Acknowledgement
We thank Dr. Ho-Keun Kwon, Yonsei University College of Medicine, for his insightful discussions and writing assistance. This work was supported by a faculty research grant of Yonsei University College of Medicine (6-2021-0155), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HV21C0050, HV22C0249), and the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (2021R1C1C1006912). Figures have been created with BioRender.
References
- Duerkop BA, Vaishnava S, Hooper LV. Immune responses to the microbiota at the intestinal mucosal surface. Immunity 2009;31:368-376. https://doi.org/10.1016/j.immuni.2009.08.009
- Kayama H, Okumura R, Takeda K. Interaction between the microbiota, epithelia, and immune cells in the intestine. Annu Rev Immunol 2020;38:23-48. https://doi.org/10.1146/annurev-immunol-070119-115104
- Belkaid Y, Harrison OJ. Homeostatic immunity and the microbiota. Immunity 2017;46:562-576. https://doi.org/10.1016/j.immuni.2017.04.008
- Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res 2020;30:492-506. https://doi.org/10.1038/s41422-020-0332-7
- Ansaldo E, Farley TK, Belkaid Y. Control of immunity by the microbiota. Annu Rev Immunol 2021;39:449-479. https://doi.org/10.1146/annurev-immunol-093019-112348
- Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016;535:75-84. https://doi.org/10.1038/nature18848
- Hacquard S, Garrido-Oter R, Gonzalez A, Spaepen S, Ackermann G, Lebeis S, McHardy AC, Dangl JL, Knight R, Ley R, et al. Microbiota and host nutrition across plant and animal kingdoms. Cell Host Microbe 2015;17:603-616. https://doi.org/10.1016/j.chom.2015.04.009
- Lynch JB, Hsiao EY. Microbiomes as sources of emergent host phenotypes. Science 2019;365:1405-1409. https://doi.org/10.1126/science.aay0240
- Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012;489:231-241. https://doi.org/10.1038/nature11551
- Kayama H, Takeda K. Regulation of intestinal homeostasis by innate and adaptive immunity. Int Immunol 2012;24:673-680. https://doi.org/10.1093/intimm/dxs094
- Sun M, He C, Cong Y, Liu Z. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol 2015;8:969-978. https://doi.org/10.1038/mi.2015.49
- Zhang M, Sun K, Wu Y, Yang Y, Tso P, Wu Z. Interactions between intestinal microbiota and host immune response in inflammatory bowel disease. Front Immunol 2017;8:942.
- Kang M, Martin A. Microbiome and colorectal cancer: Unraveling host-microbiota interactions in colitisassociated colorectal cancer development. Semin Immunol 2017;32:3-13. https://doi.org/10.1016/j.smim.2017.04.003
- Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 2018;33:570-580. https://doi.org/10.1016/j.ccell.2018.03.015
- Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ, Odden AR, Shellito JE, Bagby GJ, Nelson S, et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med 2005;202:761-769. https://doi.org/10.1084/jem.20050193
- Nakamoto N, Sasaki N, Aoki R, Miyamoto K, Suda W, Teratani T, Suzuki T, Koda Y, Chu PS, Taniki N, et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat Microbiol 2019;4:492-503. https://doi.org/10.1038/s41564-018-0333-1
- Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, Migaud M, Israel L, Chrabieh M, Audry M, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011;332:65-68. https://doi.org/10.1126/science.1200439
- Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, Alzahrani M, Al-Muhsen S, Halwani R, Ma CS, et al. IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 2015;349:606-613. https://doi.org/10.1126/science.aaa4282
- Lin X, Gaudino SJ, Jang KK, Bahadur T, Singh A, Banerjee A, Beaupre M, Chu T, Wong HT, Kim CK, et al. IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment. Immunity 2022;55:237-253.e8. https://doi.org/10.1016/j.immuni.2021.12.016
- Stockinger B, Omenetti S. The dichotomous nature of T helper 17 cells. Nat Rev Immunol 2017;17:535-544. https://doi.org/10.1038/nri.2017.50
- Wang K, Karin M. The IL-23 to IL-17 cascade inflammation-related cancers. Clin Exp Rheumatol 2015;33 Suppl 92:S87-S90.
- Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 2012;11:763-776. https://doi.org/10.1038/nrd3794
- Wang K, Kim MK, Di Caro G, Wong J, Shalapour S, Wan J, Zhang W, Zhong Z, Sanchez-Lopez E, Wu LW, et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity 2014;41:1052-1063. https://doi.org/10.1016/j.immuni.2014.11.009
- Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014;157:121-141. https://doi.org/10.1016/j.cell.2014.03.011
- Tan TG, Sefik E, Geva-Zatorsky N, Kua L, Naskar D, Teng F, Pasman L, Ortiz-Lopez A, Jupp R, Wu HJ, et al. Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proc Natl Acad Sci U S A 2016;113:E8141-E8150. https://doi.org/10.1073/pnas.1617460113
- Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009;139:485-498. https://doi.org/10.1016/j.cell.2009.09.033
- Ivanov II, Frutos RL, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 2008;4:337-349. https://doi.org/10.1016/j.chom.2008.09.009
- Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, Peterson DA, Stappenbeck TS, Hsieh CS. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011;478:250-254. https://doi.org/10.1038/nature10434
- Ohnmacht C, Park JH, Cording S, Wing JB, Atarashi K, Obata Y, Gaboriau-Routhiau V, Marques R, Dulauroy S, Fedoseeva M, et al. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 2015;349:989-993. https://doi.org/10.1126/science.aac4263
- Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, Burzyn D, Ortiz-Lopez A, Lobera M, Yang J, et al. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 2015;349:993-997. https://doi.org/10.1126/science.aaa9420
- Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013;500:232-236. https://doi.org/10.1038/nature12331
- Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, Narushima S, Suda W, Imaoka A, Setoyama H, Nagamori T, et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 2015;163:367-380. https://doi.org/10.1016/j.cell.2015.08.058
- Britton GJ, Contijoch EJ, Mogno I, Vennaro OH, Llewellyn SR, Ng R, Li Z, Mortha A, Merad M, Das A, 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 2019;50:212-224.e4. https://doi.org/10.1016/j.immuni.2018.12.015
- Van Kaer L, Parekh VV, Wu L. The response of CD1d-restricted invariant NKT cells to microbial pathogens and their products. Front Immunol 2015;6:226.
- Howson LJ, Salio M, Cerundolo V. MR1-restricted mucosal-associated invariant T cells and their activation during infectious diseases. Front Immunol 2015;6:303.
- Harriff MJ, McMurtrey C, Froyd CA, Jin H, Cansler M, Null M, Worley A, Meermeier EW, Swarbrick G, Nilsen A, et al. MR1 displays the microbial metabolome driving selective MR1-restricted T cell receptor usage. Sci Immunol 2018;3:eaao2556.
- Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 2012;13:991-999. https://doi.org/10.1038/ni.2416
- Lee JY, Hall JA, Kroehling L, Wu L, Najar T, Nguyen HH, Lin WY, Yeung ST, Silva HM, Li D, et al. Serum amyloid A proteins induce pathogenic Th17 cells and promote inflammatory disease. Cell 2020;180:79-91.e16. https://doi.org/10.1016/j.cell.2019.11.026
- Omenetti S, Bussi C, Metidji A, Iseppon A, Lee S, Tolaini M, Li Y, Kelly G, Chakravarty P, Shoaie S, et al. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells. Immunity 2019;51:77-89.e6. https://doi.org/10.1016/j.immuni.2019.05.004
- Geem D, Medina-Contreras O, McBride M, Newberry RD, Koni PA, Denning TL. Specific microbiotainduced intestinal Th17 differentiation requires MHC class II but not GALT and mesenteric lymph nodes. J Immunol 2014;193:431-438. https://doi.org/10.4049/jimmunol.1303167
- Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M, Linehan JL, Alonzo F, Ng C, Chen A, Lin X, et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 2014;510:152-156. https://doi.org/10.1038/nature13279
- Sano T, Huang W, Hall JA, Yang Y, Chen A, Gavzy SJ, Lee JY, Ziel JW, Miraldi ER, Domingos AI, et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell 2015;163:381-393. https://doi.org/10.1016/j.cell.2015.08.061
- Brockmann L, Giannou AD, Gagliani N, Huber S. Regulation of TH17 cells and associated cytokines in wound healing, tissue regeneration, and carcinogenesis. Int J Mol Sci 2017;18:E1033.
- Kempski J, Brockmann L, Gagliani N, Huber S. TH17 cell and epithelial cell crosstalk during inflammatory bowel disease and carcinogenesis. Front Immunol 2017;8:1373.
- Kumar P, Monin L, Castillo P, Elsegeiny W, Horne W, Eddens T, Vikram A, Good M, Schoenborn AA, Bibby K, et al. Intestinal Interleukin-17 receptor signaling mediates reciprocal control of the gut microbiota and autoimmune inflammation. Immunity 2016;44:659-671. https://doi.org/10.1016/j.immuni.2016.02.007
- Chow J, Tang H, Mazmanian SK. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol 2011;23:473-480. https://doi.org/10.1016/j.coi.2011.07.010
- Xu M, Pokrovskii M, Ding Y, Yi R, Au C, Harrison OJ, Galan C, Belkaid Y, Bonneau R, Littman DR. c-MAFdependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 2018;554:373-377. https://doi.org/10.1038/nature25500
- Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, Cua DJ, Powrie F, Cheever AW, Maloy KJ, et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 2006;203:2485-2494. https://doi.org/10.1084/jem.20061082
- Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 2006;203:2473-2483. https://doi.org/10.1084/jem.20061099
- Repoila F, Le Bohec F, Guerin C, Lacoux C, Tiwari S, Jaiswal AK, Santana MP, Kennedy SP, Quinquis B, Rainteau D, et al. Adaptation of the gut pathobiont Enterococcus faecalis to deoxycholate and taurocholate bile acids. Sci Rep 2022;12:8485.
