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  • Review Article
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Gut microbiota-derived metabolites as key actors in inflammatory bowel disease

Nature Reviews Gastroenterology & Hepatology volume 17, pages 223–237 (2020)Cite this article

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Abstract

A key role of the gut microbiota in the establishment and maintenance of health, as well as in the pathogenesis of disease, has been identified over the past two decades. One of the primary modes by which the gut microbiota interacts with the host is by means of metabolites, which are small molecules that are produced as intermediate or end products of microbial metabolism. These metabolites can derive from bacterial metabolism of dietary substrates, modification of host molecules, such as bile acids, or directly from bacteria. Signals from microbial metabolites influence immune maturation, immune homeostasis, host energy metabolism and maintenance of mucosal integrity. Alterations in the composition and function of the microbiota have been described in many studies on IBD. Alterations have also been described in the metabolite profiles of patients with IBD. Furthermore, specific classes of metabolites, notably bile acids, short-chain fatty acids and tryptophan metabolites, have been implicated in the pathogenesis of IBD. This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation.

Key points

  • IBD, which includes Crohn’s disease and ulcerative colitis, is a set of clinically important, chronic inflammatory conditions of the gastrointestinal tract in which altered host processing of gut microbiota-derived signals, in addition to altered composition and function of the gut microbiota, have been strongly implicated.

  • Gut microbiota-derived metabolites are key molecular mediators between the microbiota and host.

  • Several untargeted studies have demonstrated broad disturbances of the gut metabolome in IBD, which is in keeping with the known dysbiosis in gut communities.

  • Metabolite groups of interest include short-chain fatty acids, bile acid metabolites and tryptophan metabolites, with essential roles for these metabolites in normal immune development, homeostasis and IBD.

  • Multinational, longitudinal cohorts, multi-omics characterization, sampling and analysis standardization and model systems will be required to expand our knowledge of these associations.

  • Such approaches show promise for identifying new host targets and the microbial tools with which to target them.

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Fig. 1: Schematic workflow for microbiome–metabolomics discovery projects.
Fig. 2: SCFAs and their effects on the host.
Fig. 3: Bile acid metabolism in homeostasis and disease.
Fig. 4: Tryptophan metabolism is dysregulated in IBD.
Fig. 5: The cycle of circular causality in IBD.

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References

  1. Cummings, J. H. & Macfarlane, G. T. Role of intestinal bacteria in nutrient metabolism. JPEN J. Parenter. Enter. Nutr. 21, 357–365 (1997).

    Article  CAS  Google Scholar 

  2. Buffie, C. G. et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015).

    Article  CAS  PubMed  Google Scholar 

  3. Wilson, I. D. & Nicholson, J. K. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl. Res. 179, 204–222 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013). This is a key study demonstrating the importance of SCFA-producing gut microorganisms in the development of regulatory T cells.

    Article  CAS  PubMed  Google Scholar 

  5. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

    Article  PubMed  Google Scholar 

  6. Cordain, L. et al. Origins and evolution of the western diet: health implications for the 21st century. Am. J. Clin. Nutr. 81, 341–354 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769–2778 (2017).

    Article  PubMed  Google Scholar 

  11. Burisch, J., Jess, T., Martinato, M. & Lakatos, P. L. The burden of inflammatory bowel disease in Europe. J. Crohns Colitis 7, 322–337 (2013).

    Article  PubMed  Google Scholar 

  12. Knights, D., Lassen, K. G. & Xavier, R. J. Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 62, 1505–1510 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Holmes, E., Li, J. V., Athanasiou, T., Ashrafian, H. & Nicholson, J. K. Understanding the role of gut microbiome–host metabolic signal disruption in health and disease. Trends Microbiol. 19, 349–359 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Krishnan, S. et al. Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep. 23, 1099–1111 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Del Rio, D. et al. The gut microbial metabolite trimethylamine-N-oxide is present in human cerebrospinal fluid. Nutrients 9, 4 (2017).

