1932

Abstract

The intestine is the largest peripheral lymphoid organ in animals, including humans, and interacts with a vast array of microorganisms called the gut microbiota. Comprehending the symbiotic relationship between the gut microbiota and our immune system is essential not only for the field of immunology but also for understanding the pathogenesis of various systemic diseases, including cancer, cardiometabolic disorders, and extraintestinal autoimmune conditions. Whereas microbe-derived antigens are crucial for activating the intestinal immune system, particularly T and B cells, as environmental cues, microbes and their metabolites play a critical role in directing the differentiation of these immune cells. Microbial metabolites are regarded as messengers from the gut microbiota, since bacteria have the ability to produce unique molecules that humans cannot, and many immune cells in the intestine express receptors for these molecules. This review highlights the distinct relationships between microbial metabolites and the differentiation and function of the immune system.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-090222-102035
2024-06-28
2024-06-30
Loading full text...

Full text loading...

/deliver/fulltext/immunol/42/1/annurev-immunol-090222-102035.html?itemId=/content/journals/10.1146/annurev-immunol-090222-102035&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Maynard CL, Elson CO, Hatton RD, Weaver CT. 2012.. Reciprocal interactions of the intestinal microbiota and immune system. . Nature 489:(7415):23141
    [Crossref] [Google Scholar]
  2. 2.
    Belkaid Y, Harrison OJ. 2017.. Homeostatic immunity and the microbiota. . Immunity 46:(4):56276
    [Crossref] [Google Scholar]
  3. 3.
    Sender R, Fuchs S, Milo R. 2016.. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. . Cell 164:(3):33740
    [Crossref] [Google Scholar]
  4. 4.
    Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R. 2018.. Current understanding of the human microbiome. . Nat. Med. 24:(4):392400
    [Crossref] [Google Scholar]
  5. 5.
    Crabbé PA, Bazin H, Eyssen H, Heremans JF. 1968.. The normal microbial flora as a major stimulus for proliferation of plasma cells synthesizing IgA in the gut. . Int. Arch. Allergy Immunol. 34:(4):36275
    [Crossref] [Google Scholar]
  6. 6.
    Pollard M, Sharon N. 1970.. Responses of the Peyer's patches in germ-free mice to antigenic stimulation. . Infect. Immun. 2:(1):96100
    [Crossref] [Google Scholar]
  7. 7.
    Ivanov II, de Llanos Frutos R, Manel N, Yoshinaga K, Rifkin DB, et al. 2008.. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. . Cell Host Microbe 4:(4):33749
    [Crossref] [Google Scholar]
  8. 8.
    Thompson CL, Vier R, Mikaelyan A, Wienemann T, Brune A. 2012.. “ Candidatus Arthromitus” revised: Segmented filamentous bacteria in arthropod guts are members of Lachnospiraceae. . Environ. Microbiol. 14:(6):145465
    [Crossref] [Google Scholar]
  9. 9.
    Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, et al. 2009.. Induction of intestinal Th17 cells by segmented filamentous bacteria. . Cell 139:(3):48598
    [Crossref] [Google Scholar]
  10. 10.
    Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, et al. 2015.. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. . Cell 163:(2):36780
    [Crossref] [Google Scholar]
  11. 11.
    Sczesnak A, Segata N, Qin X, Gevers D, Petrosino JF, et al. 2011.. The genome of Th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. . Cell Host Microbe 10:(3):26072
    [Crossref] [Google Scholar]
  12. 12.
    Yin Y, Wang Y, Zhu L, Liu W, Liao N, et al. 2013.. Comparative analysis of the distribution of segmented filamentous bacteria in humans, mice and chickens. . ISME J. 7:(3):61521
    [Crossref] [Google Scholar]
  13. 13.
    Wishart DS, Oler E, Peters H, Guo A, Girod S, et al. 2023.. MiMeDB: the Human Microbial Metabolome Database. . Nucleic Acids Res. 51:(D1):D61120
    [Crossref] [Google Scholar]
  14. 14.
    Topping DL, Clifton PM. 2001.. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. . Physiol. Rev. 81:(3):103164
    [Crossref] [Google Scholar]
  15. 15.
    Oliphant K, Allen-Vercoe E. 2019.. Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health. . Microbiome 7:(1):91
    [Crossref] [Google Scholar]
  16. 16.
    Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. 2014.. Bile acids and the gut microbiome. . Curr. Opin. Gastroenterol. 30:(3):33238
    [Crossref] [Google Scholar]
  17. 17.
    Zeng H, Umar S, Rust B, Lazarova D, Bordonaro M. 2019.. Secondary bile acids and short chain fatty acids in the colon: a focus on colonic microbiome, cell proliferation, inflammation, and cancer. . Int. J. Mol. Sci. 20:(5):1214
    [Crossref] [Google Scholar]
  18. 18.
    Wishart DS. 2016.. Emerging applications of metabolomics in drug discovery and precision medicine. . Nat. Rev. Drug Discov. 15:(7):47384
    [Crossref] [Google Scholar]
  19. 19.
    Liu X, Locasale JW. 2017.. Metabolomics: a primer. . Trends Biochem. Sci. 42:(4):27484
    [Crossref] [Google Scholar]
  20. 20.
    Primec M, Mičetić-Turk D, Langerholc T. 2017.. Analysis of short-chain fatty acids in human feces: a scoping review. . Anal. Biochem. 526::921
    [Crossref] [Google Scholar]
  21. 21.
    Tumanov S, Bulusu V, Gottlieb E, Kamphorst JJ. 2016.. A rapid method for quantifying free and bound acetate based on alkylation and GC-MS analysis. . Cancer Metab. 4:(1):17
    [Crossref] [Google Scholar]
  22. 22.
    Yao L, Davidson EA, Shaikh MW, Forsyth CB, Prenni JE, Broeckling CD. 2022.. Quantitative analysis of short-chain fatty acids in human plasma and serum by GC–MS. . Anal. Bioanal. Chem. 414:(15):439199
    [Crossref] [Google Scholar]
  23. 23.