- Balish E, Warner T. Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am J Pathol 2002;160:2253-2257. https://doi.org/10.1016/S0002-9440(10)61172-8
- Cahill RJ, Foltz CJ, Fox JG, Dangler CA, Powrie F, Schauer DB. Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect Immun 1997;65:3126-3131. https://doi.org/10.1128/iai.65.8.3126-3131.1997
- Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ, Powrie F. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 2010;33:279-288. https://doi.org/10.1016/j.immuni.2010.08.010
- Neumann C, Blume J, Roy U, Teh PP, Vasanthakumar A, Beller A, Liao Y, Heinrich F, Arenzana TL, Hackney JA, et al. c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes hostmicrobiota homeostasis. Nat Immunol 2019;20:471-481. https://doi.org/10.1038/s41590-019-0316-2
- Rutz S, Noubade R, Eidenschenk C, Ota N, Zeng W, Zheng Y, Hackney J, Ding J, Singh H, Ouyang W. Transcription factor c-Maf mediates the TGF-β-dependent suppression of IL-22 production in T(H)17 cells. Nat Immunol 2011;12:1238-1245. https://doi.org/10.1038/ni.2134
- Gaublomme JT, Yosef N, Lee Y, Gertner RS, Yang LV, Wu C, Pandolfi PP, Mak T, Satija R, Shalek AK, et al. Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell 2015;163:1400-1412. https://doi.org/10.1016/j.cell.2015.11.009
- Schnell A, Huang L, Singer M, Singaraju A, Barilla RM, Regan BM, Bollhagen A, Thakore PI, Dionne D, Delorey TM, et al. Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity. Cell 2021;184:6281-6298.e23. https://doi.org/10.1016/j.cell.2021.11.018
- Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, Mention JJ, Thiam K, Cerf-Bensussan N, Mandelboim O, et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 2008;29:958-970. https://doi.org/10.1016/j.immuni.2008.11.001
- Melo-Gonzalez F, Hepworth MR. Functional and phenotypic heterogeneity of group 3 innate lymphoid cells. Immunology 2017;150:265-275. https://doi.org/10.1111/imm.12697
- Sanos SL, Bui VL, Mortha A, Oberle K, Heners C, Johner C, Diefenbach A. RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol 2009;10:83-91. https://doi.org/10.1038/ni.1684
- Jarade A, Di Santo JP, Serafini N. Group 3 innate lymphoid cells mediate host defense against attaching and effacing pathogens. Curr Opin Microbiol 2021;63:83-91. https://doi.org/10.1016/j.mib.2021.06.005
- Klose CS, Kiss EA, Schwierzeck V, Ebert K, Hoyler T, d'Hargues Y, Goppert N, Croxford AL, Waisman A, Tanriver Y, et al. A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells. Nature 2013;494:261-265. https://doi.org/10.1038/nature11813
- Diefenbach A, Gnafakis S, Shomrat O. Innate lymphoid cell-epithelial cell modules sustain intestinal homeostasis. Immunity 2020;52:452-463. https://doi.org/10.1016/j.immuni.2020.02.016
- Goto Y, Obata T, Kunisawa J, Sato S, Ivanov II, Lamichhane A, Takeyama N, Kamioka M, Sakamoto M, Matsuki T, et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 2014;345:1254009. https://doi.org/10.1126/science.1254009
- Talbot J, Hahn P, Kroehling L, Nguyen H, Li D, Littman DR. Feeding-dependent VIP neuron-ILC3 circuit regulates the intestinal barrier. Nature 2020;579:575-580. https://doi.org/10.1038/s41586-020-2039-9
- Eckle SB, Corbett AJ, Keller AN, Chen Z, Godfrey DI, Liu L, Mak JY, Fairlie DP, Rossjohn J, McCluskey J. Recognition of vitamin B precursors and byproducts by mucosal associated invariant T cells. J Biol Chem 2015;290:30204-30211. https://doi.org/10.1074/jbc.R115.685990
- Amini A, Pang D, Hackstein CP, Klenerman P. MAIT cells in barrier tissues: lessons from immediate neighbors. Front Immunol 2020;11:584521.
- Constantinides MG, Link VM, Tamoutounour S, Wong AC, Perez-Chaparro PJ, Han SJ, Chen YE, Li K, Farhat S, Weckel A, et al. MAIT cells are imprinted by the microbiota in early life and promote tissue repair. Science 2019;366:eaax6624.
- Leng T, Akther HD, Hackstein CP, Powell K, King T, Friedrich M, Christoforidou Z, McCuaig S, Neyazi M, Arancibia-Carcamo CV, et al. TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions. Cell Reports 2019;28:3077-3091.e5. https://doi.org/10.1016/j.celrep.2019.08.050
- Nel I, Bertrand L, Toubal A, Lehuen A. MAIT cells, guardians of skin and mucosa? Mucosal Immunol 2021;14:803-814. https://doi.org/10.1038/s41385-021-00391-w
- Hinks TS, Zhang XW. MAIT cell activation and functions. Front Immunol 2020;11:1014.
