Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The potential of tailoring the gut microbiome to prevent and treat cardiometabolic disease

Abstract

Despite milestones in preventive measures and treatment, cardiovascular disease (CVD) remains associated with a high burden of morbidity and mortality. The protracted nature of the development and progression of CVD motivates the identification of early and complementary targets that might explain and alleviate any residual risk in treated patients. The gut microbiota has emerged as a sentinel between our inner milieu and outer environment and relays a modified risk associated with these factors to the host. Accordingly, numerous mechanistic studies in animal models support a causal role of the gut microbiome in CVD via specific microbial or shared microbiota–host metabolites and have identified converging mammalian targets for these signals. Similarly, large-scale cohort studies have repeatedly reported perturbations of the gut microbial community in CVD, supporting the translational potential of targeting this ecological niche, but the move from bench to bedside has not been smooth. In this Review, we provide an overview of the current evidence on the interconnectedness of the gut microbiome and CVD against the noisy backdrop of highly prevalent confounders in advanced CVD, such as increased metabolic burden and polypharmacy. We further aim to conceptualize the molecular mechanisms at the centre of these associations and identify actionable gut microbiome-based targets, while contextualizing the current knowledge within the clinical scenario and emphasizing the limitations of the field that need to be overcome.

Key points

  • The gut microbiome has been causally linked with cardiometabolic and cardiovascular disorders and is a potential complementary target to understand and reduce the residual risk of cardiovascular disease.

  • Cardiometabolic and cardiovascular disease progression is reflected in a reduction in gut microbiome diversity and butyrate producers, together with a reduction in pathogen exclusion and increased systemic inflammation.

  • Metabolites produced by gut microbiome metabolism or host–microbiome co-metabolism signal between the gut and peripheral organs to convey a modified exposure and disease risk, providing potential targets for individualized prevention and treatment.

  • A complex interaction exists between medication and the gut microbiome, whereby the microbiome influences drug bioavailability and treatment effects, and medication affects the microbial environment, composition and function, adding both complexity and opportunities for drug repurposing.

  • Next-generation, gut microbiome-based therapeutics require biotic and abiotic characteristics influencing grafting of probiotics, metabolic activity and microbial interactions with the resident bacteria to be addressed; emerging strategies should be paired with improved storage stability, improved viability and targeted delivery.

  • Increasing collaborative efforts to characterize the human gut microbiome diversity in depth are moving us towards the development of more precise and personalized approaches to circumvent disease.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: ‘Devolution’ of the gut microbiome during the development and progression of cardiovascular disease.
Fig. 2: Intestinal metabolism and cardiometabolic and cardiovascular disease.
Fig. 3: Gut microbial metabolites contribute directly to vascular and cellular factors at all stages of atherosclerosis development.

References

  1. Virani, S. S. et al. Heart disease and stroke statistics — 2020 update: a report from the American Heart Association. Circulation 141, e139–e596 (2020).

    Article  PubMed  Google Scholar 

  2. Roth, G. A. et al. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J. Am. Coll. Cardiol. 76, 2982–3021 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fernández-Friera, L. et al. Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort. Circulation 131, 2104–2113 (2015).

    Article  PubMed  Google Scholar 

  4. Ford, E. S., Li, C. & Sattar, N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care 31, 1898–1904 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gami, A. S. et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J. Am. Coll. Cardiol. 49, 403–414 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Koh, K. K., Han, S. H. & Quon, M. J. Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J. Am. Coll. Cardiol. 46, 1978–1985 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Ridker, P. M., Buring, J. E., Cook, N. R. & Rifai, N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 107, 391–397 (2003).

    Article  PubMed  Google Scholar 

  8. Borén, J. et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 41, 2313–2330 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Arnett, D. K. et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J. Am. Coll. Cardiol. 74, 1376–1414 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).

    Article  PubMed  Google Scholar 

  14. Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916.e7 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. DeFilipp, Z. et al. Drug-resistant bacteremia transmitted by fecal microbiota transplant. N. Engl. J. Med. 381, 2043–2050 (2019).

    Article  PubMed  Google Scholar 

  16. Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bäckhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl Acad. Sci. USA 104, 979–984 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sze, M. A. & Schloss, P. D. Looking for a signal in the noise: revisiting obesity and the microbiome. mBio 7, e01018-16 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Walters, W. A., Xu, Z. & Knight, R. Meta-analyses of human gut microbes associated with obesity and IBD. FEBS Lett. 588, 4223–4233 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Faintuch, J. & Faintuch, S. Microbiome and Metabolome in Diagnosis, Therapy, and other Strategic Applications (Academic, 2019).

  21. Duvallet, C., Gibbons, S. M., Gurry, T., Irizarry, R. A. & Alm, E. J. Meta-analysis of gut microbiome studies identifies disease-specific and shared responses. Nat. Commun. 8, 1784 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Pasolli, E., Truong, D. T., Malik, F., Waldron, L. & Segata, N. Machine learning meta-analysis of large metagenomic datasets: tools and biological insights. PLoS Comput. Biol. 12, e1004977 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Duncan, S. H. et al. Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Appl. Environ. Microbiol. 73, 1073–1078 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Waters, J. L. & Ley, R. E. The human gut bacteria Christensenellaceae are widespread, heritable, and associated with health. BMC Biol. 17, 83 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Olsson, L. M. et al. Gut microbiota of obese subjects with Prader-Willi syndrome is linked to metabolic health. Gut 69, 1229–1238 (2020).

