The gut microbiota contributes to host physiology through the production of a myriad of metabolites. These metabolites exert their effects within the host as signalling molecules and substrates for metabolic reactions. Although the study of host–microbiota interactions remains challenging due to the high degree of crosstalk both within and between kingdoms, metabolite-focused research has identified multiple actionable microbial targets that are relevant for host health. Metabolites, as the functional output of combined host and microorganism interactions, provide a snapshot in time of an extraordinarily complex multi-organism system. Although substantial work remains towards understanding host–microbiota interactions and the underlying mechanisms, we review the current state of knowledge for each of the major classes of microbial metabolites with emphasis on clinical and translational research implications. We provide an overview of methodologies available for measurement of microbial metabolites, and in addition to discussion of key challenges, we provide a potential framework for integration of discovery-based metabolite studies with mechanistic work. Finally, we highlight examples in the literature where this approach has led to substantial progress in understanding host–microbiota interactions.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sender, R., Fuchs, S. & Milo, R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164, 337–340 (2016).
Tierney, B. T. et al. The landscape of genetic content in the gut and oral human microbiome. Cell Host Microbe 26, 283–295.e8 (2019).
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).
Dodd, D. et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 551, 648–652 (2017).
Martin, F.-P. J. et al. Panorganismal gut microbiome–host metabolic crosstalk. J. Proteome Res. 8, 2090–2105 (2009).
Claus, S. P. et al. Systemic multicompartmental effects of the gut microbiome on mouse metabolic phenotypes. Mol. Syst. Biol. 4, 219 (2008).
Lupton, J. R. Microbial degradation products influence colon cancer risk: the butyrate controversy. J. Nutr. 134, 479–482 (2004).
Donohoe, D. R. et al. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol. Cell 48, 612–626 (2012).
Wahlström, A., Sayin, S. I., Marschall, H.-U. & Bäckhed, F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016).
Singh, V. et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell 175, 679–694.e22 (2018).
Devlin, A. S. et al. Modulation of a circulating uremic solute via rational genetic manipulation of the gut microbiota. Cell Host Microbe 20, 709–715 (2016).
Deschasaux, M. et al. Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography. Nat. Med. 24, 1526–1531 (2018).
Martínez, I. et al. The gut microbiota of rural Papua New Guineans: composition, diversity patterns, and ecological processes. Cell Rep. 11, 527–538 (2015).
Martínez, I., Kim, J., Duffy, P. R., Schlegel, V. L. & Walter, J. Resistant starches types 2 and 4 have differential effects on the composition of the fecal microbiota in human subjects. PLoS ONE 5, e15046 (2010).
Jha, A. R. et al. Gut microbiome transition across a lifestyle gradient in Himalaya. PLoS Biol. 16, e2005396 (2018).
Vangay, P. et al. US immigration westernizes the human gut microbiome. Cell 175, 962–972.e10 (2018).
Smits, S. A. et al. Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania. Science 357, 802–806 (2017).
Davis, L. M. G., Martínez, I., Walter, J., Goin, C. & Hutkins, R. W. Barcoded pyrosequencing reveals that consumption of galactooligosaccharides results in a highly specific bifidogenic response in humans. PLoS ONE 6, e25200 (2011).
Desai, M. S. et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353.e21 (2016).
Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Bäckhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016).
Macfarlane, S. & Macfarlane, G. T. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 62, 67–72 (2007).
Makki, K., Deehan, E. C., Walter, J. & Bäckhed, F. The impact of dietary fiber on gut microbiota in host health and disease. Cell Host Microbe 23, 705–715 (2018).
Kaoutari, A. E., Armougom, F., Gordon, J. I., Raoult, D. & Henrissat, B. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. Nat. Rev. Microbiol. 11, 497–504 (2013).
Bhattacharya, T., Ghosh, T. S. & Mande, S. S. Global profiling of carbohydrate active enzymes in human gut microbiome. PLoS ONE 10, e0142038 (2015).
McNeil, N. I. The contribution of the large intestine to energy supplies in man. Am. J. Clin. Nutr. 39, 338–342 (1984).
