Recent advances in modulation of cardiovascular diseases by the gut microbiota

Sepiso K Masenga, Benson Hamooya, Joy Hangoma, Valerie Hayumbu, Lale A Ertuglu, Jeanne Ishimwe, Sharla Rahman, Mohammad Saleem, Cheryl L Laffer, Fernando Elijovich, Annet Kirabo, Sepiso K Masenga, Benson Hamooya, Joy Hangoma, Valerie Hayumbu, Lale A Ertuglu, Jeanne Ishimwe, Sharla Rahman, Mohammad Saleem, Cheryl L Laffer, Fernando Elijovich, Annet Kirabo

Abstract

The gut microbiota has recently gained attention due to its association with cardiovascular health, cancers, gastrointestinal disorders, and non-communicable diseases. One critical question is how the composition of the microbiota contributes to cardiovascular diseases (CVDs). Insightful reviews on the gut microbiota, its metabolites and the mechanisms that underlie its contribution to CVD are limited. Hence, the aim of this review was to describe linkages between the composition of the microbiota and CVD, CVD risk factors such as hypertension, diet, ageing, and sex differences. We have also highlighted potential therapies for improving the composition of the gut microbiota, which may result in better cardiovascular health.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Diseases associated with dysbiosis.
Fig. 1. Diseases associated with dysbiosis.
Abnormal changes in the composition of the microbiota (dysbiosis) is positively associated with pathogenesis and propagation of heart disease, atherosclerosis, hypertension, obesity, type 2 diabetes mellitus, cancer, and gastrointestinal disorders.
Fig. 2. Microbiota’s contribution to atherosclerosis and…
Fig. 2. Microbiota’s contribution to atherosclerosis and CVD.
Ammonia (NH3) and ammonium hydroxide (NH4OH) resulting from kidney disease or the action of microbial urease and HIV infection in the gut contributes to microbial translocation and systemic inflammation. Microbes colonize atherosclerotic plaques enhancing progression of various atherosclerotic processes. Dysbiosis contributes to decreased bile formation that results in decreased cholesterol elimination and increased plasma levels of low-density lipoproteins. LEESE Lactobacillus, Esherichia, Enterococcus, Shigella, and Streptococcus, FREBS Faecalibacterium, Roseburia, Eubacterium rectale, Bacteroides fragilis, and Subdoligranulum.
Fig. 3. Gut microbiota and high blood…
Fig. 3. Gut microbiota and high blood pressure.
Microbiota metabolites SCFAs modulate distinct GPCRs and thereby affect blood pressure. For example, activation of Gpr43 and 41 results in vasodilation and blood pressure attenuation. In contrast, activation of olfr78 increases SNA and renin secretion resulting in blood pressure elevation. Moreover, high salt depletes lactobacillus spp. causing dysbiosis and activation of inflammatory immune response by releasing IL-17 and other inflammatory signaling molecules consequently causing blood pressure elevation. FMT is strong evidence to show that gut microbiota plays an indispensable role in the contribution of high blood pressure. SCFAs short-chain fatty acids, GPCRs G protein-coupled receptors, SNA sympathetic nerve activity, FMT fecal microbiota transplantation, GF germ free.
Fig. 4. TMAO biosynthesis and metabolism.
Fig. 4. TMAO biosynthesis and metabolism.
Choline, phosphatidylcholine, and l-carnitine found in fish, red meat and eggs are metabolized into TMA by colonic microbiota. The TMA that enters the systemic circulation is oxidized into TMAO by FMO3 in the liver, which is released back into the circulation, leading to platelet and inflammatory pathway activation. Inflammatory injury in the endothelium, along with increased foam cell formation and platelet activation, contributes to the progression of atherosclerosis and development of atherothrombotic events.

References

    1. Avery EG, Bartolomaeus H, Maifeld A, Marko L, Wiig H, Wilck N, et al. The gut microbiome in hypertension. Circulation Res. 2021;128:934–50.
    1. Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Ther Adv Gastroenterol. 2013;6:295–308.