    Article  CAS  PubMed  Google Scholar 

  27. Zhong, X. et al. Gut microbiota associations with metabolic health and obesity status in older adults. Nutrients 12, 2364 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  28. Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

    Article  PubMed  Google Scholar 

  29. Herder, C. & Roden, M. A novel diabetes typology: towards precision diabetology from pathogenesis to treatment. Diabetologia 65, 1770–1781 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zhou, W. et al. Longitudinal multi-omics of host-microbe dynamics in prediabetes. Nature 569, 663–671 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wu, H. et al. The gut microbiota in prediabetes and diabetes: a population-based cross-sectional study. Cell Metab. 32, 379–390.e3 (2020).

    Article  CAS  PubMed  Google Scholar 

  32. Schüssler-Fiorenza Rose, S. M. et al. A longitudinal big data approach for precision health. Nat. Med. 25, 792–804 (2019).

    Article  PubMed  Google Scholar 

  33. Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Alvarez-Silva, C. et al. Trans-ethnic gut microbiota signatures of type 2 diabetes in Denmark and India. Genome Med. 13, 37 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Allin, K. H. et al. Aberrant intestinal microbiota in individuals with prediabetes. Diabetologia 61, 810–820 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Forslund, S. K. et al. Combinatorial, additive and dose-dependent drug-microbiome associations. Nature 600, 500–505 (2021).

    Article  CAS  PubMed  Google Scholar 

  39. Olsson, L. M. et al. Dynamics of the normal gut microbiota: a longitudinal one-year population study in Sweden. Cell Host Microbe 30, 726–739.e3 (2022).

    Article  CAS  PubMed  Google Scholar 

  40. Thingholm, L. B. et al. Obese individuals with and without type 2 diabetes show different gut microbial functional capacity and composition. Cell Host Microbe 26, 252–264.e10 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Belda, E. et al. Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism. Gut https://doi.org/10.1136/gutjnl-2021-325753 (2022).

    Article  PubMed  Google Scholar 

  42. Urpi-Sarda, M. et al. Metabolomics for biomarkers of type 2 diabetes mellitus: advances and nutritional intervention trends. Curr. Cardiovasc. Risk Rep. 9, 280–291 (2015).

    Article  Google Scholar 

  43. Cotillard, A. et al. Dietary intervention impact on gut microbial gene richness. Nature 500, 585–588 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Fu, J. et al. The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circ. Res. 117, 817–824 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kenny, D. J. et al. Cholesterol metabolism by uncultured human gut bacteria influences host cholesterol level. Cell Host Microbe 28, 245–257.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Perino, A. & Schoonjans, K. Metabolic messengers: bile acids. Nat. Metab. 4, 416–423 (2022).

    Article  CAS  PubMed  Google Scholar 

  47. Mills, K. T., Stefanescu, A. & He, J. The global epidemiology of hypertension. Nat. Rev. Nephrol. 16, 223–237 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jama, H. A., Kaye, D. M. & Marques, F. Z. The gut microbiota and blood pressure in experimental models. Curr. Opin. Nephrol. Hypertens. 28, 97–104 (2019).

    Article  PubMed  Google Scholar 

  49. Evangelou, E. et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat. Genet. 50, 1412–1425 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Verhaar, B. J. H. et al. Associations between gut microbiota, faecal short-chain fatty acids, and blood pressure across ethnic groups: the HELIUS study. Eur. Heart J. 41, 4259–4267 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Louca, P. et al. Gut microbiome diversity and composition is associated with hypertension in women. J. Hypertens. 39, 1810–1816 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sun, S. et al. Gut microbiota composition and blood pressure. Hypertension 73, 998–1006 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Li, J. et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 5, 14 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Palmu, J. et al. Association between the gut microbiota and blood pressure in a population cohort of 6953 individuals. J. Am. Heart Assoc. 9, e016641 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Menni, C. et al. Gut microbial diversity is associated with lower arterial stiffness in women. Eur. Heart J. 39, 2390–2397 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jama, H. A., Beale, A., Shihata, W. A. & Marques, F. Z. The effect of diet on hypertensive pathology: is there a link via gut microbiota-driven immunometabolism? Cardiovasc. Res. 115, 1435–1447 (2019).

    Article  CAS  PubMed  Google Scholar 

  57. Calderón-Pérez, L. et al. Gut metagenomic and short chain fatty acids signature in hypertension: a cross-sectional study. Sci. Rep. 10, 6436 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Saikku, P. et al. Serological evidence of an association of a novel chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 2, 983–986 (1988).

    Article  CAS  PubMed  Google Scholar 

  59. Gelfand, E. V. & Cannon, C. P. Antibiotics for secondary prevention of coronary artery disease: an ACES hypothesis but we need to PROVE IT. Am. Heart J. 147, 202–209 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Winkel, P. et al. Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10 years in the CLARICOR randomised, blinded clinical trial. Int. J. Cardiol. 182, 459–465 (2015).

    Article  PubMed  Google Scholar 

  61. Koren, O. et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc. Natl Acad. Sci. USA 108, 4592–4598 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Yin, J. et al. Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J. Am. Heart Assoc. 4, e002699 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Kelly, T. N. et al. Gut microbiome associates with lifetime cardiovascular disease risk profile among Bogalusa Heart Study participants. Circ. Res. 119, 956–964 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhu, Q. et al. Dysbiosis signatures of gut microbiota in coronary artery disease. Physiol. Genomics 50, 893–903 (2018).