Cummings, J. H., Pomare, E. W., Branch, W. J., Naylor, C. P. & Macfarlane, G. T. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28, 1221–1227 (1987).
Besten, G. den 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).
Smith, E. A. & Macfarlane, G. T. Dissimilatory amino acid metabolism in human colonic bacteria. Anaerobe 3, 327–337 (1997).
Macfarlane, G. T., Gibson, G. R., Beatty, E. & Cummings, J. H. Estimation of short-chain fatty acid production from protein by human intestinal bacteria based on branched-chain fatty acid measurements. FEMS Microbiol. Lett. 101, 81–88 (1992).
Dalile, B., Oudenhove, L. V., Vervliet, B. & Verbeke, K. The role of short-chain fatty acids in microbiota–gut–brain communication. Nat. Rev. Gastroenterol. 12, 453 (2019).
Johansson, M. E. V., Sjövall, H. & Hansson, G. C. The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. 10, 352–361 (2013).
Schroeder, B. O. Fight them or feed them: how the intestinal mucus layer manages the gut microbiota. Gastroenterol. Rep. 7, 3–12 (2019).
Martens, E. C., Chiang, H. C. & Gordon, J. I. Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. Cell Host Microbe 4, 447–457 (2008).
Sonnenburg, J. L. et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307, 1955–1959 (2005).
Cummings, J. H. & Macfarlane, G. T. The control and consequences of bacterial fermentation in the human colon. J. Appl. Bacteriol. 70, 443–459 (1991).
Kukral, J. C., Adams, A. P. & Preston, F. W. Protein producing capacity of the human exocrine pancreas. Ann. Surg. 162, 63–73 (1965).
Silberberg, M. et al. The bioavailability of polyphenols is highly governed by the capacity of the intestine and of the liver to secrete conjugated metabolites. Eur. J. Nutr. 45, 88–96 (2006).
Cardona, F., Andrés-Lacueva, C., Tulipani, S., Tinahones, F. J. & Queipo-Ortuño, M. I. Benefits of polyphenols on gut microbiota and implications in human health. J. Nutr.Biochem. 24, 1415–1422 (2013).
Puupponen-Pimiä, R. et al. Development of functional ingredients for gut health. Trends Food Sci. Tech. 13, 3–11 (2002).
Marín, L., Miguélez, E. M., Villar, C. J. & Lombó, F. Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. Biomed. Res. Int. 2015, 1–18 (2015).
Roopchand, D. E. et al. Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome. Diabetes 64, 2847–2858 (2015).
Zeng, S.-L. et al. Citrus polymethoxyflavones attenuate metabolic syndrome by regulating gut microbiome and amino acid metabolism. Sci. Adv. 6, eaax6208 (2020).
Ze, X., Duncan, S. H., Louis, P. & Flint, H. J. Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon. ISME J. 6, 1535–1543 (2012).
Deehan, E. C. et al. Precision microbiome modulation with discrete dietary fiber structures directs short-chain fatty acid production. Cell Host Microbe 27, 389–404.e6 (2020).
Bry, L., Falk, P. G., Midtvedt, T. & Gordon, J. I. A model of host–microbial interactions in an open mammalian ecosystem. Science 273, 1380–1383 (1996).
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2013).
Turnbaugh, P. J. et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14 (2009).
Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).
Sonnenburg, E. D. et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212–215 (2016).
Clemente, J. C. et al. The microbiome of uncontacted Amerindians. Sci. Adv. 1, e1500183 (2015).
Holmes, A. J. et al. Diet–microbiome interactions in health are controlled by intestinal nitrogen source constraints. Cell Metab. 25, 140–151 (2017).
Besten, G. den et al. Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G900–G910 (2013).
Reniere, M. L. Reduce, induce, thrive: bacterial redox sensing during pathogenesis. J. Bacteriol. 200, e00128-18 (2018).
Hylemon, P. B., Harris, S. C. & Ridlon, J. M. Metabolism of hydrogen gases and bile acids in the gut microbiome. FEBS Lett. 592, 2070–2082 (2018).