- Hoytema van Konijnenburg DP, Reis BS, Pedicord VA, Farache J, Victora GD, Mucida D. Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection. Cell 2017;171:783-794.e13. https://doi.org/10.1016/j.cell.2017.08.046
- Agerholm R, Bekiaris V. Evolved to protect, designed to destroy: IL-17-producing γδ T cells in infection, inflammation, and cancer. Eur J Immunol 2021;51:2164-2177. https://doi.org/10.1002/eji.202049119
- Duan J, Chung H, Troy E, Kasper DL. Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing γ/δ T cells. Cell Host Microbe 2010;7:140-150. https://doi.org/10.1016/j.chom.2010.01.005
- Chen YS, Chen IB, Pham G, Shao TY, Bangar H, Way SS, Haslam DB. IL-17-producing γδ T cells protect against Clostridium difficile infection. J Clin Invest 2020;130:2377-2390. https://doi.org/10.1172/JCI127242
- Eberl M. Antigen recognition by human γδ T cells: one step closer to knowing. Immunol Cell Biol 2020;98:351-354. https://doi.org/10.1111/imcb.12334
- Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X, Koren O, Ley R, Wakeland EK, Hooper LV. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 2011;334:255-258. https://doi.org/10.1126/science.1209791
- Ismail AS, Severson KM, Vaishnava S, Behrendt CL, Yu X, Benjamin JL, Ruhn KA, Hou B, DeFranco AL, Yarovinsky F, et al. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci U S A 2011;108:8743-8748. https://doi.org/10.1073/pnas.1019574108
- Sag D, Ozkan M, Kronenberg M, Wingender G. Improved detection of cytokines produced by invariant NKT cells. Sci Rep 2017;7:16607.
- Selvanantham T, Lin Q, Guo CX, Surendra A, Fieve S, Escalante NK, Guttman DS, Streutker CJ, Robertson SJ, Philpott DJ, et al. NKT cell-deficient mice harbor an altered microbiota that fuels intestinal inflammation during chemically induced colitis. J Immunol 2016;197:4464-4472. https://doi.org/10.4049/jimmunol.1601410
- Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, Glickman JN, Siebert R, Baron RM, Kasper DL, et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 2012;336:489-493. https://doi.org/10.1126/science.1219328
- Kushwah R, Hu J. Complexity of dendritic cell subsets and their function in the host immune system. Immunology 2011;133:409-419. https://doi.org/10.1111/j.1365-2567.2011.03457.x
- Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J Exp Med 2007;204:1757-1764. https://doi.org/10.1084/jem.20070590
- Diehl GE, Longman RS, Zhang JX, Breart B, Galan C, Cuesta A, Schwab SR, Littman DR. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX(3)CR1(hi) cells. Nature 2013;494:116-120. https://doi.org/10.1038/nature11809
- Panea C, Farkas AM, Goto Y, Abdollahi-Roodsaz S, Lee C, Koscso B, Gowda K, Hohl TM, Bogunovic M, Ivanov II. Intestinal monocyte-derived macrophages control commensal-specific Th17 responses. Cell Reports 2015;12:1314-1324. https://doi.org/10.1016/j.celrep.2015.07.040
- Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, Segura E, Tussiwand R, Yona S. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol 2014;14:571-578. https://doi.org/10.1038/nri3712
- Hepworth MR, Fung TC, Masur SH, Kelsen JR, McConnell FM, Dubrot J, Withers DR, Hugues S, Farrar MA, Reith W, et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 2015;348:1031-1035. https://doi.org/10.1126/science.aaa4812
- Sonnenberg GF, Hepworth MR. Functional interactions between innate lymphoid cells and adaptive immunity. Nat Rev Immunol 2019;19:599-613. https://doi.org/10.1038/s41577-019-0194-8
- Biton M, Haber AL, Rogel N, Burgin G, Beyaz S, Schnell A, Ashenberg O, Su CW, Smillie C, Shekhar K, et al. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 2018;175:1307-1320.e22. https://doi.org/10.1016/j.cell.2018.10.008
- Goto Y, Panea C, Nakato G, Cebula A, Lee C, Diez MG, Laufer TM, Ignatowicz L, Ivanov II. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 2014;40:594-607. https://doi.org/10.1016/j.immuni.2014.03.005
- Martinez-Lopez M, Iborra S, Conde-Garrosa R, Mastrangelo A, Danne C, Mann ER, Reid DM, GaboriauRouthiau V, Chaparro M, Lorenzo MP, et al. Microbiota sensing by Mincle-Syk axis in dendritic cells regulates interleukin-17 and -22 production and promotes intestinal barrier integrity. Immunity 2019;50:446-461.e9. https://doi.org/10.1016/j.immuni.2018.12.020
- Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A, Dalod M, Soumelis V, Amigorena S. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity 2013;38:336-348. https://doi.org/10.1016/j.immuni.2012.10.018
- Hepworth MR, Monticelli LA, Fung TC, Ziegler CG, Grunberg S, Sinha R, Mantegazza AR, Ma HL, Crawford A, Angelosanto JM, et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 2013;498:113-117. https://doi.org/10.1038/nature12240
- Kedmi R, Najar T, Mesa KR, Grayson A, Kroehling L, Hao Y, Hao S, Pokrovskii M, Xu M, Talbot J, et al. Antigen presentation by type 3 innate lymphoid cells instructs the differentiation of gut microbiotaspecific regulatory T cells. bioRxiv. 2021.11.19.469318; doi:
- Melo-Gonzalez F, Kammoun H, Evren E, Dutton EE, Papadopoulou M, Bradford BM, Tanes C, FardusReid F, Swann JR, Bittinger K, et al. Antigen-presenting ILC3 regulate T cell-dependent IgA responses to colonic mucosal bacteria. J Exp Med 2019;216:728-742. https://doi.org/10.1084/jem.20180871
- Lehmann FM, von Burg N, Ivanek R, Teufel C, Horvath E, Peter A, Turchinovich G, Staehli D, Eichlisberger T, Gomez de Aguero M, et al. Microbiota-induced tissue signals regulate ILC3-mediated antigen presentation. Nat Commun 2020;11:1794.
- Gaudino SJ, Kumar P. Cross-talk between antigen presenting cells and T cells impacts intestinal homeostasis, bacterial infections, and tumorigenesis. Front Immunol 2019;10:360.
- Bland P. MHC class II expression by the gut epithelium. Immunol Today 1988;9:174-178. https://doi.org/10.1016/0167-5699(88)91293-5
- Koyama M, Mukhopadhyay P, Schuster IS, Henden AS, Hulsdunker J, Varelias A, Vetizou M, Kuns RD, Robb RJ, Zhang P, et al. MHC class II antigen presentation by the intestinal epithelium initiates graftversus-host disease and is influenced by the microbiota. Immunity 2019;51:885-898.e7. https://doi.org/10.1016/j.immuni.2019.08.011
- Jamwal DR, Laubitz D, Harrison CA, Figliuolo da Paz V, Cox CM, Wong R, Midura-Kiela M, Gurney MA, Besselsen DG, Setty P, et al. Intestinal epithelial expression of MHCII determines severity of chemical, T-cell-induced, and infectious colitis in mice. Gastroenterology 2020;159:1342-1356.e6. https://doi.org/10.1053/j.gastro.2020.06.049
- Stephens WZ, Kubinak JL, Ghazaryan A, Bauer KM, Bell R, Buhrke K, Chiaro TR, Weis AM, Tang WW, Monts JK, et al. Epithelial-myeloid exchange of MHC class II constrains immunity and microbiota composition. Cell Reports 2021;37:109916.
- Ladinsky MS, Araujo LP, Zhang X, Veltri J, Galan-Diez M, Soualhi S, Lee C, Irie K, Pinker EY, Narushima S, et al. Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science 2019;363:eaat4042.
- Devlin AS, Fischbach MA. A biosynthetic pathway for a prominent class of microbiota-derived bile acids. Nat Chem Biol 2015;11:685-690. https://doi.org/10.1038/nchembio.1864
- Song X, Sun X, Oh SF, Wu M, Zhang Y, Zheng W, Geva-Zatorsky N, Jupp R, Mathis D, Benoist C, et al. Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis. Nature 2020;577:410-415. https://doi.org/10.1038/s41586-019-1865-0
- Hang S, Paik D, Yao L, Kim E, Trinath J, Lu J, Ha S, Nelson BN, Kelly SP, Wu L, et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 2019;576:143-148. https://doi.org/10.1038/s41586-019-1785-z
- Li W, Hang S, Fang Y, Bae S, Zhang Y, Zhang M, Wang G, McCurry MD, Bae M, Paik D, et al. A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1. Cell Host Microbe 2021;29:1366-1377.e9. https://doi.org/10.1016/j.chom.2021.07.013
- Kim CH. Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids. Cell Mol Immunol 2021;18:1161-1171. https://doi.org/10.1038/s41423-020-00625-0
- Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013;504:446-450. https://doi.org/10.1038/nature12721
- Luu M, Pautz S, Kohl V, Singh R, Romero R, Lucas S, Hofmann J, Raifer H, Vachharajani N, Carrascosa LC, et al. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolicepigenetic crosstalk in lymphocytes. Nat Commun 2019;10:760.