    Article  CAS  PubMed  Google Scholar 

  65. Liu, H. et al. Alterations in the gut microbiome and metabolism with coronary artery disease severity. Microbiome 7, 68 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Toya, T. et al. Coronary artery disease is associated with an altered gut microbiome composition. PLoS ONE 15, e0227147 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cui, X. et al. Metagenomic and metabolomic analyses unveil dysbiosis of gut microbiota in chronic heart failure patients. Sci. Rep. 8, 635 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Karlsson, F. H. et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat. Commun. 3, 1245 (2012).

    Article  PubMed  Google Scholar 

  69. Feng, Q. et al. Integrated metabolomics and metagenomics analysis of plasma and urine identified microbial metabolites associated with coronary heart disease. Sci. Rep. 6, 22525 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jie, Z. et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 8, 845 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Liu, S., Zhao, W., Liu, X. & Cheng, L. Metagenomic analysis of the gut microbiome in atherosclerosis patients identify cross-cohort microbial signatures and potential therapeutic target. FASEB J. 34, 14166–14181 (2020).

    Article  CAS  PubMed  Google Scholar 

  72. Ott, S. J. et al. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease. Circulation 113, 929–937 (2006).

    Article  PubMed  Google Scholar 

  73. Zheng, Y.-Y. et al. Gut microbiome-based diagnostic model to predict coronary artery disease. J. Agric. Food Chem. 68, 3548–3557 (2020).

    Article  CAS  PubMed  Google Scholar 

  74. Talmor-Barkan, Y. et al. Metabolomic and microbiome profiling reveals personalized risk factors for coronary artery disease. Nat. Med. 28, 295–302 (2022).

    Article  CAS  PubMed  Google Scholar 

  75. Fromentin, S. et al. Microbiome and metabolome features of the cardiometabolic disease spectrum. Nat. Med. 28, 303–314 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Vandeputte, D. et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature 551, 507–511 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Vieira-Silva, S. et al. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis. Nature 581, 310–315 (2020).

    Article  CAS  PubMed  Google Scholar 

  78. Kasahara, K. et al. Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model. Nat. Microbiol. 3, 1461–1471 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nemet, I. et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell 180, 862–877.e22 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wehedy, E., Shatat, I. F. & Al Khodor, S. The human microbiome in chronic kidney disease: a double-edged sword. Front. Med. 8, 790783 (2021).

    Article  Google Scholar 

  81. Medina, D. A. et al. Cross-regional view of functional and taxonomic microbiota composition in obesity and post-obesity treatment shows country specific microbial contribution. Front. Microbiol. 10, 2346 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Heianza, Y., Ma, W., Manson, J. E., Rexrode, K. M. & Qi, L. Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies. J. Am. Heart Assoc. 6, e004947 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Filippo, C. D. et al. Diet, environments, and gut microbiota. A preliminary investigation in children living in rural and urban Burkina Faso and Italy. Front. Microbiol. 8, 1979 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Bergman, E. N. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol. Rev. 70, 567–590 (1990).

    Article  CAS  PubMed  Google Scholar 

  85. Vinolo, M. A. R., Rodrigues, H. G., Nachbar, R. T. & Curi, R. Regulation of inflammation by short chain fatty acids. Nutrients 3, 858–876 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tan, J. et al. The role of short-chain fatty acids in health and disease. Adv. Immunol. 121, 91–119 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. 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  Google Scholar 

  88. Byndloss, M. X. et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357, 570–575 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Clemente, J. C. et al. The microbiome of uncontacted Amerindians. Sci. Adv. 1, e1500183 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Arora, T. & Bäckhed, F. The gut microbiota and metabolic disease: current understanding and future perspectives. J. Intern. Med. 280, 339–349 (2016).

    Article  CAS  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  Google Scholar 

  92. Koh, A. & Bäckhed, F. From association to causality: the role of the gut microbiota and its functional products on host metabolism. Mol. Cell 78, 584–596 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014).

    Article  PubMed  Google Scholar 

  94. Mortensen, F. V., Nielsen, H., Mulvany, M. J. & Hessov, I. Short chain fatty acids dilate isolated human colonic resistance arteries. Gut 31, 1391–1394 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Natarajan, N. et al. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41. Physiol. Genomics 48, 826–834 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Natarajan, N., Hori, D., Berkowitz, D. E. & Pluznick, J. L. Microbial short chain fatty acid (SCFA) metabolites lower blood pressure (BP) via endothelial G-protein coupled receptor 41 (gpr41) [abstract 030]. Hypertension 66, A030 (2015).

    Article  Google Scholar 

  97. Haghikia, A. et al. Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism. Eur. Heart J. 43, 518–533 (2022).

    Article  CAS  PubMed  Google Scholar 

  98. Sonnenburg, E. D. et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212–215 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Boets, E. et al. Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study. J. Physiol. 595, 541–555 (2017).

    Article  CAS  PubMed  Google Scholar 

  100. Senthong, V. et al. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J. Am. Coll. Cardiol. 67, 2620–2628 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tang, W. H. W. 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 

  102. Schiattarella, G. G. et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur. Heart J. 38, 2948–2956 (2017).

    Article  CAS  PubMed  Google Scholar 

  103. Haghikia, A. et al. Gut microbiota-dependent trimethylamine N-oxide predicts risk of cardiovascular events in patients with stroke and is related to proinflammatory monocytes. Arterioscler. Thromb. Vasc. Biol. 38, 2225–2235 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Gregory, J. C. et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J. Biol. Chem. 290, 5647–5660 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Wang, Z. et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur. Heart J. 35, 904–910 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Janeiro, M. H., Ramírez, M. J., Milagro, F. I., Martínez, J. A. & Solas, M. Implication of trimethylamine N-oxide (TMAO) in disease: potential biomarker or new therapeutic target. Nutrients 10, 1398 (2018).

