|Year : 2018 | Volume
| Issue : 1 | Page : 10-14
Insights into the human gut microbiome and cardiovascular diseases
Soumalya Sarkar1, Bhabatosh Das2, Sanjay K Banerjee1
1 Drug Discovery Research Center, Translational Health Science and Technology Institute, Faridabad, Haryana, India
2 Molecular Genetics Laboratory, Centre for Human Microbial Ecology, Translational Health Science and Technology Institute, Faridabad, Haryana, India
|Date of Web Publication||4-May-2018|
Dr. Bhabatosh Das
Molecular Genetics Laboratory, Centre for Human Microbial Ecology, Translational Health Science and Technology Institute, Faridabad, Haryana
Dr. Sanjay K Banerjee
Drug Discovery Research Center, Translational Health Science and Technology Institute, Faridabad, Haryana
Source of Support: None, Conflict of Interest: None
The microbiome comprises all of the genetic materials within a microbiota. This can also be referred to as the metagenome of the microbiota. Dysbiosis, a change in the composition of the gut microbiota, has been associated with pathology, including cardiovascular diseases (CVDs). The recently discovered contribution of gut microbiota-derived molecules in the development of heart disease and its risk factors has significantly increased attention toward the connection between our gut and heart. The gut microbiome is virtually an endocrine organ, capable of contributing to and reacting to circulating signaling molecules within the host. Gut microbiota-host interactions occur through many pathways, including trimethylamine-N-oxide and short-chain fatty acids. These molecules and others have been linked to chronic kidney disease, atherosclerosis, and hypertension. Dysbiosis has been implicated in CVD as well as many aspects of obesity, hypertension, chronic kidney disease, and diabetes.
Keywords: Dysbiosis, genomic, microbiota
|How to cite this article:|
Sarkar S, Das B, Banerjee SK. Insights into the human gut microbiome and cardiovascular diseases. J Pract Cardiovasc Sci 2018;4:10-4
|How to cite this URL:|
Sarkar S, Das B, Banerjee SK. Insights into the human gut microbiome and cardiovascular diseases. J Pract Cardiovasc Sci [serial online] 2018 [cited 2018 Nov 18];4:10-4. Available from: http://www.j-pcs.org/text.asp?2018/4/1/10/231932
| Introduction|| |
Microbiome is the entire genomic content of microbial community including prokaryotes, viruses, and microbial eukaryotes that populate an ecosystem. Microbiome contributes significantly for a plethora of chemical transformations, which are of utmost significance for host physiology and surrounding environment on the planet Earth. Robust exploration has been going on to decipher the responsibility of microbiome in human well-being over the past few decades.
The human body harbors trillion of microbial flora representing thousands of microbial species from all three domains of life. The estimated number of bacteria living on the healthy adult human (age 20–30 years, weight 70 kg, height 170 cm) is 3.9 × 1013, the vast majority of them are commensal reside in the colon (3.9 × 1013), followed by the skin (1012). The rest of the human body contains <1012 bacteria. Metagenomic analysis of the human gut microbiome has revealed that there are 5 million unique microbial genes in human gut, 200 times more genes than our own genome. The microbiota present in the human gastro intestinal tract contributes significantly in bile salts metabolism, repression of virulence factors in enteric pathogens, transformation of prodrugs into active drugs, and metabolism of xenobiotic compounds including antibiotics by chemical transformation., In addition, the gut microbiota also contributes in the synthesis of vitamins, neurotransmitters, and signaling molecules, which are the key elements of human physiology and can educate host immunity, production of cytokine and immunoglobulin, gut-associated lymphoid tissues' development, and prevention of colonization of enteric pathogens in the gut milieu.,, Microbial homeostasis and healthy immune system are crucial for human health. Abrupt changes in gut microbiota (dysbiosis) can induce different health disorders including inflammatory bowel disease, malnourishment, colorectal cancer, metabolic and neuronal diseases, coronary heart disease, rheumatoid arthritis, autoimmune and psychiatric disorders., In recent times, as we evolve with our deteriorating food habits and environmental conditions, our microbiota also evolves to exhibit a symbiotic relationship with its host by regulating different body systems. Although the development of metabolic disorder including diabetes is well explored with individual microbiome, limited knowledge is available with cardiovascular diseases (CVDs).
Globally, one of the looming causes of morbidity and mortality is CVDs. The etiology of CVDs is not very clearly understood although most evident reasons include genetic aberrations and environmental insults. In the present review, we have discussed the role of microbiome in CVDs and its future scope and opportunity.
| Microbiome and Cardiovascular Diseases|| |
Both host genetics and environmental factors play important role in the development and progression of CVDs. Gut microbial dysbiosis and/or metabolites produced by the gut microbiota can induce inflammation and pathogenesis of atherosclerotic heart disease. There have been several studies, which have tried to establish the relationship between microbiota and CVDs. A study conducted on animals revealed that recurrent Porphyromonas gingivalis bacteremia induces aortic and coronary lesions consistent with atherosclerosis in normocholesterolemic pigs and further increases aortic and coronary atherosclerosis in hypercholesterolemic pigs. Another study with human subjects showed that periodontal bacterial burden was related to carotid intima-media thickness. All the available data do provide some evidence which shows the relationship between the periodontal infection and atherosclerotic diseases. However, further well-designed human studies are required to find the association and direct effect of periodontal infection with atherosclerosis.