    Saha S, Day-Walsh P, Shehata E, Kroon PA. 2021.. Development and validation of a LC-MS/MS technique for the analysis of short chain fatty acids in tissues and biological fluids without derivatisation using isotope labelled internal standards. . Molecules 26:(21):6444
    [Crossref] [Google Scholar]
  24. 24.
    Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. 1987.. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. . Gut 28:(10):122127
    [Crossref] [Google Scholar]
  25. 25.
    Rey FE, Faith JJ, Bain J, Muehlbauer MJ, Stevens RD, et al. 2010.. Dissecting the in vivo metabolic potential of two human gut acetogens. . J. Biol. Chem. 285:(29):2208290
    [Crossref] [Google Scholar]
  26. 26.
    Fukuda S, Toh H, Hase K, Oshima K, Nakanishi Y, et al. 2011.. Bifidobacteria can protect from enteropathogenic infection through production of acetate. . Nature 469:(7331):54347
    [Crossref] [Google Scholar]
  27. 27.
    Reichardt N, Duncan SH, Young P, Belenguer A, McWilliam Leitch C, et al. 2014.. Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. . ISME J. 8:(6):132335
    [Crossref] [Google Scholar]
  28. 28.
    Louis P, Young P, Holtrop G, Flint HJ. 2010.. Diversity of human colonic butyrate-producing bacteria revealed by analysis of the butyryl-CoA:acetate CoA-transferase gene. . Environ. Microbiol. 12:(2):30414
    [Crossref] [Google Scholar]
  29. 29.
    Louis P, Flint HJ. 2017.. Formation of propionate and butyrate by the human colonic microbiota. . Environ. Microbiol. 19:(1):2941
    [Crossref] [Google Scholar]
  30. 30.
    Deleu S, Machiels K, Raes J, Verbeke K, Vermeire S. 2021.. Short chain fatty acids and its producing organisms: an overlooked therapy for IBD?. eBioMedicine 66::103293
    [Crossref] [Google Scholar]
  31. 31.
    Morrison DJ, Preston T. 2016.. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. . Gut Microbes 7:(3):189200
    [Crossref] [Google Scholar]
  32. 32.
    van der Hee B, Wells JM. 2021.. Microbial regulation of host physiology by short-chain fatty acids. . Trends Microbiol. 29:(8):70012
    [Crossref] [Google Scholar]
  33. 33.
    Le Poul E, Loison C, Struyf S, Springael J-Y, Lannoy V, et al. 2003.. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. . J. Biol. Chem. 278:(28):2548189
    [Crossref] [Google Scholar]
  34. 34.
    Taggart AKP, Kero J, Gan X, Cai T-Q, Cheng K, et al. 2005.. (d)-β-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. . J. Biol. Chem. 280:(29):2664952
    [Crossref] [Google Scholar]
  35. 35.
    Davie JR. 2003.. Inhibition of histone deacetylase activity by butyrate. . J. Nutr. 133:(Suppl. 7):2485S93S
    [Crossref] [Google Scholar]
  36. 36.
    Waldecker M, Kautenburger T, Daumann H, Busch C, Schrenk D. 2008.. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. . J. Nutr. Biochem. 19:(9):58793
    [Crossref] [Google Scholar]
  37. 37.
    Luu M, Visekruna A. 2019.. Short-chain fatty acids: bacterial messengers modulating the immuno-metabolism of T cells. . Eur. J. Immunol. 49:(6):84248
    [Crossref] [Google Scholar]
  38. 38.
    Moffett JR, Puthillathu N, Vengilote R, Jaworski DM, Namboodiri AM. 2020.. Acetate revisited: a key biomolecule at the nexus of metabolism, epigenetics and oncogenesis—part 1: acetyl-CoA, acetogenesis and acyl-CoA short-chain synthetases. . Front. Physiol. 11::580167
    [Crossref] [Google Scholar]
  39. 39.
    Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, et al. 2013.. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. . Nature 504:(7480):44650
    [Crossref] [Google Scholar]
  40. 40.
    Hosono A, Ozawa A, Kato R, Ohnishi Y, Nakanishi Y, et al. 2003.. Dietary fructooligosaccharides induce immunoregulation of intestinal IgA secretion by murine Peyer's patch cells. . Biosci. Biotechnol. Biochem. 67:(4):75864
    [Crossref] [Google Scholar]
  41. 41.
    Nakamura Y, Nosaka S, Suzuki M, Nagafuchi S, Takahashi T, et al. 2004.. Dietary fructooligosaccharides up-regulate immunoglobulin A response and polymeric immunoglobulin receptor expression in intestines of infant mice. . Clin. Exp. Immunol. 137:(1):5258
    [Crossref] [Google Scholar]
  42. 42.
    Nakajima A, Sasaki T, Itoh K, Kitahara T, Takema Y, et al. 2020.. A soluble fiber diet increases Bacteroides fragilis group abundance and immunoglobulin A production in the gut. . Appl. Environ. Microbiol. 86:(13):e00405
    [Crossref] [Google Scholar]
  43. 43.
    Kim M, Qie Y, Park J, Kim CH. 2016.. Gut microbial metabolites fuel host antibody responses. . Cell Host Microbe 20:(2):20214
    [Crossref] [Google Scholar]
  44. 44.
    Wu W, Sun M, Chen F, Cao AT, Liu H, et al. 2017.. Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. . Mucosal Immunol. 10:(4):94656
    [Crossref] [Google Scholar]
  45. 45.
    Yang W, Xiao Y, Huang X, Chen F, Sun M, et al. 2019.. Microbiota metabolite short-chain fatty acids facilitate mucosal adjuvant activity of cholera toxin through GPR43. . J. Immunol. 203:(1):28292
    [Crossref] [Google Scholar]
  46. 46.
    Isobe J, Maeda S, Obata Y, Iizuka K, Nakamura Y, et al. 2020.. Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon. . Int. Immunol. 32:(4):24358
    [Crossref] [Google Scholar]
  47. 47.