    Article  PubMed Central  Google Scholar 

  109. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ma, G. et al. Trimethylamine N-oxide in atherogenesis: impairing endothelial self-repair capacity and enhancing monocyte adhesion. Biosci. Rep. 37, BSR20160244 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chen, K., Zheng, X., Feng, M., Li, D. & Zhang, H. Gut microbiota-dependent metabolite trimethylamine N-oxide contributes to cardiac dysfunction in western diet-induced obese mice. Front. Physiol. 8, 139 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Farhangi, M. A. & Vajdi, M. Novel findings of the association between gut microbiota-derived metabolite trimethylamine oxide and inflammation: results from a systematic review and dose-response meta-analysis. Crit. Rev. Food Sci. Nutr. 60, 2801–2823 (2020).

    Article  CAS  PubMed  Google Scholar 

  114. Chou, R.-H. et al. Trimethylamine N-oxide, circulating endothelial progenitor cells, and endothelial function in patients with stable angina. Sci. Rep. 9, 4249 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Tan, Y. et al. Plasma trimethylamine N-oxide as a novel biomarker for plaque rupture in patients with ST-segment-elevation myocardial infarction. Circ. Cardiovasc. Interv. 12, e007281 (2019).

    Article  CAS  PubMed  Google Scholar 

  116. Li, Z. et al. Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis. Lab. Invest. 99, 346–357 (2019).

    Article  CAS  PubMed  Google Scholar 

  117. Jiang, S. et al. Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II-induced hypertension. Redox Biol. 46, 102115 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Abbasalizad Farhangi, M. & Vajdi, M. Gut microbiota-associated trimethylamine N-oxide and increased cardiometabolic risk in adults: a systematic review and dose-response meta-analysis. Nutr. Rev. 79, 1022–1042 (2021).

    Article  PubMed  Google Scholar 

  119. Tang, W. H. W. et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ. Res. 116, 448–455 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Papandreou, C., Moré, M. & Bellamine, A. Trimethylamine N-oxide in relation to cardiometabolic health–cause or effect? Nutrients 12, 1330 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  121. Meyer, K. A. et al. Microbiota-dependent metabolite trimethylamine N-oxide and coronary artery calcium in the coronary artery risk development in young adults study (CARDIA). J. Am. Heart Assoc. 5, e003970 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Molinaro, A. et al. Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology. Nat. Commun. 11, 5881 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Koh, A. et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell 175, 947–961.e17 (2018).

    Article  CAS  PubMed  Google Scholar 

  124. Koh, A. et al. Microbial imidazole propionate affects responses to metformin through p38γ-dependent inhibitory AMPK phosphorylation. Cell Metab. 32, 643–653.e4 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Liao, Y. et al. Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism. Cardiovasc. Res. 67, 705–713 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Krautkramer, K. A., Fan, J. & Bäckhed, F. Gut microbial metabolites as multi-kingdom intermediates. Nat. Rev. Microbiol. 19, 77–94 (2021).

    Article  CAS  PubMed  Google Scholar 

  127. Molinaro, A., Wahlström, A. & Marschall, H.-U. Role of bile acids in metabolic control. Trends Endocrinol. Metab. 29, 31–41 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Chong Nguyen, C. et al. Circulating bile acids concentration is predictive of coronary artery disease in human. Sci. Rep. 11, 22661 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ryan, P. M., Stanton, C. & Caplice, N. M. Bile acids at the cross-roads of gut microbiome-host cardiometabolic interactions. Diabetol. Metab. Syndr. 9, 102 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Wu, Q. et al. Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis. J. Clin. Invest. 131, e142865 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  131. Siddiqui, M. S. et al. Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J. Hepatol. 72, 25–33 (2020).

    Article  CAS  PubMed  Google Scholar 

  132. Desai, M. S. et al. Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. Hepatology 65, 189–201 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Fuller, A. T. Is p-aminobenzenesulphonamide the active agent in prontosil therapy? Lancet 229, 194–198 (1937).

    Article  Google Scholar 

  134. Spanogiannopoulos, P., Bess, E. N., Carmody, R. N. & Turnbaugh, P. J. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat. Rev. Microbiol. 14, 273–287 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Klünemann, M. et al. Bioaccumulation of therapeutic drugs by human gut bacteria. Nature 597, 533–538 (2021).

    Article  PubMed  Google Scholar 

  136. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes — 2022. Diabetes Care 45, S125–S143 (2022).

    Article  Google Scholar 

  137. No authors listed. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 854–865 (1998).

    Article  Google Scholar 

  138. Buse, J. B. et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 39, 198–205 (2016).

    Article  CAS  PubMed  Google Scholar 

  139. Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017).

    Article  CAS  PubMed  Google Scholar 

  140. Caspary, W. F. et al. Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides. Diabetologia 13, 187–193 (1977).

    Article  CAS  PubMed  Google Scholar 

  141. Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167–177 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Beysen, C. et al. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia 55, 432–442 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. Cabreiro, F. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228–239 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Reinstatler, L., Qi, Y. P., Williamson, R. S., Garn, J. V. & Oakley, G. P. Jr. Association of biochemical B12 deficiency with metformin therapy and vitamin B12 supplements: the National Health and Nutrition Examination Survey, 1999–2006. Diabetes Care 35, 327–333 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wilcock, C. & Bailey, C. J. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 24, 49–57 (1994).