- Zhou L, Zhang M, Wang Y, Dorfman RG, Liu H, Yu T, Chen X, Tang D, Xu L, Yin Y, et al. Faecalibacterium prausnitzii produces butyrate to maintain Th17/Treg balance and to ameliorate colorectal colitis by inhibiting Histone Deacetylase 1. Inflamm Bowel Dis 2018;24:1926-1940. https://doi.org/10.1093/ibd/izy182
- Dupraz L, Magniez A, Rolhion N, Richard ML, Da Costa G, Touch S, Mayeur C, Planchais J, Agus A, Danne C, et al. Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ T cells. Cell Reports 2021;36:109332.
- Chun E, Lavoie S, Fonseca-Pereira D, Bae S, Michaud M, Hoveyda HR, Fraser GL, Gallini Comeau CA, Glickman JN, Fuller MH, et al. Metabolite-sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity. Immunity 2019;51:871-884.e6. https://doi.org/10.1016/j.immuni.2019.09.014
- Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 2018;23:716-724. https://doi.org/10.1016/j.chom.2018.05.003
- Shinde R, McGaha TL. The aryl hydrocarbon receptor: Connecting immunity to the microenvironment. Trends Immunol 2018;39:1005-1020. https://doi.org/10.1016/j.it.2018.10.010
- Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008;453:65-71. https://doi.org/10.1038/nature06880
- Veldhoen M, Hirota K, Christensen J, O'Garra A, Stockinger B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 2009;206:43-49. https://doi.org/10.1084/jem.20081438
- Chinen I, Nakahama T, Kimura A, Nguyen NT, Takemori H, Kumagai A, Kayama H, Takeda K, Lee S, Hanieh H, et al. The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis. Int Immunol 2015;27:405-415. https://doi.org/10.1093/intimm/dxv015
- Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limon P, Paiva RS, Ching T, et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015;523:221-225. https://doi.org/10.1038/nature14452
- Ye J, Qiu J, Bostick JW, Ueda A, Schjerven H, Li S, Jobin C, Chen ZE, Zhou L. The aryl hydrocarbon receptor preferentially marks and promotes gut regulatory T cells. Cell Reports 2017;21:2277-2290. https://doi.org/10.1016/j.celrep.2017.10.114
- Xiong L, Dean JW, Fu Z, Oliff KN, Bostick JW, Ye J, Chen ZE, Muhlbauer M, Zhou L. Ahr-Foxp3-RORγt axis controls gut homing of CD4+ T cells by regulating GPR15. Sci Immunol 2020;5:eaaz7277.
- Schiering C, Wincent E, Metidji A, Iseppon A, Li Y, Potocnik AJ, Omenetti S, Henderson CJ, Wolf CR, Nebert DW, et al. Feedback control of AHR signalling regulates intestinal immunity. Nature 2017;542:242-245. https://doi.org/10.1038/nature21080
- Davis TA, Conradie D, Shridas P, de Beer FC, Engelbrecht AM, de Villiers WJ. Serum amyloid A promotes inflammation-associated damage and tumorigenesis in a mouse model of colitis-associated cancer. Cell Mol Gastroenterol Hepatol 2021;12:1329-1341. https://doi.org/10.1016/j.jcmgh.2021.06.016
- Gattu S, Bang YJ, Pendse M, Dende C, Chara AL, Harris TA, Wang Y, Ruhn KA, Kuang Z, Sockanathan S, et al. Epithelial retinoic acid receptor β regulates serum amyloid A expression and vitamin A-dependent intestinal immunity. Proc Natl Acad Sci U S A 2019;116:10911-10916. https://doi.org/10.1073/pnas.1812069116
- Bang YJ, Hu Z, Li Y, Gattu S, Ruhn KA, Raj P, Herz J, Hooper LV. Serum amyloid A delivers retinol to intestinal myeloid cells to promote adaptive immunity. Science 2021;373:eabf9232.
- Caruso R, Lo BC, Nunez G. Host-microbiota interactions in inflammatory bowel disease. Nat Rev Immunol 2020;20:411-426. https://doi.org/10.1038/s41577-019-0268-7
- Zhao J, Lu Q, Liu Y, Shi Z, Hu L, Zeng Z, Tu Y, Xiao Z, Xu Q. Th17 cells in inflammatory bowel disease: Cytokines, plasticity, and therapies. J Immunol Res 2021;2021:8816041.
- Hovhannisyan Z, Treatman J, Littman DR, Mayer L. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology 2011;140:957-965. https://doi.org/10.1053/j.gastro.2010.12.002
- Quevrain E, Maubert MA, Michon C, Chain F, Marquant R, Tailhades J, Miquel S, Carlier L, BermudezHumaran LG, Pigneur B, et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease. Gut 2016;65:415-425. https://doi.org/10.1136/gutjnl-2014-307649
- Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011;331:337-341. https://doi.org/10.1126/science.1198469
- Patterson AM, Mulder IE, Travis AJ, Lan A, Cerf-Bensussan N, Gaboriau-Routhiau V, Garden K, Logan E, Delday MI, Coutts AG, et al. Human gut symbiont Roseburia hominis promotes and regulates innate immunity. Front Immunol 2017;8:1166.
