REVIEW

Microbial sensing in the intestine

  • Tingting Wan 1 ,
  • Yalong Wang 1 ,
  • Kaixin He 1 ,
  • Shu Zhu , 1,2,3
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  • 1. Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
  • 2. Department of Digestive Disease, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China
  • 3. Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China
zhushu@ustc.edu.cn

Received date: 21 Mar 2023

Accepted date: 04 May 2023

Published date: 15 Nov 2023

Copyright

2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.

Abstract

The gut microbiota plays a key role in host health and disease, particularly through their interactions with the immune system. Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota, which is influenced by the highly co-evolved immune–microbiota interactions. The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system. In this review, we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes. We further highlight the essential roles of pattern recognition receptors (PRRs), the G protein-coupled receptors (GPCRs), aryl hydrocarbon receptor (AHR) and the nuclear receptors expressed in the intestinal epithelial cells (IECs) and the intestine-resident immune cells. We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease (IBD).

Cite this article

Tingting Wan , Yalong Wang , Kaixin He , Shu Zhu . Microbial sensing in the intestine[J]. Protein & Cell, 2023 , 14(11) : 824 -860 . DOI: 10.1093/procel/pwad028

1
Abdel-Gadir A, Stephen-Victor E, Gerber GK et al. Microbiota therapy acts via a regulatory T cell MyD88/RORγt pathway to suppress food allergy. Nat Med 2019;25:1164–1174.

DOI

2
Adiliaghdam F, Amatullah H, Digumarthi S et al. Human enteric viruses autonomously shape inflammatory bowel disease phenotype through divergent innate immunomodulation. Sci Immunol 2022;7:eabn6660.

DOI

3
Afrazi A, Branca MF, Sodhi CP et al. Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis. J Biol Chem 2014;289:9584–9599.

DOI

4
Afshan FU, Masood A, Nissar B et al. Promoter hypermethylation regulates vitamin D receptor (VDR) expression in colorectal cancer—a study from Kashmir valley. Cancer Genet 2021;252–253:96–106.

DOI

5
Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 2018;23:716–724.

DOI

6
Aksentijevich I, Nowak M, Mallah M et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 2002;46:3340–3348.

DOI

7
Albaugh VL, Banan B, Antoun J et al. Role of bile acids and GLP-1 in mediating the metabolic improvements of bariatric surgery. Gastroenterology 2019;156:1041–1051.e1044.

DOI

8
Alemi F, Poole DP, Chiu J et al. The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 2013;144:145–154.

DOI

9
Aliprantis AO, Yang RB, Mark MR et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 1999;285:736–739.

DOI

10
Allam R, Maillard MH, Tardivel A et al. Epithelial NAIPs protect against colonic tumorigenesis. J Exp Med 2015;212:369–383.

DOI

11
Allen IC, TeKippe EM, Woodford RM et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis- associated cancer. J Exp Med 2010;207:1045–1056.

DOI

12
Allen IC, Wilson JE, Schneider M et al. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling. Immunity 2012;36:742–754.

DOI

13
Anand PK, Malireddi RK, Lukens JR et al. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 2012;488:389–393.

DOI

14
Anitha M, Vijay-Kumar M, Sitaraman SV et al. Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology 2012;143:1006–1016.e1004.

DOI

15
Armstrong HK, Bording-Jorgensen M, Santer DM et al. Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients. Gastroenterology 2023;164:228–240.

DOI

16
Arpaia N, Campbell C, Fan X et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013;504:451–455.

DOI

17
Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol 2008;8:411–420.

DOI

18
Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911–920.

DOI

19
Bae M, Cassilly CD, Liu X et al. Akkermansia muciniphila phospholipid induces homeostatic immune responses. Nature 2022;608:168–173.

DOI

20
Banerjee A, Herring CA, Chen B et al. Succinate produced by intestinal microbes promotes specification of tuft cells to suppress ileal inflammation. Gastroenterology 2020;159:2101–2115.e2105.

DOI

21
Bauer C, Duewell P, Mayer C et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 2010;59:1192–1199.

DOI

22
Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet 2007;369:1627–1640.

DOI

23
Becker L, Spear ET, Sinha SR et al. Age-related changes in gut microbiota alter phenotype of Muscularis macrophages and disrupt gastrointestinal motility. Cell Mol Gastroenterol Hepatol 2019;7:243–245.e242.

DOI

24
Beilmann-Lehtonen I, Hagström J, Mustonen H et al. High tissue TLR5 expression predicts better outcomes in colorectal cancer patients. Oncology (Huntingt) 2021;99:589–600.

DOI

25
Bendix M, Dige A, Deleuran B et al. Flow cytometry detection of vitamin D receptor changes during vitamin D treatment in Crohn’s disease. Clin Exp Immunol 2015;181:19–28.

DOI

26
Beraud D, Maguire-Zeiss KA. Misfolded alpha-synuclein and Toll-like receptors: therapeutic targets for Parkinson’s disease. Parkinsonism Relat Disord 2012;18:S17–S20.

DOI

27
Bhinder G, Stahl M, Sham HP et al. Intestinal epithelium-specific MyD88 signaling impacts host susceptibility to infectious colitis by promoting protective goblet cell and antimicrobial responses. Infect Immun 2014;82:3753–3763.

DOI

28
Biagioli M, Carino A, Cipriani S et al. The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis. J Immunol 2017;199:718–733.

DOI

29
Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 2012;30:733–758.

DOI

30
Birchenough GM, Nyström EE, Johansson ME et al. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science 2016;352:1535–1542.

DOI

31
Biswas A, Liu YJ, Hao L et al. Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc Natl Acad Sci USA 2010;107:14739–14744.

DOI

32
Bódi N, Egyed-Kolumbán A, Onhausz B et al. Intestinal region-dependent alterations of toll-like receptor 4 expression in myenteric neurons of Type 1 diabetic rats. Biomedicines 2023;11:129.

DOI

33
Booshehri LM, Hoffman HM. CAPS and NLRP3. J Clin Immunol 2019;39:277–286.

DOI

34
Bostick JW, Zhou L. Innate lymphoid cells in intestinal immunity and inflammation. Cell Mol Life Sci 2016;73:237–252.

DOI

35
Bouskra D, Brezillon C, Berard M et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 2008;456:507–510.

DOI

36
Brackett CM, Kojouharov B, Veith J et al. Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8+ T-cell axis. Proc Natl Acad Sci USA 2016;113:E874–E883.

DOI

37
Brevini T, Maes M, Webb GJ et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature 2023a;615(7950):134–142. Epub 2022 Dec 5.

38
Brevini T, Maes M, Webb GJ et al. UK-PBC Consortium. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature 2023b;615:134–142.

39
Brisse M, Ly H. Comparative structure and function analysis of the RIG-I-like receptors: RIG-I and MDA5. Front Immunol 2019;10:1586.

DOI

40
Broquet AH, Hirata Y, McAllister CS et al. RIG-I/MDA5/MAVS are required to signal a protective IFN response in rotavirus-in-fected intestinal epithelium. J Immunol 2011;186:1618–1626.

DOI

41
Brubaker SW, Bonham KS, Zanoni I et al. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 2015;33:257–290.

DOI

42
Brun P, Giron MC, Qesari M et al. Toll-like receptor 2 regulates intestinal inflammation by controlling integrity of the enteric nervous system. Gastroenterology 2013;145:1323–1333.

DOI

43
Bruns AM, Leser GP, Lamb RA et al. The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5–RNA interaction and filament assembly. Mol Cell 2014;55:771–781.

DOI

44
Burgueno JF, Abreu MT. Epithelial toll-like receptors and their role in gut homeostasis and disease. Nat Rev Gastroenterol Hepatol 2020;17:263–278.

DOI

45
Burgueño JF, Barba A, Eyre E et al. TLR2 and TLR9 modulate enteric nervous system inflammatory responses to lipopolysaccharide. J Neuroinflammation 2016;13:187.

DOI

46
Burgueño JF, Fritsch J, González EE et al. Epithelial TLR4 signaling activates DUOX2 to induce microbiota-driven tumorigenesis. Gastroenterology 2021;160:797–808.e796.

DOI

47
Cadwell K, Patel KK, Maloney NS et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 2010;141:1135–1145.

DOI

48
Caesar R, Tremaroli V, Kovatcheva-Datchary P et al. Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab 2015;22:658–668.

DOI

49
Candia E, Díaz-Jiménez D, Langjahr P et al. Increased production of soluble TLR2 by lamina propria mononuclear cells from ulcerative colitis patients. Immunobiology 2012;217:634–642.

DOI

50
Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761–1772.

DOI

51
Cani PD, Bibiloni R, Knauf C et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–1481.

DOI

52
Cao AT, Yao S, Gong B et al. Interleukin (IL)-21 promotes intestinal IgA response to microbiota. Mucosal Immunol 2015;8:1072–1082.

DOI

53
Caramalho I, Lopes-Carvalho T, Ostler D et al. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 2003;197:403–411.

DOI

54
Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 2000;68:7010–7017.

DOI

55
Cario E, Gerken G, Podolsky DK. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 2007;132:1359–1374.

DOI

56
Carvalho FA, Koren O, Goodrich JK et al. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 2012a;12:139–152.

DOI

57
Carvalho FA, Nalbantoglu I, Aitken JD et al. Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges. Mucosal Immunol 2012b;5:288–298.

DOI

58
Carvalho FA, Nalbantoglu I, Ortega-Fernandez S et al. Interleukin-1β (IL-1β) promotes susceptibility of Toll-like receptor 5 (TLR5) deficient mice to colitis. Gut 2012c;61:373–384.

DOI

59
Castro FA, Försti A, Buch S et al. TLR-3 polymorphism is an independent prognostic marker for stage II colorectal cancer. Eur J Cancer 2011;47:1203–1210.

DOI

60
Ceglia S, Berthelette A, Howley K et al. An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells. Nat Immunol 2023;24(3):531–544. Epub 2023 Jan 19.

DOI

61
Chamaillard M, Hashimoto M, Horie Y et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 2003;4:702–707.

DOI

62
Chan GC, Chan WK, Sze DM. The effects of beta-glucan on human immune and cancer cells. J Hematol Oncol 2009;2:25.

DOI

63
Chang PV, Hao L, Offermanns S et al. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA 2014;111:2247–2252.

DOI

64
Chaniotou Z, Giannogonas P, Theoharis S et al. Corticotropin-releasing factor regulates TLR4 expression in the colon and protects mice from colitis. Gastroenterology 2010;139:2083–2092.

DOI

65
Chassaing B, Ley RE, Gewirtz AT. Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice. Gastroenterology 2014;147:1363–77.e1317.

DOI

66
Chatterjee I, Zhang Y, Zhang J et al. Overexpression of Vitamin D receptor in intestinal epithelia protects against colitis via upregulating tight junction protein Claudin 15. J Crohns Colitis 2021;15:1720–1736.

DOI

67
Chaudhari SN, Harris DA, Aliakbarian H et al. Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects. Nat Chem Biol 2021;17:20–29.

DOI

68
Chehoud C, Albenberg LG, Judge C et al. Fungal signature in the gut microbiota of pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2015;21:1948–1956.

DOI

69
Chen Q, Davidson TS, Huter EN et al. Engagement of TLR2 does not reverse the suppressor function of mouse regulatory T cells, but promotes their survival. J Immunol 2009;183:4458–4466.

DOI

70
Chen GY, Liu M, Wang F et al. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J Immunol 2011;186:7187–7194.

DOI

71
Chen SG, Stribinskis V, Rane MJ et al. Exposure to the functional bacterial amyloid protein Curli enhances alpha-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans. Sci Rep 2016;6:34477.

DOI

72
Chen L, Wilson JE, Koenigsknecht MJ et al. NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat Immunol 2017;18:541–551.