    Article  CAS  PubMed  Google Scholar 

  146. Martinez-Guryn, K. et al. Small intestine microbiota regulate host digestive and absorptive adaptive responses to dietary lipids. Cell Host Microbe 23, 458–469.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wilmanski, T. et al. Heterogeneity in statin responses explained by variation in the human gut microbiome. Med 3, 388–405.e6 (2022).

    Article  CAS  PubMed  Google Scholar 

  148. Kitamura, S., Sugihara, K., Kuwasako, M. & Tatsumi, K. The role of mammalian intestinal bacteria in the reductive metabolism of zonisamide. J. Pharm. Pharmacol. 49, 253–256 (2011).

    Article  Google Scholar 

  149. Zhao, R. et al. Aspirin reduces colorectal tumor development in mice and gut microbes reduce its bioavailability and chemopreventive effects. Gastroenterology 159, 969–983.e4 (2020).

    Article  CAS  PubMed  Google Scholar 

  150. Kim, I. S. et al. Reduced metabolic activity of gut microbiota by antibiotics can potentiate the antithrombotic effect of aspirin. Biochem. Pharmacol. 122, 72–79 (2016).

    Article  CAS  PubMed  Google Scholar 

  151. Imhann, F. et al. Proton pump inhibitors affect the gut microbiome. Gut 65, 740–748 (2016).

    Article  CAS  PubMed  Google Scholar 

  152. Falony, G. et al. Population-level analysis of gut microbiome variation. Science 352, 560–564 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Vich Vila, A. et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat. Commun. 11, 362 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Tsuda, A. et al. Influence of proton-pump inhibitors on the luminal microbiota in the gastrointestinal tract. Clin. Transl. Gastroenterol. 6, e89 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Cheng, Y.-J. et al. The role of macrolide antibiotics in increasing cardiovascular risk. J. Am. Coll. Cardiol. 66, 2173–2184 (2015).

    Article  CAS  PubMed  Google Scholar 

  157. Gaci, N., Borrel, G., Tottey, W., O’Toole, P. W. & Brugère, J.-F. Archaea and the human gut: new beginning of an old story. World J. Gastroenterol. 20, 16062–16078 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Haiser, H. J. et al. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341, 295–298 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Pryor, R. et al. Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy. Cell 178, 1299–1312.e29 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Salminen, S. et al. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat. Rev. Gastroenterol. Hepatol. 18, 649–667 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  161. 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).

    Article  CAS  PubMed  Google Scholar 

  162. Flint, H. J., Duncan, S. H. & Louis, P. The impact of nutrition on intestinal bacterial communities. Curr. Opin. Microbiol. 38, 59–65 (2017).

    Article  CAS  PubMed  Google Scholar 

  163. Wastyk, H. C. et al. Gut-microbiota-targeted diets modulate human immune status. Cell 184, 4137–4153.e14 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Fragiadakis, G. K. et al. Long-term dietary intervention reveals resilience of the gut microbiota despite changes in diet and weight. Am. J. Clin. Nutr. 111, 1127–1136 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Guthrie, L. et al. Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes. Cell Host Microbe 30, 863–874.e4 (2022).

    Article  CAS  PubMed  Google Scholar 

  166. Kolodziejczyk, A. A., Zheng, D. & Elinav, E. Diet-microbiota interactions and personalized nutrition. Nat. Rev. Microbiol. 17, 742–753 (2019).

    Article  CAS  PubMed  Google Scholar 

  167. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bui, T. P. N. & de Vos, W. M. Next-generation therapeutic bacteria for treatment of obesity, diabetes, and other endocrine diseases. Best Pract. Res. Clin. Endocrinol. Metab. 35, 101504 (2021).

    Article  CAS  PubMed  Google Scholar 

  169. Ochoa-Reparaz, J. & Mangalam, A. K. (eds) The Role of the Gut Microbiota in Health and Inflammatory Diseases (Frontiers, 2020).

  170. Jiang, J. et al. Effects of probiotic supplementation on cardiovascular risk factors in hypercholesterolemia: a systematic review and meta-analysis of randomized clinical trial. J. Funct. Foods 74, 104177 (2020).

    Article  CAS  Google Scholar 

  171. Hadi, A., Ghaedi, E., Khalesi, S., Pourmasoumi, M. & Arab, A. Effects of synbiotic consumption on lipid profile: a systematic review and meta-analysis of randomized controlled clinical trials. Eur. J. Nutr. 59, 2857–2874 (2020).

    Article  PubMed  Google Scholar 

  172. Qu, H., Song, L., Zhang, Y., Gao, Z.-Y. & Shi, D.-Z. The effect of prebiotic products on decreasing adiposity parameters in overweight and obese individuals: a systematic review and meta-analysis. Curr. Med. Chem. 28, 419–431 (2021).

    Article  CAS  PubMed  Google Scholar 

  173. Bock, P. M. et al. The effect of probiotics, prebiotics or synbiotics on metabolic outcomes in individuals with diabetes: a systematic review and meta-analysis. Diabetologia 64, 26–41 (2021).

    Article  CAS  PubMed  Google Scholar 

  174. Lin, M. Y. & Chang, F. J. Antioxidative effect of intestinal bacteria Bifidobacterium longum ATCC 15708 and Lactobacillus acidophilus ATCC 4356. Dig. Dis. Sci. 45, 1617–1622 (2000).

