Gut Microbiota Involvement in Ventricular Remodeling Post–Myocardial Infarction
2019; Lippincott Williams & Wilkins; Volume: 139; Issue: 5 Linguagem: Inglês
10.1161/circulationaha.118.037384
ISSN1524-4539
AutoresAmy McMillan, Stanley L. Hazen,
Tópico(s)Frailty in Older Adults
ResumoHomeCirculationVol. 139, No. 5Gut Microbiota Involvement in Ventricular Remodeling Post–Myocardial Infarction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBGut Microbiota Involvement in Ventricular Remodeling Post–Myocardial InfarctionNew Insights Into How to Heal a Broken Heart Amy McMillan, PhD and Stanley L. Hazen, MD, PhD Amy McMillanAmy McMillan Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute (A.M., S.L.H.) Center for Microbiome & Human Health (A.M., S.L.H.) and Stanley L. HazenStanley L. Hazen Stanley L. Hazen, MD, PhD, Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic, 9500 Euclid Ave, Mail Code NC-10, Cleveland, OH 44195. Email E-mail Address: [email protected] Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute (A.M., S.L.H.) Center for Microbiome & Human Health (A.M., S.L.H.) Department of Cardiovascular Medicine, Cleveland Clinic, OH (S.L.H.). Originally published28 Jan 2019https://doi.org/10.1161/CIRCULATIONAHA.118.037384Circulation. 2019;139:660–662This article is a commentary on the followingLoss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac RepairArticle, see p 647It is now well recognized that gut microbiota play a vital role in the maintenance of health and disease susceptibility. The number of bacterial genes encoded within the human gut vastly outnumber the total complement of genes in Homo sapiens, endowing the gut microbiome with enormous potential for the production of a range of functionally active metabolites. Indeed, gut microbiota function as an endocrine organ, converting environment-driven nutritional cues into hormone-like signals that can impact host metabolic phenotypes.1 The mechanisms linking gut microbiota to cardiovascular disease (CVD) are multifaceted, and include direct effects of microbial metabolites on atherosclerosis and thrombosis development, as well as immune modulation by bacteria and their products. The case of trimethylamine N-oxide (TMAO),2,3 a microbiota-dependent metabolite derived from nutrients abundant in a Western diet, represents the first of now a multitude of bacterial products with evidence for a contributory role in CVD. For example, short-chain fatty acids (SCFAs) produced during microbial fermentation of complex carbohydrates possess immunomodulatory properties that may impact CVD risk.1Because of recent connections drawn between microbial metabolism and CVD, the gut microbiome has emerged as an intriguing target for the prevention and treatment of a variety of cardiometabolic conditions. Modulation of gut microbiota with probiotics, diet, or nonlethal microbial enzyme inhibitors are all areas of active research in heart failure (HF).1 Early studies by Lam et al4 were among the first to highlight the potential for microbes to impact ventricular remodeling after myocardial infarction (MI). In that study, both oral administration of the antibiotic vancomycin or the probiotic Goodbelly (containing Lactobacillus plantarum 299v and Bifidobacterium lactis Bi-07) before ischemia-reperfusion injury significantly reduced infarct size and improved myocardial function in rats. A separate study by Gan et al5 expanded on these findings with preadministration of the probiotic Lactobacillus rhamnosus GR-1, this time using a chronic coronary artery ligation model, and reported the preservation of ventricular function. Human studies with probiotics for HF remain in their infancy. However, some intriguing results were recently reported in 1 small double-blind, placebo-controlled study with Saccharomyces boulardii.6 Stable HF subjects were randomly assigned to placebo versus probiotic treatment for 3 months, with significant improvement in both ejection fraction and left atrial diameter reported in the probiotic group.6 Although the clinical trial was small, these studies highlight the potential of probiotics as a possible therapy for HF. Mechanisms involved in the observed beneficial effects with probiotics on the whole are unknown, but may include changes in inflammation, gut leakiness, and leptin.In this issue of Circulation, Tang and colleagues7 add to the growing data linking gut microbiota to myocardial function and repair after MI. Their studies begin with the remarkable observation that gut microbiota suppression with an oral cocktail of poorly absorbed antibiotics markedly enhanced the rates of post-MI ventricular rupture and death in a murine model of chronic left anterior descending artery ligation. It is important to note that they also showed that microbial reconstitution with fecal transplantation from untreated donors before MI significantly improved survival, suggesting gut microbiota involvement in early myocardial repair. The new mechanistic insight surrounding the impact of gut microbiota on ventricular remodeling is provided via a series of add-back experiments, which suggest that the salutary effects in the post-MI setting may be mediated in part by gut microbiota–generated SCFAs, which induced recruitment of myeloid cells to the heart. Either dietary supplementation with SCFAs or intravenous infusion of the monocytic cell line RAW264.7 provided 1 day after MI significantly reversed the adverse effects of antibiotics on mortality and ventricular rupture rates. The authors also demonstrate that a SCFA-producing probiotic mixture (Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus casei, Lactobacillus paracasei, and L rhamnosus), although it had no effect on survival post-MI, was associated with improved ejection fraction in antibiotic-treated animals versus controls. Probiotic treatment was also associated with both increased levels of myeloid cells in the hearts of antibiotic-treated mice and enhanced propionate levels, and some of these effects were recapitulated with propionate supplementation alone. This work expands on our understanding of the links between gut microbiota, the immune system, and myocardial repair after injury.Clinical intervention trials targeting microbiota for the treatment of CVD have mainly involved antibiotics for Chlamydia pneumoniae, driven by epidemiological and mechanistic links between this organism and CVD. Results from these studies have been disappointing, with chronic antimicrobials proving to be ineffective in preventing secondary CVD events.1 Few studies have assessed the impact of antibiotics on ventricular remodeling in the immediate post-MI setting. One