    1. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124:837–48.
    1. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65.
    1. Zhao Y, Wang Z. Gut microbiome and cardiovascular disease. Curr Opin Cardiol. 2020;35:207–18.
    1. Zhou W, Cheng Y, Zhu P, Nasser MI, Zhang X, Zhao M. Implication of gut microbiota in cardiovascular diseases. Oxid Med Cell Longev. 2020;2020:5394096.
    1. Ahmad AF, Dwivedi G, O’Gara F, Caparros-Martin J, Ward NC. The gut microbiome and cardiovascular disease: current knowledge and clinical potential. Am J Physiol-Heart Circ Physiol. 2019;317:H923–H938..
    1. Tang WHW, Kitai T, Hazen SL. Gut microbiota in cardiovascular health and disease. Circ Res. 2017;120:1183–96.
    1. Witkowski M, Weeks TL, Hazen SL. Gut microbiota and cardiovascular disease. Circ Res. 2020;127:553–70.
    1. Jain A, Li XH, Chen WN. An untargeted fecal and urine metabolomics analysis of the interplay between the gut microbiome, diet and human metabolism in Indian and Chinese adults. Sci Rep. 2019;9:9191.
    1. Zhang Y, Wang Y, Ke B, Du J. TMAO: how gut microbiota contributes to heart failure. Transl Res. 2021;228:109–25.
    1. Wong J, Piceno YM, DeSantis TZ, Pahl M, Andersen GL, Vaziri ND. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am J Nephrol. 2014;39:230–7.
    1. Toubal A, Kiaf B, Beaudoin L, Cagninacci L, Rhimi M, Fruchet B, et al. Mucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity. Nat Commun. 2020;11:3755.
    1. Tuomisto S, Huhtala H, Martiskainen M, Goebeler S, Lehtimäki T, Karhunen PJ. Age-dependent association of gut bacteria with coronary atherosclerosis: Tampere Sudden Death Study. PLoS ONE. 2019;14:e0221345.
    1. Matsui M, Fukunishi S, Nakano T, Ueno T, Higuchi K, Asai A. Ileal bile acid transporter inhibitor improves hepatic steatosis by ameliorating gut microbiota dysbiosis in NAFLD model mice. mBio. 2021;12:e0115521.
    1. Brantsæter AL, Myhre R, Haugen M, Myking S, Sengpiel V, Magnus P, et al. Intake of probiotic food and risk of preeclampsia in primiparous women: The Norwegian Mother and Child Cohort Study. Am J Epidemiol. 2011;174:807–15.
    1. Wilck N, Matus MG, Kearney SM, Olesen SW, Forslund K, Bartolomaeus H, et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature. 2017;551:585–9.
    1. Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM, et al. Gut dysbiosis is linked to hypertension. Hypertension. 2015;65:1331–40.
    1. De Filippis F, Pellegrini N, Vannini L, Jeffery IB, La Storia A, Laghi L, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2016;65:1812–21.
    1. Dan X, Mushi Z, Baili W, Han L, Enqi W, Huanhu Z, et al. Differential analysis of hypertension-associated intestinal microbiota. Int J Med Sci. 2019;16:872–81.
    1. De la Cuesta-Zuluaga J, Mueller NT, Álvarez-Quintero R, Velásquez-Mejía EP, Sierra JA, Corrales-Agudelo V, et al. Higher fecal short-chain fatty acid levels are associated with gut microbiome dysbiosis, obesity, hypertension and cardiometabolic disease risk factors. Nutrients. 2019;11:51.
    1. Li J, Zhao F, Wang Y, Chen J, Tao J, Tian G, et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome. 2017;5:14.
    1. Sun S, Lulla A, Sioda M, Winglee K, Wu MC, Jacobs DR, et al. Gut microbiota composition and blood pressure. Hypertension. 2019;73:998–1006.