- Glassner KL, Abraham BP, Quigley EM. The microbiome and inflammatory bowel disease. J Allergy Clin Immunol 2020;145:16-27. https://doi.org/10.1016/j.jaci.2019.11.003
- Ryan FJ, Ahern AM, Fitzgerald RS, Laserna-Mendieta EJ, Power EM, Clooney AG, O'Donoghue KW, McMurdie PJ, Iwai S, Crits-Christoph A, et al. Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease. Nat Commun 2020;11:1512.
- Mar JS, LaMere BJ, Lin DL, Levan S, Nazareth M, Mahadevan U, Lynch SV. Disease severity and immune activity relate to distinct interkingdom gut microbiome states in ethnically distinct ulcerative colitis patients. MBio 2016;7:e01072-16.
- Viljoen KS, Dakshinamurthy A, Goldberg P, Blackburn JM. Quantitative profiling of colorectal cancerassociated bacteria reveals associations between fusobacterium spp., enterotoxigenic Bacteroides fragilis (ETBF) and clinicopathological features of colorectal cancer. PLoS One 2015;10:e0119462.
- Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, et al. Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells. Cell Host Microbe 2018;23:203-214.e5. https://doi.org/10.1016/j.chom.2018.01.007
- Lo Presti E, Di Mitri R, Mocciaro F, Di Stefano AB, Scibetta N, Unti E, Cicero G, Pecoraro G, Conte E, Dieli F, et al. Characterization of γδT cells in intestinal mucosa from patients with early-onset or long-standing inflammatory bowel disease and their correlation with clinical status. J Crohn's Colitis 2019;13:873-883. https://doi.org/10.1093/ecco-jcc/jjz015
- Sinha SR, Haileselassie Y, Nguyen LP, Tropini C, Wang M, Becker LS, Sim D, Jarr K, Spear ET, Singh G, et al. Dysbiosis-induced secondary bile acid deficiency promotes intestinal inflammation. Cell Host Microbe 2020;27:659-670.e5. https://doi.org/10.1016/j.chom.2020.01.021
- Zhu C, Song K, Shen Z, Quan Y, Tan B, Luo W, Wu S, Tang K, Yang Z, Wang X. Roseburia intestinalis inhibits interleukin-17 excretion and promotes regulatory T cells differentiation in colitis. Mol Med Rep 2018;17:7567-7574. https://doi.org/10.3892/mmr.2018.8833
- Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005;122:107-118. https://doi.org/10.1016/j.cell.2005.05.007
- Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 2008;453:620-625. https://doi.org/10.1038/nature07008
- Zamani S, Hesam Shariati S, Zali MR, Asadzadeh Aghdaei H, Sarabi Asiabar A, Bokaie S, Nomanpour B, Sechi LA, Feizabadi MM. Detection of enterotoxigenic Bacteroides fragilis in patients with ulcerative colitis. Gut Pathog 2017;9:53.
- Png CW, Linden SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, McGuckin MA, Florin TH. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 2010;105:2420-2428. https://doi.org/10.1038/ajg.2010.281
- Geuking MB, Burkhard R. Microbial modulation of intestinal T helper cell responses and implications for disease and therapy. Mucosal Immunol 2020;13:855-866. https://doi.org/10.1038/s41385-020-00335-w
- Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, Vandamme P, Vermeire S. Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives. Gut 2011;60:631-637. https://doi.org/10.1136/gut.2010.223263
- Khan I, Ullah N, Zha L, Bai Y, Khan A, Zhao T, Che T, Zhang C. Alteration of gut microbiota in inflammatory bowel disease (IBD): Cause or consequence? IBD treatment targeting the gut microbiome. Pathogens 2019;8:E126.
- Bilsborough J, Targan SR, Snapper SB. Therapeutic targets in inflammatory bowel disease: current and future. The American Journal of Gastroenterology Supplements 2016;3:27-37. https://doi.org/10.1038/ajgsup.2016.18
- James KR, Elmentaite R, Teichmann SA, Hold GL. Redefining intestinal immunity with single-cell transcriptomics. Mucosal Immunol 2022;15:531-541. https://doi.org/10.1038/s41385-021-00470-y
- Jaeger N, Gamini R, Cella M, Schettini JL, Bugatti M, Zhao S, Rosadini CV, Esaulova E, Di Luccia B, Kinnett B, et al. Single-cell analyses of Crohn's disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions. Nat Commun 2021;12:1921.