DOI

73
Chen T, Li Q, Wu J et al. Fusobacterium nucleatum promotes M2 polarization of macrophages in the microenvironment of colorectal tumours via a TLR4-dependent mechanism. Cancer Immunol Immunother 2018;67:1635–1646.

DOI

74
Chen D, Jin D, Huang S et al. Clostridium butyricum, a butyrate-producing probiotic, inhibits intestinal tumor development through modulating Wnt signaling and gut microbiota. Cancer Lett 2020a;469:456–467.

DOI

75
Chen X, Yang X, de Anda J et al. Clostridioides difficile toxin A remodels membranes and mediates DNA entry into cells to activate toll-like receptor 9 signaling. Gastroenterology 2020b;159:2181–2192.e2181.

DOI

76
Chen C, Fang S, Wei H et al. Prevotella copri increases fat accumulation in pigs fed with formula diets. Microbiome 2021a;9:175.

DOI

77
Chen E, Chuang LS, Giri M et al. Inflamed ulcerative colitis regions associated With MRGPRX2-mediated mast cell degranulation and cell activation modules, defining a new therapeutic target. Gastroenterology 2021b;160:1709–1724.

DOI

78
Chen L, Jiao T, Liu W et al. Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal. Cell Stem Cell 2022;29:1366–1381.e9.

DOI

79
Cheng K, Gao M, Godfroy JI et al. Specific activation of the TLR1–TLR2 heterodimer by small-molecule agonists. Sci Adv 2015;1(3):e1400139.

DOI

80
Chinen I, Nakahama T, Kimura A 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.

DOI

81
Chou WC, Guo Z, Guo H et al. AIM2 in regulatory T cells restrains autoimmune diseases. Nature 2021;591:300–305.

DOI

82
Chu H, Khosravi A, Kusumawardhani IP et al. Gene–microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 2016;352:1116–1120.

DOI

83
Chuang T, Ulevitch RJ. Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim Biophys Acta 2001;1518:157–161.

DOI

84
Chun E, Lavoie S, Fonseca-Pereira D et al. Metabolite-sensing receptor Ffar2 regulates colonic Group 3 innate lymphoid cells and gut immunity. Immunity 2019;51:871–884.e876.

DOI

85
Cipriani S, Mencarelli A, Chini MG et al. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One 2011;6:e25637.

DOI

86
Clasen SJ, Bell MEW, Borbón A et al. Silent recognition of flagellins from human gut commensal bacteria by Toll-like receptor 5. Sci Immunol 2023;8:eabq7001.

DOI

87
Cleynen I, González JR, Figueroa C et al. Genetic factors conferring an increased susceptibility to develop Crohn’s disease also influence disease phenotype: results from the IBDchip European Project. Gut 2013;62:1556–1565.

DOI

88
Cohen LJ, Kang HS, Chu J et al. Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist. Proc Natl Acad Sci USA 2015;112:E4825–E4834.

DOI

89
Cohen LJ, Esterhazy D, Kim SH et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature 2017;549:48–53.

DOI

90
Cohen-Kedar S, Baram L, Elad H et al. Human intestinal epithelial cells respond to beta-glucans via Dectin-1 and Syk. Eur J Immunol 2014;44:3729–3740.

DOI

91
Coll RC, Schroder K, Pelegrín P. NLRP3 and pyroptosis blockers for treating inflammatory diseases. Trends Pharmacol Sci 2022;43:653–668.

DOI

92
Coman D, Coales I, Roberts LB et al. Helper-like Type-1 innate lymphoid cells in inflammatory bowel disease. Front Immunol 2022;13:903688.

DOI

93
Conforti-Andreoni C, Ricciardi-Castagnoli P, Mortellaro A. The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond. Cell Mol Immunol 2011;8:135–145.

DOI

94
Cooney R, Baker J, Brain O et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 2010;16:90–97.

DOI

95
Couturier-Maillard A, Secher T, Rehman A et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest 2013;123:700–711.

DOI

96
Cuevas-Ramos G, Petit CR, Marcq I et al. Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc Natl Acad Sci USA 2010;107:11537–11542.

DOI

97
Cui S, Wang C, Bai W et al. CD1d1 intrinsic signaling in macrophages controls NLRP3 inflammasome expression during inflammation. Sci Adv 2020;6(43):eaaz7290.

DOI

98
Cullender TC, Chassaing B, Janzon A et al. Innate and adaptive immunity interact to quench microbiome flagellar motility in the gut. Cell Host Microbe 2013;14:571–581.

DOI

99
Cummings JR, Cooney RM, Clarke G et al. The genetics of NOD-like receptors in Crohn’s disease. Tissue Antigens 2010;76:48–56.

DOI

100
D’Aldebert E, Biyeyeme Bi Mve MJ, Mergey M et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology 2009;136:1435–1443.

DOI

101
Dang EV, McDonald JG, Russell DW et al. Oxysterol restraint of cholesterol synthesis prevents AIM2 inflammasome activation. Cell 2017;171:1057–1071.e1011.

DOI

102
DeMoss RD, Moser K. Tryptophanase in diverse bacterial species. J Bacteriol 1969;98:167–171.

DOI

103
Depommier C, Everard A, Druart C et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 2019;25:1096–1103.

DOI

104
De Salvo C, Buela KA, Creyns B et al. NOD2 drives early IL-33-dependent expansion of group 2 innate lymphoid cells during Crohn’s disease-like ileitis. J Clin Invest 2021;131(5):e140624.

DOI

105
De Vadder F, Kovatcheva-Datchary P, Goncalves D et al. Microbiota-generated metabolites promote metabolic benefits via gut–brain neural circuits. Cell 2014;156:84–96.

DOI

106
de Zoete MR, Flavell RA. Interactions between nod-like receptors and intestinal bacteria. Front Immunol 2013;4:462.

DOI

107
de Zoete MR, Palm NW, Zhu S et al. Inflammasomes. Cold Spring Harb Perspect Biol 2014;6:a016287.

DOI

108
Díaz-Díaz CJ, Ronnekleiv-Kelly SM, Nukaya M et al. The Aryl Hydrocarbon Receptor is a repressor of inflammation-associated colorectal tumorigenesis in mouse. Ann Surg 2016;264:429–436.

DOI

109
Dinan TG, Stilling RM, Stanton C et al. Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res 2015;63:1–9.

DOI

110
Ding L, Sousa KM, Jin L et al. Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice. Hepatology 2016;64:760–773.

DOI

111
Docampo MD, da Silva MB, Lazrak A et al. Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease. Blood 2022;139:2392–2405.

DOI

112
Du J, Chen Y, Shi Y et al. 1,25-Dihydroxyvitamin D protects intestinal epithelial barrier by regulating the Myosin Light Chain Kinase Signaling Pathway. Inflamm Bowel Dis 2015;21:2495–2506.

DOI

113
Duan JL, He HQ, Yu Y et al. E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation. Sci Adv 2021;7(19):eabe5171.

DOI

114
Elinav E, Strowig T, Kau AL et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 2011;145:745–757.

DOI

115
Elson CO, Alexander KL. Host–microbiota interactions in the intestine. Dig Dis 2015;33:131–136.

DOI

116
Eriksson M, Johannssen T, von Smolinski D et al. The C-Type lectin receptor SIGNR3 binds to fungi present in commensal microbiota and influences immune regulation in experimental colitis. Front Immunol 2013;4:196.

DOI

117
Eshleman EM, Alenghat T. Epithelial sensing of microbiota-derived signals. Genes Immun 2021;22:237–246.

DOI

118
Fagarasan S, Muramatsu M, Suzuki K et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science 2002;298:1424–1427.

DOI

119
Fang S, Suh JM, Reilly SM et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015;21:159–165.

DOI

120
Fang Y, Yan C, Zhao Q et al. The association between gut microbiota, toll-like receptors, and colorectal cancer. Clin Med Insights Oncol 2022;16:11795549221130549.

DOI

121
Feldmann J, Prieur AM, Quartier P et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 2002;71:198–203.

DOI

122
Fernández-Barral A, Costales-Carrera A, Buira SP et al. Vitamin D differentially regulates colon stem cells in patient-derived normal and tumor organoids. FEBS J 2020;287:53–72.

DOI

123
Fischer JC, Bscheider M, Eisenkolb G et al. RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. Sci Transl Med 2017;9(386):eaag2513.

DOI

124
Flannigan KL, Ngo VL, Geem D et al. IL-17A-mediated neutrophil recruitment limits expansion of segmented filamentous bacteria. Mucosal Immunol 2017;10:673–684.

DOI

125
Franchi L, Amer A, Body-Malapel M et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella- infected macrophages. Nat Immunol 2006;7:576–582.

DOI

126
Franchi L, Kamada N, Nakamura Y et al. NLRC4-driven production of IL-1beta discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat Immunol 2012;13:449–456.

DOI

127
Frank M, Hennenberg EM, Eyking A et al. TLR signaling modulates side effects of anticancer therapy in the small intestine. J Immunol 2015;194:1983–1995.

DOI

128
Franzosa EA, Hsu T, Sirota-Madi A et al. Sequencing and beyond: integrating molecular ‘omics’ for microbial community profiling. Nat Rev Microbiol 2015;13:360–372.

DOI

129
Friedland RP. Mechanisms of molecular mimicry involving the microbiota in neurodegeneration. J Alzheimers Dis 2015;45:349–362.

DOI

130
Fritz JH, Ferrero RL, Philpott DJ et al. Nod-like proteins in immunity, inflammation and disease. Nat Immunol 2006;7:1250–1257.

DOI

131
Frosali S, Pagliari D, Gambassi G et al. How the intricate interaction among toll-like receptors, microbiota, and intestinal immunity can influence gastrointestinal pathology. J Immunol Res 2015;2015:489821.

DOI

132
Fu T, Coulter S, Yoshihara E et al. FXR regulates intestinal cancer stem cell proliferation. Cell 2019;176:1098–1112.e1018.

DOI

133
Fujiwara H, Docampo MD, Riwes M et al. Microbial metabolite sensor GPR43 controls severity of experimental GVHD. Nat Commun 2018;9:3674.

DOI

134
Fukata M, Michelsen KS, Eri R et al. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol 2005;288:G1055–G1065.

DOI

135
Fukata M, Breglio K, Chen A et al. The myeloid differentiation factor 88 (MyD88) is required for CD4+ T cell effector function in a murine model of inflammatory bowel disease. J Immunol 2008;180:1886–1894.

DOI

136
Fulde M, Sommer F, Chassaing B et al. Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition. Nature 2018;560:489–493.

DOI

137
Furman D, Chang J, Lartigue L et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat Med 2017;23:174–184.

DOI

138
Furusawa Y, Obata Y, Fukuda S et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013;504:446–450.

DOI

139
Gadaleta RM, van Erpecum KJ, Oldenburg B et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011;60:463–472.

DOI

140
Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 2003;3:710–720.

DOI

141
Gao C, Qiao T, Zhang B et al. TLR9 signaling activation at different stages in colorectal cancer and NF-kappaB expression. Onco Targets Ther 2018;11:5963–5971.

DOI

142
Gao H, Luo Z, Ji Y et al. Accumulation of microbial DNAs promotes to islet inflammation and β cell abnormalities in obesity in mice. Nat Commun 2022a;13:565.

DOI

143
Gao J, Zhao X, Hu S et al. Gut microbial dl-endopeptidase alleviates Crohn’s disease via the NOD2 pathway. Cell Host Microbe 2022b;30:1435–1449.e9.

DOI

144
Gao H, Zhou H, Zhang Z et al. Vitamin D3 alleviates inflammation in ulcerative colitis by activating the VDR-NLRP6 signaling pathway. Front Immunol 2023;14:1135930.