    Article  CAS  PubMed  Google Scholar 

  175. Kim, K.-T. et al. Antioxidant and anti-inflammatory effect and probiotic properties of lactic acid bacteria isolated from canine and feline feces. Microorganisms 9, 1971 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Malik, M. et al. Lactobacillus plantarum 299v supplementation improves vascular endothelial function and reduces inflammatory biomarkers in men with stable coronary artery disease. Circ. Res. 123, 1091–1102 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Tolonen, A. C. et al. Synthetic glycans control gut microbiome structure and mitigate colitis in mice. Nat. Commun. 13, 1244 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Han, N. D. et al. Microbial liberation of N-methylserotonin from orange fiber in gnotobiotic mice and humans. Cell 185, 2495–2509.e11 (2022).

    Article  CAS  PubMed  Google Scholar 

  179. Lawson, C. E. et al. Common principles and best practices for engineering microbiomes. Nat. Rev. Microbiol. 17, 725–741 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Jimenez, M., Langer, R. & Traverso, G. Microbial therapeutics: new opportunities for drug delivery. J. Exp. Med. 216, 1005–1009 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Albright, M. B. N. et al. Solutions in microbiome engineering: prioritizing barriers to organism establishment. ISME J. 16, 331–338 (2022).

    Article  PubMed  Google Scholar 

  182. Feuerstadt, P. et al. SER-109, an oral microbiome therapy for recurrent infection. N. Engl. J. Med. 386, 220–229 (2022).

    Article  CAS  PubMed  Google Scholar 

  183. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03751007 (2021).

  184. Delannoy-Bruno, O. et al. Evaluating microbiome-directed fibre snacks in gnotobiotic mice and humans. Nature 595, 91–95 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Depommier, C. et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat. Med. 25, 1096–1103 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Arora, T. & Tremaroli, V. Therapeutic potential of butyrate for treatment of type 2 diabetes. Front. Endocrinol. 12, 761834 (2021).

    Article  Google Scholar 

  187. Roshanravan, N. et al. Effect of butyrate and inulin supplementation on glycemic status, lipid profile and glucagon-like peptide 1 level in patients with type 2 diabetes: a randomized double-blind, placebo-controlled trial. Horm. Metab. Res. 49, 886–891 (2017).

    Article  CAS  PubMed  Google Scholar 

  188. Cleophas, M. C. P. et al. Effects of oral butyrate supplementation on inflammatory potential of circulating peripheral blood mononuclear cells in healthy and obese males. Sci. Rep. 9, 775 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Bouter, K. et al. Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects. Clin. Transl. Gastroenterol. 9, 155 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Yu, Z. et al. Oral supplementation with butyrate improves myocardial ischemia/reperfusion injury via a gut-brain neural circuit. Front. Cardiovasc. Med. 8, 718674 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. 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  PubMed  Google Scholar 

  192. Chambers, E. S. et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 64, 1744–1754 (2015).

    Article  CAS  PubMed  Google Scholar 

  193. Pingitore, A. et al. The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro. Diabetes Obes. Metab. 19, 257–265 (2017).

    Article  CAS  PubMed  Google Scholar 

  194. Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Roberts, A. B. et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat. Med. 24, 1407–1417 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Robert, S. et al. Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice. Diabetes 63, 2876–2887 (2014).

    Article  CAS  PubMed  Google Scholar 

  197. Arora, T. et al. Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice. Mol. Metab. 5, 725–730 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Mimee, M., Tucker, A. C., Voigt, C. A. & Lu, T. K. Programming a human commensal bacterium, Bacteroides thetaiotaomicron, to sense and respond to stimuli in the murine gut microbiota. Cell Syst. 2, 214 (2016).

    Article  CAS  PubMed  Google Scholar 

  199. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Bhattarai, Y. et al. Bacterially derived tryptamine increases mucus release by activating a host receptor in a mouse model of inflammatory bowel disease. iScience 23, 101798 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Funabashi, M. et al. A metabolic pathway for bile acid dehydroxylation by the gut microbiome. Nature 582, 566–570 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Heianza, Y. et al. Duration and life-stage of antibiotic use and risks of all-cause and cause-specific mortality: prospective cohort study. Circ. Res. 126, 364–373 (2020).

    Article  CAS  PubMed  Google Scholar 

  203. Kwiatek, M., Parasion, S. & Nakonieczna, A. Therapeutic bacteriophages as a rescue treatment for drug-resistant infections – an in vivo studies overview. J. Appl. Microbiol. 128, 985–1002 (2020).

    Article  CAS  PubMed  Google Scholar 

  204. Sutton, T. D. S. & Hill, C. Gut bacteriophage: current understanding and challenges. Front. Endocrinol. 10, 784 (2019).

    Article  Google Scholar 

  205. Lam, K. N. et al. Phage-delivered CRISPR-Cas9 for strain-specific depletion and genomic deletions in the gut microbiome. Cell Rep. 37, 109930 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Lee, J.-Y., Tsolis, R. M. & Bäumler, A. J. The microbiome and gut homeostasis. Science 377, eabp9960 (2022).

    Article  CAS  PubMed  Google Scholar 

  207. Atarashi, K. et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science 358, 359–365 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Martinez-Guryn, K., Leone, V. & Chang, E. B. Regional diversity of the gastrointestinal microbiome. Cell Host Microbe 26, 314–324 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Human Microbiome Project Consortium. A framework for human microbiome research. Nature 486, 215–221 (2012).

    Article  Google Scholar 

  210. Chain, P. S. G. et al. Genome Project standards in a new era of sequencing. Science 326, 236–237 (2009).

    Article  CAS  PubMed  Google Scholar 

  211. 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 

  212. Sczyrba, A. et al. Critical Assessment of Metagenome Interpretation–a benchmark of metagenomics software. Nat. Methods 14, 1063–1071 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Wilmanski, T. et al. Blood metabolome predicts gut microbiome α-diversity in humans. Nat. Biotechnol. 37, 1217–1228 (2019).