- Martin JC, Chang C, Boschetti G, Ungaro R, Giri M, Grout JA, Gettler K, Chuang LS, Nayar S, Greenstein AJ, et al. Single-cell analysis of Crohn's disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell 2019;178:1493-1508.e20. https://doi.org/10.1016/j.cell.2019.08.008
- Li G, Zhang B, Hao J, Chu X, Wiestler M, Cornberg M, Xu CJ, Liu X, Li Y. Identification of novel population-specific cell subsets in Chinese Ulcerative Colitis patients using single-cell RNA sequencing. Cell Mol Gastroenterol Hepatol 2021;12:99-117. https://doi.org/10.1016/j.jcmgh.2021.01.020
- Smillie CS, Biton M, Ordovas-Montanes J, Sullivan KM, Burgin G, Graham DB, Herbst RH, Rogel N, Slyper M, Waldman J, et al. Intra- and inter-cellular rewiring of the human colon during Ulcerative Colitis. Cell 2019;178:714-730.e22. https://doi.org/10.1016/j.cell.2019.06.029
- Bigaeva E, Uniken Venema WT, Weersma RK, Festen EA. Understanding human gut diseases at singlecell resolution. Hum Mol Genet 2020;29 R1:R51-R58. https://doi.org/10.1093/hmg/ddaa130
- Kameyama H, Nagahashi M, Shimada Y, Tajima Y, Ichikawa H, Nakano M, Sakata J, Kobayashi T, Narayanan S, Takabe K, et al. Genomic characterization of colitis-associated colorectal cancer. World J Surg Oncol 2018;16:121.
- Ning C, Li YY, Wang Y, Han GC, Wang RX, Xiao H, Li XY, Hou CM, Ma YF, Sheng DS, et al. Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1β/IL-17A axis. Mucosal Immunol 2015;8:1275-1284. https://doi.org/10.1038/mi.2015.18
- Baxter NT, Zackular JP, Chen GY, Schloss PD. Structure of the gut microbiome following colonization with human feces determines colonic tumor burden. Microbiome 2014;2:20.
- Ahn J, Sinha R, Pei Z, Dominianni C, Wu J, Shi J, Goedert JJ, Hayes RB, Yang L. Human gut microbiome and risk for colorectal cancer. J Natl Cancer Inst 2013;105:1907-1911. https://doi.org/10.1093/jnci/djt300
- Richard ML, Liguori G, Lamas B, Brandi G, da Costa G, Hoffmann TW, Pierluigi Di Simone M, Calabrese C, Poggioli G, Langella P, et al. Mucosa-associated microbiota dysbiosis in colitis associated cancer. Gut Microbes 2018;9:131-142. https://doi.org/10.1080/19490976.2017.1379637
- Shao X, Sun S, Zhou Y, Wang H, Yu Y, Hu T, Yao Y, Zhou C. Bacteroides fragilis restricts colitis-associated cancer via negative regulation of the NLRP3 axis. Cancer Lett 2021;523:170-181. https://doi.org/10.1016/j.canlet.2021.10.002
- Wang Z, Hua W, Li C, Chang H, Liu R, Ni Y, Sun H, Li Y, Wang X, Hou M, et al. Protective role of fecal microbiota transplantation on colitis and colitis-associated colon cancer in mice is associated with Treg cells. Front Microbiol 2019;10:2498.
- Panaccione R, Sandborn WJ, Gordon GL, Lee SD, Safdi A, Sedghi S, Feagan BG, Hanauer S, Reinisch W, Valentine JF, et al. Briakinumab for treatment of Crohn's disease: results of a randomized trial. Inflamm Bowel Dis 2015;21:1329-1340. https://doi.org/10.1097/MIB.0000000000000366
- Ito H, Takazoe M, Fukuda Y, Hibi T, Kusugami K, Andoh A, Matsumoto T, Yamamura T, Azuma J, Nishimoto N. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 2004;126:989-996. https://doi.org/10.1053/j.gastro.2004.01.012
- Targan SR, Feagan BG, Vermeire S, Panaccione R, Melmed GY, Blosch C, Newmark R, Zhang N, Chon Y, Lin SL, et al. Mo2083 a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of AMG 827 in subjects with moderate to severe Crohn's disease. Gastroenterology 2012;143:e26.
- Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, Johanns J, Blank M, Rutgeerts P; Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 2008;135:1130-1141. https://doi.org/10.1053/j.gastro.2008.07.014
- Cai Z, Wang S, Li J. Treatment of inflammatory bowel disease: a comprehensive review. Front Med (Lausanne) 2021;8:765474.
- Henn MR, O'Brien EJ, Diao L, Feagan BG, Sandborn WJ, Huttenhower C, Wortman JR, McGovern BH, Wang-Weigand S, Lichter DI, et al. A phase 1b safety study of SER-287, a spore-based microbiome therapeutic, for active mild to moderate ulcerative colitis. Gastroenterology 2021;160:115-127.e30. https://doi.org/10.1053/j.gastro.2020.07.048
- Silber J, Norman J, Kanno T, Crossette E, Szabady R, Menon R, Marko M, Olle B, Lamouse-Smith E. Randomized, double-blind, placebo (PBO)-controlled, single- and multiple-dose phase 1 study of VE202, a defined bacterial consortium for treatment of IBD: safety and colonization dynamics of a novel live biotherapeutic product (LBP) in healthy adults. Inflamm Bowel Dis 2022;28 Suppl 1:S65-S66. https://doi.org/10.1093/ibd/izac015.106