DOI

145
Gelman AE, LaRosa DF, Zhang J et al. The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation. Immunity 2006;25:783–793.

DOI

146
Geremia A, Biancheri P, Allan P et al. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev 2014;13:3–10.

DOI

147
Geuking MB, Cahenzli J, Lawson MA et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 2011;34:794–806.

DOI

148
Gewirtz AT, Navas TA, Lyons S et al. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 2001;167:1882–1885.

DOI

149
Ghimire L, Paudel S, Jin L et al. NLRP6 negatively regulates pulmonary host defense in Gram-positive bacterial infection through modulating neutrophil recruitment and function. PLoS Pathog 2018;14:e1007308.

DOI

150
Giles DA, Moreno-Fernandez ME, Stankiewicz TE et al. Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling. Nat Med 2017;23:829–838.

DOI

151
Girardin SE, Boneca IG, Carneiro LA et al. Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science 2003a;300:1584–1587.

DOI

152
Girardin SE, Boneca IG, Viala J et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003b;278:8869–8872.

DOI

153
Goettel JA, Gandhi R, Kenison JE et al. AHR activation is protective against colitis driven by T Cells in humanized mice. Cell Rep 2016;17:1318–1329.

DOI

154
Golan MA, Liu W, Shi Y et al. Transgenic expression of Vitamin D receptor in gut epithelial cells ameliorates spontaneous colitis caused by Interleukin-10 deficiency. Dig Dis Sci 2015;60:1941–1947.

DOI

155
Gopalakrishnan V, Helmink BA, Spencer CN et al. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 2018;33:570–580.

DOI

156
Gorecki AM, Bakeberg MC, Theunissen F et al. Single nucleotide polymorphisms associated with gut homeostasis influence risk and age-at-onset of Parkinson’s Disease. Front Aging Neurosci 2020;12:603849.

DOI

157
Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011;29:415–445.

DOI

158
Gribble FM, Reimann F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat Rev Endocrinol 2019;15:226–237.

DOI

159
Gronke K, Hernández PP, Zimmermann J et al. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature 2019;566:249–253.

DOI

160
Group NHW, Peterson J, Garges S et al. The NIH Human Microbiome Project. Genome Res 2009;19:2317–2323.

DOI

161
Guo W, Sun Y, Liu W et al. Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer. Autophagy 2014;10:972–985.

DOI

162
Guo H, Gibson SA, Ting JPY. Gut microbiota, NLR proteins, and intestinal homeostasis. J Exp Med 2020;217(10):e20181832.

DOI

163
Gury-BenAri M, Thaiss CA, Serafini N et al. The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell 2016;166:1231–1246.e1213.

DOI

164
Hackam DJ, Sodhi CP. Bench to bedside—new insights into the pathogenesis of necrotizing enterocolitis. Nat Rev Gastroenterol Hepatol 2022;19:468–479.

DOI

165
Hampe J, Cuthbert A, Croucher PJ et al. Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 2001;357:1925–1928.

DOI

166
Hang S, Paik D, Yao L et al. Bile acid metabolites control T(H)17 and T(reg) cell differentiation. Nature 2019;576:143–148.

DOI

167
Hara H, Seregin SS, Yang D et al. The NLRP6 inflammasome recognizes lipoteichoic acid and regulates gram-positive pathogen infection. Cell 2018;175:1651–1664.e1614.

DOI

168
Harapas CR, Idiiatullina E, Al-Azab M et al. Organellar homeostasis and innate immune sensing. Nat Rev Immunol 2022;22:535–549.

DOI

169
Hartmann P, Haimerl M, Mazagova M et al. Toll-like receptor 2-mediated intestinal injury and enteric tumor necrosis factor receptor I contribute to liver fibrosis in mice. Gastroenterology 2012;143:1330–1340.e1331.

DOI

170
Hasegawa M, Yang K, Hashimoto M et al. Differential release and distribution of Nod1 and Nod2 immunostimulatory molecules among bacterial species and environments. J Biol Chem 2006;281:29054–29063.

DOI

171
Hausmann M, Kiessling S, Mestermann S et al. Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation. Gastroenterology 2002;122:1987–2000.

DOI

172
He L, Liu T, Shi Y et al. Gut epithelial Vitamin D receptor regulates microbiota-dependent mucosal inflammation by suppressing intestinal epithelial cell apoptosis. Endocrinology 2018;159:967–979.

DOI

173
He Z, Ma Y, Yang S et al. Gut microbiota-derived ursodeoxycholic acid from neonatal dairy calves improves intestinal homeostasis and colitis to attenuate extended-spectrum β-lactamase-producing enteroaggregative Escherichia coli infection. Microbiome 2022;10:79.

DOI

174
Heimesaat MM, Nogai A, Bereswill S et al. MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut 2010;59:1079–1087.

DOI

175
Heinsbroek SE, Oei A, Roelofs JJ et al. Genetic deletion of dectin-1 does not affect the course of murine experimental colitis. BMC Gastroenterol 2012;12:33.

DOI

176
Henao-Mejia J, Elinav E, Jin C et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012;482:179–185.

DOI

177
Hennessy C, O’Connell S, Egan LJ et al. Inhibition of anti-viral responses in intestinal epithelial cells by epigenetic modifying drugs is mediated by a reduction in viral pattern recognition receptor expression and activity. Immunopharmacol Immunotoxicol 2019;41:527–537.

DOI

178
Higuchi S, Ahmad TR, Argueta DA et al. Bile acid composition regulates GPR119-dependent intestinal lipid sensing and food intake regulation in mice. Gut 2020;69:1620–1628.

DOI

179
Hirasawa A, Tsumaya K, Awaji T et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 2005;11:90–94.

DOI

180
Hirota SA, Ng J, Lueng A et al. NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis. Inflamm Bowel Dis 2011;17:1359–1372.

DOI

181
Hoffman HM, Mueller JL, Broide DH et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet 2001;29:301–305.

DOI

182
Hörmann N, Brandão I, Jäckel S et al. Gut microbial colonization orchestrates TLR2 expression, signaling and epithelial proliferation in the small intestinal mucosa. PLoS One 2014;9:e113080.

DOI

183
Horuluoglu BH, Kayraklioglu N, Tross D et al. PAM3 protects against DSS-induced colitis by altering the M2:M1 ratio. Sci Rep 2020;10:6078.

DOI

184
Hou Q, Ye L, Liu H et al. Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell Death Differ 2018;25:1657–1670.

DOI

185
Howitt MR, Lavoie S, Michaud M et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 2016;351:1329–1333.

DOI

186
Hu B, Elinav E, Huber S et al. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc Natl Acad Sci USA 2010;107:21635–21640.

DOI

187
Hu S, Peng L, Kwak YT et al. The DNA sensor AIM2 maintains intestinal homeostasis via regulation of epithelial antimicrobial host defense. Cell Rep 2015;13:1922–1936.

DOI

188
Hu B, Jin C, Li HB et al. The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science 2016;354:765–768.

DOI

189
Hu S, Fang Y, Chen X et al. cGAS restricts colon cancer development by protecting intestinal barrier integrity. Proc Natl Acad Sci USA 2021;118(23):e2105747118.

DOI

190
Huang H, Fang M, Jostins L et al. International Inflammatory Bowel Disease Genetics Consortium. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 2017;547:173–178.

DOI

191
Huang H, Hong JY, Wu YJ et al. Vitamin D receptor interacts with NLRP3 to restrict the allergic response. Clin Exp Immunol 2018;194:17–26.

DOI

192
Huang X, Feng Z, Jiang Y et al. VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1β in macrophages. Sci Adv 2019;5:eaau7426.

DOI

193
Hubbard TD, Murray IA, Perdew GH. Indole and tryptophan metabolism: endogenous and dietary routes to Ah receptor activation. Drug Metab Dispos 2015;43:1522–1535.

DOI

194
Hugot JP, Chamaillard M, Zouali H et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411:599–603.

DOI

195
Huhta H, Helminen O, Kauppila JH et al. The expression of Toll-like receptors in normal human and murine gastrointestinal organs and the effect of microbiome and cancer. J Histochem Cytochem 2016;64:470–482.

DOI

196
Huo X, Li D, Wu F et al. Cultivated human intestinal fungus Candida metapsilosis M2006B attenuates colitis by secreting acyclic sesquiterpenoids as FXR agonists. Gut 2022;71:2205–2217.

DOI

197
Huus KE, Bauer KC, Brown EM et al. Commensal bacteria modulate immunoglobulin a binding in response to host nutrition. Cell Host Microbe 2020;27:909–921.e905.

DOI

198
Ichimura A, Hirasawa A, Poulain-Godefroy O et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 2012;483:350–354.

DOI

199
Iliev ID, Funari VA, Taylor KD et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 2012;336:1314–1317.

DOI

200
Imamura R, Wang Y, Kinoshita T et al. Anti-inflammatory activity of PYNOD and its mechanism in humans and mice. J Immunol 2010;184:5874–5884.

DOI

201
Inagaki T, Moschetta A, Lee YK et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA 2006;103:3920–3925.

DOI

202
Ismailova A, White JH. Vitamin D, infections and immunity. Rev Endocr Metab Disord 2022;23:265–277.

DOI

203
Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science 2010;327:291–295.

DOI

204
Iyer SS, Gensollen T, Gandhi A et al. Dietary and microbial Oxazoles induce intestinal inflammation by modulating aryl hydrocarbon receptor responses. Cell 2018;173:1123–1134.e1111.

DOI

205
Jain U, Ver Heul AM, Xiong S et al. Debaryomyces is enriched in Crohn’s disease intestinal tissue and impairs healing in mice. Science 2021;371:1154–1159.

DOI

206
Janeway CA Jr., Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20:197–216.

DOI

207
Janney A, Powrie F, Mann EH. Host-microbiota maladaptation in colorectal cancer. Nature 2020;585:509–517.

DOI

208
Jia DJ, Wang QW, Hu YY et al. Lactobacillus johnsonii alleviates colitis by TLR1/2-STAT3 mediated CD206(+) macrophages(IL-10) acti-vation. Gut Microbes 2022;14:2145843.

DOI

209
Jiang C, Xie C, Lv Y et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 2015;6:10166.

DOI

210
Jiang HY, Najmeh S, Martel G et al. Activation of the pattern recognition receptor NOD1 augments colon cancer metastasis. Protein Cell 2020;11:187–201.

DOI

211
Jostins L, Ripke S, Weersma RK et al. International IBD Genetics Consortium (IIBDGC). Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012;491:119–124.

DOI

212
Kabelitz D. Expression and function of Toll-like receptors in T lymphocytes. Curr Opin Immunol 2007;19:39–45.

DOI

213
Kaiko GE, Ryu SH, Koues OI et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 2016;165:1708–1720.

DOI

214
Kalantari P, DeOliveira RB, Chan J et al. Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria. Cell Rep 2014;6:196–210.

DOI

215
Karki R, Man SM, Malireddi RKS et al. NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer. Nature 2016;540:583–587.

DOI

216
Karki R, Malireddi RKS, Zhu Q et al. NLRC3 regulates cellular proliferation and apoptosis to attenuate the development of colorectal cancer. Cell Cycle 2017;16:1243–1251.

DOI

217
Kashiwagi I, Morita R, Schichita T et al. Smad2 and Smad3 inversely regulate TGF-β autoinduction in Clostridium butyricum-activated dendritic cells. Immunity 2015;43:65–79.

DOI

218
Kataoka K, Muta T, Yamazaki S et al. Activation of macrophages by linear (1right-arrow3)-beta-d-glucans. Implications for the recognition of fungi by innate immunity. J Biol Chem 2002;277:36825–36831.

DOI

219
Kato LM, Kawamoto S, Maruya M et al. The role of the adaptive immune system in regulation of gut microbiota. Immunol Rev 2014;260:67–75.