    Article  CAS  PubMed  Google Scholar 

  214. Pasolli, E. et al. Large-scale genome-wide analysis links lactic acid bacteria from food with the gut microbiome. Nat. Commun. 11, 2610 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Hildebrand, F. Ultra-resolution metagenomics: when enough is not enough. mSystems 6, e0088121 (2021).

    Article  Google Scholar 

  216. Ahlqvist, E. et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 6, 361–369 (2018).

    Article  PubMed  Google Scholar 

  217. Zou, Y. et al. 1,520 reference genomes from cultivated human gut bacteria enable functional microbiome analyses. Nat. Biotechnol. 37, 179–185 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Zaneveld, J. R., McMinds, R. & Vega Thurber, R. Stress and stability: applying the Anna Karenina principle to animal microbiomes. Nat. Microbiol. 2, 17121 (2017).

    Article  CAS  PubMed  Google Scholar 

  219. Poyet, M. et al. A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research. Nat. Med. 25, 1442–1452 (2019).

    Article  CAS  PubMed  Google Scholar 

  220. Brüssow, H. Problems with the concept of gut microbiota dysbiosis. Microb. Biotechnol. 13, 423–434 (2020).

    Article  PubMed  Google Scholar 

  221. Debré, P. Louis Pasteur and Claude Bernard: about a posthumous controversy [French]. Biol. Aujourdhui 211, 161–164 (2017).

    Article  PubMed  Google Scholar 

  222. Gilbert, J. A. & Gibbons, S. M. Integrating microbiomes into clinical trials–the importance of time. BioTechniques https://www.biotechniques.com/microbiology/microbiome_sptl-integrating-microbiomes-into-clinical-trials-the-importance-of-time/ (2020).

  223. Holst, J. J. From the incretin concept and the discovery of GLP-1 to today’s diabetes therapy. Front. Endocrinol. 10, 260 (2019).

    Article  Google Scholar 

  224. Petersen, C. & Round, J. L. Defining dysbiosis and its influence on host immunity and disease. Cell. Microbiol. 16, 1024–1033 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Parks, D. J. et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 284, 1365–1368 (1999).

    Article  CAS  PubMed  Google Scholar 

  226. Hung, S.-C., Kuo, K.-L., Wu, C.-C. & Tarng, D.-C. Indoxyl sulfate: a novel cardiovascular risk factor in chronic kidney disease. J. Am. Heart Assoc. 6, e005022 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Tumur, Z. & Niwa, T. Indoxyl sulfate inhibits nitric oxide production and cell viability by inducing oxidative stress in vascular endothelial cells. Am. J. Nephrol. 29, 551–557 (2009).

    Article  CAS  PubMed  Google Scholar 

  228. Tanaka, S. et al. Indoxyl sulfate contributes to adipose tissue inflammation through the activation of NADPH oxidase. Toxins 12, 502 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  229. Yisireyili, M. et al. Indoxyl sulfate promotes cardiac fibrosis with enhanced oxidative stress in hypertensive rats. Life Sci. 92, 1180–1185 (2013).

    Article  CAS  PubMed  Google Scholar 

  230. Asai, H., Hirata, J. & Watanabe-Akanuma, M. Indoxyl glucuronide, a protein-bound uremic toxin, inhibits hypoxia-inducible factor-dependent erythropoietin expression through activation of aryl hydrocarbon receptor. Biochem. Biophys. Res. Commun. 504, 538–544 (2018).

    Article  CAS  PubMed  Google Scholar 

  231. Karbowska, M. et al. Indoxyl sulfate promotes arterial thrombosis in rat model via increased levels of complex TF/VII, PAI-1, platelet activation as well as decreased contents of SIRT1 and SIRT3. Front. Physiol. 9, 1623 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Ley, R. E., Lozupone, C. A., Hamady, M., Knight, R. & Gordon, J. I. Worlds within worlds: evolution of the vertebrate gut microbiota. Nat. Rev. Microbiol. 6, 776–788 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Jankowski, J., Floege, J., Fliser, D., Böhm, M. & Marx, N. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 143, 1157–1172 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Graboski, A. L. & Redinbo, M. R. Gut-derived protein-bound uremic toxins. Toxins 12, 590 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  235. Natividad, J. M. et al. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab. 28, 737–749.e4 (2018).

    Article  CAS  PubMed  Google Scholar 

  236. Cason, C. A. et al. Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes. J. Vasc. Surg. 68, 1552–1562.e7 (2018).

    Article  PubMed  Google Scholar 

  237. Chen, L. et al. The long-term genetic stability and individual specificity of the human gut microbiome. Cell 184, 2302–2315.e12 (2021).

    Article  CAS  PubMed  Google Scholar 

  238. Wu, I.-W. et al. Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients – a prospective cohort study. Nephrol. Dial. Transpl. 27, 1169–1175 (2012).

    Article  CAS  Google Scholar 

  239. Guerrero, F. et al. Role of endothelial microvesicles released by p-cresol on endothelial dysfunction. Sci. Rep. 10, 10657 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Han, H. et al. p‐Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes. J. Am. Heart Assoc. 4, e001852 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Lin, C.-J., Wu, V., Wu, P.-C. & Wu, C.-J. Meta-analysis of the associations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure. PLoS ONE 10, e0132589 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  242. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. 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).