    Goverse G, Molenaar R, Macia L, Tan J, Erkelens MN, et al. 2017.. Diet-derived short chain fatty acids stimulate intestinal epithelial cells to induce mucosal tolerogenic dendritic cells. . J. Immunol. 198:(5):217281
    [Crossref] [Google Scholar]
  48. 48.
    Takeuchi T, Miyauchi E, Kanaya T, Kato T, Nakanishi Y, et al. 2021.. Acetate differentially regulates IgA reactivity to commensal bacteria. . Nature 595::56064
    [Crossref] [Google Scholar]
  49. 49.
    Balmer ML, Ma EH, Thompson AJ, Epple R, Unterstab G, et al. 2020.. Memory CD8+ T cells balance pro- and anti-inflammatory activity by reprogramming cellular acetate handling at sites of infection. . Cell Metab. 32:(3):45767.e5
    [Crossref] [Google Scholar]
  50. 50.
    Qiu J, Villa M, Sanin DE, Buck MD, O'Sullivan D, et al. 2019.. Acetate promotes T cell effector function during glucose restriction. . Cell Rep. 27:(7):206374.e5
    [Crossref] [Google Scholar]
  51. 51.
    Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, et al. 2013.. Regulatory T cells: recommendations to simplify the nomenclature. . Nat. Immunol. 14:(4):3078
    [Crossref] [Google Scholar]
  52. 52.
    Tanoue T, Atarashi K, Honda K. 2016.. Development and maintenance of intestinal regulatory T cells. . Nat. Rev. Immunol. 16:(5):295309
    [Crossref] [Google Scholar]
  53. 53.
    Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio C-W, et al. 2011.. Peripheral education of the immune system by colonic commensal microbiota. . Nature 478:(7368):25054
    [Crossref] [Google Scholar]
  54. 54.
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, et al. 2011.. Induction of colonic regulatory T cells by indigenous Clostridium species. . Science 331:(6015):33741
    [Crossref] [Google Scholar]
  55. 55.
    Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, et al. 2013.. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. . Nature 504:(7480):45155
    [Crossref] [Google Scholar]
  56. 56.
    Pomare EW, Branch WJ, Cummings JH. 1985.. Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood. . J. Clin. Invest. 75:(5):144854
    [Crossref] [Google Scholar]
  57. 57.
    Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, et al. 2013.. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. . Science 341:(6145):56973
    [Crossref] [Google Scholar]
  58. 58.
    Park J, Kim M, Kang SG, Jannasch AH, Cooper B, et al. 2015.. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6K pathway. . Mucosal Immunol. 8:(1):8093
    [Crossref] [Google Scholar]
  59. 59.
    Zhou L, Zhang M, Wang Y, Dorfman RG, Liu H, et al. 2018.. Faecalibacterium prausnitzii produces butyrate to maintain Th17/Treg balance and to ameliorate colorectal colitis by inhibiting histone deacetylase 1. . Inflamm. Bowel Dis. 24:(9):192640
    [Crossref] [Google Scholar]
  60. 60.
    Hartog A, Belle FN, Bastiaans J, de Graaff P, Garssen J, et al. 2015.. A potential role for regulatory T-cells in the amelioration of DSS induced colitis by dietary non-digestible polysaccharides. . J. Nutr. Biochem. 26:(3):22733
    [Crossref] [Google Scholar]
  61. 61.
    Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, et al. 2014.. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. . Immunity 40:(1):12839
    [Crossref] [Google Scholar]
  62. 62.
    Mariño E, Richards JL, McLeod KH, Stanley D, Yap YA, et al. 2017.. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. . Nat. Immunol. 18:(5):55262
    [Crossref] [Google Scholar]
  63. 63.
    Takahashi D, Hoshina N, Kabumoto Y, Maeda Y, Suzuki A, et al. 2020.. Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells. . eBioMedicine 58::102913
    [Crossref] [Google Scholar]
  64. 64.
    Thorburn AN, McKenzie CI, Shen S, Stanley D, Macia L, et al. 2015.. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. . Nat. Commun. 6::7320
    [Crossref] [Google Scholar]
  65. 65.
    Luu M, Weigand K, Wedi F, Breidenbend C, Leister H, et al. 2018.. Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate. . Sci. Rep. 8:(1):14430
    [Crossref] [Google Scholar]
  66. 66.
    Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, et al. 2021.. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. . Nat. Commun. 12:(1):4077
    [Crossref] [Google Scholar]
  67. 67.
    He Y, Fu L, Li Y, Wang W, Gong M, et al. 2021.. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. . Cell Metab. 33:(5):9881000.e7
    [Crossref] [Google Scholar]
  68. 68.
    Nastasi C, Fredholm S, Willerslev-Olsen A, Hansen M, Bonefeld CM, et al. 2017.. Butyrate and propionate inhibit antigen-specific CD8+ T cell activation by suppressing IL-12 production by antigen-presenting cells. . Sci. Rep. 7:(1):14516
    [Crossref] [Google Scholar]
  69. 69.
    Sun M, Wu W, Chen L, Yang W, Huang X, et al. 2018.. Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. . Nat. Commun. 9:(1):3555
    [Crossref] [Google Scholar]
  70. 70.
    Dupraz L, Magniez A, Rolhion N, Richard ML, Da Costa G, et al. 2021.. Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ T cells. . Cell Rep. 36:(1):109332
    [Crossref] [Google Scholar]
  71. 71.
    Kespohl M, Vachharajani N, Luu M, Harb H, Pautz S, et al. 2017.. The microbial metabolite butyrate induces expression of Th1-associated factors in CD4+ T cells. . Front. Immunol. 8::1036
    [Crossref] [Google Scholar]
  72. 72.
    Chang PV, Hao L, Offermanns S, Medzhitov R. 2014.. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. . PNAS 111:(6):224752
    [Crossref] [Google Scholar]
  73. 73.
    Schulthess J, Pandey S, Capitani M, Rue-Albrecht KC, Arnold I, et al. 2019.. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. . Immunity 50:(2):43245.e7
    [Crossref] [Google Scholar]
  74. 74.