Peng, L., Li, Z.-R., Green, R. S., Holzman, I. R. & Lin, J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J. Nutr. 139, 1619–1625 (2009).
Lewis, K. et al. Enhanced translocation of bacteria across metabolically stressed epithelia is reduced by butyrate. Inflamm. Bowel Dis. 16, 1138–1148 (2010).
Cherbut, C. et al. Short-chain fatty acids modify colonic motility through nerves and polypeptide YY release in the rat. Am. J. Physiol. Gastrointest. Liver Physiol. 275, G1415–G1422 (1998).
Soret, R. et al. Short-chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats. Gastroenterology 138, 1772–1782.e4 (2010).
Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).
Martin, A. M., Sun, E. W., Rogers, G. B. & Keating, D. J. The influence of the gut microbiome on host metabolism through the regulation of gut hormone release. Front. Physiol. 10, 428 (2019).
Fukumoto, S. et al. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1269–R1276 (2003).
Krautkramer, K. A. et al. Diet–microbiota interactions mediate global epigenetic programming in multiple host tissues. Mol. Cell 64, 982–992 (2016).
Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1708–1720 (2016).
Donohoe, D. R. et al. A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Discov. 4, 1387–1397 (2014).
Donohoe, D. R. et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526 (2011).
Vadder, F. D. et al. Microbiota-generated metabolites promote metabolic benefits via gut–brain neural circuits. Cell 156, 84–96 (2014).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Bachem, A. et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity 51, 285–297.e5 (2019).
Kasahara, K. et al. Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model. Nat. Microbiol. 474, 327 (2018).
Samuel, B. S. et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl Acad. Sci. USA 105, 16767–16772 (2008).
Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).
Canfora, E. E., Meex, R. C. R., Venema, K. & Blaak, E. E. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat. Rev. Endocrinol. 15, 261–273 (2019).
Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014).
Husted, A. S., Trauelsen, M., Rudenko, O., Hjorth, S. A. & Schwartz, T. W. GPCR-mediated signaling of metabolites. Cell Metab. 25, 777–796 (2017).
Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).
Newgard, C. B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 15, 606–614 (2012).
Pedersen, H. K. et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376–381 (2016).
Ericksen, R. E. et al. Loss of BCAA catabolism during carcinogenesis enhances mTORC1 activity and promotes tumor development and progression. Cell Metab. 29, 1151–1165.e6 (2019).
VanDusseldorp, T. A. et al. Effect of branched-chain amino acid supplementation on recovery following acute eccentric exercise. Nutrients 10, 1389 (2018).
Evenepoel, P. et al. Amount and fate of egg protein escaping assimilation in the small intestine of humans. Am. J. Physiol. Gastrointest. Liver Physiol. 277, G935–G943 (1999).
Mahé, S., Huneau, J. F., Marteau, P., Thuillier, F. & Tomé, D. Gastroileal nitrogen and electrolyte movements after bovine milk ingestion in humans. Am. J. Clin. Nutr. 56, 410–416 (1992).
Neis, E. P. J. G., Dejong, C. H. C. & Rensen, S. S. The role of microbial amino acid metabolism in host metabolism. Nutrients 7, 2930–2946 (2015).
Ratzke, C. & Gore, J. Modifying and reacting to the environmental pH can drive bacterial interactions. PLoS Biol. 16, e2004248 (2018).
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. 81, 288–302 (1996).
Birkett, A., Muir, J., Phillips, J., Jones, G. & O’Dea, K. Resistant starch lowers fecal concentrations of ammonia and phenols in humans. Am. J. Clin. Nutr. 63, 766–772 (1996).
Stephen, A. M. & Cummings, J. H. Mechanism of action of dietary fibre in the human colon. Nature 284, 283–284 (1980).
Sridharan, G. V. et al. Prediction and quantification of bioactive microbiota metabolites in the mouse gut. Nat. Commun. 5, 5492 (2014).
Alkhalaf, L. M. & Ryan, K. S. Biosynthetic manipulation of tryptophan in bacteria: pathways and mechanisms. Chem. Biol. 22, 317–328 (2015).
Agus, A., Planchais, J. & Sokol, H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23, 716–724 (2018).
Cervenka, I., Agudelo, L. Z. & Ruas, J. L. Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Science 357, eaaf9794 (2017).
Houtkooper, R. H., Cantó, C., Wanders, R. J. & Auwerx, J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr. Rev. 31, 194–223 (2010).
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2010).
Rhee, S. J., Walker, W. A. & Cherayil, B. J. Developmentally regulated intestinal expression of IFN-γ and its target genes and the age-specific response to enteric Salmonella infection. J. Immunol. 175, 1127–1136 (2005).
Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).
Vujkovic-Cvijin, I. et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci. Transl. Med. 5, 193ra91–193ra91 (2013).
Agudelo, L. Z. et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159, 33–45 (2014).
Hubbard, T. D. et al. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 5, 12689 (2015).
Walther, D. J. et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76–76 (2003).
Mawe, G. M. & Hoffman, J. M. Serotonin signalling in the gut — functions, dysfunctions and therapeutic targets. Nat. Rev. Gastroenterol. 10, 473–486 (2013).
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 (2014).
Valles-Colomer, M. et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat. Microbiol. 4, 623–632 (2019).
Lukić, I. et al. Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior. Transl. Psychiat 9, 133 (2019).
Fung, T. C. et al. Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut. Nat. Microbiol. 4, 2064–2073 (2019).
Bhattarai, Y. et al. Gut microbiota-produced tryptamine activates an epithelial G-protein-coupled receptor to increase colonic secretion. Cell Host Microbe 23, 775–785.e5 (2018).
Barcik, W., Wawrzyniak, M., Akdis, C. A. & O’Mahony, L. Immune regulation by histamine and histamine-secreting bacteria. Curr. Opin. Immunol. 48, 108–113 (2017).
Koh, A. et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell 175, 947–961.e17 (2018).
Rekdal, V. M., Bess, E. N., Bisanz, J. E., Turnbaugh, P. J. & Balskus, E. P. Discovery and inhibition of an interspecies gut bacterial pathway for levodopa metabolism. Science 364, eaau6323 (2019).
Kessel, S. P. van et al. Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease. Nat. Commun. 10, 310 (2019).
Nallu, A., Sharma, S., Ramezani, A., Muralidharan, J. & Raj, D. Gut microbiome in chronic kidney disease: challenges and opportunities. Transl. Res. 179, 24–37 (2017).
Vanholder, R., Schepers, E., Pletinck, A., Nagler, E. V. & Glorieux, G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J. Am. Soc. Nephrol. 25, 1897–1907 (2014).
Hatch, M. & Vaziri, N. D. Enhanced enteric excretion of urate in rats with chronic renal failure. Clin. Sci. 86, 511–516 (1994).
Einheber, A. & Carter, D. The role of the microbial flora in uremia. J. Exp. Med. 123, 239–250 (1966).
Werder, A. A., Amos, M. A., Nielsen, A. H. & Wolfe, G. H. Comparative effects of germfree and ambient environments on the development of cystic kidney disease in CFWwd mice. J. Lab. Clin. Med. 103, 399–407 (1984).
Hallman, T. M. et al. The mitochondrial and kidney disease phenotypes of kd/kd mice under germfree conditions. J. Autoimmun. 26, 1–6 (2006).
Consortium, C. K. D. P. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375, 2073–2081 (2010).
Poesen, R. et al. Microbiota-derived phenylacetylglutamine associates with overall mortality and cardiovascular disease in patients with CKD. J. Am. Soc. Nephrol. 27, 3479–3487 (2016).
Nemet, I. et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell 180, 862–877.e22 (2020).
de Aguiar Vallim, T. Q., Tarling, E. J. & Edwards, P. A. Pleiotropic roles of bile acids in metabolism. Cell Metab. 17, 657–669 (2013).
Sayin, S. I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-β-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013).
Quinn, R. A. et al. Global chemical effects of the microbiome include new bile-acid conjugations. Nature 579, 123–129 (2020).
Funabashi, M. et al. A metabolic pathway for bile acid dehydroxylation by the gut microbiome. Nature 582, 566–570 (2020).
Schramm, C. Bile acids, the microbiome, immunity, and liver tumors. N. Engl. J. Med. 379, 888–890 (2018).
Jia, W., Xie, G. & Jia, W. Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat. Rev. Gastroenterol. Hepatol. 15, 111–128 (2017).
Lund, M. L. et al. L-cell differentiation is induced by bile acids through GPBAR1 and paracrine GLP-1 and serotonin signaling. Diabetes 69, 614–623 (2020).
Inagaki, T. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2, 217–225 (2005).
Ryan, K. K. et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509, 183–188 (2014).
Flynn, C. R. et al. Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery. Nat. Commun. 6, 7715 (2015).
Schmitt, J. et al. Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal. Liver Int. 35, 1133–1144 (2014).
Jiang, C. et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6, 10166 (2015).
Li, F. et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun. 4, 2384 (2013).
Sjöström, L. et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 10, 653–662 (2009).
Sjöström, L. et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N. Engl. J. Med. 351, 2683–2693 (2004).
Tremaroli, V., Karlsson, F. & Werling, M. et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 22, 228–238 (2015).
Gottardi, A. D. et al. The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer. Dig. Dis. Sci. 49, 982–989 (2004).
Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).
Gadaleta, R. M. et al. Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine. Biochim. Biophys. Acta 1812, 851–858 (2011).
Bailey, A. M. et al. FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G48–G58 (2014).
Degirolamo, C. et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology 61, 161–170 (2014).
Yang, F. et al. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 67, 863–867 (2007).
Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360, eaan5931 (2018).
Ducker, G. S. & Rabinowitz, J. D. One-carbon metabolism in health and disease. Cell Metab. 25, 27–42 (2016).
Zeisel, S. H. & Costa, K. D. Choline: an essential nutrient for public health. Nutr. Rev. 67, 615–623 (2009).
Craciun, S. & Balskus, E. P. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc. Natl Acad. Sci. USA 109, 21307–21312 (2012).
Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016).
Tang, W. H. W. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).
Li, X. S. et al. Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur. Heart J. 38, 814–824 (2017).
Seldin, M. M. et al. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J. Am. Heart Assoc. 5, e002767 (2016).
Koeth, R. A. et al. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J. Clin. Invest. 129, 373–387 (2018).
Li, X. S. et al. Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes. Eur. Heart J. 40, 2700–2709 (2019).
Hill, M. J. Intestinal flora and endogenous vitamin synthesis. Eur. J. Cancer Prev. 6 (Suppl 1), S43–S45 (1997).
Magnúsdóttir, S., Ravcheev, D., Crécy-Lagard, V. de & Thiele, I. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front. Genet. 6, 1–18 (2015).
Aufreiter, S. et al. Folate is absorbed across the colon of adults: evidence from cecal infusion of 13C-labeled [6S]-5-formyltetrahydrofolic acid. Am. J. Clin. Nutr. 90, 116–123 (2009).
Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).
Roberts, A. B. et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat. Med. 24, 1407–1417 (2018).
Zimmermann, M., Zimmermann-Kogadeeva, M., Wegmann, R. & Goodman, A. L. Separating host and microbiome contributions to drug pharmacokinetics and toxicity. Science 363, eaat9931 (2019).
Ackerman, D. & Schutze, H. The formation of trimethylamine by Bacterium prodigiosum. Zentralb. Physiol. 24, 210–211 (1910).
Romano, K. A., Vivas, E. I., Amador-Noguez, D. & Rey, F. E. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. Mbio 6, e02481 (2015).
Gregory, J. C. et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J. Biol. Chem. 290, 5647–5660 (2015).
Guo, C.-J. et al. Discovery of reactive microbiota-derived metabolites that inhibit host proteases. Cell 168, 517–526.e18 (2017).
Lloyd-Price, J. et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569, 655–662 (2019).
McDonald, L. C. et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin. Infect. Dis. 66, e1–e48 (2018).
Mullish, B. H. et al. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. Gut 67, 1920 (2018).
DeFilipp, Z. et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. New Engl. J. Med. 381, 2043–2050 (2019).
Korem, T. et al. Bread affects clinical parameters and induces gut microbiome-associated personal glycemic responses. Cell Metab. 25, 1243–1253.e5 (2017).
Zeevi, D. et al. Personalized nutrition by prediction of glycemic responses. Cell 163, 1079–1094 (2015).
Zhang, L. S. & Davies, S. S. Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions. Genome Med. 8, 46 (2016).
Williams, B. B. et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 16, 495–503 (2014).
Saito, Y., Sato, T., Nomoto, K. & Tsuji, H. Identification of phenol- and p-cresol-producing intestinal bacteria by using media supplemented with tyrosine and its metabolites. Fems. Microbiol. Ecol. 94, fiy125 (2018).
Eyssen, H., Pauw, G. D., Stragier, J. & Verhulst, A. Cooperative formation of ω-muricholic acid by intestinal microorganisms. Appl. Env. Microb. 45, 141–147 (1983).
Madsen, D., Beaver, M., Chang, L., Bruckner-Kardoss, E. & Wostmann, B. Analysis of bile acids in conventional and germfree rats. J. Lipid Res. 17, 107–111 (1976).
Ragsdale, S. W. & Pierce, E. Acetogenesis and the Wood–Ljungdahl pathway of CO2 fixation. Biochim. Biophys. Acta 1784, 1873–1898 (2008).
Duncan, S. H., Barcenilla, A., Stewart, C. S., Pryde, S. E. & Flint, H. J. Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Appl. Env. Microb. 68, 5186–5190 (2002).
Cloutier, N. et al. Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration. Proc. Natl Acad. Sci. USA 115, 201720553 (2018).
Fiehn, O. Metabolomics by gas chromatography–mass spectrometry: combined targeted and untargeted profiling. Curr. Protoc. Mol. Biol. 114, 30.4.1–30.4.32 (2016).
Berry, D. & Loy, A. Stable-isotope probing of human and animal microbiome function. Trends Microbiol. 26, 999–1007 (2018).
Röth, D. et al. Two-carbon folate cycle of commensal Lactobacillus reuteri 6475 gives rise to immunomodulatory ethionine, a source for histone ethylation. FASEB J. 33, 3536–3548 (2019).
Jang, C. et al. The small intestine converts dietary fructose into glucose and organic acids. Cell Metab. 27, 351–361.e3 (2018).
Rath, C. M. et al. Molecular analysis of model gut microbiotas by imaging mass spectrometry and nanodesorption electrospray ionization reveals dietary metabolite transformations. Anal. Chem. 84, 9259–9267 (2012).
Wagner, M. Single-cell ecophysiology of microbes as revealed by Raman microspectroscopy or secondary ion mass spectrometry imaging. Annu. Rev. Microbiol. 63, 411–429 (2009).
Lourenço, C. et al. Monitoring type 2 diabetes from volatile faecal metabolome in Cushing’s syndrome and single Afmid mouse models via a longitudinal study. Sci. Rep. 9, 18779 (2019).
Hoving, L. R., Heijink, M., Harmelen, V., Dijk, K. W. van & Giera, M. Methods in molecular biology. Meth. Mol. Biol. 1730, 247–256 (2018).
Zhang, X.-S. et al. Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity. eLife 7, e1002358 (2018).
Robinson, J. I. et al. Metabolomic networks connect host–microbiome processes to human Clostridioides difficile infections. J. Clin. Invest. 129, 3792–3806 (2019).
Fujisaka, S. et al. Diet, genetics, and the gut microbiome drive dynamic changes in plasma metabolites. Cell Rep. 22, 3072–3086 (2018).
Zierer, J. et al. The fecal metabolome as a functional readout of the gut microbiome. Nat. Genet. 50, 790–795 (2018).
Paul, H. A., Bomhof, M. R., Vogel, H. J. & Reimer, R. A. Diet-induced changes in maternal gut microbiota and metabolomic profiles influence programming of offspring obesity risk in rats. Sci. Rep. 6, 20683 (2016).
Lamichhane, S. et al. Strategy for nuclear-magnetic-resonance-based metabolomics of human feces. Anal. Chem. 87, 5930–5937 (2015).
Zhang, C. et al. Dietary modulation of gut microbiota contributes to alleviation of both genetic and simple obesity in children. Ebiomedicine 2, 968–984 (2015).
Bui, T. P. N. et al. Production of butyrate from lysine and the Amadori product fructoselysine by a human gut commensal. Nat. Commun. 6, 10062 (2015).
Lin, Y. et al. NMR-based fecal metabolomics fingerprinting as predictors of earlier diagnosis in patients with colorectal cancer. Oncotarget 7, 29454–29464 (2015).
Kim, M., Qie, Y., Park, J. & Kim, C. H. Gut microbial metabolites fuel host antibody responses. Cell Host Microbe 20, 202–214 (2016).
Etchegaray, J.-P. & Mostoslavsky, R. Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Mol. Cell 62, 695–711 (2016).
Krautkramer, K. A., Rey, F. E. & Denu, J. M. Chemical signaling between gut microbiota and host chromatin: what is your gut really saying? J. Biol. Chem. 292, 8582–8593 (2017).
Allen, J. & Sears, C. L. Impact of the gut microbiome on the genome and epigenome of colon epithelial cells: contributions to colorectal cancer development. Genome Med. 11, 11 (2019).
Fan, J., Krautkramer, K. A., Feldman, J. L. & Denu, J. M. Metabolic regulation of histone post-translational modifications. ACS Chem. Biol. 10, 95–108 (2015).
Zhao, Y. & Garcia, B. A. Comprehensive catalog of currently documented histone modifications. Cold Spring Harb. Perspect. Biol. 7, a025064 (2015).
Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).
Badeaux, A. I. & Shi, Y. Emerging roles for chromatin as a signal integration and storage platform. Nat. Rev. Mol. Cell Bio. 14, 211 (2013).
Zhu, Q., Stöger, R. & Alberio, R. A lexicon of DNA modifications: their roles in embryo development and the germline. Front. Cell Dev. Biol. 6, 24 (2018).
Riggs, M. G., Whittaker, R. G., Neumann, J. R. & Ingram, V. M. n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268, 462–464 (1977).
Thaiss, C. A. et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510.e12 (2016).
Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).
Sánchez-Romero, M. A. & Casadesús, J. The bacterial epigenome. Nat. Rev. Microbiol. 18, 7–20 (2020).
Dorman, C. J. & Dorman, M. J. DNA supercoiling is a fundamental regulatory principle in the control of bacterial gene expression. Biophys. Rev. 8, 89–100 (2016).
Liu, S. et al. The host shapes the gut microbiota via fecal microRNA. Cell Host Microbe 19, 32–43 (2016).
Yassour, M. et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci. Transl. Med. 8, 343ra81–343ra81 (2016).
Kimura, I. et al. Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice. Science 367, eaaw8429 (2020).
Waterland, R. A. et al. Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet. 6, e1001252 (2010).
Romano, K. A. et al. Metabolic, epigenetic, and transgenerational effects of gut bacterial choline consumption. Cell Host Microbe 22, 279–290.e7 (2017).
K.A.K acknowledges support from the Fulbright United States Scholar Program (US Fulbright Scholar Award) and the Human Frontier Science Program (HFSP; Long-term Fellowship LT000195/2018-L). Work in the Bäckhed laboratory is supported by Transatlantic Networks of Excellence Award from the Leducq Foundation (17CVD01), JPI (A healthy diet for a healthy life; 2017-01996_3), AFA insurances, the Swedish Research Council (2019-01599), the Swedish Heart Lung Foundation (20180600), the Knut and Alice Wallenberg Foundation (2017.0026), the Novo Nordisk Foundation (NNF19OC0057271, NNF17OC0028232 and NNF15OC0016798), grants from the Swedish state under the agreement between the Swedish government and the county councils, and the ALF-agreement (ALFGBG-718101). F.B. is Torsten Söderberg Professor in Medicine and recipient of an ERC Consolidator Grant (European Research Council; Consolidator grant 615362-METABASE).
F.B. receives research support from Biogaia AB and is founder and shareholder in Implexion pharma AB. All other authors declare no competing interests.
Peer review information
Nature Reviews Microbiology thanks P. Dorrestein, E. Gentry and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
An epithelial layer comprising epithelial cells and mucus-secreting cells, among other specialized cell types, that lines multiple body surfaces (gastrointestinal tract, oropharynx, airways and vaginal tract) and functions as an innate barrier.
The chemical breakdown of organic substrates (for example, carbohydrates and amino acids) by various enzymes in the absence of molecular oxygen.
- Gas chromatography–mass spectrometry
(GC-MS). An analytical method that couples chromatographic separation of complex biological samples in the gas phase to mass spectrometry for the identification and quantification of the compounds that comprise the sample.
- Liquid chromatography–mass spectrometry
(LC-MS). An analytical method that couples chromatographic separation of complex biological samples in the liquid phase to mass spectrometry for the identification and quantification of the compounds that comprise the sample.
- Desorption electrospray ionization mass spectrometry
A soft electrospray ionization technique that relies on solvent extraction directly on the sample under ambient conditions that is primarily used on tissues for imaging mass spectrometry.
- Raman spectroscopy
A vibrational spectroscopy technique wherein a biological sample is subjected to a beam of light and differences in photon scatter (based on the molecular composition of the sample) are used to produce a unique chemical fingerprint.
- Carbohydrate-active enzymes
(CAZymes). A collective term for enzymes that can synthesize or break down saccharides.
- Microbial accessible carbohydrates
(MACs). Complex polysaccharides and oligosaccharides that are available to the gut microbiome’s vast repertoire of carbohydrate-active enzymes.
A gel-like layer(s) secreted by and resting on top of the mucosa comprising mucins and functions as an essential barrier between the environment and the mucosal layer.
Large, heavily decorated proteins characterized by proline-rich, serine-rich and threonine-rich tandem repeats (PTS domains) that are modified by complex O-glycans and form large polymeric protein networks that function as the building blocks of mucus in the intestinal tract.
Enzymes that hydrolyse the glycosidic bond at the terminal monosaccharide in a polysaccharide or oligosaccharide.
Enzymes that hydrolyse polysaccharides to form smaller saccharide chains.
A general term for enzymes that hydrolyse glycosidic bonds in polysaccharides and oligosaccharides.
A highly structured nucleoprotein complex in eukaryotes that consists of the nucleic acids and histone proteins around which double-stranded genomic DNA winds to ultimately form chromosomes.
- Germ-free mice
Mice born and raised in the complete absence of any microorganisms, frequently in a laminar flow glovebox isolator or IsoCage setting
- Conventionally raised mice
Mice born and raised in a normal (‘conventional’) mouse colony setting with exposure to normal environmental microorganisms from birth onwards.
- Bile salt hydrolases
Microbial enzymes that hydrolyse the amide bond in taurine and glycine-conjugated primary bile acids to yield a deconjugated bile acid.
- Nuclear magnetic resonance spectroscopy
An analytical method frequently used in structural, quantitative and imaging applications wherein unique spectra are obtained for biomolecules based on nuclear resonance transitions that occur when atomic nuclei are immersed in a magnetic field and then subjected to specific magnetic energy levels.
- Faecal microbiota transplantation
Delivery of processed stool from a donor into the intestinal tract of a recipient with the goal of stable engraftment.
Variants in human microbial community composition based on empirical population measurements that are dominated by a single genus (for example, Bacteroides, Ruminococcus or Prevotella).
About this article
Cite this article
Krautkramer, K.A., Fan, J. & Bäckhed, F. Gut microbial metabolites as multi-kingdom intermediates. Nat Rev Microbiol 19, 77–94 (2021). https://doi.org/10.1038/s41579-020-0438-4
Genome Biology (2021)
Genes & Immunity (2021)
Mammalian Genome (2021)
Impact of acute lymphoblastic leukemia induction therapy: findings from metabolomics on non-fasted plasma samples from a biorepository