.C. Bendelac A. Natural polyreactive IgA antibodies coat the intestinal microbiota.Science. 2017; 358: eaan6619Crossref PubMed Scopus (82) Google Scholar). The intestinal mucosa is rich in neutralizing commensal-specific IgA, which differs from other immunoglobulin isotypes that engage host cellular effector mechanisms, such as the complement system and Fc receptors. Accordingly, the immune system does not sterilize the lumen in an antigen-specific manner and is generally not equipped for killing lumenal microbes/pathogens. For example, adaptive immunity to C. difficile does not eradicate the bacterium from the lumen, but can instead inhibit infection of host mucosal tissue and systemic infection. Thus, coordinated T and B cell responses confer immunity to commensals, with T cells providing cytokine support for B cell functions including antibody class switch recombination, somatic hypermutation, and affinity maturation. In particular, T cell-dependent anti-commensal IgG responses are associated with future diagnosis of type 1 diabetes (T1D) and depended on HLA genotype (Paun et al., 2019Paun A. Yau C. Meshkibaf S. Daigneault M.C. Marandi L. Mortin-Toth S. Bar-Or A. Allen-Vercoe E. Poussier P. Danska J.S. Association of HLA-dependent islet autoimmunity with systemic antibody responses to intestinal commensal bacteria in children.Sci. Immunol. 2019; 4: eaau8125Crossref PubMed Scopus (4) Google Scholar). Similar mechanisms may apply to IBD, as CD patients exhibit higher levels of immunoglobulins directed toward food antigens and commensal species (Lerner et al., 1989Lerner A. Rossi T.M. Park B. Albini B. Lebenthal E. Serum antibodies to cow’s milk proteins in pediatric inflammatory bowel disease. Crohn’s disease versus ulcerative colitis.Acta Paediatr. Scand. 1989; 78: 384-389Crossref PubMed Google Scholar, Paun et al., 2019Paun A. Yau C. Meshkibaf S. Daigneault M.C. Marandi L. Mortin-Toth S. Bar-Or A. Allen-Vercoe E. Poussier P. Danska J.S. Association of HLA-dependent islet autoimmunity with systemic antibody responses to intestinal commensal bacteria in children.Sci. Immunol. 2019; 4: eaau8125Crossref PubMed Scopus (4) Google Scholar). These findings suggest impaired self-tolerance in T cell-dependent antibody responses. Recent studies showed that commensal-reactive B cells can evade autoreactivity by undergoing receptor editing, a process in which B cells re-rearrange light chain loci to mitigate local hyper-reactivity (Wesemann et al., 2013Wesemann D.R. Portuguese A.J. Meyers R.M. Gallagher M.P. Cluff-Jones K. Magee J.M. Panchakshari R.A. Rodig S.J. Kepler T.B. Alt F.W. Microbial colonization influences early B-lineage development in the gut lamina propria.Nature. 2013; 501: 112-115Crossref PubMed Scopus (111) Google Scholar). While an analogous process in T cells has not been conclusively demonstrated, commensal-specific T cells have been identified that express dual T cell receptors (TCRs) with two distinct alpha chains. T cell reactivity toward segmented filamentous bacteria (SFB) is associated with dual TCR usage in lung autoimmune T cells, suggesting that dual-specificity T cells directed against microbiome antigens and autoantigens may contribute to autoimmune pathologies (Bradley et al., 2017Bradley C.P. Teng F. Felix K.M. Sano T. Naskar D. Block K.E. Huang H. Knox K.S. Littman D.R. Wu H.-J.J. Segmented Filamentous Bacteria Provoke Lung Autoimmunity by Inducing Gut-Lung Axis Th17 Cells Expressing Dual TCRs.Cell Host Microbe. 2017; 22: 697-704Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). If we consider the microbiome to be a “self” tissue, how is tolerance established and maintained? Commensal-reactive T cells that develop in the thymus are not subject to the typical negative selection mechanisms that enforce central tolerance. Instead, multiple peripheral tolerance mechanisms control immune responses mediated by T cells expressing TCRs with high affinity to commensal antigens (Figure 2A). However, T cells expressing TCRs with low affinity and/or avidity for non-cognate commensal epitopes may function as positively selecting self ligands in the periphery that aid in T cell survival and tuning of TCR activation thresholds (Figure 2A). Recent studies demonstrated the importance of these ligands for conditioning T cell responses (Persaud et al., 2014Persaud S.P. Parker C.R. Lo W.-L. Weber K.S. Allen P.M. Intrinsic CD4+ T cell sensitivity and response to a pathogen are set and sustained by avidity for thymic and peripheral complexes of self peptide and MHC.Nat. Immunol. 2014; 15: 266-274Crossref PubMed Scopus (87) Google Scholar, Wegorzewska et al., 2019Wegorzewska M.M. Glowacki R.W.P. Hsieh S.A. Donermeyer D.L. Hickey C.A. Horvath S.C. Martens E.C. Stappenbeck T.S. Allen P.M. Diet modulates colonic T cell responses by regulating the expression of a Bacteroides thetaiotaomicron antigen.Sci. Immunol. 2019; 4: eaau9079Crossref PubMed Scopus (12) Google Scholar). Thus, peripheral T cell maintenance may be promoted by tonic TCR signaling induced by interactions with weak self or commensal peptide ligands presented by MHCII. Taken together, commensal epitopes may function as weak self ligands that condition host T cell responses