    1. Verhaar BJH, Collard D, Prodan A, Levels JHM, Zwinderman AH, Bäckhed F, et al. Associations between gut microbiota, faecal short-chain fatty acids, and blood pressure across ethnic groups: the HELIUS study. Eur Heart J. 2020;41:4259–67.
    1. Yan Q, Gu Y, Li X, Yang W, Jia L, Chen C et al. Alterations of the gut microbiome in hypertension. Front Cell Infect Microbiol. 2017. 10.3389/fcimb.2017.00381.
    1. Kim S, Goel R, Kumar A, Qi Y, Lobaton G, Hosaka K, et al. Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure. Clin Sci. 2018;132:701–18.
    1. Huart J, Leenders J, Taminiau B, Descy J, Saint-Remy A, Daube G, et al. Gut microbiota and fecal levels of short-chain fatty acids differ upon 24-hour blood pressure levels in men. Hypertension. 2019;74:1005–13.
    1. Jackson MA, Verdi S, Maxan M-E, Shin CM, Zierer J, Bowyer RCE, et al. Gut microbiota associations with common diseases and prescription medications in a population-based cohort. Nat Commun. 2018;9:2655.
    1. Adnan S, Nelson JW, Ajami NJ, Venna VR, Petrosino JF, Bryan RM, et al. Alterations in the gut microbiota can elicit hypertension in rats. Physiol Genomics. 2017;49:96–104.
    1. Yan X, Jin J, Su X, Yin X, Gao J, Wang X, et al. Intestinal flora modulates blood pressure by regulating the synthesis of intestinal-derived corticosterone in high salt-induced hypertension. Circ Res. 2020;126:839–53.
    1. Mell B, Jala VR, Mathew AV, Byun J, Waghulde H, Zhang Y, et al. Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol Genomics. 2015;47:187–97.
    1. Kaye DM, Shihata WA, Jama HA, Tsyganov K, Ziemann M, Kiriazis H, et al. Deficiency of prebiotic fiber and insufficient signaling through gut metabolite-sensing receptors leads to cardiovascular disease. Circulation. 2020;141:1393–403.
    1. Marques FZ, Nelson E, Chu P-Y, Horlock D, Fiedler A, Ziemann M, et al. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation. 2017;135:964–77.
    1. Santisteban MM, Qi Y, Zubcevic J, Kim S, Yang T, Shenoy V, et al. Hypertension-linked pathophysiological alterations in the gut. Circulation Res. 2017;120:312–23.
    1. Robles-Vera I, Toral M, Visitación N, de la, Sánchez M, Gómez-Guzmán M, Muñoz R, et al. Changes to the gut microbiota induced by losartan contributes to its antihypertensive effects. Br J Pharmacol. 2020;177:2006–23.
    1. Toral M, Gómez-Guzmán M, Jiménez R, Romero M, Sánchez M, Utrilla MP, et al. The probiotic Lactobacillus coryniformis CECT5711 reduces the vascular pro-oxidant and pro-inflammatory status in obese mice. Clin Sci. 2014;127:33–45.
    1. Chen L, He FJ, Dong Y, Huang Y, Wang C, Harshfield GA, et al. Modest sodium reduction increases circulating short-chain fatty acids in untreated hypertensives. Hypertension. 2020;76:73–79.
    1. Khalesi S, Sun J, Buys N, Jayasinghe R. Effect of probiotics on blood pressure. Hypertension. 2014;64:897–903.
    1. Razavi AC, Potts KS, Kelly TN, Bazzano LA. Sex, gut microbiome, and cardiovascular disease risk. Biol Sex Differ. 2019;10:29.
    1. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.
    1. Kahleova H, Rembert E, Alwarith J, Yonas WN, Tura A, Holubkov R, et al. Effects of a low-fat vegan diet on gut microbiota in overweight individuals and relationships with body weight, body composition, and insulin sensitivity. A Randomized Clinical Trial. Nutrients. 2020;12:E2917.
    1. Bin Waleed K, Lu Y, Liu Q, Zeng F, Tu H, Wei Y, et al. Association of trimethylamine N-oxide with coronary atherosclerotic burden in patients with non-ST-segment elevation myocardial infarction. Medicine. 2020;99:e20794.
    1. Sheng Z, Tan Y, Liu C, Zhou P, Li J, Zhou J, et al. Relation of circulating trimethylamine N-oxide with coronary atherosclerotic burden in patients with ST-segment elevation myocardial infarction. Am J Cardiol. 2019;123:894–8.
    1. Zhu Y, Li Q, Jiang H. Gut microbiota in atherosclerosis: focus on trimethylamine N‐oxide. APMIS. 2020;128:353–66.
    1. Chleilat F, Schick A, Reimer RA. Microbiota changes in fathers consuming a high prebiotic fiber diet have minimal effects on male and female offspring in rats. Nutrients. 2021;13:820.
    1. Thomas S, Izard J, Walsh E, Batich K, Chongsathidkiet P, Clarke G, et al. The host microbiome regulates and maintains human health: a primer and perspective for non-microbiologists. Cancer Res. 2017;77:1783–812.
    1. Kim CH, Park J, Kim M. Gut microbiota-derived short-chain fatty acids, T cells, and inflammation. Immune Netw. 2014;14:277–88.
    1. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–73.
    1. Vaziri ND, Liu S-M, Lau WL, Khazaeli M, Nazertehrani S, Farzaneh SH, et al. High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease. PLoS ONE. 2014;9:e114881.
    1. Naqvi S, Asar TO, Kumar V, Al-Abbasi FA, Alhayyani S, Kamal MA, et al. A cross-talk between gut microbiome, salt and hypertension. Biomed Pharmacother. 2021;134:111156.
    1. Elijovich F, Laffer CL, Sahinoz M, Pitzer A, Ferguson JF, Kirabo A. The gut microbiome, inflammation, and salt-sensitive hypertension. Curr Hypertens Rep. 2020. 10.1007/s11906-020-01091-9.
    1. Tanaka M, Itoh H. Hypertension as a metabolic disorder and the novel role of the gut. Curr Hypertens Rep. 2019;21:63.
    1. Elderman M, Hugenholtz F, Belzer C, Boekschoten M, van Beek A, de Haan B, et al. Sex and strain dependent differences in mucosal immunology and microbiota composition in mice. Biol Sex Differ. 2018;9:26.
    1. Org E, Mehrabian M, Parks BW, Shipkova P, Liu X, Drake TA, et al. Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes. 2016;7:313–22.
    1. Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Nature. 2014;509:357–60.
    1. Kim YS, Unno T, Kim B-Y, Park M-S. Sex differences in gut microbiota. World J Men’s Health. 2020;38:48–60.
    1. North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circulation Res. 2012;110:1097–108.
    1. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222–7.
    1. Ishimwe JA. Maternal microbiome in preeclampsia pathophysiology and implications on offspring health. Physiol Rep. 2021;9:e14875.
    1. Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, Weerd H, de, Flannery E, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci USA. 2011;108:4586–91.
    1. Woodmansey EJ, McMurdo MET, Macfarlane GT, Macfarlane S. Comparison of compositions and metabolic activities of fecal microbiotas in young adults and in antibiotic-treated and non-antibiotic-treated elderly subjects. Appl Environ Microbiol. 2004;70:6113–22.
    1. Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, et al. Gut microbiota and extreme longevity. Curr Biol. 2016;26:1480–5.
    1. Mariat D, Firmesse O, Levenez F, Guimarăes V, Sokol H, Doré J, et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 2009;9:123.
    1. Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE. 2010;5:e10667.
    1. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21:455–.e4.
    1. Binyamin D, Werbner N, Nuriel-Ohayon M, Uzan A, Mor H, Abbas A, et al. The aging mouse microbiome has obesogenic characteristics. Genome Med. 2020;12:87.
    1. Ahmadi S, Razazan A, Nagpal R, Jain S, Wang B, Mishra SP, et al. Metformin reduces aging-related leaky gut and improves cognitive function by beneficially modulating gut microbiome/goblet cell/mucin axis. J Gerontol A Biol Sci Med Sci. 2020;75:e9–e21..
    1. Calder PC, Bosco N, Bourdet-Sicard R, Capuron L, Delzenne N, Doré J, et al. Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Res Rev. 2017;40:95–119.
    1. Fransen F, van Beek AA, Borghuis T, Aidy SE, Hugenholtz F, van der Gaast-de Jongh C, et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol. 2017;8:1385.
    1. Brunt VE, Gioscia-Ryan RA, Casso AG, VanDongen NS, Ziemba BP, Sapinsley ZJ, et al. Trimethylamine-N-Oxide promotes age-related vascular oxidative stress and endothelial dysfunction in mice and healthy humans. Hypertension. 2020;76:101–12.
    1. Li DY, Tang WHW. Contributory role of gut microbiota and their metabolites toward cardiovascular complications in chronic kidney disease. Semin Nephrol. 2018;38:193–205.
    1. Wang Z, Bergeron N, Levison BS, Li XS, Chiu S, Jia X, et al. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur Heart J. 2019;40:583–94.
    1. Moszak M, Szulińska M, Bogdański P. You are what you eat—the relationship between diet, microbiota, and metabolic disorders—a review. Nutrients. 2020;12:1096.
    1. Hügel HM, Jackson N, May B, Zhang AL, Xue CC. Polyphenol protection and treatment of hypertension. Phytomedicine. 2016;23:220–31.
    1. Potì F, Santi D, Spaggiari G, Zimetti F, Zanotti I. Polyphenol health effects on cardiovascular and neurodegenerative disorders: a review and meta-analysis. Int J Mol Sci. 2019;20:E351.
    1. Chakraborty S, Galla S, Cheng X, Yeo J-Y, Mell B, Singh V, et al. Salt-responsive metabolite, β-hydroxybutyrate, attenuates hypertension. Cell Rep. 2018;25:677–.e4.
    1. Ishimwe JA, Garrett MR, Sasser JM. 1,3-Butanediol attenuates hypertension and suppresses kidney injury in female rats. Am J Physiol Ren Physiol. 2020;319:F106–F114..
    1. Beli E, Yan Y, Moldovan L, Vieira CP, Gao R, Duan Y, et al. Restructuring of the gut microbiome by intermittent fasting prevents retinopathy and prolongs survival in db/db mice. Diabetes. 2018;67:1867–79.
    1. Winston JA, Theriot CM. Diversification of host bile acids by members of the gut microbiota. Gut Microbes. 2020;11:158–71.
    1. Cao Y, Xiao Y, Zhou K, Yan J, Wang P, Yan W, et al. FXR agonist GW4064 improves liver and intestinal pathology and alters bile acid metabolism in rats undergoing small intestinal resection. Am J Physiol Gastrointest Liver Physiol. 2019;317:G108–G115..
    1. Fu ZD, Klaassen CD. Increased bile acids in enterohepatic circulation by short-term calorie restriction in male mice. Toxicol Appl Pharmacol. 2013;273:680–90.
    1. Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity. 2016;45:802–16.
    1. Han M, Li S, Xie H, Liu Q, Wang A, Hu S, et al. Activation of TGR5 restores AQP2 expression via the HIF pathway in renal ischemia-reperfusion injury. Am J Physiol-Ren Physiol. 2021;320:F308–F321..
    1. Shi H, Zhang B, Abo-Hamzy T, Nelson JW, Ambati CSR, Petrosino JF, et al. Restructuring the gut microbiota by intermittent fasting lowers blood pressure. Circ Res. 2021;128:1240–54.
    1. Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC, et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell. 2014;159:514–29.
    1. Voigt RM, Forsyth CB, Green SJ, Engen PA, Keshavarzian A. Chapter Nine - Circadian Rhythm and the Gut Microbiome. In: Cryan JF, Clarke G (eds). International Review of Neurobiology. Academic Press; 2016. p. 193–205.

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