    Nastasi C, Candela M, Bonefeld CM, Geisler C, Hansen M, et al. 2015.. The effect of short-chain fatty acids on human monocyte-derived dendritic cells. . Sci. Rep. 5::16148
    [Crossref] [Google Scholar]
  75. 75.
    Li G, Lin J, Zhang C, Gao H, Lu H, et al. 2021.. Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease. . Gut Microbes 13:(1):1968257
    [Crossref] [Google Scholar]
  76. 76.
    Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, et al. 2009.. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. . Nature 461:(7268):128286
    [Crossref] [Google Scholar]
  77. 77.
    Ito T, Nakanishi Y, Shibata R, Sato N, Jinnohara T, et al. 2023.. The propionate-GPR41 axis in infancy protects from subsequent bronchial asthma onset. . Gut Microbes 15:(1):2206507
    [Crossref] [Google Scholar]
  78. 78.
    Chun E, Lavoie S, Fonseca-Pereira D, Bae S, Michaud M, et al. 2019.. Metabolite-sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity. . Immunity 51:(5):87184.e6
    [Crossref] [Google Scholar]
  79. 79.
    Kim S-H, Cho B-H, Kiyono H, Jang Y-S. 2017.. Microbiota-derived butyrate suppresses group 3 innate lymphoid cells in terminal ileal Peyer's patches. . Sci. Rep. 7:(1):3980
    [Crossref] [Google Scholar]
  80. 80.
    Roediger WE. 1982.. Utilization of nutrients by isolated epithelial cells of the rat colon. . Gastroenterology 83:(2):42429
    [Crossref] [Google Scholar]
  81. 81.
    Donohoe DR, Garge N, Zhang X, Sun W, O'Connell TM, et al. 2011.. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. . Cell Metab. 13:(5):51726
    [Crossref] [Google Scholar]
  82. 82.
    Zeng X, Sunkara LT, Jiang W, Bible M, Carter S, et al. 2013.. Induction of porcine host defense peptide gene expression by short-chain fatty acids and their analogs. . PLOS ONE 8:(8):e72922
    [Crossref] [Google Scholar]
  83. 83.
    Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, et al. 2015.. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. . Cell Host Microbe 17:(5):66271
    [Crossref] [Google Scholar]
  84. 84.
    Zhao Y, Chen F, Wu W, Sun M, Bilotta AJ, et al. 2018.. GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. . Mucosal Immunol. 11:(3):75262
    [Crossref] [Google Scholar]
  85. 85.
    Fujiwara H, Docampo MD, Riwes M, Peltier D, Toubai T, et al. 2018.. Microbial metabolite sensor GPR43 controls severity of experimental GVHD. . Nat. Commun. 9:(1):3674
    [Crossref] [Google Scholar]
  86. 86.
    Bell KJ, Saad S, Tillett BJ, McGuire HM, Bordbar S, et al. 2022.. Metabolite-based dietary supplementation in human type 1 diabetes is associated with microbiota and immune modulation. . Microbiome 10:(1):9
    [Crossref] [Google Scholar]
  87. 87.
    Duscha A, Gisevius B, Hirschberg S, Yissachar N, Stangl GI, et al. 2020.. Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. . Cell 180:(6):106780.e16
    [Crossref] [Google Scholar]
  88. 88.
    Haghikia A, Jörg S, Duscha A, Berg J, Manzel A, et al. 2015.. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. . Immunity 43:(4):81729
    [Crossref] [Google Scholar]
  89. 89.
    Meyer F, Seibert FS, Nienen M, Welzel M, Beisser D, et al. 2020.. Propionate supplementation promotes the expansion of peripheral regulatory T-cells in patients with end-stage renal disease. . J. Nephrol. 33:(4):81727
    [Crossref] [Google Scholar]
  90. 90.
    Scheppach W, Sommer H, Kirchner T, Paganelli GM, Bartram P, et al. 1992.. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. . Gastroenterology 103:(1):5156
    [Crossref] [Google Scholar]
  91. 91.
    Steinhart AH, Hiruki T, Brzezinski A, Baker JP. 1996.. Treatment of left-sided ulcerative colitis with butyrate enemas: a controlled trial. . Alim. Pharmacol. Ther. 10:(5):72936
    [Crossref] [Google Scholar]
  92. 92.
    Hamer HM, Jonkers DMAE, Vanhoutvin SALW, Troost FJ, Rijkers G, et al. 2010.. Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission. . Clin. Nutr. 29:(6):73844
    [Crossref] [Google Scholar]
  93. 93.
    Kato T, Fukuda S, Fujiwara A, Suda W, Hattori M, et al. 2014.. Multiple omics uncovers host-gut microbial mutualism during prebiotic fructooligosaccharide supplementation. . DNA Res. 21:(5):46980
    [Crossref] [Google Scholar]
  94. 94.
    Wastyk HC, Fragiadakis GK, Perelman D, Dahan D, Merrill BD, et al. 2021.. Gut-microbiota-targeted diets modulate human immune status. . Cell 184:(16):413753.e14
    [Crossref] [Google Scholar]
  95. 95.
    Makarova K, Slesarev A, Wolf Y, Sorokin A, Mirkin B, et al. 2006.. Comparative genomics of the lactic acid bacteria. . PNAS 103:(42):1561116
    [Crossref] [Google Scholar]
  96. 96.
    Palframan RJ, Gibson GR, Rastall RA. 2003.. Carbohydrate preferences of Bifidobacterium species isolated from the human gut. . Curr. Issues Intest. Microbiol. 4:(2):7175
    [Google Scholar]
  97. 97.
    Vernia P, Caprilli R, Latella G, Barbetti F, Magliocca FM, Cittadini M. 1988.. Fecal lactate and ulcerative colitis. . Gastroenterology 95:(6):156468
    [Crossref] [Google Scholar]
  98. 98.
    Adeva-Andany M, López-Ojén M, Funcasta-Calderón R, Ameneiros-Rodríguez E, Donapetry-García C, et al. 2014.. Comprehensive review on lactate metabolism in human health. . Mitochondrion 17::76100
    [Crossref] [Google Scholar]
  99. 99.