potential exception to this was the PROVE IT-TIMI22 trial (Pravastatin or Atorvastatin Evalution and Infection Therapy-Thrombolysis in Myocardial Infarction 22), in which long-term treatment with gatifloxasin versus placebo was evaluated for the prevention of major adverse cardiovascular events in subjects with recent acute coronary syndrome.8 No effects on either cardiovascular events or mortality were observed with antibiotics. An alternative study, the TIPTOP trial (Tetracycline [Doxycycline] and Post Myocardial Infarction Remodeling), was a single-center open-label, randomized intervention trial in which patients with ST-segment–elevation MI and left ventricular dysfunction were randomly assigned to doxycycline for 7 days in addition to standard therapy versus standard care. Significant improvements in left ventricular end-diastolic volume index, infarct size, and severity at 6 months postintervention were noted among the doxycycline recipients.9 The mechanistic rationale attributed to the beneficial effects was that the matrix metalloproteinase–inhibiting properties of doxycycline may have attenuated adverse ventricular remodeling.9 In contrast, the studies by Tang and colleagues7 used a cocktail of poorly absorbed broad-spectrum antibiotics to suppress gut microbiota. This may in part account for the seemingly divergent observed effects of the antibiotic cocktail on heart function in comparison with the results of the TIPTOP trial. In addition, the timing of antibiotic treatment in relation to MI induction may also be of importance. In this regard, little is known concerning the impact of antibiotic use before MI on ventricular remodeling in subjects. The animal model studies by Tang and colleagues suggest that an intact gut microbial community is required around the time of injury for proper myocardial repair.As noted above, antibiotics can have effects on the host beyond their antimicrobial properties. It therefore is possible that some of the adverse effects of antibiotic pretreatment reported by Tang and colleagues may be independent of gut microbiota. However, the ability of fecal microbial transplantation, probiotics, or a microbiota downstream end product (propionate) to mitigate some of the adverse effects of antibiotics all point toward the involvement of gut microbiota in myocardial repair.7 Antibiotics in the absence of MI significantly increased systemic tumor necrosis factor α in their model,7 which in other studies has been associated with cardiac hypertrophy, ventricular dilatation, and fibrosis. It was also of interest that the beneficial effects of SCFAs on reversing antibiotics-induced reduction in survival were incomplete (only ≈50%). Hence, assuming that the observed effects of antibiotics result from gut microbiota suppression, other microbial metabolites may impact cardiac repair. In fact, the use of broad-spectrum antibiotics to globally suppress gut microbiota theoretically would impact both potentially helpful (eg, propionate) and harmful (eg, TMAO) gut microbial pathways.2,3 In addition to the strong association between TMAO and major adverse cardiac events,1–3 this metabolite has recently been implicated in HF through both human and animal model investigations.10,11 Plasma TMAO is both increased in patients with HF and associated with poorer long-term survival.10 Animal studies have further demonstrated that targeting of the TMAO pathway through either diet or microbial enzyme inhibitors impacts ventricular remodeling in mice.11 The adverse phenotype reported by Tang and colleagues argues for the suppression of a beneficial effect of gut microbiota, not suppression of an adverse microbiota-dependent pathway. Although not examined in their studies, secondary bile acids are yet another class of microbiota-derived metabolites with evidence for a potential role in HF. Both the composition and size of the bile acid pool are altered in patients with HF12; and, in a small (n=17) prospective, double-blind, randomized, placebo-controlled crossover study, clinically stable patients with HF were reported to have modest improvements in blood flow with the administration of the secondary bile acid ursodeoxycholic acid.13 Finally, bacterial products of aromatic amino acid metabolism have been linked to the severity of MI in rats, suggesting that numerous additional gut microbiota–derived metabolites may also play a role in cardiac repair.14In summary, the work by Tang and colleagues contributes to a growing body of evidence implicating gut microbiota in cardiac repair processes. These findings open the door for new treatment strategies for MI and HF, which might be anywhere along the diet→gut microbiota→host receptor/effector pathways involved.1 The current study suggests that specific probiotics, SCFAs, or other microbiota-targeted/driven interventions warrant further investigation in human clinical intervention studies. Much work remains to prove the benefits of any of these or alternative approaches, like nonlethal small-molecule inhibitors of specific microbial enzymes,15 for the treatment of CVD and metabolic disorders. Finally, this research exposes impaired cardiac repair as yet another potential side effect of antibiotics use. Whether these findings replicate in humans is of considerable clinical interest.DisclosuresDr Hazen reports grant support from the National Institutes of Health and the Office of Dietary Supplements (HL103866 and HL126827), and an award from the Leducq Foundation. He is named as coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics or therapeutics and reports having the right to receive royalty payment for inventions or discoveries related to cardiovascular diagnostics from Cleveland Heart Laboratory Inc and Quest Diagnostics. Dr Hazen also reports having been paid as a consultant for P&G and receiving research funds from Astra Zeneca, P&G, Pfizer Inc, and Roche Diagnostics. Dr McMillan reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circStanley L. Hazen, MD, PhD, Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic, 9500 Euclid Ave, Mail Code NC-10, Cleveland, OH 44195. Email [email protected]orgReferences1. Brown JM, Hazen SL. 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Circulation. 2019;139:647-659 January 29, 2019Vol 139, Issue 5 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.037384PMID: 30689425 Originally publishedJanuary 28, 2019 Keywordsmodels, animalcardiovascular diseasesEditorialsgastrointestinal microbiomeheart failureanti-bacterial agentsfatty acids, volatilePDF download Advertisement SubjectsAnimal Models of Human Disease
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