DOI

220
Kau AL, Planer JD, Liu J et al. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. Sci Transl Med 2015;7:276ra224.

DOI

221
Kawamoto S, Maruya M, Kato LM et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 2014;41:152–165.

DOI

222
Kawashima T, Kosaka A, Yan H et al. Double-stranded RNA of intestinal commensal but not pathogenic bacteria triggers production of protective interferon-β. Immunity 2013;38:1187–1197.

DOI

223
Kaye DM, Shihata WA, Jama HA et al. Deficiency of prebiotic fiber and insufficient signaling through gut metabolite-sensing receptors leads to cardiovascular disease. Circulation 2020;141:1393–1403.

DOI

224
Keogh CE, Rude KM, Gareau MG. Role of pattern recognition receptors and the microbiota in neurological disorders. J Physiol 2021;599:1379–1389.

DOI

225
Kesselring R, Glaesner J, Hiergeist A et al. IRAK-M expression in tumor cells supports colorectal cancer progression through reduction of antimicrobial defense and stabilization of STAT3. Cancer Cell 2016;29:684–696.

DOI

226
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011;474:307–317.

DOI

227
Kim KA, Gu W, Lee IA et al. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 2012;7:e47713.

DOI

228
Kim MH, Kang SG, Park JH et al. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 2013;145:396–406.e1.

DOI

229
Kim YK, Shin JS, Nahm MH. NOD-Like receptors in infection, immunity, and diseases. Yonsei Med J 2016;57:5–14.

DOI

230
Kim TK, Lee JC, Im SH et al. Amelioration of autoimmune diabetes of NOD mice by immunomodulating probiotics. Front Immunol 2020;11:1832.

DOI

231
Kimura I, Miyamoto J, Ohue-Kitano R et al. Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice. Science 2020;367(6481):eaaw8429.

DOI

232
Kiss EA, Vonarbourg C, Kopfmann S et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 2011;334:1561–1565.

DOI

233
Kofoed EM, Vance RE. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 2011;477:592–595.

DOI

234
Koo JE, Shin SW, Um SH et al. X-shaped DNA potentiates therapeutic efficacy in colitis-associated colon cancer through dual activation of TLR9 and inflammasomes. Mol Cancer 2015;14:104.

DOI

235
Kovler ML, Gonzalez Salazar AJ, Fulton WB et al. Toll-like receptor 4-mediated enteric glia loss is critical for the development of necrotizing enterocolitis. Sci Transl Med 2021;13:eabg3459.

DOI

236
Krishnan S, Ding Y, Saedi N et al. Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep 2018;23:1099–1111.

DOI

237
Kruglov AA, Grivennikov SI, Kuprash DV et al. Nonredundant function of soluble LTalpha3 produced by innate lymphoid cells in intestinal homeostasis. Science 2013;342:1243–1246.

DOI

238
Kubinak JL, Petersen C, Stephens WZ et al. MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe 2015;17:153–163.

DOI

239
Kunac N, Degoricija M, Viculin J et al. Activation of cGAS-STING Pathway Is associated with MSI-H Stage IV colorectal cancer. Cancers (Basel) 2022;15(1):221.

DOI

240
Kuo WT, Lee TC, Yang HY et al. LPS receptor subunits have antagonistic roles in epithelial apoptosis and colonic carcinogenesis. Cell Death Differ 2015;22:1590–1604.

DOI

241
Lala S, Ogura Y, Osborne C et al. Crohn’s disease and the NOD2 gene: a role for paneth cells. Gastroenterology 2003;125:47–57.

DOI

242
Lamas B, Richard ML, Leducq V et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 2016;22:598–605.

DOI

243
Lanis JM, Alexeev EE, Curtis VF et al. Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. Mucosal Immunol 2017;10:1133–1144.

DOI

244
Latacz M, Rozmus D, Fiedorowicz E et al. Vitamin D Receptor (VDR) gene polymorphism in patients diagnosed with colorectal cancer. Nutrients 2021;13:200.

DOI

245
Lathrop SK, Bloom SM, Rao SM et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011;478:250–254.

DOI

246
Lavelle A, Sokol H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020;17:223–237.

DOI

247
Lax S, Schauer G, Prein K et al. Expression of the nuclear bile acid receptor/farnesoid X receptor is reduced in human colon carcinoma compared to non-neoplastic mucosa independent from site and may be associated with adverse prognosis. Int J Cancer 2012;130:2232–2239.

DOI

248
Layunta E, Latorre E, Forcén R et al. NOD1 downregulates intestinal serotonin transporter and interacts with other pattern recognition receptors. J Cell Physiol 2018;233:4183–4193.

DOI

249
Lee J, Mo JH, Katakura K et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol 2006;8:1327–1336.

DOI

250
Lee GS, Subramanian N, Kim AI et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 2012;492:123–127.

DOI

251
Leibowitz BJ, Zhao G, Wei L et al. Interferon b drives intestinal regeneration after radiation. Sci Adv 2021;7:eabi5253.

DOI

252
Leite JA, Pessenda G, Guerra-Gomes IC et al. The DNA sensor AIM2 protects against streptozotocin-induced Type 1 diabetes by regulating intestinal homeostasis via the IL-18 pathway. Cells 2020;9:959.

DOI

253
Lemire P, Robertson SJ, Maughan H et al. The NLR protein NLRP6 does not impact gut microbiota composition. Cell Rep 2017;21:3653–3661.

DOI

254
Leng F, Yin H, Qin S et al. NLRP6 self-assembles into a linear molecular platform following LPS binding and ATP stimulation. Sci Rep 2020;10:198.

DOI

255
Leonardi I, Gao IH, Lin WY et al. Mucosal fungi promote gut barrier function and social behavior via Type 17 immunity. Cell 2022;185:831–846.e814.

DOI

256
Letran SE, Lee SJ, Atif SM et al. TLR5-deficient mice lack basal inflammatory and metabolic defects but exhibit impaired CD4 T cell responses to a flagellated pathogen. J Immunol 2011;186:5406–5412.

DOI

257
Levy M, Thaiss CA, Zeevi D et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 2015;163:1428–1443.

DOI

258
Levy M, Thaiss CA, Elinav E. Metabolites: messengers between the microbiota and the immune system. Genes Dev 2016;30:1589–1597.

DOI

259
Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 2014;66:948–983.

DOI

260
Li D, Wu M. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther 2021;6:291.

DOI

261
Li R, Zhu S. NLRP6 inflammasome. Mol Aspects Med 2020;76:100859.

DOI

262
Li XD, Chiu YH, Ismail AS et al. Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis. Proc Natl Acad Sci USA 2011a;108:17390–17395.

DOI

263
Li Y, Innocentin S, Withers DR et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 2011b;147:629–640.

DOI

264
Li XX, Sun GP, Meng J et al. Role of toll-like receptor 4 in colorectal carcinogenesis: a meta-analysis. PLoS One 2014;9:e93904.

DOI

265
Li S, Bostick JW, Ye J et al. Aryl hydrocarbon receptor signaling cell intrinsically inhibits intestinal Group 2 innate lymphoid cell function. Immunity 2018;49:915–928.e915.

DOI

266
Li JM, Yu R, Zhang LP et al. Dietary fructose-induced gut dysbiosis promotes mouse hippocampal neuroinflammation: a benefit of short-chain fatty acids. Microbiome 2019a;7:98.

DOI

267
Li R, Zhou R, Wang H et al. Gut microbiota-stimulated cathepsin K secretion mediates TLR4-dependent M2 macrophage polarization and promotes tumor metastasis in colorectal cancer. Cell Death Differ 2019b;26:2447–2463.

DOI

268
Li X, Deng M, Petrucelli AS et al. Viral DNA binding to NLRC3, an inhibitory nucleic acid sensor, unleashes STING, a cyclic dinucleotide receptor that activates Type I interferon. Immunity 2019c;50:591–599.e596.

DOI

269
Li Z, Song A, Yu H. Interaction between toll-like receptor 4 (TLR4) gene and alcohol drinking on Parkinson’s disease risk in Chinese Han population. J Clin Neurosci 2019d;62:128–132.

DOI

270
Li R, Zan Y, Sui K et al. The latest breakthrough on NLRP6 inflammasome. Precis Clin Med 2022a;5:pbac022.

DOI

271
Li XV, Leonardi I, Putzel GG et al. Immune regulation by fungal strain diversity in inflammatory bowel disease. Nature 2022b;603:672–678.

DOI

272
Lian Q, Xu J, Yan S et al. Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double- strand DNA via AIM2 inflammasome activation. Cell Res 2017;27:784–800.

DOI

273
Lightfoot YL, Selle K, Yang T et al. SIGNR3-dependent immune regulation by Lactobacillus acidophilus surface layer protein A in colitis. EMBO J 2015;34:881–895.

DOI

274
Lin JD, Devlin JC, Yeung F et al. Rewilding Nod2 and Atg16l1 mutant mice uncovers genetic and environmental contributions to microbial responses and immune cell composition. Cell Host Microbe 2020;27:830–840.e834.

DOI

275
Lindholm HT, Parmar N, Drurey C et al. BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13-driven tuft cell hyperplasia. Sci Immunol 2022;7:eabl6543.

DOI

276
Liu J, Cao X. Cellular and molecular regulation of innate inflammatory responses. Cell Mol Immunol 2016;13:711–721.

DOI

277
Liu H, Komai-Koma M, Xu D et al. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 2006;103:7048–7053.

DOI

278
Liu JZ, van Sommeren S, Huang H et al. International Multiple Sclerosis Genetics Consortium. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 2015a;47:979–986.

279
Liu R, Truax AD, Chen L et al. Expression profile of innate immune receptors, NLRs and AIM2, in human colorectal cancer: correlation with cancer stages and inflammasome components. Oncotarget 2015b;6:33456–33469.

DOI

280
Liu L, Gong T, Tao W et al. Commensal viruses maintain intestinal intraepithelial lymphocytes via noncanonical RIG-I signaling. Nat Immunol 2019;20:1681–1691.

DOI

281
Liu L, Liu Z, Li H et al. Naturally occurring TPE-CA maintains gut microbiota and bile acids homeostasis via FXR signaling modulation of the liver–gut axis. Front Pharmacol 2020;11:12.

DOI

282
Liu X, Li C, Wan Z et al. Analogous comparison unravels heightened antiviral defense and boosted viral infection upon immunosuppression in bat organoids. Signal Transduct Target Ther 2022a;7:392.

DOI

283
Liu Y, Yang M, Tang L et al. TLR4 regulates RORγt(+) regulatory T-cell responses and susceptibility to colon inflammation through interaction with Akkermansia muciniphila. Microbiome 2022b;10:98.

DOI

284
Lloyd-Price J, Arze C, Ananthakrishnan AN et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 2019;569:655–662.

DOI

285
Lodes MJ, Cong Y, Elson CO et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 2004;113:1296–1306.

DOI

286
López-Haber C, Netting DJ, Hutchins Z et al. The phagosomal solute transporter SLC15A4 promotes inflammasome activity via mTORC1 signaling and autophagy restraint in dendritic cells. EMBO J 2022;41:e111161.

DOI

287
Lotz M, Gütle D, Walther S et al. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 2006;203:973–984.

DOI

288
Lu Y, Fan C, Li P et al. Short chain fatty acids prevent high-fat-diet-induced obesity in mice by regulating G protein-coupled receptors and gut microbiota. Sci Rep 2016;6:37589.

DOI

289
Lu R, Shang M, Zhang YG et al. Lactic acid bacteria isolated From Korean Kimchi activate the Vitamin D receptor-autophagy signaling pathways. Inflamm Bowel Dis 2020;26:1199–1211.