    Morita N, Umemoto E, Fujita S, Hayashi A, Kikuta J, et al. 2019.. GPR31-dependent dendrite protrusion of intestinal CX3CR1+ cells by bacterial metabolites. . Nature 566:(7742):11014
    [Crossref] [Google Scholar]
  100. 100.
    Liu Q, Umemoto E, Morita N, Kayama H, Baba Y, et al. 2022.. Pyruvate enhances oral tolerance via GPR31. . Int. Immunol. 34:(7):34352
    [Crossref] [Google Scholar]
  101. 101.
    Spencer SP, Silva EGL, Caffery EB, Carter MM, Culver RN, et al. 2022.. Fermented foods restructure gut microbiota and promote immune regulation via microbial metabolites. . bioRxiv 2022.05.11.490523. https://doi.org/10.1101/2022.05.11.490523
  102. 102.
    Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, et al. 2021.. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. . Nature 591:(7851):64551
    [Crossref] [Google Scholar]
  103. 103.
    Okada T, Fukuda S, Hase K, Nishiumi S, Izumi Y, et al. 2013.. Microbiota-derived lactate accelerates colon epithelial cell turnover in starvation-refed mice. . Nat. Commun. 4::1654
    [Crossref] [Google Scholar]
  104. 104.
    Fernández-Veledo S, Vendrell J. 2019.. Gut microbiota-derived succinate: friend or foe in human metabolic diseases?. Rev. Endocr. Metab. Disord. 20:(4):43947
    [Crossref] [Google Scholar]
  105. 105.
    De Vadder F, Kovatcheva-Datchary P, Zitoun C, Duchampt A, Bäckhed F, Mithieux G. 2016.. Microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis. . Cell Metab. 24:(1):15157
    [Crossref] [Google Scholar]
  106. 106.
    Zhao T, Mu X, You Q. 2017.. Succinate: an initiator in tumorigenesis and progression. . Oncotarget 8:(32):5381928
    [Crossref] [Google Scholar]
  107. 107.
    Nadjsombati MS, McGinty JW, Lyons-Cohen MR, Jaffe JB, DiPeso L, et al. 2018.. Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit. . Immunity 49:(1):3341.e7
    [Crossref] [Google Scholar]
  108. 108.
    Banerjee A, Herring CA, Chen B, Kim H, Simmons AJ, et al. 2020.. Succinate produced by intestinal microbes promotes specification of tuft cells to suppress ileal inflammation. . Gastroenterology 159:(6):210115.e5
    [Crossref] [Google Scholar]
  109. 109.
    Fremder M, Kim SW, Khamaysi A, Shimshilashvili L, Eini-Rider H, et al. 2021.. A transepithelial pathway delivers succinate to macrophages, thus perpetuating their pro-inflammatory metabolic state. . Cell Rep. 36:(6):109521
    [Crossref] [Google Scholar]
  110. 110.
    Ooi M, Nishiumi S, Yoshie T, Shiomi Y, Kohashi M, et al. 2011.. GC/MS-based profiling of amino acids and TCA cycle-related molecules in ulcerative colitis. . Inflamm. Res. 60:(9):83140
    [Crossref] [Google Scholar]
  111. 111.
    Macias-Ceja DC, Ortiz-Masiá D, Salvador P, Gisbert-Ferrándiz L, Hernández C, et al. 2019.. Succinate receptor mediates intestinal inflammation and fibrosis. . Mucosal Immunol. 12:(1):17887
    [Crossref] [Google Scholar]
  112. 112.
    Harber KJ, de Goede KE, Verberk SGS, Meinster E, de Vries HE, et al. 2020.. Succinate is an inflammation-induced immunoregulatory metabolite in macrophages. . Metabolites 10:(9):372
    [Crossref] [Google Scholar]
  113. 113.
    Keiran N, Ceperuelo-Mallafré V, Calvo E, Hernández-Alvarez MI, Ejarque M, et al. 2019.. SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity. . Nat. Immunol. 20:(5):58192
    [Crossref] [Google Scholar]
  114. 114.
    Jiang S-S, Xie Y-L, Xiao X-Y, Kang Z-R, Lin X-L, et al. 2023.. Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer. . Cell Host Microbe 31:(5):78797.e9
    [Crossref] [Google Scholar]
  115. 115.
    Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. 2013.. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. . Cell Host Microbe 14:(2):195206
    [Crossref] [Google Scholar]
  116. 116.
    Mima K, Nishihara R, Qian ZR, Cao Y, Sukawa Y, et al. 2016.. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. . Gut 65:(12):197380
    [Crossref] [Google Scholar]
  117. 117.
    Abed J, Emgård JEM, Zamir G, Faroja M, Almogy G, et al. 2016.. Fap2 mediates Fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. . Cell Host Microbe 20:(2):21525
    [Crossref] [Google Scholar]
  118. 118.
    Ternes D, Tsenkova M, Pozdeev VI, Meyers M, Koncina E, et al. 2022.. The gut microbial metabolite formate exacerbates colorectal cancer progression. . Nat. Metab. 4:(4):45875
    [Crossref] [Google Scholar]
  119. 119.
    Zeng X, Xing X, Gupta M, Keber FC, Lopez JG, et al. 2022.. Gut bacterial nutrient preferences quantified in vivo. . Cell 185:(18):344156.e19
    [Crossref] [Google Scholar]
  120. 120.
    Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, et al. 2015.. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. . Cell 161:(2):26476
    [Crossref] [Google Scholar]
  121. 121.
    Strandwitz P. 2018.. Neurotransmitter modulation by the gut microbiota. . Brain Res. 1693:(Pt. B):12833
    [Crossref] [Google Scholar]
  122. 122.
    Sanidad KZ, Rager SL, Ananthanarayanan A, Callaghan R, Li T, et al. 2022.. Gut bacteria-derived serotonin promotes immune tolerance in early life. . bioRxiv. 2022.09.25.509428. https://doi.org/10.1101/2022.09.25.509428
  123. 123.
    Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, et al. 2008.. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. . Nature 453:(7191):1069
    [Crossref] [Google Scholar]
  124. 124.
    Vaidyanathan B, Chaudhry A, Yewdell WT, Angeletti D, Yen W-F, et al. 2017.. The aryl hydrocarbon receptor controls cell-fate decisions in B cells. . J. Exp. Med. 214:(1):197208
    [Crossref] [Google Scholar]
  125. 125.
    Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, et al. 2013.. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. . Immunity 39:(2):37285
    [Crossref] [Google Scholar]
  126. 126.
    Qiu J, Heller JJ, Guo X, Chen ZE, Fish K, et al. 2012.. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. . Immunity 36:(1):92104
    [Crossref] [Google Scholar]
  127. 127.
    Ramirez J-M, Brembilla NC, Sorg O, Chicheportiche R, Matthes T, et al. 2010.. Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells. . Eur. J. Immunol. 40:(9):245059
    [Crossref] [Google Scholar]
  128. 128.
    Lamas B, Richard ML, Leducq V, Pham H-P, Michel M-L, et al. 2016.. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. . Nat. Med. 22:(6):598605
    [Crossref] [Google Scholar]
  129. 129.
    Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, et al. 2008.. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. . Nature 453:(7191):6571
    [Crossref] [Google Scholar]
  130. 130.
    Ye J, Qiu J, Bostick JW, Ueda A, Schjerven H, et al. 2017.. The aryl hydrocarbon receptor preferentially marks and promotes gut regulatory T cells. . Cell Rep. 21:(8):227790
    [Crossref] [Google Scholar]
  131. 131.
    Yoshimatsu Y, Sujino T, Miyamoto K, Harada Y, Tanemoto S, et al. 2022.. Aryl hydrocarbon receptor signals in epithelial cells govern the recruitment and location of Helios+ Tregs in the gut. . Cell Rep. 39:(6):110773
    [Crossref] [Google Scholar]
  132. 132.
    Campesato LF, Budhu S, Tchaicha J, Weng C-H, Gigoux M, et al. 2020.. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. . Nat. Commun. 11:(1):4011
    [Crossref] [Google Scholar]
  133. 133.
    Cui X, Ye Z, Wang D, Yang Y, Jiao C, et al. 2022.. Aryl hydrocarbon receptor activation ameliorates experimental colitis by modulating the tolerogenic dendritic and regulatory T cell formation. . Cell Biosci. 12:(1):46
    [Crossref] [Google Scholar]
  134. 134.
    Zhang Q, Zhu Y, Lv C, Fang Y, Liao M, et al. 2023.. AhR activation promotes Treg cell generation by enhancing Lkb1-mediated fatty acid oxidation via the Skp2/K63-ubiquitination pathway. . Immunology 169:(4):41230
    [Crossref] [Google Scholar]
  135. 135.
    Aoki R, Aoki-Yoshida A, Suzuki C, Takayama Y. 2018.. Indole-3-pyruvic acid, an aryl hydrocarbon receptor activator, suppresses experimental colitis in mice. . J. Immunol. 201:(12):368393
    [Crossref] [Google Scholar]
  136. 136.
    Shen J, Yang L, You K, Chen T, Su Z, et al. 2022.. Indole-3-acetic acid alters intestinal microbiota and alleviates ankylosing spondylitis in mice. . Front. Immunol. 13::762580
    [Crossref] [Google Scholar]
  137. 137.
    Rankin LC, Kaiser KA, de Los Santos-Alexis K, Park H, Uhlemann A-C, et al. 2023.. Dietary tryptophan deficiency promotes gut RORγt+ Treg cells at the expense of Gata3+ Treg cells and alters commensal microbiota metabolism. . Cell Rep. 42:(3):112135
    [Crossref] [Google Scholar]
  138. 138.
    Yamada T, Horimoto H, Kameyama T, Hayakawa S, Yamato H, et al. 2016.. Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense. . Nat. Immunol. 17:(6):68794
    [Crossref] [Google Scholar]
  139. 139.
    Laursen MF, Sakanaka M, von Burg N, Mörbe U, Andersen D, et al. 2021.. Bifidobacterium species associated with breastfeeding produce aromatic lactic acids in the infant gut. . Nat. Microbiol. 6:(11):136782
    [Crossref] [Google Scholar]
  140. 140.
    Ehrlich AM, Pacheco AR, Henrick BM, Taft D, Xu G, et al. 2020.. Indole-3-lactic acid associated with Bifidobacterium-dominated microbiota significantly decreases inflammation in intestinal epithelial cells. . BMC Microbiol. 20:(1):357
    [Crossref] [Google Scholar]
  141. 141.
    Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, et al. 2023.. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. . Nature 615:(7950):16874
    [Crossref] [Google Scholar]
  142. 142.
    Bender MJ, McPherson AC, Phelps CM, Pandey SP, Laughlin CR, et al. 2023.. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. . Cell 186:(9):184662.e26
    [Crossref] [Google Scholar]
  143. 143.
    Holbert CE, Cullen MT, Casero RA, Stewart TM. 2022.. Polyamines in cancer: integrating organismal metabolism and antitumour immunity. . Nat. Rev. Cancer 22:(8):46780
    [Crossref] [Google Scholar]
  144. 144.
    Kitada Y, Muramatsu K, Toju H, Kibe R, Benno Y, et al. 2018.. Bioactive polyamine production by a novel hybrid system comprising multiple indigenous gut bacterial strategies. . Sci. Adv. 4:(6):eaat0062
    [Crossref] [Google Scholar]
  145. 145.
    Pugin B, Barcik W, Westermann P, Heider A, Wawrzyniak M, et al. 2017.. A wide diversity of bacteria from the human gut produces and degrades biogenic amines. . Microb. Ecol. Health Dis. 28:(1):1353881
    [Google Scholar]
  146. 146.
    Levy M, Thaiss CA, Zeevi D, Dohnalová L, Zilberman-Schapira G, et al. 2015.. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. . Cell 163:(6):142843
    [Crossref] [Google Scholar]
  147. 147.