Two dominant phyla in the human distal gut, Bacteroidetes and Firmicutes, account for 90% of the bacterial flora [Figure 1]. There are 1000–1200 bacterial species which colonize the human intestinal tract of which 150–200 play major role in human physiology. Contemporary studies state that the gut microbiome possesses a risk of several diseases including CVDs by manipulating the common risk factors of plasma lipids, resistance to insulin and obesity. The gut microbiome of individuals with atherosclerotic CVD (ACVD) deviates from the healthy one by increased abundance of Enterobacteriaceae (Escherichia coli, Klebsiella Spp. Enterobacter aerogenes) and Streptococcus spp. The abundance of Eggerthella lenta, the gut Actinobacterium species well known for deactivating the cardiac glycoside drug digoxin into dihydrodigoxin, was higher in ACVD. In contrast, commensal bacterial species contribute significantly in butyrate production including Roseburia intestinalis and Faecalibacterium prausnitzii were depleted in the ACVD individuals. Recent studies have also shown reproducible correlations twixt CVDs and microbes Chlamydia pneumoniae, P. gingivalis, Helicobacter pylori, and Aggregatibacter actinomycetemcomitans. Interesting fact is that that these microbes are localized to intestine as well as atheroma, signifying possibilities of engagement of pattern recognition receptors in extremely distinctive microenvironments. In addition, they also generate metabolites such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acids which affect CVD pathogenesis. These metabolites can act in situ or ex situ affecting the host's physiology and pathology. The metabolome consists of various methylamines, polyamines, polysaccharides, SCFAs, secondary bile acids, B vitamins, uremic toxins, such as p- cresol sulfate and indoxyl sulfate, 4-ethylphenylsulfate and dihydrodigoxin, plus a long list of xenobiotic-derived metabolites. Three classes of metabolites (trimethylamines [TMAs], SCFAs, and secondary bile acids) are basically linked to CVDs according to latest human and mouse model studies.
| Trimethylamine-N-Oxide and Cardiovascular Diseases|| |
The gut microbiota can metabolize dietary choline, phosphatidylcholine, and l-carnitine to produce TMA, which is then oxidized in the hepatic cells into the proatherogenic inflammatory metabolite, TMAO. Gut microbiota-derived metabolite TMAO has been linked with CVD risks. It also serves as an initiator of atherothrombotic diseases. The mechanism by which it is formed is well demonstrated., First, the nutrients such as phosphatidylcholine, choline, l-carnitine, and other TMA-containing nutrients present in high fat foods are metabolized to generate the primary metabolite TMA by a plethora of gut microbial enzyme complexes. Then, the TMA is introduced in the hepatic-portal system and is further biotransformed, in hepatocytes into TMAO by host enzymes known as flavin-containing monooxygenase (predominantly the dimethylaniline monooxygenase [N-oxide-forming] 3 [FMO3] isoform). All the recent data concluded that the gut microbes-derived TMAO has significant clinical prognostic value and can promote atherosclerosis and thrombotic vascular disease in mouse models. It was found that TMAO-affected pathway is also related to other cardiometabolic diseases in humans such as cardiac hypertrophy, cardiac fibrosis, chronic kidney disease, Type-II diabetes, and obesity through unknown receptor-mediated pathways. TMAO rapidly increases the calcium ion (Ca 2+) release due to certain stimulus in platelets which in turn activates prothrombotic pathways. In endothelial cells and smooth muscle cells, TMAO swiftly activates mitogen-activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B-cells which in turn facilitates the expression of adhesion molecules such as E-selectin. TMAO can also regulate the differentiation of monocytes into macrophages and foam cells. It can also initiate profibrotic processes in heart and kidney through transforming growth factor-β phospho-SMAD3 signaling axis. The conglomerate of all these cellular proceedings accelerates atherosclerosis, thrombotic vascular disease, and related renal impairment. Hence, understanding the molecular mechanism of TMAO [Figure 2] and discovery of its unknown receptors through which TMAO shows its adverse effects will have a much wider implication to clear the picture of the fragmented puzzle in human pathogenesis.
|Figure 2: Schematic diagram showing the effect of trimethylamine-N-oxide on cardiovascular diseases.|
Click here to view
| Short Chain Fatty Acids and Cardiovascular Diseases|| |
SCFAs, the carboxylic acids with aliphatic tails < 6 carbons, are the primary end products of nondigestible carbohydrate and most abundant microbial fermented products in the lumen environment that serve as major energy source for the colonocytes. SCFAs play important role in shaping the population structure of gut microbial ecosystem and in alteration of host immunity and metabolic disease. The acetate moieties are produced by a huge amount of enteric bacteria such as Ruminococcus sp., Prevotella sp., and Bifidobacterium sp. Propionates can be generated through three distinctive biochemical pathways from Bacteroides sp., Phascolarctobacterium succinatutens, and Dialister sp. Fermentation of resistant starch is the major pathway of butyrate production in the colon. Several species of firmicutes dominated by F. prausnitzii, Eubacterium rectale, Eubacterium hallii, and Ruminococcus bromii contribute majorly in resistant starch fermentation and butyrate production. These SCFAs can function either as macronutrients or hormone-like signaling molecules, and when introduced into portal circulation, it activates downstream pathways through host receptor systems (mainly through G-protein couple receptors [GPCR-41/43/109A]) to ultimately regulate innate immunity and host metabolism.