DOI

290
Lu R, Zhang YG, Xia Y et al. Paneth cell alertness to pathogens maintained by Vitamin D receptors. Gastroenterology 2021;160:1269–1283.

DOI

291
Lu H, Xu X, Fu D et al. Butyrate-producing Eubacterium rectale suppresses lymphomagenesis by alleviating the TNF-induced TLR4/MyD88/NF-κB axis. Cell Host Microbe 2022;30:1139–1150.e1137.

DOI

292
Lukasova M, Malaval C, Gille A et al. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J Clin Invest 2011;121:1163–1173.

DOI

293
Lukens JR, Gurung P, Shaw PJ et al. The NLRP12 sensor negatively regulates autoinflammatory disease by modulating Interleukin-4 production in T cells. Immunity 2015;42:654–664.

DOI

294
Luo Q, Zeng L, Tang C et al. TLR9 induces colitis-associated colorectal carcinogenesis by regulating NF-κB expression levels. Oncol Lett 2020;20:110.

DOI

295
Lyte M. Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. Bioessays 2011;33:574–581.

DOI

296
Macia L, Tan J, Vieira AT et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun 2015;6:6734.

DOI

297
Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004;303:1662–1665.

DOI

298
Magalhaes JG, Fritz JH, Le Bourhis L et al. Nod2-dependent Th2 polarization of antigen-specific immunity. J Immunol 2008;181:7925–7935.

DOI

299
Maisonneuve C, Tsang DKL, Foerster EG et al. Nod1 promotes colorectal carcinogenesis by regulating the immunosuppressive functions of tumor-infiltrating myeloid cells. Cell Rep 2021;34:108677.

DOI

300
Mamantopoulos M, Ronchi F, Van Hauwermeiren F et al. Nlrp6- and ASC-dependent inflammasomes do not shape the commensal gut microbiota composition. Immunity 2017;47:339–348.e4.

DOI

301
Man SM, Zhu Q, Zhu L et al. Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell 2015;162:45–58.

DOI

302
Mao C, Xiao P, Tao XN et al. Unsaturated bond recognition leads to biased signal in a fatty acid receptor. Science 2023:380(6640):eadd6220. Epub 2023 Apr 7.

DOI

303
Maran RR, Thomas A, Roth M et al. Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. J Pharmacol Exp Ther 2009;328:469–477.

DOI

304
Mariño E, Richards JL, McLeod KH et al. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat Immunol 2017;18:552–562.

DOI

305
Maslowski KM, Vieira AT, Ng A et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009;461:1282–1286.

DOI

306
Matheis F, Muller PA, Graves CL et al. Adrenergic signaling in Muscularis macrophages limits infection-induced neuronal loss. Cell 2020;180:64–78.e16.

DOI

307
Mathur R, Zeng W, Hayden MS et al. Mice lacking TLR11 exhibit variable Salmonella typhi susceptibility. Cell 2016;164:829–830.

DOI

308
Matzinger P. The danger model: a renewed sense of self. Science 2002;296:301–305.

DOI

309
McAlpine W, Sun L, Wang KW et al. Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8–WDR41–C9ORF72 complex function. Proc Natl Acad Sci USA 2018;115:E11523–E11531.

DOI

310
Meckel K, Li YC, Lim J et al. Serum 25-hydroxyvitamin D concentration is inversely associated with mucosal inflammation in patients with ulcerative colitis. Am J Clin Nutr 2016;104:113–120.

DOI

311
Medzhitov R, Janeway C Jr. Innate immune recognition: mechanisms and pathways. Immunol Rev 2000;173:89–97.

DOI

312
Mehto S, Jena KK, Nath P et al. The Crohn’s Disease Risk Factor IRGM limits NLRP3 inflammasome activation by impeding its assembly and by mediating its selective autophagy. Mol Cell 2019;73:429–445.e427.

DOI

313
Menendez A, Willing BP, Montero M et al. Bacterial stimulation of the TLR-MyD88 pathway modulates the homeostatic expression of ileal Paneth cell alpha-defensins. J Innate Immun 2013;5:39–49.

DOI

314
Meng S, Li Y, Zang X et al. Effect of TLR2 on the proliferation of inflammation-related colorectal cancer and sporadic colorectal cancer. Cancer Cell Int 2020;20:95.

DOI

315
Merrell MA, Ilvesaro JM, Lehtonen N et al. Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol Cancer Res 2006;4:437–447.

DOI

316
Messaritakis I, Koulouridi A, Sfakianaki M et al. The role of Vitamin D receptor gene polymorphisms in colorectal cancer risk. Cancers (Basel) 2020;12(6):1379.

DOI

317
Messaritakis I, Koulouridi A, Boukla E et al. Investigation of microbial translocation, TLR and VDR gene polymorphisms, and recurrence risk in Stage III colorectal cancer patients. Cancers (Basel) 2022;14(18):4407.

DOI

318
Metidji A, Omenetti S, Crotta S et al. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 2018;49:353–362.e355.

DOI

319
Miani M, Le Naour J, Waeckel-Enée E et al. Gut microbiota-stimulated innate lymphoid cells support β-defensin 14 expression in pancreatic endocrine cells, preventing autoimmune diabetes. Cell Metab 2018;28:557–572.e556.

DOI

320
Miao EA, Alpuche-Aranda CM, Dors M et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 2006;7:569–575.

DOI

321
Miao EA, Mao DP, Yudkovsky N et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci USA 2010;107:3076–3080.

DOI

322
Mishima Y, Oka A, Liu B et al. Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells. J Clin Invest 2019;129:3702–3716.

DOI

323
Miyauchi E, Shimokawa C, Steimle A et al. The impact of the gut microbiome on extra-intestinal autoimmune diseases. Nat Rev Immunol 2023;23:9–23.

DOI

324
Mobraten K, Haug TM, Kleiveland CR et al. Omega-3 and omega-6 PUFAs induce the same GPR120-mediated signalling events, but with different kinetics and intensity in Caco-2 cells. Lipids Health Dis 2013;12:101.

DOI

325
Modica S, Murzilli S, Salvatore L et al. Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res 2008;68:9589–9594.

DOI

326
Modica S, Gofflot F, Murzilli S et al. The intestinal nuclear receptor signature with epithelial localization patterns and expression modulation in tumors. Gastroenterology 2010;138:636–48, 648. e631–612.

DOI

327
Molofsky AB, Byrne BG, Whitfield NN et al. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J Exp Med 2006;203:1093–1104.

DOI

328
Monteleone I, Rizzo A, Sarra M et al. Aryl hydrocarbon receptor- induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 2011;141:237–48, 248.e231.

DOI

329
Moon C, Stappenbeck TS. Viral interactions with the host and microbiota in the intestine. Curr Opin Immunol 2012;24:405–410.

DOI

330
Moradi-Marjaneh R, Hassanian SM, Fiuji H et al. Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer. J Cell Physiol 2018;233:5613–5622.

DOI

331
Mori Y, Yin J, Rashid A et al. Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability. Cancer Res 2001;61:6046–6049.

332
Morland B, Midtvedt T. Phagocytosis, peritoneal influx, and enzyme activities in peritoneal macrophages from germfree, conventional, and ex-germfree mice. Infect Immun 1984;44:750–752.

DOI

333
Mortha A, Chudnovskiy A, Hashimoto D et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 2014;343:1249288.

DOI

334
Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol 2014;14:667–685.

DOI

335
Mukherjee S, Kumar R, Tsakem Lenou E et al. Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation. Nat Immunol 2020;21:626–635.

DOI

336
Muller PA, Matheis F, Schneeberger M et al. Microbiota-modulated CART(+) enteric neurons autonomously regulate blood glucose. Science 2020;370:314–321.

DOI

337
Münzker J, Haase N, Till A et al. Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity. Microbiome 2022;10:96.

DOI

338
Naama M, Telpaz S, Awad A et al. Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress. Cell Host Microbe 2023;31:433–446.e434.

DOI

339
Nadjsombati MS, McGinty JW, Lyons-Cohen MR et al. Detection of succinate by intestinal tuft cells triggers a Type 2 innate immune circuit. Immunity 2018;49:33–41.e37.

DOI

340
Nakamura A, Kurihara S, Takahashi D et al. Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon. Nat Commun 2021;12:2105.

DOI

341
Natividad JM, Agus A, Planchais J et al. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab 2018;28:737–749.e734.

DOI

342
Nayar S, Morrison JK, Giri M et al. A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn’s disease. Nature 2021;593:275–281.

DOI

343
Neal MD, Leaphart C, Levy R et al. Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J Immunol 2006;176:3070–3079.

DOI

344
Neal MD, Sodhi CP, Jia H et al. Toll-like receptor 4 is expressed on intestinal stem cells and regulates their proliferation and apoptosis via the p53 up-regulated modulator of apoptosis. J Biol Chem 2012;287:37296–37308.

DOI

345
Negishi H, Yanai H, Nakajima A et al. Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses. Nat Immunol 2012;13:659–666.

DOI

346
Nell P, Kattler K, Feuerborn D et al. Identification of an FXR-modulated liver-intestine hybrid state in iPSC-derived hepatocyte-like cells. J Hepatol 2022;77:1386–1398.

DOI

347
Nigro G, Rossi R, Commere PH et al. The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration. Cell Host Microbe 2014;15:792–798.

DOI

348
Nordlander S, Pott J, Maloy KJ. NLRC4 expression in intestinal epithelial cells mediates protection against an enteric pathogen. Mucosal Immunol 2014;7:775–785.

DOI

349
Ntunzwenimana JC, Boucher G, Paquette J et al. iGenoMed Consortium. Functional screen of inflammatory bowel disease genes reveals key epithelial functions. Genome Med 2021;13:181.

DOI

350
O’Leary CE, Schneider C, Locksley RM. Tuft cells-systemically dispersed sensory epithelia integrating immune and neural circuitry. Annu Rev Immunol 2019;37:47–72.

DOI

351
O’Mahony C, Clooney A, Clarke SF et al. Dietary-induced bacterial metabolites reduce inflammation and inflammation-associated cancer via Vitamin D Pathway. Int J Mol Sci 2023;24(3):1864.

DOI

352
Obata Y, Castaño A, Boeing S et al. Neuronal programming by microbiota regulates intestinal physiology. Nature 2020;578:284–289.

DOI

353
Obermeier F, Dunger N, Strauch UG et al. CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation. Gastroenterology 2005;129:913–927.

DOI

354
Ogura Y, Bonen DK, Inohara N et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001;411:603–606.

DOI

355
Oh DY, Talukdar S, Bae EJ et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010;142:687–698.

DOI

356
Ohnmacht C, Park JH, Cording S et al. The microbiota regulates type 2 immunity through RORgammat(+) T cells. Science 2015;349:989–993.

DOI

357
Ooi JH, Li Y, Rogers CJ et al. Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis. J Nutr 2013;143:1679–1686.

DOI

358
Oppong GO, Rapsinski GJ, Newman TN et al. Epithelial cells augment barrier function via activation of the Toll-like receptor 2/phosphatidylinositol 3-kinase pathway upon recognition of Salmonella enterica serovar Typhimurium curli fibrils in the gut. Infect Immun 2013;81:478–486.

DOI

359
Pallett LJ, Swadling L, Diniz M et al. Tissue CD14(+)CD8(+) T cells reprogrammed by myeloid cells and modulated by LPS. Nature 2023;614:334–342.

DOI

360
Palm NW, de Zoete MR, Cullen TW et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 2014;158:1000–1010.

DOI

361
Palm NW, de Zoete MR, Flavell RA. Immune–microbiota interactions in health and disease. Clin Immunol 2015;159:122–127.

DOI

362
Panda SK, Peng V, Sudan R et al. Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes. Immunity 2023;56(4):797–812.e4. Epub 2023 Feb 16.