    Google Scholar 

  16. Wikoff, W. R. et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl Acad. Sci. USA 106, 3698–3703 (2009). This study identifies the importance of microbial-derived metabolites on the host blood metabolome.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Claus, S. P. et al. Systemic multicompartmental effects of the gut microbiome on mouse metabolic phenotypes. Mol. Syst. Biol. 4, 219 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yap, I. K. et al. Metabonomic and microbiological analysis of the dynamic effect of vancomycin-induced gut microbiota modification in the mouse. J. Proteome Res. 7, 3718–3728 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Swann, J. R. et al. Variation in antibiotic-induced microbial recolonization impacts on the host metabolic phenotypes of rats. J. Proteome Res. 10, 3590–3603 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Dodd, D. et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 551, 648–652 (2017). A seminal study that identifies the importance of a specific bacterial pathway for amino acid metabolism, the significance of a single metabolite for host intestinal health and the application of genetic manipulation to address questions of microorganism–host interactions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zierer, J. et al. The fecal metabolome as a functional readout of the gut microbiome. Nat. Genet. 50, 790–795 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Integrative HMP (iHMP) Research Network Consortium et al. The integrative human microbiome project: dynamic analysis of microbiome-host omics profiles during periods of human health and disease. Cell Host Microbe 16, 276–289 (2014).

    Article  CAS  Google Scholar 

  23. Knight, R. et al. Best practices for analysing microbiomes. Nat. Rev. Microbiol. 16, 410–422 (2018). An excellent review on best practice in microbiome science.

    Article  CAS  PubMed  Google Scholar 

  24. Skelly, A. N., Sato, Y., Kearney, S. & Honda, K. Mining the microbiota for microbial and metabolite-based immunotherapies. Nat. Rev. Immunol. 19, 305–323 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Pascal, V. et al. A microbial signature for Crohn’s disease. Gut 66, 813–822 (2017).

    Article  CAS  PubMed  Google Scholar 

  26. Morgan, X. C. et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 13, R79 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schirmer, M. et al. Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat. Microbiol. 3, 337–346 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Franzosa, E. A. et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat. Microbiol. 4, 293–305 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, A., Sun, H., Wang, P., Han, Y. & Wang, X. Modern analytical techniques in metabolomics analysis. Analyst 137, 293–300 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Melnik, A. V. et al. Coupling targeted and untargeted mass spectrometry for metabolome-microbiome-wide association studies of human fecal samples. Anal. Chem. 89, 7549–7559 (2017).

    Article  CAS  PubMed  Google Scholar 

  31. Mushtaq, M. Y., Choi, Y. H., Verpoorte, R. & Wilson, E. G. Extraction for metabolomics: access to the metabolome. Phytochem. Anal. 25, 291–306 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Guijas, C. et al. METLIN: a technology platform for identifying knowns and unknowns. Anal. Chem. 90, 3156–3164 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wishart, D. S. et al. HMDB: the human metabolome database. Nucleic Acids Res. 35, D521–D526 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Peisl, B. Y. L., Schymanski, E. L. & Wilmes, P. Dark matter in host-microbiome metabolomics: tackling the unknowns — a review. Anal. Chim. Acta 1037, 13–27 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Tsugawa, H. Advances in computational metabolomics and databases deepen the understanding of metabolisms. Curr. Opin. Biotechnol. 54, 10–17 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Jansson, J. et al. Metabolomics reveals metabolic biomarkers of Crohn’s disease. PLoS One 4, e6386 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Le Gall, G. et al. Metabolomics of fecal extracts detects altered metabolic activity of gut microbiota in ulcerative colitis and irritable bowel syndrome. J. Proteome Res. 10, 4208–4218 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. De Preter, V. et al. Faecal metabolite profiling identifies medium-chain fatty acids as discriminating compounds in IBD. Gut 64, 447–458 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Santoru, M. L. et al. Cross sectional evaluation of the gut-microbiome metabolome axis in an Italian cohort of IBD patients. Sci. Rep. 7, 9523 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Marchesi, J. R. et al. Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. J. Proteome Res. 6, 546–551 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Bjerrum, J. T. et al. Metabonomics of human fecal extracts characterize ulcerative colitis, Crohn’s disease and healthy individuals. Metabolomics 11, 122–133 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Kolho, K.-L., Pessia, A., Jaakkola, T., de Vos, W. M. & Velagapudi, V. Faecal and serum metabolomics in paediatric inflammatory bowel disease. J. Crohns Colitis 11, 321–334 (2017).

