The Gut Microbiome and Its Role in Cardiovascular Diseases

HomeCirculationVol. 135, No. 11The Gut Microbiome and Its Role in Cardiovascular Diseases Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessArticle CommentaryPDF/EPUBThe Gut Microbiome and Its Role in Cardiovascular Diseases W. H. Wilson Tang, MD and Stanley L. Hazen, MD, PhD W. H. Wilson TangW. H. Wilson Tang From Department of Cellular and Molecular Medicine, Lerner Research Institute (W.H.W.T., S.L.H.); Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T., S.L.H.); Center for Microbiome and Human Health (W.H.W.T., S.L.H.), and Center for Clinical Genomics (W.H.W.T.), Cleveland Clinic, OH. and Stanley L. HazenStanley L. Hazen From Department of Cellular and Molecular Medicine, Lerner Research Institute (W.H.W.T., S.L.H.); Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T., S.L.H.); Center for Microbiome and Human Health (W.H.W.T., S.L.H.), and Center for Clinical Genomics (W.H.W.T.), Cleveland Clinic, OH. Originally published14 Mar 2017https://doi.org/10.1161/CIRCULATIONAHA.116.024251Circulation. 2017;135:1008–1010The human gastrointestinal tract is predominantly a bacterial ecosystem (microbiome) that harbors >100 trillion microbial cells, with the highest microbe densities found in the colon. Gut microbes are for the most part codependent, both on one another and on their host, requiring metabolic support from additional members of the community for survival and a symbiotic relationship with the host. For example, gut microbes help with the digestion of nutrients, prevent significant colonization of pathogens, and promote gut immunity, while the host provides a favorable environment for microbial survival.Gut microbiome changes (so-called dysbiosis) leading to increased long-term susceptibility to disease can originate early in life, similar to traditional risk factors. There is a growing awareness that microbial inhabitants within the host often contribute to global metabolism within the host, and dysbiosis can fuel enhanced susceptibility for metabolic and immunological diseases, sometimes emerging decades later. Indeed, alterations in the composition of the human gut-associated microbiome and accompanying functional changes in metabolism have been implicated in the pathogenesis of several chronic conditions ranging from atherosclerosis and thrombosis to obesity and insulin resistance.Gut Microbial Involvement in Cardiovascular Disease PathogenesisIt is increasingly appreciated that gut microbes represent a filter of our greatest environmental exposure: what we eat. It is now clear that we each experience a given meal differently on the basis of our distinct gut microbial communities. Microbial metabolites such as short-chain fatty acids are fermentation byproducts of carbohydrates and proteins that escape absorption in the small intestine during digestion. A microbial origin for short-chain fatty acids is perhaps best observed by the demonstration that plasma levels of short-chain fatty acids in germ-free mice are nearly undetectable. Short-chain fatty acids help maintain gut barrier function by reducing luminal pH and inhibiting some pathogenic microorganisms. In addition, in another clear example of symbiosis, gut microbe–derived short-chain fatty acids are used as a source of energy by colonocytes and bacterial communities. Furthermore, they may have distinct physiological effects, including host-signaling mechanisms (such as the G-protein–coupled receptors Gpr41 and Olfr78) that can directly and indirectly modulate blood pressure control.Meanwhile, gut microbe–derived metabolites that are biologically active such as trimethylamine N-oxide (TMAO) are now recognized as contributors to atherogenesis (Figure). Using untargeted metabolomics as a discovery platform, we identified TMAO as a strong predictor of coronary artery disease risk and then through animal studies revealed the causal link of TMAO to atherogenesis.1 Our mechanistic studies show an obligatory role for gut microbes in TMAO generation from trimethylamine-containing nutrients such as phosphatidylcholine, choline, and L-carnitine in both mice and humans.1–3 In humans, circulating TMAO levels increase 4 to 8 hours after ingestion of phosphatidylcholine or L-carnitine and are largely normalized within 24 hours in the setting of preserved renal clearance. Consistent with the effects of dietary exposure affecting microbial function, vegetarians and vegans (without L-carnitine dietary intake) produce less TMAO compared with omnivorous subjects, with correspondingly distinct microbiota composition.2 We have also confirmed a mechanistic role for both gut microbes and trimethylamine/TMAO generation in atherogenesis, tissue cholesterol balance, and thrombosis risks.1–4 In mice, diet-induced increases in systemic TMAO levels decrease reverse cholesterol transport and alters bile acid transport, composition and pool size.2Download figureDownload PowerPointFigure. The TMAO metaorganismal pathway links gut microbiota to cardiovascular diseases. NFκB indicates nuclear factor-κB; SRA, scavenger receptor class A;.TGF-β, transforming growth factor-β; TMA, trimethylamine; and TMAO, trimethylamine N-oxide.Fulfilling one of the essential Koch