DOI

363
Pandey S, Kawai T, Akira S. Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb Perspect Biol 2014;7:a016246.

DOI

364
Park JH, Kotani T, Konno T et al. Promotion of intestinal epithelial cell turnover by commensal bacteria: role of short-chain fatty acids. PLoS One 2016;11:e0156334.

DOI

365
Paschoal VA, Walenta E, Talukdar S et al. Positive reinforcing mechanisms between GPR120 and PPARγ modulate insulin sensitivity. Cell Metab 2020;31:1173–1188.e1175.

DOI

366
Pathak P, Xie C, Nichols RG et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 2018;68:1574–1588.

DOI

367
van de Pavert SA, Ferreira M, Domingues RG et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 2014;508:123–127.

DOI

368
Peck BCE, Shanahan MT, Singh AP et al. Gut microbial influences on the mammalian intestinal stem cell Niche. Stem Cells Int 2017;2017:5604727.

DOI

369
Peng G, Guo Z, Kiniwa Y et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 2005;309:1380–1384.

DOI

370
Perez-Pardo P, Dodiya HB, Engen PA et al. Role of TLR4 in the gut–brain axis in Parkinson’s disease: a translational study from men to mice. Gut 2019;68:829–843.

DOI

371
Petnicki-Ocwieja T, Hrncir T, Liu YJ et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci USA 2009;106:15813–15818.

DOI

372
Pi Y, Wu Y, Zhang X et al. Gut microbiota-derived ursodeoxycholic acid alleviates low birth weight-induced colonic inflammation by enhancing M2 macrophage polarization. Microbiome 2023;11:19.

DOI

373
Pierik M, Joossens S, Van Steen K et al. Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflamm Bowel Dis 2006;12:1–8.

DOI

374
Piya MK, McTernan PG, Kumar S. Adipokine inflammation and insulin resistance: the role of glucose, lipids and endotoxin. J Endocrinol 2013;216:T1–T15.

DOI

375
Plovier H, Everard A, Druart C et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med 2017;23:107–113.

DOI

376
Podolsky DK, Gerken G, Eyking A et al. Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency. Gastroenterology 2009;137:209–220.

DOI

377
Poole DP, Godfrey C, Cattaruzza F et al. Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil 2010;22:814–25, e227–818.

DOI

378
Pott J, Hornef M. Innate immune signalling at the intestinal epithelium in homeostasis and disease. EMBO Rep 2012;13:684–698.

DOI

379
Price AE, Shamardani K, Lugo KA et al. A map of toll-like receptor expression in the intestinal epithelium reveals distinct spatial, cell type-specific, and temporal patterns. Immunity 2018;49:560–575.e566.

DOI

380
Próchnicki T, Vasconcelos MB, Robinson KS et al. Mitochondrial damage activates the NLRP10 inflammasome. Nat Immunol 2023;24:595–603.

DOI

381
Pusceddu MM, Barboza M, Keogh CE et al. Nod-like receptors are critical for gut–brain axis signalling in mice. J Physiol 2019;597:5777–5797.

DOI

382
Qiao S, Lv C, Tao Y et al. Arctigenin disrupts NLRP3 inflammasome assembly in colonic macrophages via downregulating fatty acid oxidation to prevent colitis-associated cancer. Cancer Lett 2020;491:162–179.

DOI

383
Qiu J, Heller JJ, Guo X et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 2012;36:92–104.

DOI

384
Qiu J, Guo X, Chen ZM et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 2013;39:386–399.

DOI

385
Rachmilewitz D, Katakura K, Karmeli F et al. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 2004;126:520–528.

DOI

386
Raisch J, Rolhion N, Dubois A et al. Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression. Lab Invest 2015;95:296–307.

DOI

387
Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004;118:229–241.

DOI

388
Ramadoss P, Marcus C, Perdew GH. Role of the aryl hydrocarbon receptor in drug metabolism. Expert Opin Drug Metab Toxicol 2005;1:9–21.

DOI

389
Ramanan D, Tang MS, Bowcutt R et al. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity 2014;41:311–324.

DOI

390
Ranjan K, Hedl M, Sinha S et al. Ubiquitination of ATF6 by disease- associated RNF186 promotes the innate receptor-induced unfolded protein response. J Clin Invest 2021;131(17):e145472.

DOI

391
Ratsimandresy RA, Indramohan M, Dorfleutner A et al. The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway. Cell Mol Immunol 2017;14:127–142.

DOI

392
Rauch I, Deets KA, Ji DX et al. NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with Eicosanoid and IL-18 release via activation of Caspase-1 and -8. Immunity 2017;46:649–659.

DOI

393
Reardon S. Gut–brain link grabs neuroscientists. Nature 2014;515:175–177.

DOI

394
Reiser ML, Mosaheb MM, Lisk C et al. The TLR2 binding Neisserial Porin PorB enhances antigen presenting cell trafficking and cross-presentation. Sci Rep 2017;7:736.

DOI

395
Roberts RL, Topless RK, Phipps-Green AJ et al. Evidence of interaction of CARD8 rs2043211 with NALP3 rs35829419 in Crohn’s disease. Genes Immun 2010;11:351–356.

DOI

396
Rochereau N, Drocourt D, Perouzel E et al. Dectin-1 is essential for reverse transcytosis of glycosylated SIgA-antigen complexes by intestinal M cells. PLoS Biol 2013;11:e1001658.

DOI

397
Rochereau N, Roblin X, Michaud E et al. NOD2 deficiency increases retrograde transport of secretory IgA complexes in Crohn’s disease. Nat Commun 2021;12:261.

DOI

398
Rock FL, Hardiman G, Timans JC et al. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 1998;95:588–593.

DOI

399
Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol 2016;16:341–352.

DOI

400
Rose WA 2nd, Sakamoto K, Leifer CA. TLR9 is important for protection against intestinal damage and for intestinal repair. Sci Rep 2012;2:574.

DOI

401
Rothhammer V, Borucki DM, Tjon EC et al. Microglial control of astrocytes in response to microbial metabolites. Nature 2018;557:724–728.

DOI

402
Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 2009;9:313–323.

DOI

403
Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA 2010;107:12204–12209.

DOI

404
Round JL, Lee SM, Li J et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 2011;332:974–977.

DOI

405
Rubbino F, Garlatti V, Garzarelli V et al. GPR120 prevents colorectal adenocarcinoma progression by sustaining the mucosal barrier integrity. Sci Rep 2022;12:381.

DOI

406
Ruiz PA, Morón B, Becker HM et al. Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome. Gut 2017;66:1216–1224.

DOI

407
Russell WR, Duncan SH, Scobbie L et al. Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res 2013;57:523–535.

DOI

408
Ryan KK, Tremaroli V, Clemmensen C et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 2014;509:183–188.

DOI

409
Sabbah A, Chang TH, Harnack R et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol 2009;10:1073–1080.

DOI

410
Saez A, Gomez-Bris R, Herrero-Fernandez B et al. Innate lymphoid cells in intestinal homeostasis and inflammatory bowel disease. Int J Mol Sci 2021;22(14):7618.

DOI

411
Sainathan SK, Bishnupuri KS, Aden K et al. Toll-like receptor-7 ligand Imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis. Inflamm Bowel Dis 2012;18:955–967.

DOI

412
Salzman NH, Ghosh D, Huttner KM et al. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 2003;422:522–526.

DOI

413
Sampson TR, Challis C, Jain N et al. A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice. Elife 2020;9:e53111.

DOI

414
Samuel BS, Shaito A, Motoike T et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci USA 2008;105:16767–16772.

DOI

415
Sanchez-Lopez E, Zhong Z, Stubelius A et al. Choline uptake and metabolism modulate macrophage IL-1β and IL-18 production. Cell Metab 2019;29:1350–1362.e1357.

DOI

416
Sanmarco LM, Chao CC, Wang YC et al. Identification of environmental factors that promote intestinal inflammation. Nature 2022;611:801–809.

DOI

417
Santaolalla R, Sussman DA, Ruiz JR et al. TLR4 activates the β-catenin pathway to cause intestinal neoplasia. PLoS One 2013;8:e63298.

DOI

418
Sawa S, Lochner M, Satoh-Takayama N et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol 2011;12:320–326.

DOI

419
Scheeren FA, Kuo AH, van Weele LJ et al. A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. Nat Cell Biol 2014;16:1238–1248.

DOI

420
Scheithauer TPM, Herrema H, Yu H et al. Gut-derived bacterial flagellin induces beta-cell inflammation and dysfunction. Gut Microbes 2022;14:2111951.

DOI

421
Schenten D, Medzhitov R. The control of adaptive immune responses by the innate immune system. Adv Immunol 2011;109:87–124.

DOI

422
Schenten D, Nish SA, Yu S et al. Signaling through the adaptor molecule MyD88 in CD4+ T cells is required to overcome suppression by regulatory T cells. Immunity 2014;40:78–90.

DOI

423
Schieber AM, Lee YM, Chang MW et al. Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. Science 2015;350:558–563.

DOI

424
Schiering C, Wincent E, Metidji A et al. Feedback control of AHR signalling regulates intestinal immunity. Nature 2017;542:242–245.

DOI

425
Schill EM, Floyd AN, Newberry RD. Neonatal development of intestinal neuroimmune interactions. Trends Neurosci 2022;45:928–941.

DOI

426
Schneider M, Zimmermann AG, Roberts RA et al. The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB. Nat Immunol 2012;13:823–831.

DOI

427
Schoultz I, Verma D, Halfvarsson J et al. Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn’s disease in Swedish men. Am J Gastroenterol 2009;104:1180–1188.

DOI

428
Schulmann K, Brasch FE, Kunstmann E et al. German HNPCC Consortium. HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology 2005;128:590–599.

DOI

429
Schulthess J, Pandey S, Capitani M et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 2019;50:432–445.e437.

DOI

430
Schwarzer M, Gautam UK, Makki K et al. Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice. Science 2023;379:826–833.

DOI

431
Sefik E, Geva-Zatorsky N, Oh S et al. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 2015;349:993–997.

DOI

432
Sen A, Pruijssers AJ, Dermody TS et al. The early interferon response to rotavirus is regulated by PKR and depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3. J Virol 2011;85:3717–3732.

DOI

433
Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 2016a;164:337–340.

DOI

434
Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 2016b;14:e1002533.

DOI

435
Seo B, Jeon K, Moon S et al. Roseburia spp. abundance associates with alcohol consumption in humans and its administration ameliorates alcoholic fatty liver in mice. Cell Host Microbe 2020;27:25–40.e26.

DOI

436
Sepahi A, Liu Q, Friesen L et al. Dietary fiber metabolites regulate innate lymphoid cell responses. Mucosal Immunol 2021;14:317–330.

DOI

437
Sham HP, Yu EY, Gulen MF et al. SIGIRR, a negative regulator of TLR/ IL-1R signalling promotes microbiota dependent resistance to colonization by enteric bacterial pathogens. PLoS Pathog 2013;9:e1003539.

DOI

438
Shanahan MT, Carroll IM, Grossniklaus E et al. Mouse Paneth cell antimicrobial function is independent of Nod2. Gut 2014;63:903–910.

DOI

439
Shao X, Sun S, Zhou Y et al. Bacteroides fragilis restricts colitis-associated cancer via negative regulation of the NLRP3 axis. Cancer Lett 2021;523:170–181.

DOI

440
Sharifinejad N, Mozhgani SH, Bakhtiyari M et al. Association of LRRK2 rs11564258 single nucleotide polymorphisms with type and extent of gastrointestinal mycobiome in ulcerative colitis: a case-control study. Gut Pathog 2021;13:56.

DOI

441
Shen C, Li R, Negro R et al. Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome. Cell 2021;184:5759–5774.e5720.

DOI

442
Shi D, Das J, Das G. Inflammatory bowel disease requires the interplay between innate and adaptive immune signals. Cell Res 2006a;16:70–74.