    Article  PubMed  Google Scholar 

  43. Jacobs, J. P. et al. A disease-associated microbial and metabolomics state in relatives of pediatric inflammatory bowel disease patients. Cell. Mol. Gastroenterol. Hepatol. 2, 750–766 (2016). This study uses microbiome and metabolome analysis of paediatric patients with IBD and their relatives to identify IBD-associated metabotypes.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lloyd-Price, J. et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569, 655–662 (2019). The results of the IBD arm of the iHMP incorporate multi-omics, longitudinal sampling and rich metadata and are a resource for future research in IBD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Williams, H. R. et al. Characterization of inflammatory bowel disease with urinary metabolic profiling. Am. J. Gastroenterol. 104, 1435–1444 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Williams, H. R. et al. Differences in gut microbial metabolism are responsible for reduced hippurate synthesis in Crohn’s disease. BMC Gastroenterol. 10, 108 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schicho, R. et al. Quantitative metabolomic profiling of serum, plasma, and urine by 1H NMR spectroscopy discriminates between patients with inflammatory bowel disease and healthy individuals. J. Proteome Res. 11, 3344–3357 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Stephens, N. S. et al. Urinary NMR metabolomic profiles discriminate inflammatory bowel disease from healthy. J. Crohns Colitis 7, e42–e48 (2013).

    Article  PubMed  Google Scholar 

  49. Dawiskiba, T. et al. Serum and urine metabolomic fingerprinting in diagnostics of inflammatory bowel diseases. World J. Gastroenterol. 20, 163–174 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ooi, M. et al. GC/MS-based profiling of amino acids and TCA cycle-related molecules in ulcerative colitis. Inflamm. Res. 60, 831–840 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Hisamatsu, T. et al. Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease. PLoS One 7, e31131 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, Y. et al. 1H NMR-based spectroscopy detects metabolic alterations in serum of patients with early-stage ulcerative colitis. Biochem. Biophys. Res. Commun. 433, 547–551 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Bezabeh, T. et al. The use of 1H magnetic resonance spectroscopy in inflammatory bowel diseases: distinguishing ulcerative colitis from Crohn’s disease. Am. J. Gastroenterol. 96, 442–448 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Lees, H. J., Swann, J. R., Wilson, I. D., Nicholson, J. K. & Holmes, E. Hippurate: the natural history of a mammalian–microbial cometabolite. J. Proteome Res. 12, 1527–1546 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Lai, Y. et al. Serum metabolomics identifies altered bioenergetics, signaling cascades in parallel with exposome markers in Crohn’s disease. Molecules 24, 449 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  56. Sonnenburg, E. D. & Sonnenburg, J. L. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab. 20, 779–786 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Velázquez, M., Davies, C., Marett, R., Slavin, J. L. & Feirtag, J. M. Effect of oligosaccharides and fibre substitutes on short-chain fatty acid production by human faecal microflora. Anaerobe 6, 87–92 (2000).

    Article  Google Scholar 

  58. De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691–14696 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Miller, T. L. & Wolin, M. J. Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora. Appl. Environ. Microbiol. 62, 1589–1592 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Salonen, A. et al. Impact of diet and individual variation on intestinal microbiota composition and fermentation products in obese men. ISME J. 8, 2218–2230 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012). A seminal study that links diet, the microbiota, bile acid metabolism, genetic risk and colitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hall, A. B. et al. A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med. 9, 103 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Davie, J. R. Inhibition of histone deacetylase activity by butyrate. J. Nutr. 133, 2485S–2493S (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chang, P. V., Hao, L., Offermanns, S. & Medzhitov, R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl Acad. Sci. USA 111, 2247–2252 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Frost, G. et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5, 3611 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Kimura, I. et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 4, 1829 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Larraufie, P. et al. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci. Rep. 8, 74 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tolhurst, G. et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61, 364–371 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1708–1720 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Macia, L. et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Kim, M., Qie, Y., Park, J. & Kim, C. H. Gut microbial metabolites fuel host antibody responses. Cell Host Microbe 20, 202–214 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Al Nabhani, Z. et al. A weaning reaction to microbiota is required for resistance to immunopathologies in the adult. Immunity 50, 1276–1288.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  75. Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731–16736 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Machiels, K. et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63, 1275–1283 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Harig, J. M., Soergel, K. H., Komorowski, R. A. & Wood, C. M. Treatment of diversion colitis with short-chain-fatty acid irrigation. N. Engl. J. Med. 320, 23–28 (1989).