postulates, microbial transplantation studies have confirmed gut microbe–dependent trimethylamine/TMAO involvement in atherosclerotic plaque development and, more recently, TMAO-dependent enhanced susceptibility for thrombosis.4 This latter finding followed the discovery that TMAO modulates stimulus-dependent calcium mobilization in platelets, enhancing platelet responsiveness and thrombosis potential in vivo.4 In recent proof-of-concept studies, small-molecule inhibitors of microbial trimethylamine and TMAO production have been used to directly inhibit diet-induced atherosclerosis in animal models without altering microbial survival (in contrast to antibiotic therapy),5 which brings a therapeutic strategy of “drugging” the microbiome closer to reality.Challenges and Potential PitfallsMany studies explore the role of gut microbiome in cardiovascular diseases by characterizing traditional ecological indicators of microbial community composition and diversity between those with and those without cardiovascular disease. However, these approaches often preclude investigations into the functional alterations of specific organisms and their adverse consequences despite broad availability of vast genomic sequencing data. Systems biology approaches that combine genomic with proteomic/metabolomic data hold promise for developing a more integrated understanding of the relationship between microbes and their host, yet available data are often static (ie, at a single time point), largely associative in nature, and primarily hypothesis generating. Even pathogenic pathways with proof-of-concept demonstrations in animal models that fulfill Koch postulates and have mechanism biomarkers (such as trimethylamine/TMAO) will still require prospective validation with clinical studies testing specific interventions targeting these pathways to lower major adverse cardiac events.ConclusionsThe trimethylamine/TMAO pathway likely represents only one of many microbe-dependent pathways that will ultimately be linked to cardiovascular disease pathogenesis, and proven to be an important diagnostic and therapeutic target for cardiovascular diseases. Key to the discovery of this pathway were untargeted metabolomics studies in large patient cohorts to demonstrate reproducibility of associations and then, more important, performance of animal model studies to test for causal connections beyond associations. Such approaches will be critical to understanding new microbial participants and pathways linked to the development of atherosclerosis and thrombosis. It is important to note that these studies also help us better understand how nutrition is linked to host health and disease susceptibility, requiring a global examination and view of nutrition, microbe community composition and function, and host genetics. It is not only conceivable but probable that multiple distinct microbial pathways contribute to and protect against cardiovascular and other metabolic disorders. Their identification and the discovery of the mechanisms through which they participate in cardiovascular disease susceptibility are exciting new and important fields of investigation. Once revealed, novel diagnostic, therapeutic, and preventive strategies that leverage their identification may become part of our arsenal for halting and reversing cardiovascular diseases.Sources of FundingDrs Tang and Hazen are supported by grants from the National Institutes of Health and the Office of Dietary Supplements (R01HL103866, P20HL113452, R01DK106000, R01HL126827) related to the content of this article. Dr Hazen was partially supported by a gift from the Leonard Krieger endowment.DisclosuresDr Hazen is named as inventor on pending patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Dr Hazen is a paid consultant for Esperion and P&G. Dr Hazen has received research funds from P&G, Pfizer Inc, Roche Diagnostics, and Takeda. Dr Hazen has received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, Siemens, Esperion, and Frantz Biomarkers, LLC. Dr Tang reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.The podcast and transcript are available as an online-only Data Supplement at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.116.024251/-/DC1.Circulation is available at http://circ.ahajournals.org.Correspondence to: W. H. Wilson Tang, MD, Cleveland Clinic Foundation, Cardiovascular Medicine, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH 44195. E-mail [email protected]References1. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature. 2011; 472:57–63. doi: 10.1038/nature09922.CrossrefMedlineGoogle Scholar2. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.Nat Med. 2013; 19:576–585. doi: 10.1038/nm.3145.CrossrefMedlineGoogle Scholar3. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.N Engl J Med. 2013; 368:1575–1584. doi: 10.1056/NEJMoa1109400.CrossrefMedlineGoogle Scholar4. Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, Sartor RB, McIntyre TM, Silverstein RL, Tang WH, DiDonato JA, Brown JM, Lusis AJ, Hazen SL. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk.Cell. 2016; 165:111–124. doi: 10.1016/j.cell.2016.02.011.CrossrefMedlineGoogle Scholar5. 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