DOI

443
Shi H, Kokoeva MV, Inouye K et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006b;116:3015–3025.

DOI

444
Shi J, Zhao Y, Wang Y et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014;514:187–192.

DOI

445
Shigemoto T, Kageyama M, Hirai R et al. Identification of loss of function mutations in human genes encoding RIG-I and MDA5: implications for resistance to type I diabetes. J Biol Chem 2009;284:13348–13354.

DOI

446
Shmuel-Galia L, Humphries F, Lei X et al. Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells. Immunity 2021;54:1137–1153.e1138.

DOI

447
Si W, Liang H, Bugno J et al. Lactobacillus rhamnosus GG induces cGAS/ STING-dependent type I interferon and improves response to immune checkpoint blockade. Gut 2022;71:521–533.

DOI

448
Silveira TN, Gomes MT, Oliveira LS et al. NLRP12 negatively regulates proinflammatory cytokine production and host defense against Brucella abortus. Eur J Immunol 2017;47:51–59.

DOI

449
Sinal CJ, Tohkin M, Miyata M et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000;102:731–744.

DOI

450
Singh N, Gurav A, Sivaprakasam S et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 2014;40:128–139.

DOI

451
Singh V, Chassaing B, Zhang L et al. Microbiota-dependent hepatic lipogenesis mediated by Stearoyl CoA Desaturase 1 (SCD1) promotes metabolic syndrome in TLR5-deficient mice. Cell Metab 2015;22:983–996.

DOI

452
Singh R, Chandrashekharappa S, Bodduluri SR et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun 2019a;10:89.

DOI

453
Singh V, Yeoh BS, Walker RE et al. Microbiota fermentation–NLRP3 axis shapes the impact of dietary fibres on intestinal inflammation. Gut 2019b;68:1801–1812.

DOI

454
Sinha SR, Haileselassie Y, Nguyen LP et al. Dysbiosis-induced secondary bile acid deficiency promotes intestinal inflammation. Cell Host Microbe 2020;27:659–670.e5.

DOI

455
Smith PM, Howitt MR, Panikov N et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013;341:569–573.

DOI

456
Smyth DJ, Cooper JD, Bailey R et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon- induced helicase (IFIH1) region. Nat Genet 2006;38:617–619.

DOI

457
Smythies LE, Sellers M, Clements RH et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest 2005;115:66–75.

DOI

458
Socała K, Doboszewska U, Szopa A et al. The role of microbiota–gut–brain axis in neuropsychiatric and neurological disorders. Pharmacol Res 2021;172:105840.

DOI

459
Sodhi CP, Neal MD, Siggers R et al. Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice. Gastroenterology 2012;143:708–718.e701–705.

DOI

460
Somineni HK, Nagpal S, Venkateswaran S et al. Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease. Am J Hum Genet 2021;108:431–445.

DOI

461
Sommer F, Bäckhed F. The gut microbiota—masters of host development and physiology. Nat Rev Microbiol 2013;11:227–238.

DOI

462
Song X, He X, Li X et al. The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity. Cell Mol Immunol 2016;13:418–431.

DOI

463
Song J, Zhao W, Zhang X et al. Mutant RIG-I enhances cancer-related inflammation through activation of circRIG-I signaling. Nat Commun 2022;13:7096.

DOI

464
Sorrentino G, Perino A, Yildiz E et al. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration. Gastroenterology 2020;159:956–968.e958.

DOI

465
Spencer SP, Wilhelm C, Yang Q et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 2014;343:432–437.

DOI

466
Spindler MP, Siu S, Mogno I et al. Human gut microbiota stimulate defined innate immune responses that vary from phylum to strain. Cell Host Microbe 2022;30:1481–1498.e1485.

DOI

467
Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol 2011;12:21–27.

DOI

468
Stafford CA, Gassauer AM, de Oliveira Mann CC et al. Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. Nature 2022;609:590–596.

DOI

469
Stanifer ML, Mukenhirn M, Muenchau S et al. Asymmetric distribution of TLR3 leads to a polarized immune response in human intestinal epithelial cells. Nat Microbiol 2020;5:181–191.

DOI

470
Stefan KL, Kim MV, Iwasaki A et al. Commensal microbiota modulation of natural resistance to virus infection. Cell 2020;183:1312–1324.e1310.

DOI

471
Steiner A, Reygaerts T, Pontillo A et al. Recessive NLRC4-autoinflammatory disease reveals an ulcerative colitis locus. J Clin Immunol 2022;42:325–335.

DOI

472
Stockinger B, Shah K, Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function. Nat Rev Gastroenterol Hepatol 2021;18:559–570.

DOI

473
Sun L, Xie C, Wang G et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med 2018a;24:1919–1929.

DOI

474
Sun M, Wu W, Chen L et al. Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nat Commun 2018b;9:3555.

DOI

475
Sun T, Nguyen A, Gommerman JL. Dendritic cell subsets in intestinal immunity and inflammation. J Immunol 2020;204:1075–1083.

DOI

476
Sun L, Cai J, Gonzalez FJ. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 2021;18:335–347.

DOI

477
Sutmuller RP, den Brok MH, Kramer M et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 2006;116:485–494.

DOI

478
Syed SK, Bui HH, Beavers LS et al. Regulation of GPR119 receptor activity with endocannabinoid-like lipids. Am J Physiol Endocrinol Metab 2012;303:E1469–E1478.

DOI

479
Takatori H, Kanno Y, Watford WT et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 2009;206:35–41.

DOI

480
Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010;140:805–820.

DOI

481
Tan G, Li RH, Li C et al. Down-regulation of human enteric antimicrobial peptides by NOD2 during differentiation of the paneth cell lineage. Sci Rep 2015;5:8383.

DOI

482
Tan J, McKenzie C, Vuillermin PJ et al. Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep 2016;15:2809–2824.

DOI

483
Tan JK, McKenzie C, Mariño E et al. Metabolite-sensing G protein-coupled receptors-facilitators of diet-related immune regulation. Annu Rev Immunol 2017;35:371–402.

DOI

484
Tanaka T, Katsuma S, Adachi T et al. Free fatty acids induce cholecystokinin secretion through GPR120. Naunyn Schmiedebergs Arch Pharmacol 2008;377:523–527.

DOI

485
Tang Y, Chen Y, Jiang H et al. G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer. Int J Cancer 2011;128:847–856.

DOI

486
Tang C, Ahmed K, Gille A et al. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med 2015a;21:173–177.

DOI

487
Tang C, Kamiya T, Liu Y et al. Inhibition of Dectin-1 signaling ameliorates colitis by inducing lactobacillus-mediated regulatory T cell expansion in the intestine. Cell Host Microbe 2015b;18:183–197.

DOI

488
Temperley ND, Berlin S, Paton IR et al. Evolution of the chicken Toll-like receptor gene family: a story of gene gain and gene loss. BMC Genom 2008;9:62.

DOI

489
Thangaraju M, Cresci GA, Liu K et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res 2009;69:2826–2832.

DOI

490
Thomas C, Gioiello A, Noriega L et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009;10:167–177.

DOI

491
Thorburn AN, McKenzie CI, Shen S et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun 2015;6:7320.

DOI

492
Tlaskalova-Hogenova H, Stepankova R, Kozakova H et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell Mol Immunol 2011;8:110–120.

DOI

493
Toubai T, Fujiwara H, Rossi C et al. Host NLRP6 exacerbates graftversus-host disease independent of gut microbial composition. Nat Microbiol 2019;4:800–812.

DOI

494
Touitou I, Lesage S, McDermott M et al. Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum Mutat 2004;24:194–198.

DOI

495
Trabelsi MS, Daoudi M, Prawitt J et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun 2015;6:7629.

DOI

496
Trompette A, Gollwitzer ES, Yadava K et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014;20:159–166.

DOI

497
Truax AD, Chen L, Tam JW et al. The inhibitory innate immune sensor NLRP12 maintains a threshold against obesity by regulating gut microbiota homeostasis. Cell Host Microbe 2018;24:364–378.e366.

DOI

498
Tsoi H, Chu ESH, Zhang X et al. Peptostreptococcus anaerobius induces intracellular cholesterol biosynthesis in colon cells to induce proliferation and causes dysplasia in mice. Gastroenterology 2017;152:1419–1433.e1415.

DOI

499
Tuladhar S, Kanneganti TD. NLRP12 in innate immunity and inflammation. Mol Aspects Med 2020;76:100887.

DOI

500
Turnbaugh PJ, Ley RE, Mahowald MA et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–1031.

DOI

501
Uchimura T, Oyama Y, Deng M et al. The innate immune sensor NLRC3 acts as a rheostat that fine-tunes T Cell responses in infection and autoimmunity. Immunity 2018;49:1049–1061.e1046.

DOI

502
Uematsu S, Jang MH, Chevrier N et al. Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat Immunol 2006;7:868–874.

DOI

503
Uematsu S, Fujimoto K, Jang MH et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol 2008;9:769–776.

DOI

504
Vaishnava S, Behrendt CL, Ismail AS et al. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA 2008;105:20858–20863.

DOI

505
Vanaja SK, Russo AJ, Behl B et al. Bacterial outer membrane vesicles mediate cytosolic localization of LPS and Caspase-11 activation. Cell 2016;165:1106–1119.

DOI

506
Vandanmagsar B, Youm YH, Ravussin A et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011;17:179–188.

DOI

507
VanDussen KL, Liu TC, Li D et al. Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn’s disease. Gastroenterology 2014;146:200–209.

DOI

508
Vanhove W, Peeters PM, Staelens D et al. Strong upregulation of AIM2 and IFI16 inflammasomes in the mucosa of patients with active inflammatory bowel disease. Inflamm Bowel Dis 2015;21:2673–2682.

DOI

509
Vatanen T, Franzosa EA, Schwager R et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature 2018;562:589–594.

DOI

510
Vijay-Kumar M, Sanders CJ, Taylor RT et al. Deletion of TLR5 results in spontaneous colitis in mice. J Clin Invest 2007;117:3909–3921.

DOI

511
Vijay-Kumar M, Aitken JD, Kumar A et al. Toll-like receptor 5-deficient mice have dysregulated intestinal gene expression and nonspecific resistance to Salmonella-induced typhoid-like disease. Infect Immun 2008a;76:1276–1281.

DOI

512
Vijay-Kumar M, Aitken JD, Sanders CJ et al. Flagellin treatment protects against chemicals, bacteria, viruses, and radiation. J Immunol 2008b;180:8280–8285.

DOI

513
Vijay-Kumar M, Aitken JD, Carvalho FA et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010;328:228–231.

DOI

514
Villani AC, Lemire M, Fortin G et al. Common variants in the NLRP3 region contribute to Crohn’s disease susceptibility. Nat Genet 2009;41:71–76.

DOI

515
Vladimer GI, Weng D, Paquette SW et al. The NLRP12 inflammasome recognizes Yersinia pestis. Immunity 2012;37:96–107.

DOI

516
Volk JK, Nyström EEL, van der Post S et al. The Nlrp6 inflammasome is not required for baseline colonic inner mucus layer formation or function. J Exp Med 2019;216:2602–2618.

DOI

517
Vora P, Youdim A, Thomas LS et al. Beta-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells. J Immunol 2004;173:5398–5405.

DOI

518
Wada K, Tanaka H, Maeda K et al. Vitamin D receptor expression is associated with colon cancer in ulcerative colitis. Oncol Rep 2009;22:1021–1025.

DOI

519
Wada T, Sunaga H, Miyata K et al. Aryl hydrocarbon receptor plays protective roles against High Fat Diet (HFD)-induced hepatic steatosis and the subsequent lipotoxicity via direct transcriptional regulation of Socs3 Gene Expression*. J Biol Chem 2016;291:7004–7016.