    Carriche GM, Almeida L, Stüve P, Velasquez L, Dhillon-LaBrooy A, et al. 2021.. Regulating T-cell differentiation through the polyamine spermidine. . J. Allergy Clin. Immunol. 147:(1):33548.e11
    [Crossref] [Google Scholar]
  148. 148.
    Puleston DJ, Baixauli F, Sanin DE, Edwards-Hicks J, Villa M, et al. 2021.. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. . Cell 184:(16):4186202.e20
    [Crossref] [Google Scholar]
  149. 149.
    Wagner A, Wang C, Fessler J, DeTomaso D, Avila-Pacheco J, et al. 2021.. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. . Cell 184:(16):416885.e21
    [Crossref] [Google Scholar]
  150. 150.
    Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, et al. 1999.. Identification of a nuclear receptor for bile acids. . Science 284:(5418):136265
    [Crossref] [Google Scholar]
  151. 151.
    Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, et al. 2002.. Identification of membrane-type receptor for bile acids (M-BAR). . Biochem. Biophys. Res. Commun. 298:(5):71419
    [Crossref] [Google Scholar]
  152. 152.
    Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, et al. 1999.. Bile acids: natural ligands for an orphan nuclear receptor. . Science 284:(5418):136568
    [Crossref] [Google Scholar]
  153. 153.
    Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, et al. 2002.. Vitamin D receptor as an intestinal bile acid sensor. . Science 296:(5571):131316
    [Crossref] [Google Scholar]
  154. 154.
    Moore LB, Maglich JM, McKee DD, Wisely B, Willson TM, et al. 2002.. Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. . Mol. Endocrinol. 16:(5):97786
    [Crossref] [Google Scholar]
  155. 155.
    Kliewer SA, Goodwin B, Willson TM. 2002.. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. . Endocr. Rev. 23:(5):687702
    [Crossref] [Google Scholar]
  156. 156.
    Hang S, Paik D, Yao L, Kim E, Trinath J, et al. 2019.. Bile acid metabolites control TH17 and Treg cell differentiation. . Nature 576:(7785):14348
    [Crossref] [Google Scholar]
  157. 157.
    Li W, Hang S, Fang Y, Bae S, Zhang Y, et al. 2021.. A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1. . Cell Host Microbe 29:(9):136677.e9
    [Crossref] [Google Scholar]
  158. 158.
    Paik D, Yao L, Zhang Y, Bae S, D'Agostino GD, et al. 2022.. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites. . Nature 603:(7903):90712
    [Crossref] [Google Scholar]
  159. 159.
    Campbell C, McKenney PT, Konstantinovsky D, Isaeva OI, Schizas M, et al. 2020.. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. . Nature 581:(7809):47579
    [Crossref] [Google Scholar]
  160. 160.
    Song X, Sun X, Oh SF, Wu M, Zhang Y, et al. 2020.. Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis. . Nature 577:(7790):41015
    [Crossref] [Google Scholar]
  161. 161.
    Pols TWH, Puchner T, Korkmaz HI, Vos M, Soeters MR, de Vries CJM. 2017.. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the vitamin D receptor. . PLOS ONE 12:(5):e0176715
    [Crossref] [Google Scholar]
  162. 162.
    Cao W, Kayama H, Chen ML, Delmas A, Sun A, et al. 2017.. The xenobiotic transporter Mdr1 enforces T cell homeostasis in the presence of intestinal bile acids. . Immunity 47:(6):118296.e10
    [Crossref] [Google Scholar]
  163. 163.
    Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S. 2009.. The bile acid receptor FXR is a modulator of intestinal innate immunity. . J. Immunol. 183:(10):625161
    [Crossref] [Google Scholar]
  164. 164.
    Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen ECL, Renooij W, et al. 2011.. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. . Gut 60:(4):46372
    [Crossref] [Google Scholar]
  165. 165.
    Hao H, Cao L, Jiang C, Che Y, Zhang S, et al. 2017.. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. . Cell Metab. 25:(4):85667.e5
    [Crossref] [Google Scholar]
  166. 166.
    Fu T, Li Y, Oh TG, Cayabyab F, He N, et al. 2022.. FXR mediates ILC-intrinsic responses to intestinal inflammation. . PNAS 119:(51):e2213041119
    [Crossref] [Google Scholar]
  167. 167.
    Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen ECL, Renooij W, et al. 2011.. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. . Gut 60:(4):46372
    [Crossref] [Google Scholar]
  168. 168.
    Fu T, Coulter S, Yoshihara E, Oh TG, Fang S, et al. 2019.. FXR regulates intestinal cancer stem cell proliferation. . Cell 176:(5):1098112.e18
    [Crossref] [Google Scholar]
  169. 169.
    Biagioli M, Carino A, Cipriani S, Francisci D, Marchianò S, et al. 2017.. The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis. . J. Immunol. 199:(2):71833
    [Crossref] [Google Scholar]
  170. 170.
    Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, et al. 2011.. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. . PLOS ONE 6:(10):e25637
    [Crossref] [Google Scholar]
  171. 171.
    Guo C, Xie S, Chi Z, Zhang J, Liu Y, et al. 2016.. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. . Immunity 45:(4):80216
    [Crossref] [Google Scholar]
  172. 172.
    Ichikawa R, Takayama T, Yoneno K, Kamada N, Kitazume MT, et al. 2012.. Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. . Immunology 136:(2):15362
    [Crossref] [Google Scholar]
  173. 173.
    Yoneno K, Hisamatsu T, Shimamura K, Kamada N, Ichikawa R, et al. 2013.. TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease. . Immunology 139:(1):1929
    [Crossref] [Google Scholar]
  174. 174.
    Hu J, Wang C, Huang X, Yi S, Pan S, et al. 2021.. Gut microbiota-mediated secondary bile acids regulate dendritic cells to attenuate autoimmune uveitis through TGR5 signaling. . Cell Rep. 36:(12):109726
    [Crossref] [Google Scholar]
  175. 175.
    Yao B, He J, Yin X, Shi Y, Wan J, Tian Z. 2019.. The protective effect of lithocholic acid on the intestinal epithelial barrier is mediated by the vitamin D receptor via a SIRT1/Nrf2 and NF-κB dependent mechanism in Caco-2 cells. . Toxicol. Lett. 316::10918
    [Crossref] [Google Scholar]
  176. 176.
    Raimondi F, Santoro P, Barone MV, Pappacoda S, Barretta ML, et al. 2008.. Bile acids modulate tight junction structure and barrier function of Caco-2 monolayers via EGFR activation. . Am. J. Physiol. Gastrointest. Liver Physiol. 294:(4):G90613
    [Crossref] [Google Scholar]
  177. 177.
    Münch A, Ström M, Söderholm JD. 2007.. Dihydroxy bile acids increase mucosal permeability and bacterial uptake in human colon biopsies. . Scand. J. Gastroenterol. 42:(10):116774
    [Crossref] [Google Scholar]
  178. 178.
    Colosimo S, Tomlinson JW. 2022.. Bile acids as drivers and biomarkers of hepatocellular carcinoma. . World J. Hepatol. 14:(9):173038
    [Crossref] [Google Scholar]
  179. 179.
    Stepien M, Keski-Rahkonen P, Kiss A, Robinot N, Duarte-Salles T, et al. 2021.. Metabolic perturbations prior to hepatocellular carcinoma diagnosis: findings from a prospective observational cohort study. . Int. J. Cancer 148:(3):60925
    [Crossref] [Google Scholar]
  180. 180.
    Thomas CE, Luu HN, Wang R, Xie G, Adams-Haduch J, et al. 2021.. Association between pre-diagnostic serum bile acids and hepatocellular carcinoma: the Singapore Chinese Health Study. . Cancers 13:(11):2648
    [Crossref] [Google Scholar]
  181. 181.
    Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, et al. 2013.. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. . Nature 499:(7456):97101
    [Crossref] [Google Scholar]
  182. 182.
    Ma C, Han M, Heinrich B, Fu Q, Zhang Q, et al. 2018.. Gut microbiome–mediated bile acid metabolism regulates liver cancer via NKT cells. . Science 360:(6391):eaan5931
    [Crossref] [Google Scholar]
  183. 183.
    Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, et al. 2011.. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. . Nature 472:(7341):5765
    [Crossref] [Google Scholar]
  184. 184.
    Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, et al. 2013.. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. . Nat. Med. 19:(5):57685
    [Crossref] [Google Scholar]
  185. 185.
    Wang Z, Roberts AB, Buffa JA, Didonato JA, Lusis AJ, et al. 2015.. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. . Cell 163::158595
    [Crossref] [Google Scholar]
  186. 186.
    Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, et al. 2016.. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. . Cell 165:(1):11124
    [Crossref] [Google Scholar]
  187. 187.
    Danesh J, Whincup P, Walker M, Lennon L, Thomson A, et al. 2000.. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. . BMJ 321:(7255):199204
    [Crossref] [Google Scholar]
  188. 188.
    Sun X, Jiao X, Ma Y, Liu Y, Zhang L, et al. 2016.. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. . Biochem. Biophys. Res. Commun. 481:(1–2):6370
    [Crossref] [Google Scholar]
  189. 189.
    Chen M-L, Zhu X-H, Ran L, Lang H-D, Yi L, Mi M-T. 2017.. Trimethylamine-N-oxide induces vascular inflammation by activating the NLRP3 inflammasome through the SIRT3-SOD2-mtROS signaling pathway. . J. Am. Heart Assoc. 6:(9):e006347. Correction . J. Am. Heart Assoc. 6:(11):e002238
    [Google Scholar]
  190. 190.
    Wu K, Yuan Y, Yu H, Dai X, Wang S, et al. 2020.. The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice. . Blood 136:(4):50115
    [Crossref] [Google Scholar]
  191. 191.
    Wang H, Rong X, Zhao G, Zhou Y, Xiao Y, et al. 2022.. The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer. . Cell Metab. 34:(4):58194.e8
    [Crossref] [Google Scholar]
  192. 192.
    Li X, Su C, Jiang Z, Yang Y, Zhang Y, et al. 2021.. Berberine attenuates choline-induced atherosclerosis by inhibiting trimethylamine and trimethylamine-N-oxide production via manipulating the gut microbiome. . NPJ Biofilms Microbiomes 7:(1):36
    [Crossref] [Google Scholar]
  193. 193.
    Chen M, Yi L, Zhang Y, Zhou X, Ran L, et al. 2016.. Resveratrol attenuates trimethylamine-N-oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. . mBio 7:(2):e02210
    [Crossref] [Google Scholar]
  194. 194.
    Mager LF, Burkhard R, Pett N, Cooke NCA, Brown K, et al. 2020.. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. . Science 369:(6510):148189
    [Crossref] [Google Scholar]
  195. 195.
    Lund J, Breum AW, Gil C, Falk S, Sass F, et al. 2023.. The anorectic and thermogenic effects of pharmacological lactate in male mice are confounded by treatment osmolarity and co-administered counterions. . Nat. Metab. 5:(4):67798
    [Crossref] [Google Scholar]
  196. 196.
    Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, et al. 2013.. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. . Nature 496:(7446):51822
    [Crossref] [Google Scholar]
  197. 197.
    Wilck N, Matus MG, Kearney SM, Olesen SW, Forslund K, et al. 2017.. Salt-responsive gut commensal modulates TH17 axis and disease. . Nature 551:(7682):58589
    [Crossref] [Google Scholar]
  198. 198.
    Dodd D, Spitzer MH, Van Treuren W, Merrill BD, Hryckowian AJ, et al. 2017.. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. . Nature 551:(7682):64852
    [Crossref] [Google Scholar]
  199. 199.
    Funabashi M, Grove TL, Wang M, Varma Y, McFadden ME, et al. 2020.. A metabolic pathway for bile acid dehydroxylation by the gut microbiome. . Nature 582:(7813):56670
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-immunol-090222-102035
Loading
/content/journals/10.1146/annurev-immunol-090222-102035
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error