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

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.

References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 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.

  5. 5.

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

  6. 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).

  7. 7.

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

  8. 8.

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

  9. 9.

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

  10. 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).

  11. 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).

  12. 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).

  13. 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).

  14. 14.

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

  15. 15.

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

  16. 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.

  17. 17.

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

  18. 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).

  19. 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).

  20. 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.

  21. 21.

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

  22. 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).

  23. 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.

  24. 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).

  25. 25.

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

  26. 26.

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

  27. 27.

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

  28. 28.

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

  29. 29.

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

  30. 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).

  31. 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).

  32. 32.

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

  33. 33.

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

  34. 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).

  35. 35.

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

  36. 36.

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

  37. 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).

  38. 38.

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

  39. 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).

  40. 40.

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

  41. 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).

  42. 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).

  43. 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.

  44. 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.

  45. 45.

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

  46. 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).

  47. 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).

  48. 48.

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

  49. 49.

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

  50. 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).

  51. 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).

  52. 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).

  53. 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).

  54. 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).

  55. 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).

  56. 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).

  57. 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).

  58. 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).

  59. 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).

  60. 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).

  61. 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.

  62. 62.

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

  63. 63.

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

  64. 64.

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

  65. 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).

  66. 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).

  67. 67.

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

  68. 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).

  69. 69.

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

  70. 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).

  71. 71.

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

  72. 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).

  73. 73.

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

  74. 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).

  75. 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).

  76. 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).

  77. 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).

  78. 78.

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

  79. 79.

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

  80. 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).

  81. 81.

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

  82. 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).

  83. 83.

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

  84. 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).

  85. 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).

  86. 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).

  87. 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).

  88. 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).

  89. 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).

  90. 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).

  91. 91.

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

  92. 92.

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

  93. 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).

  94. 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.

  95. 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).

  96. 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).

  97. 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).

  98. 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).

  99. 99.

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

  100. 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).

  101. 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.

  102. 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).

  103. 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.

  104. 104.

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

  105. 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).

  106. 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).

  107. 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).

  108. 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).

  109. 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).

  110. 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).

  111. 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).

  112. 112.

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

  113. 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).

  114. 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).

  115. 115.

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

  116. 116.

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

  117. 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).

  118. 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).

  119. 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).

  120. 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.

  121. 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).

  122. 122.

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

  123. 123.

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

  124. 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).

  125. 125.

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

  126. 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).

  127. 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).

  128. 128.

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

  129. 129.

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

  130. 130.

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

  131. 131.

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

  132. 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).

  133. 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.

  134. 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).

  135. 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).

  136. 136.

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

  137. 137.

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

  138. 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).

  139. 139.

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

  140. 140.

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

  141. 141.

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

  142. 142.

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

  143. 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).

  144. 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).

  145. 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).

  146. 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).

  147. 147.

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

  148. 148.

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

  149. 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.

  150. 150.

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

  151. 151.

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

  152. 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).

  153. 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).

  154. 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).

  155. 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).

  156. 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).

  157. 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).

  158. 158.

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

  159. 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).

  160. 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).

  161. 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).

  162. 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).

  163. 163.

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

  164. 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).

  165. 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).

  166. 166.

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

  167. 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).

  168. 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. 169.

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

  170. 170.

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

  171. 171.

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

  172. 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).

  173. 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).

  174. 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.

  175. 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).

  176. 176.

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

  177. 177.

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

  178. 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).

  179. 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).

  180. 180.

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

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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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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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