    Article  CAS  PubMed  Google Scholar 

  244. Loo, R. L., Zou, X., Appel, L. J., Nicholson, J. K. & Holmes, E. Characterization of metabolic responses to healthy diets and association with blood pressure: application to the optimal macronutrient intake trial for heart health (OmniHeart), a randomized controlled study. Am. J. Clin. Nutr. 107, 323–334 (2018).

    Article  PubMed  Google Scholar 

  245. Menni, C. et al. Metabolomic study of carotid-femoral pulse-wave velocity in women. J. Hypertens. 33, 791–796 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Patel, Y. & Joseph, J. Sodium intake and heart failure. Int. J. Mol. Sci. 21, 9474 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  247. Wilck, N. et al. Salt-responsive gut commensal modulates T17 axis and disease. Nature 551, 585–589 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Rothhammer, V. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22, 586–597 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  250. 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 

  251. 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 

  252. Narula, N. et al. Systematic review and meta-analysis: fecal microbiota transplantation for treatment of active ulcerative colitis. Inflamm. Bowel Dis. 23, 1702–1709 (2017).

    Article  PubMed  Google Scholar 

  253. 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 

  254. Kootte, R. S. et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab. 26, 611–619.e6 (2017).

    Article  CAS  PubMed  Google Scholar 

  255. Rinott, E. et al. Effects of diet-modulated autologous fecal microbiota transplantation on weight regain. Gastroenterology 160, 158–173.e10 (2021).

    Article  CAS  PubMed  Google Scholar 

  256. Mocanu, V. et al. Fecal microbial transplantation and fiber supplementation in patients with severe obesity and metabolic syndrome: a randomized double-blind, placebo-controlled phase 2 trial. Nat. Med. 27, 1272–1279 (2021).

    Article  CAS  PubMed  Google Scholar 

  257. Smits, L. P. et al. Effect of vegan fecal microbiota transplantation on carnitine- and choline-derived trimethylamine-N-oxide production and vascular inflammation in patients with metabolic syndrome. J. Am. Heart Assoc. 7, e008342 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  258. Blount, K. F., Shannon, W. D., Deych, E. & Jones, C. Restoration of bacterial microbiome composition and diversity among treatment responders in a phase 2 trial of RBX2660: an investigational microbiome restoration therapeutic. Open Forum Infect. Dis. 6, ofz095 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank V. Tremaroli and K. Makki (University of Gothenburg, Sweden) for vibrant and rewarding scientific discussions. R.M.C.’s research work is supported by a Walter Benjamin Fellowship grant from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation). Work in F.B.’s laboratory is supported in part by Transatlantic Networks of Excellence Award from the Leducq Foundation (17CVD01), AFA insurances, Swedish Heart Lung Foundation (20180600), the Knut and Alice Wallenberg Foundation (2017.0026), and grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG- 718101). F.B. is the Torsten Söderberg Professor in Medicine and Wallenberg Scholar.

Author information

Authors and Affiliations

Authors

Contributions

R.M.C. researched data for the article, and all the authors contributed to discussion of its content. R.M.C. and F.B. wrote the manuscript, and all the authors reviewed and/or edited it before submission.

Corresponding author

Correspondence to Fredrik Bäckhed.

Ethics declarations

Competing interests

F.B. is a shareholder in Implexion Pharma AB, is on the scientific advisory board of Bactolife A/S and receives research funds from BioGaia AB. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cardiology thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Genomic Standards Consortium: https://www.gensc.org/

International Human Microbiome Standards: http://www.human-microbiome.org/index.php

NIH Human Microbiome Project: https://hmpdacc.org/

Glossary

Microbiota

The collection of all living microorganisms present in a specific ecosystem or environment.

Xenobiotics

Any chemical substances found in an organism that are not naturally produced or expected to be present in that organism.

Microbiome

The combination of the microbiota together with elements that are crucial to their function; this ‘theatre of activity’ includes the collective genomes of the microorganisms present.

Diversity

Some high-level measures, such as α-diversity and β-diversity, can be used to describe the microbiome; α-diversity estimates diversity within a single sample, whereas β-diversity describes the diversity (dissimilarity) of two or more communities (samples).

Richness

A measure of α-diversity that refers to the total number of features at a prespecified taxonomic level in a sample or community.

Opportunistic pathogens

Microorganisms that can colonize, but usually do not cause infections, in healthy hosts; under specific conditions, for example in immunocompromised hosts, these microorganisms can cause disease.

Pathobionts

Any potentially pathological organism which, under normal circumstances, lives as a non-harming symbiont; they opportunistically emerge as a result of perturbations in the healthy microbiome owing to complex interactions of genetic, exposomal, microbial and host factors that lead to their selection and expansion.

Probiotics

Live microorganisms selected to provide health benefits when consumed, generally by improving or restoring the gut microbiota.

Synbiotics

Mixtures of probiotics and prebiotics that beneficially affect the host by improving the survival and implantation of live microbial dietary supplements in the gastrointestinal tract.

Postbiotics

Soluble factors (metabolic products or byproducts) that are secreted by live bacteria or are released after bacterial lysis and that provide physiological benefits to the host.

Obligate anaerobes

Bacteria and Archaea that grow only in the absence of oxygen.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chakaroun, R.M., Olsson, L.M. & Bäckhed, F. The potential of tailoring the gut microbiome to prevent and treat cardiometabolic disease. Nat Rev Cardiol (2022). https://doi.org/10.1038/s41569-022-00771-0

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41569-022-00771-0

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing