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Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis

Xiaomin Su, Yunhuan Gao, Rongcun Yang

Cells · 2022 · Review · CC BY

doi:10.3390/cells11152296 (opens in a new tab)

Abstract

Tryptophan is an essential amino acid from dietary proteins. It can be metabolized into different metabolites in both the gut microbiota and tissue cells. Tryptophan metabolites such as indole-3-lactate (ILA), indole-3-acrylate (IAC), indole-3-propionate (IPA), indole-3-aldehyde (IAID), indoleacetic acid (IAA), indole-3-acetaldehyde and Kyn can be produced by intestinal microorganisms through direct Trp transformation and also, partly, the kynurenine (Kyn) pathway. These metabolites play a critical role in maintaining the homeostasis of the gut and systematic immunity and also potentially affect the occurrence and development of diseases such as inflammatory bowel diseases, tumors, obesity and metabolic syndrome, diseases in the nervous system, infectious diseases, vascular inflammation and cardiovascular diseases and hepatic fibrosis. They can not only promote the differentiation and function of anti-inflammatory macrophages, Treg cells, CD4+CD8αα+ regulatory cells, IL-10+ and/or IL-35+B regulatory cells but also IL-22-producing innate lymphoid cells 3 (ILC3), which are involved in maintaining the gut mucosal homeostasis. These findings have important consequences in the immunotherapy against tumor and other immune-associated diseases. We will summarize here the recent advances in understanding the generation and regulation of tryptophan metabolites in the gut microbiota, the role of gut microbiota-derived tryptophan metabolites in different immune cells, the occurrence and development of diseases and immunotherapy against immune-associated diseases.

References 176

  1. 1.

    Agus A., Planchais J., Sokol H. Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host Microbe. 2018;23:716-724.

    Not in our library10.1016/j.chom.2018.05.003 (opens in a new tab)

  2. 2.

    Alexeev E.E., Lanis J.M., Kao D.J., Campbell E.L., Kelly C.J., Battista K.D., Gerich M.E., Jenkins B.R., Walk S.T., Kominsky D.J., et al. Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor. Am. J. Pathol. 2018;188:1183-1194.

    Not in our library10.1016/j.ajpath.2018.01.011 (opens in a new tab)

  3. 3.

    Hubbard T.D., Murray I.A., Perdew G.H. Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. Drug Metab. Dispos. 2015;43:1522-1535.

    Not in our library10.1124/dmd.115.064246 (opens in a new tab)

  4. 4.

    Whitehead T.R., Price N.P., Drake H.L., Cotta M.A. Catabolic pathway for the production of skatole and indoleacetic acid by the acetogen Clostridium drakei, Clostridium scatologenes, and swine manure. Appl. Environ. Microbiol. 2008;74:1950-1953.

    Not in our library10.1128/aem.02458-07 (opens in a new tab)

  5. 5.

    Smith E.A., Macfarlane G.T. Enumeration of human colonic bacteria producing phenolic and indolic compounds: Effects of pH, carbohydrate availability and retention time on dissimilatory aromatic amino acid metabolism. J. Appl. Bacteriol. 1996;81:288-302.

    Not in our library10.1111/j.1365-2672.1996.tb04331.x (opens in a new tab)

  6. 6.

    Yokoyama M.T., Carlson J.R. Microbial metabolites of tryptophan in the intestinal tract with special reference to skatole. Am. J. Clin. Nutr. 1979;32:173-178.

    Not in our library10.1093/ajcn/32.1.173 (opens in a new tab)

  7. 7.

    Vujkovic-Cvijin I., Dunham R.M., Iwai S., Maher M.C., Albright R.G., Broadhurst M.J., Hernandez R.D., Lederman M.M., Huang Y., Somsouk M., et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci. Transl. Med. 2013;5:193ra91.

    Not in our library10.1126/scitranslmed.3006438 (opens in a new tab)

  8. 8.

    Bansal T., Alaniz R.C., Wood T.K., Jayaraman A. The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc. Natl. Acad. Sci. USA. 2010;107:228-233.

    Not in our library10.1073/pnas.0906112107 (opens in a new tab)

  9. 9.

    Mawe G.M., Hoffman J.M. Serotonin signalling in the gut--functions, dysfunctions and therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 2013;10:473-486.

    Not in our library10.1038/nrgastro.2013.105 (opens in a new tab)

  10. 10.

    Holst J.J. The physiology of glucagon-like peptide 1. Physiol. Rev. 2007;87:1409-1439.

    Not in our library10.1152/physrev.00034.2006 (opens in a new tab)

  11. 11.

    Hill D.A., Artis D. Intestinal bacteria and the regulation of immune cell homeostasis. Annu. Rev. Immunol. 2010;28:623-667.

    Not in our library10.1146/annurev-immunol-030409-101330 (opens in a new tab)

  12. 12.

    Hooper L.V., Littman D.R., Macpherson A.J. Interactions between the microbiota and the immune system. Science. 2012;336:1268-1273.

    Not in our library10.1126/science.1223490 (opens in a new tab)

  13. 13.

    Shinde R., Hezaveh K., Halaby M.J., Kloetgen A., Chakravarthy A., da Silva Medina T., Deol R., Manion K.P., Baglaenko Y., Eldh M., et al. Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat. Immunol. 2018;19:571-582.

    Not in our library10.1038/s41590-018-0107-1 (opens in a new tab)

  14. 14.

    Manni G., Mondanelli G., Scalisi G., Pallotta M.T., Nardi D., Padiglioni E., Romani R., Talesa V.N., Puccetti P., Fallarino F., et al. Pharmacologic Induction of Endotoxin Tolerance in Dendritic Cells by L-Kynurenine. Front. Immunol. 2020;11:292.

    Not in our library10.3389/fimmu.2020.00292 (opens in a new tab)

  15. 15.

    Liu Y., Liang X., Dong W., Fang Y., Lv J., Zhang T., Fiskesund R., Xie J., Liu J., Yin X., et al. Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation. Cancer Cell. 2018;33:480-494.e7.

    Not in our library10.1016/j.ccell.2018.02.005 (opens in a new tab)

  16. 16.
    Aryl Hydrocarbon Receptor Contributes to the Transcriptional Program of IL-10-Producing Regulatory B Cells · 2019
    No notice
  17. 17.

    Cervantes-Barragan L., Chai J.N., Tianero M.D., Di Luccia B., Ahern P.P., Merriman J., Cortez V.S., Caparon M.G., Donia M.S., Gilfillan S., et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8α+ T cells. Science. 2017;357:806-810.

    Not in our library10.1126/science.aah5825 (opens in a new tab)

  18. 18.
    Tryptophan feeding of the IDO1-AhR axis in host-microbial symbioses · 2014
    Not checked
  19. 19.

    Schwarcz R., Stone T.W. The kynurenine pathway and the brain: Challenges, controversies and promises. Neuropharmacology. 2017;112:237-247.

    Not in our library10.1016/j.neuropharm.2016.08.003 (opens in a new tab)

  20. 20.

    Lamas B., Richard M.L., Leducq V., Pham H.P., Michel M.L., Da Costa G., Bridonneau C., Jegou S., Hoffmann T.W., Natividad J.M., et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 2016;22:598-605.

    Not in our library10.1038/nm.4102 (opens in a new tab)

  21. 21.

    Shiomi Y., Nishiumi S., Ooi M., Hatano N., Shinohara M., Yoshie T., Kondo Y., Furumatsu K., Shiomi H., Kutsumi H., et al. GCMS-based metabolomic study in mice with colitis induced by dextran sulfate sodium. Inflamm. Bowel Dis. 2011;17:2261-2274.

    Not in our library10.1002/ibd.21616 (opens in a new tab)

  22. 22.

    Botticelli A., Cerbelli B., Lionetto L., Zizzari I., Salati M., Pisano A., Federica M., Simmaco M., Nuti M., Marchetti P. Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC? J. Transl. Med. 2018;16:219.

    Not in our library10.1186/s12967-018-1595-3 (opens in a new tab)

  23. 23.
    Microbial tryptophan catabolites in health and disease · 2018
    No notice
  24. 24.
    Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism · 2018
    No notice
  25. 25.

    Khoshnevisan K., Chehrehgosha M., Conant M., Meftah A.M., Baharifar H., Ejtahed H.S., Angoorani P., Gholami M., Sharifi F., Maleki H., et al. Interactive relationship between Trp metabolites and gut microbiota: The impact on human pathology of disease. J. Appl. Microbiol. 2022;132:4186-4207.

    Not in our library10.1111/jam.15533 (opens in a new tab)

  26. 26.

    Lee J.H., Lee J. Indole as an intercellular signal in microbial communities. FEMS Microbiol. Rev. 2010;34:426-444.

    Not in our library10.1111/j.1574-6976.2009.00204.x (opens in a new tab)

  27. 27.

    Dodd D., Spitzer M.H., Van Treuren W., Merrill B.D., Hryckowian A.J., Higginbottom S.K., Le A., Cowan T.M., Nolan G.P., Fischbach M.A., et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature. 2017;551:648-652.

    Not in our library10.1038/nature24661 (opens in a new tab)

  28. 28.

    Russell W.R., Duncan S.H., Scobbie L., Duncan G., Cantlay L., Calder A.G., Anderson S.E., Flint H.J. Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol. Nutr. Food Res. 2013;57:523-535.

    Not in our library10.1002/mnfr.201200594 (opens in a new tab)

  29. 29.

    Wlodarska M., Luo C., Kolde R., d’Hennezel E., Annand J.W., Heim C.E., Krastel P., Schmitt E.K., Omar A.S., Creasey E.A., et al. Indoleacrylic Acid Produced by Commensal Peptostreptococcus Species Suppresses Inflammation. Cell Host Microbe. 2017;22:25-37.e6.

    Not in our library10.1016/j.chom.2017.06.007 (opens in a new tab)

  30. 30.

    Williams B.B., Van Benschoten A.H., Cimermancic P., Donia M.S., Zimmermann M., Taketani M., Ishihara A., Kashyap P.C., Fraser J.S., Fischbach M.A. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014;16:495-503.

    Not in our library10.1016/j.chom.2014.09.001 (opens in a new tab)

  31. 31.

    Honore A.H., Aunsbjerg S.D., Ebrahimi P., Thorsen M., Benfeldt C., Knochel S., Skov T. Metabolic footprinting for investigation of antifungal properties of Lactobacillus paracasei. Anal. Bioanal. Chem. 2016;408:83-96.

    Not in our library10.1007/s00216-015-9103-6 (opens in a new tab)

  32. 32.

    Wikoff W.R., Anfora A.T., Liu J., Schultz P.G., Lesley S.A., Peters E.C., Siuzdak G. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. USA. 2009;106:3698-3703.

    Not in our library10.1073/pnas.0812874106 (opens in a new tab)

  33. 33.

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

    Not in our library10.1038/s41575-019-0258-z (opens in a new tab)

  34. 34.

    Zelante T., Iannitti R.G., Cunha C., De Luca A., Giovannini G., Pieraccini G., Zecchi R., D’Angelo C., Massi-Benedetti C., Fallarino F., et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372-385.

    Not in our library10.1016/j.immuni.2013.08.003 (opens in a new tab)

  35. 35.

    Wilck N., Matus M.G., Kearney S.M., Olesen S.W., Forslund K., Bartolomaeus H., Haase S., Mahler A., Balogh A., Marko L., et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature. 2017;551:585-589.

    Not in our library10.1038/nature24628 (opens in a new tab)

  36. 36.

    Smith E.A., Macfarlane G.T. Formation of Phenolic and Indolic Compounds by Anaerobic Bacteria in the Human Large Intestine. Microb. Ecol. 1997;33:180-188.

    Not in our library10.1007/s002489900020 (opens in a new tab)

  37. 37.

    Koga J., Adachi T., Hidaka H. Molecular cloning of the gene for indolepyruvate decarboxylase from Enterobacter cloacae. Mol. Gen. Genet. 1991;226:10-16.

    Not in our library10.1007/bf00273581 (opens in a new tab)

  38. 38.

    Honeyfield D.C., Carlson J.R. Effect of Indoleacetic Acid and Related Indoles on Lactobacillus sp. Strain 11201 Growth, Indoleacetic Acid Catabolism, and 3-Methylindole Formation. Appl. Environ. Microbiol. 1990;56:1373-1377.

    Not in our library10.1128/aem.56.5.1373-1377.1990 (opens in a new tab)

  39. 39.

    Hamady Z.Z.R., Farrar M.D., Whitehead T.R., Holland K.T., Lodge J.P.A., Carding S.R. Identification and use of the putative Bacteroides ovatus xylanase promoter for the inducible production of recombinant human proteins. Microbiology. 2008;154:3165-3174.

    Not in our library10.1099/mic.0.2008/019109-0 (opens in a new tab)

  40. 40.

    Cook R.T., Schlueter A.J., Coleman R.A., Tygrett L., Ballas Z.K., Jerrells T.R., Nashelsky M.B., Ray N.B., Haugen T.H., Waldschmidt T.J. Thymocytes, pre-B cells, and organ changes in a mouse model of chronic ethanol ingestion—Absence of subset-specific glucocorticoid-induced immune cell loss. Alcohol. Clin. Exp. Res. 2007;31:1746-1758.

    Not in our library10.1111/j.1530-0277.2007.00478.x (opens in a new tab)

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