    Article  CAS  PubMed  Google Scholar 

  78. Vernia, P. et al. Short-chain fatty acid topical treatment in distal ulcerative colitis. Aliment. Pharmacol. Ther. 9, 309–313 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Hanai, H. et al. Germinated barley foodstuff prolongs remission in patients with ulcerative colitis. Int. J. Mol. Med. 13, 643–647 (2004).

    PubMed  Google Scholar 

  80. Fernández-Bañares, F. et al. Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Am. J. Gastroenterol. 94, 427–433 (1999).

    PubMed  Google Scholar 

  81. Roediger, W. The colonic epithelium in ulcerative colitis: an energy-deficiency disease? Lancet 316, 712–715 (1980).

    Article  Google Scholar 

  82. De Preter, V. et al. Impaired butyrate oxidation in ulcerative colitis is due to decreased butyrate uptake and a defect in the oxidation pathway. Inflamm. Bowel Dis. 18, 1127–1136 (2011).

    Article  PubMed  Google Scholar 

  83. Vernia, P. et al. Fecal lactate and ulcerative colitis. Gastroenterology 95, 1564–1568 (1988).

    Article  CAS  PubMed  Google Scholar 

  84. Vernia, P., Gnaedinger, A., Hauck, W. & Breuer, R. I. Organic anions and the diarrhea of inflammatory bowel disease. Dig. Dis. Sci. 33, 1353–1358 (1988).

    Article  CAS  PubMed  Google Scholar 

  85. Takaishi, H. et al. Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease. Int. J. Med. Microbiol. 298, 463–472 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Louis, P. et al. Restricted distribution of the butyrate kinase pathway among butyrate-producing bacteria from the human colon. J. Bacteriol. 186, 2099–2106 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Laserna-Mendieta, E. J. et al. Determinants of reduced genetic capacity for butyrate synthesis by the gut microbiome in Crohn’s disease and ulcerative colitis. J. Crohns Colitis 12, 204–216 (2017).

    Article  Google Scholar 

  88. Hove, H. & Mortensen, P. B. Influence of intestinal inflammation (IBD) and small and large bowel length on fecal short-chain fatty acids and lactate. Dig. Dis. Sci. 40, 1372–1380 (1995).

    Article  CAS  PubMed  Google Scholar 

  89. den Besten, G. et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54, 2325–2340 (2013).

    Article  CAS  Google Scholar 

  90. Quévrain, E. et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut 65, 415–425 (2016).

    Article  CAS  PubMed  Google Scholar 

  91. Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Tye, H. et al. NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. Nat. Commun. 9, 3728 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kim, I. et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J. Lipid Res. 48, 2664–2672 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Schaap, F. G., Trauner, M. & Jansen, P. L. M. Bile acid receptors as targets for drug development. Nat. Rev. Gastroenterol. Hepatol. 11, 55 (2013). An excellent review of bile acid biology.

    Article  CAS  PubMed  Google Scholar 

  95. Wang, Y.-D., Chen, W.-D., Yu, D., Forman, B. M. & Huang, W. The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) in mice. Hepatology 54, 1421–1432 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Keitel, V., Donner, M., Winandy, S., Kubitz, R. & Häussinger, D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem. Biophys. Res. Commun. 372, 78–84 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Calmus, Y. et al. Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-α production by monocytes. Hepatology 16, 719–723 (1992).