DOI

520
Wahida A, Müller M, Hiergeist A et al. XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells. Sci Immunol 2021;6:eabf7235.

DOI

521
Walker JA, Barlow JL, McKenzie AN. Innate lymphoid cells—how did we miss them? Nat Rev Immunol 2013;13:75–87.

DOI

522
Walker NM, Liu J, Young SM et al. Goblet cell hyperplasia is not epithelial- autonomous in the Cftr knockout intestine. Am J Physiol Gastrointest Liver Physiol 2022;322:G282–G293.

DOI

523
Wang X, Huycke MM. Extracellular superoxide production by Enterococcus faecalis promotes chromosomal instability in mammalian cells. Gastroenterology 2007;132:551–561.

DOI

524
Wang Y, Hasegawa M, Imamura R et al. PYNOD, a novel Apaf-1/CED4-like protein is an inhibitor of ASC and caspase-1. Int Immunol 2004;16:777–786.

DOI

525
Wang Q, McLoughlin RM, Cobb BA et al. A bacterial carbohydrate links innate and adaptive responses through Toll-like receptor 2. J Exp Med 2006;203:2853–2863.

DOI

526
Wang Y, Zhang HX, Sun YP et al. Rig-I−/− mice develop colitis associated with downregulation of G alpha i2. Cell Res 2007;17:858–868.

DOI

527
Wang P, Zhu S, Yang L et al. Nlrp6 regulates intestinal antiviral innate immunity. Science 2015a;350:826–830.

DOI

528
Wang S, Charbonnier LM, Noval Rivas M et al. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity 2015b;43:289–303.

DOI

529
Wang J, Wang P, Tian H et al. Aryl hydrocarbon receptor/IL-22/Stat3 signaling pathway is involved in the modulation of intestinal mucosa antimicrobial molecules by commensal microbiota in mice. Innate Immun 2018a;24:297–306.

DOI

530
Wang S, Lin Y, Yuan X et al. REV-ERBα integrates colon clock with experimental colitis through regulation of NF-κB/NLRP3 axis. Nat Commun 2018b;9:4246.

DOI

531
Wang Y, Spatz M, Da Costa G et al. Deletion of both Dectin-1 and Dectin-2 affects the bacterial but not fungal gut microbiota and susceptibility to colitis in mice. Microbiome 2022a;10:91.

DOI

532
Wang Y, Wei B, Wang D et al. DNA damage repair promotion in colonic epithelial cells by andrographolide downregulated cGAS‒STING pathway activation and contributed to the relief of CPT-11-induced intestinal mucositis. Acta Pharm Sin B 2022b;12:262–273.

DOI

533
Watanabe T, Kitani A, Murray PJ et al. Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. Immunity 2006;25:473–485.

DOI

534
Watanabe M, Motooka D, Yamasaki S. The kinetics of signaling through the common FcRγ chain determine cytokine profiles in dendritic cells. Sci Signal 2023;16:eabn9909.

DOI

535
Wehkamp J, Harder J, Weichenthal M et al. NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut 2004;53:1658–1664.

DOI

536
Wei X, Ye J, Pei Y et al. Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway. J Extracell Vesicles 2022;11:e12264.

DOI

537
Wen L, Ley RE, Volchkov PY et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 2008;455:1109–1113.

DOI

538
Wesch D, Beetz S, Oberg HH et al. Direct costimulatory effect of TLR3 ligand poly(I:C) on human gamma delta T lymphocytes. J Immunol 2006;176:1348–1354.

DOI

539
Willemsen LE, Koetsier MA, van Deventer SJ et al. Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts. Gut 2003;52:1442–1447.

DOI

540
Williams AM, Probert CS, Stepankova R et al. Effects of microflora on the neonatal development of gut mucosal T cells and myeloid cells in the mouse. Immunology 2006;119:470–478.

DOI

541
Wilson JE, Petrucelli AS, Chen L et al. Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat Med 2015a;21:906–913.

DOI

542
Wilson SS, Tocchi A, Holly MK et al. A small intestinal organoid model of non-invasive enteric pathogen–epithelial cell interactions. Mucosal Immunol 2015b;8:352–361.

DOI

543
Winkler ES, Shrihari S, Hykes BL Jr. et al. The intestinal microbiome restricts alphavirus infection and dissemination through a bile acid-Type I IFN signaling axis. Cell 2020;182: 901–918.e918.

DOI

544
Wlodarska M, Thaiss CA, Nowarski R et al. NLRP6 inflammasome orchestrates the colonic host–microbial interface by regulating goblet cell mucus secretion. Cell 2014;156:1045–1059.

DOI

545
Wu S, Zhang YG, Lu R et al. Intestinal epithelial Vitamin D receptor deletion leads to defective autophagy in colitis. Gut 2015;64:1082–1094.

DOI

546
Xiang W, Shi R, Zhang D et al. Dietary fats suppress the peritoneal seeding of colorectal cancer cells through the TLR4/Cxcl10 axis in adipose tissue macrophages. Signal Transduct Target Ther 2020;5:239.

DOI

547
Xiao L, Li XX, Chung HK et al. RNA-binding protein HuR regulates paneth cell function by altering membrane localization of TLR2 via post-transcriptional control of CNPY3. Gastroenterology 2019;157:731–743.

DOI

548
Xing J, Zhou X, Fang M et al. DHX15 is required to control RNA virus-induced intestinal inflammation. Cell Rep 2021;35:109205.

DOI

549
Xiong Z, Zhu X, Geng J et al. Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine. Immunity 2022;55:686–700.e687.

DOI

550
Xu ZZ, Kim YH, Bang S et al. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med 2015;21:1326–1331.

DOI

551
Yadav P, Ellinghaus D, Rémy G et al. International IBD Genetics Consortium. Genetic factors interact with tobacco smoke to modify risk for inflammatory bowel disease in humans and mice. Gastroenterology 2017;153:550–565.

DOI

552
Yan Y, Jiang W, Spinetti T et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 2013;38:1154–1163.

DOI

553
Yan X, Zhang H, Fan Q et al. Dectin-2 deficiency modulates Th1 differentiation and improves wound healing after myocardial infarction. Circ Res 2017;120:1116–1129.

DOI

554
Yang Y, Palm NW. Immunoglobulin A and the microbiome. Curr Opin Microbiol 2020;56:89–96.

DOI

555
Yang JY, Kim MS, Kim E et al. Enteric viruses ameliorate gut inflammation via Toll-like receptor 3 and Toll-like receptor 7-mediated interferon-beta production. Immunity 2016;44:889–900.

DOI

556
Yang WH, Heithoff DM, Aziz PV et al. Recurrent infection progressively disables host protection against intestinal inflammation. Science 2017;358(6370):eaao5610.

DOI

557
Yang Y, Wang H, Kouadir M et al. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis 2019;10:128.

DOI

558
Yang W, Yu T, Huang X et al. Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nat Commun 2020;11:4457.

DOI

559
Yang M, Long D, Hu L et al. AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1-Bcl-6 axis-mediated B-cell differentiation. Signal Transduct Target Ther 2021;6:341.

DOI

560
Yang W, Liu H, Xu L et al. GPR120 inhibits colitis through regulation of CD4(+) T Cell Interleukin 10 production. Gastroenterology 2022;162:150–165.

DOI

561
Yao X, Zhang C, Xing Y et al. Remodelling of the gut microbiota by hyperactive NLRP3 induces regulatory T cells to maintain homeostasis. Nat Commun 2017;8:1896.

DOI

562
Yarandi SS, Kulkarni S, Saha M et al. Intestinal bacteria maintain adult enteric nervous system and nitrergic neurons via Toll-like receptor 2-induced neurogenesis in mice. Gastroenterology 2020;159:200–213.e208.

DOI

563
Ye L, Bae M, Cassilly CD et al. Enteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways. Cell Host Microbe 2021;29:179–196.e179.

DOI

564
Yesudhas D, Gosu V, Anwar MA et al. Multiple roles of toll-like receptor 4 in colorectal cancer. Front Immunol 2014;5:334.

DOI

565
Yore MM, Syed I, Moraes-Vieira PM et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 2014;159:318–332.

DOI

566
Yu S, Gao N. Compartmentalizing intestinal epithelial cell tolllike receptors for immune surveillance. Cell Mol Life Sci 2015;72:3343–3353.

DOI

567
Yu J, Li S, Guo J et al. Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis. Cell Death Dis 2020;11:640.

DOI

568
Zaiss MM, Rapin A, Lebon L et al. The intestinal microbiota contributes to the ability of helminths to modulate allergic inflammation. Immunity 2015;43:998–1010.

DOI

569
Zaki MH, Boyd KL, Vogel P et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 2010;32:379–391.

DOI

570
Zaki MH, Vogel P, Malireddi RK et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 2011;20:649–660.

DOI

571
Zaki MH, Man SM, Vogel P et al. Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection. Proc Natl Acad Sci USA 2014;111:385–390.

DOI

572
Zelante T, Iannitti RG, Cunha C et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 2013;39:372–385.

DOI

573
Zeng MY, Cisalpino D, Varadarajan S et al. Gut microbiota-induced immunoglobulin G controls systemic infection by symbiotic bacteria and pathogens. Immunity 2016;44:647–658.

DOI

574
Zhang B, Chassaing B, Shi Z et al. Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science 2014a;346:861–865.

DOI

575
Zhang L, Mo J, Swanson KV et al. NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 2014b;40:329–341.

DOI

576
Zhang D, Chen G, Manwani D et al. Neutrophil ageing is regulated by the microbiome. Nature 2015;525:528–532.

DOI

577
Zhang Q, Pan Y, Zeng B et al. Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells. Cell Res 2019;29:516–532.

DOI

578
Zhang Z, Zou J, Shi Z et al. IL-22-induced cell extrusion and IL-18-induced cell death prevent and cure rotavirus infection. Sci Immunol 2020;5(52):eabd2876.

DOI

579
Zhang Y, Garrett S, Carroll RE et al. Vitamin D receptor upregulates tight junction protein claudin-5 against colitis-associated tumorigenesis. Mucosal Immunol 2022;15:683–697.

DOI

580
Zhao Y, Yang J, Shi J et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 2011;477:596–600.

DOI

581
Zhao J, Han X, Xue L et al. Association of TLR4 gene polymorphisms with sporadic Parkinson’s disease in a Han Chinese population. Neurol Sci 2015;36:1659–1665.

DOI

582
Zhao Y, Chen F, Wu W et al. GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunol 2018;11:752–762.

DOI

583
Zheng X, Chen T, Jiang R et al. Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism. Cell Metab 2021;33:791–803.e797.

DOI

584
Zheng D, Mohapatra G, Kern L et al. Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation. Nat Immunol 2023;24:585–594.

DOI

585
Zhong X, Du G, Wang X et al. Nanovaccines mediated subcutis-to-intestine cascade for improved protection against intestinal infections. Small 2022;18:e2105530.

DOI

586
Zhou X, Cao L, Jiang C et al. PPARα–UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis. Nat Commun 2014;5:4573.

DOI

587
Zhou L, Liu T, Huang B et al. Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development. J Allergy Clin Immunol 2021;147:267–279.

DOI

588
Zhu H, Xu WY, Hu Z et al. RNA virus receptor Rig-I monitors gut microbiota and inhibits colitis-associated colorectal cancer. J Exp Clin Cancer Res 2017a;36:2.

DOI

589
Zhu S, Ding S, Wang P et al. Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells. Nature 2017b;546:667–670.

DOI

590
Zhu C, Wang Z, Cai J et al. VDR signaling via the enzyme NAT2 inhibits colorectal cancer progression. Front Pharmacol 2021;12:727704.

DOI

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