    Article  CAS  PubMed  Google Scholar 

  98. Potthoff, M. J. et al. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1alpha pathway. Cell Metab. 13, 729–738 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Huang, W. et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312, 233–236 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Jones, B. V., Begley, M., Hill, C., Gahan, C. G. M. & Marchesi, J. R. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc. Natl Acad. Sci. USA 105, 13580–13585 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Joyce, S. A. et al. Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc. Natl Acad. Sci. USA 111, 7421–7426 (2014). An important study that highlights the profound host effects of bile acid transformation by a gut bacteria on the host.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Labbé, A., Ganopolsky, J. G., Martoni, C. J., Prakash, S. & Jones, M. L. Bacterial bile metabolising gene abundance in Crohn’s, ulcerative colitis and type 2 diabetes metagenomes. PLoS One 9, e115175 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ridlon, J. M., Kang, D.-J. & Hylemon, P. B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47, 241–259 (2006). An excellent review of gut bacterial transformations of bile acids.

    Article  CAS  PubMed  Google Scholar 

  104. Lorenzo-Zuniga, V. et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37, 551–557 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Inagaki, T. et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl Acad. Sci. USA 103, 3920–3925 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kurdi, P., Kawanishi, K., Mizutani, K. & Yokota, A. Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. J. Bacteriol. 188, 1979–1986 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. D’Aldebert, E. et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology 136, 1435–1443 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Termen, S. et al. PU.1 and bacterial metabolites regulate the human gene CAMP encoding antimicrobial peptide LL-37 in colon epithelial cells. Mol. Immunol. 45, 3947–3955 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Gadaleta, R. M. et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60, 463–472 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Islam, K. B. M. S. et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 141, 1773–1781 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Jung, D., Fantin, A. C., Scheurer, U., Fried, M. & Kullak-Ublick, G. A. Human ileal bile acid transporter gene ASBT (SLC10A2) is transactivated by the glucocorticoid receptor. Gut 53, 78–84 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jahnel, J. et al. Inflammatory bowel disease alters intestinal bile acid transporter expression. Drug Metab. Dispos. 42, 1423–1431 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Nyhlin, H., Merrick, M. V. & Eastwood, M. A. Bile acid malabsorption in Crohn’s disease and indications for its assessment using SeHCAT. Gut 35, 90–93 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Vavassori, P., Mencarelli, A., Renga, B., Distrutti, E. & Fiorucci, S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J. Immunol. 183, 6251–6261 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Song, X. et al. Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis. Nature 577, 410–415 (2020).

    Article  CAS  PubMed  Google Scholar 

  116. Vantrappen, G., Ghoos, Y., Rutgeerts, P. & Janssens, J. Bile acid studies in uncomplicated Crohn’s disease. Gut 18, 730–735 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rutgeerts, P., Ghoos, Y. & Vantrappen, G. Kinetics of primary bile acids in patients with non-operated Crohn’s disease. Eur. J. Clin. Invest. 12, 135–143 (1982).

    Article  CAS  PubMed  Google Scholar 

  118. Kruis, W., Kalek, H. D., Stellaard, F. & Paumgartner, G. Altered fecal bile acid pattern in patients with inflammatory bowel disease. Digestion 35, 189–198 (1986).

    Article  CAS  PubMed  Google Scholar 

  119. Torres, J. et al. The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease. United European Gastroenterol. J. 6, 112–122 (2018).

    Article  CAS  PubMed  Google Scholar 

  120. Duboc, H. et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 62, 531–539 (2013). This study identifies potential associations between bile acids and the microbiota in IBD.

    Article  CAS  PubMed  Google Scholar 

  121. McGarr, S. E., Ridlon, J. M. & Hylemon, P. B. Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature. J. Clin. Gastroenterol. 39, 98–109 (2005).

    PubMed  Google Scholar 

  122. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Cervenka, I., Agudelo, L. Z. & Ruas, J. L. Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Science 357, eaaf9794 (2017).

    Article  CAS  PubMed  Google Scholar 

  124. Côté, F. et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc. Natl Acad. Sci. USA 100, 13525–13530 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Desbonnet, L. et al. Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain Behav. Immun. 48, 165–173 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Reigstad, C. S. et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 29, 1395–1403 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Chimerel, C. et al. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 9, 1202–1208 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Venkatesh, M. et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 41, 296–310 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Nikolaus, S. et al. Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases. Gastroenterology 153, 1504–1516.e2 (2017). An important study that identifies the link between tryptophan metabolism and IBD in a large clinical cohort.

    Article  CAS  PubMed  Google Scholar 

  134. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237–248, 248.e1 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Hashimoto, T. et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487, 477 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Takamura, T. et al. Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis. Immunol. Cell Biol. 89, 817–822 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Alexeev, E. E. et al. Microbiota-derived indole metabolites promote human and murine intestinal homeostasis through regulation of interleukin-10 receptor. Am. J. Pathol. 188, 1183–1194 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wlodarska, M. et al. Indoleacrylic acid produced by commensal peptostreptococcus species suppresses inflammation. Cell Host Microbe 22, 25–37.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470.e13 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. De Vadder, F. et al. Microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis. Cell Metab. 24, 151–157 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Macias-Ceja, D. C. et al. Succinate receptor mediates intestinal inflammation and fibrosis. Mucosal Immunol. 12, 178–187 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Osaka, T. et al. Meta-analysis of fecal microbiota and metabolites in experimental colitic mice during the inflammatory and healing phases. Nutrients 9, 1329 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  144. Garner, C. E. et al. Volatile organic compounds from feces and their potential for diagnosis of gastrointestinal disease. FASEB J. 21, 1675–1688 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Mane, J. et al. Partial replacement of dietary (n-6) fatty acids with medium-chain triglycerides decreases the incidence of spontaneous colitis in interleukin-10-deficient mice. J. Nutr. 139, 603–610 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Baur, P. et al. Metabolic phenotyping of the Crohn’s disease-like IBD etiopathology in the TNFΔARE/WT mouse model. J. Proteome Res. 10, 5523–5535 (2011).

    Article  CAS  PubMed  Google Scholar 

  147. Donia, M. S. & Fischbach, M. A. Small molecules from the human microbiota. Science 349, 1254766 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Milshteyn, A., Colosimo, D. A. & Brady, S. F. Accessing bioactive natural products from the human microbiome. Cell Host Microbe 23, 725–736 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Cohen, L. J. et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature 549, 48 (2017). A study that uses a combination of synthetic biology and computational approaches to mine the gut microbiota for bioactive molecules.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Guo, C.-J. et al. Discovery of reactive microbiota-derived metabolites that inhibit host proteases. Cell 168, 517–526.e18 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Chen, H. et al. A forward chemical genetic screen reveals gut microbiota metabolites that modulate host physiology. Cell 177, 1217–1231.e18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. O’Toole, P. W., Marchesi, J. R. & Hill, C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat. Microbiol. 2, 17057 (2017).

    Article  CAS  PubMed  Google Scholar 

  153. Fitzgerald, C. B. et al. Comparative analysis of Faecalibacterium prausnitzii genomes shows a high level of genome plasticity and warrants separation into new species-level taxa. BMC Genomics 19, 931–931 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Martin, R. et al. The commensal bacterium Faecalibacterium prausnitzii is protective in DNBS-induced chronic moderate and severe colitis models. Inflamm. Bowel Dis. 20, 417–430 (2014).

    Article  PubMed  Google Scholar 

  155. Martín, R. et al. Functional characterization of novel Faecalibacterium prausnitzii strains isolated from healthy volunteers: a step forward in the use of F. prausnitzii as a next-generation probiotic. Front. Microbiol. 8, 1226–1226 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Gionchetti, P. et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 119, 305–309 (2000).

    Article  CAS  PubMed  Google Scholar 

  157. Yasueda, A. et al. The effect of Clostridium butyricum MIYAIRI on the prevention of pouchitis and alteration of the microbiota profile in patients with ulcerative colitis. Surg. Today 46, 939–949 (2016).

    Article  PubMed  Google Scholar 

  158. van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Francis, M. B., Allen, C. A., Shrestha, R. & Sorg, J. A. Bile acid recognition by the Clostridium difficile germinant receptor, CspC, is important for establishing infection. PLOS Pathog. 9, e1003356 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Weingarden, A. R. et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G310–G319 (2014).

    Article  CAS  PubMed  Google Scholar 

  161. Rossen, N. G. et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 149, 110–118.e4 (2015).

    Article  PubMed  Google Scholar 

  162. Moayyedi, P. et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149, 102–109.e6 (2015).

    Article  PubMed  Google Scholar 

  163. Paramsothy, S. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389, 1218–1228 (2017).

    Article  PubMed  Google Scholar 

  164. Costello, S. P. et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 321, 156–164 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Nusbaum, D. J. et al. Gut microbial and metabolomic profiles after fecal microbiota transplantation in pediatric ulcerative colitis patients. FEMS Microbiol. Ecol. 94, fiy133 (2018).

    Article  CAS  PubMed Central  Google Scholar 

  166. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03759041 (2019).

  167. Misra, B. et al. P421 SER-287, an investigational microbiome therapeutic, induces remission and endoscopic improvement in a placebo-controlled, double-blind randomised trial in patients with active mild-to-moderate ulcerative colitis. J. Crohns Colitis 12, S317–S317 (2018).

    Article  Google Scholar 

  168. Vedanta Biosciences. Vedanta Biosciences announces initiation of phase 1 clinical study with Janssen of microbiome-derived product candidate for inflammatory bowel disease. Vedanta Biosciences https://www.vedantabio.com/news-media/press-releases/detail/2491/vedanta-biosciences-announces-initiation-of-phase-1 (2019).

  169. Finch. FIN-524 for ulcerative colitis. Finch https://finchtherapeutics.com/fin524 (2019).

  170. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03832400 (2019).

  171. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03574948 (2019).

  172. Fangmann, D. et al. Targeted microbiome intervention by microencapsulated delayed-release niacin beneficially affects insulin sensitivity in humans. Diabetes Care 41, 398–405 (2018).

    Article  CAS  PubMed  Google Scholar 

  173. Li, J. et al. Niacin ameliorates ulcerative colitis via prostaglandin D2-mediated D prostanoid receptor 1 activation. EMBO Mol. Med. 9, 571–588 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Sonnenburg, E. D. et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212 (2016). An important study that highlights generational extinction of beneficial gut microbes based on diet, which has broad implications.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Sahuri-Arisoylu, M. et al. Reprogramming of hepatic fat accumulation and ‘browning’ of adipose tissue by the short-chain fatty acid acetate. Int. J. Obes. 40, 955 (2016).

    Article  CAS  Google Scholar 

  176. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446 (2013).

    Article  CAS  PubMed  Google Scholar 

  177. Costea, P. I. et al. Towards standards for human fecal sample processing in metagenomic studies. Nat. Biotechnol. 35, 1069–1076 (2017).

    Article  CAS  PubMed  Google Scholar 

  178. Sinha, R. et al. Assessment of variation in microbial community amplicon sequencing by the microbiome quality control (MBQC) project consortium. Nat. Biotechnol. 35, 1077–1086 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Rodrigues, R. R., Shulzhenko, N. & Morgun, A. Transkingdom networks: a systems biology approach to identify causal members of host-microbiota interactions. Methods Mol. Biol. 1849, 227–242 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Stappenbeck, T. S. & Virgin, H. W. Accounting for reciprocal host–microbiome interactions in experimental science. Nature 534, 191 (2016).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

A.L. has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. PCOFUND-GA-2013-609102, through the PRESTIGE programme coordinated by Campus France. H.S. received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (ERC-2016-StG-71577).

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  1. Sorbonne Université, Paris, France

    Aonghus Lavelle & Harry Sokol

  2. UMRS 938, Centre de Recherche Saint-Antoine (CRSA), Inserm, Paris, France

    Aonghus Lavelle & Harry Sokol

  3. AP-HP, Service de Gastroenterologie, Hôpital Saint Antoine, Paris, France

    Harry Sokol

  4. UMR 1319 Micalis & AgroParisTech, INRA, Jouy en Josas, France

    Harry Sokol

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The authors contributed equally to all aspects of the article.

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Correspondence to Harry Sokol.

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H.S. has received unrestricted study grants from Danone, Biocodex and Enterome; board membership, consultancy, or lecture fees from Carenity, Abbvie, Astellas, Danone, Ferring, Mayoly Spindler, MSD, Novartis, Roche, Tillots, Enterome, Maat, BiomX, Biose, Novartis and Takeda; and is a cofounder of Exeliom Biosciences. A.L. declares no competing interests.

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Lavelle, A., Sokol, H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 17, 223–237 (2020). https://doi.org/10.1038/s41575-019-0258-z

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