Several researches have been conducted to show the link between CVDs and SCFAs in animal and human models which revealed the link of SCFAs with risk factors such as obesity, diabetes, hypertension, and hepatorenal diseases, but still, further investigations are necessary. A recent study demonstrated that SCFAs can operate through olfactory receptor (Olfr78) and GPCR-41 in the kidney to control renin secretion and blood pressure. Another fermentation product of the gut flora is lactic acid which was reported to activate host GPCR-81 (also known as hydroxycarboxylic acid receptor 1) and suppresses adipose tissue lipolysis. The inhibition of lactate receptor GPCR-81 was exhibited as a potential target against ischemic brain injury in mice. Further succinate generated by Prevotella copri can activate GPCR-91 (also known as succinate receptor 1) which specifies a potential gut flora metabolite and interacts with the host receptor to modulate CVDs.,
| Secondary Bile Acids and Cardiovascular Diseases|| |
The bile acids are synthesized from cholesterol in the liver and serve important roles in host-microbe interactions and regulatory pathways in the human host. The microbial metabolism of bile acids produces surfactants, which help in digestion of fat molecules. After entering into the colonic ecosystem, the bile salts may render cytotoxicity to some gut microbes. It is hypothesized that the primary bile salts and secondary bile acids (synthesized in situ) regulate the microbial community composition by membrane surfactant property and by bringing about DNA damage in some flora. By the processes of deconjugation, oxidation, epimerization, 7α-dehydroxylation, 7β-dehydroxylation, esterification, and desulfation, gut flora chemically broadens the diversity in the bile acid pool. Later on, secondary bile acids run through the portal circulation and mimics endocrine-like signaling molecules with potent effects on host pathophysiology.
After entering into the portal circulation in postprandial state, the bacterially modified bile acids bind to the host bile receptor – farnesoid X-activated receptor (FXR or NR1H4) to regulate the synthesis of m-RNAs of the essential genes which helps in the biosynthesis of primary bile acid. Polymorphism of FXR has been linked with hyperglycemia and circulating free fatty acid levels. Recent studies showed that knocking out of FXR in mice alters the development of atherosclerosis. Transplantation of human flora into mice was shown to modify mouse bile acid composition and induce FXR activation by decreasing the quantities of the FXR antagonist (tauro-β-muricholic acid). In another study, it was found that activation of another host bile acid receptor known as the G-protein-coupled bile acid receptor 1 (GPBAR1 or TGR5) leads to increased energy expenditure whereas knocking-out this receptor prevents atheroma formation in mouse models. Secondary bile acids such as lithocholic acid have the ability to activate nuclear hormone receptor called pregnane X receptor (PXR or nuclear receptor subfamily 1 Group I member 2) which is responsible for transcriptional regulation of xenobiotic and lipid metabolism. The knocking out of PXR in mice decreases the chances of atheroma progression. The lithocholic acid and 3-oxo-lithocholic acid can also activate Vitamin D3 receptor which is again correlated with CVDs in both humans and animal studies., The taurine-conjugated bile acids are able to activate particular muscarinic acetylcholine (ACh) receptor (M2 isoform); polymorphism of these M2 receptors was associated with bradycardia and may increase mortality by myocardial infarction. All the microbiota-derived bile acid metabolites can dynamically induce a variety of endocrinal stimulus that might be of extreme therapeutic importance.
| The Future and Challenges|| |
The modern therapeutics consists of several drug targets which need to be activated or inhibited to show their therapeutic benefit. However, recent understandings of microbiome and their role in human opened up a new way of therapeutic intervention for several cardiometabolic diseases where modern therapy is not much effective. In case of certain genetic diseases, the RNA-induced silencing complex and other molecular therapies are used when gene manipulation is required. As knowledge about the microbiome is gaining altitude in the field of biomedical research, microbial pharmacology is focusing on targeting the human microbiota to provide clinically safe and effective therapy at economic costs. As several microorganisms and their metabolites are identified and characterized which are related to CVDs, targeting them or their metabolites to render clinical benefits is under extensive research. TMAO inhibitors are now recognized after proper identification of microbial metabolite-host receptor interface. In addition to that, there are several other strategies which include development of prebiotics, probiotics, and postbiotics to inhibit the microbe-host pathways involved in CVD pathogenesis. The plethora of microbiota-derived metabolites and their mechanism of actions are not very well deciphered. Proper knowledge of these is required to harness their untapped potential and use it for the betterment of mankind.
| Conclusion|| |
Understanding the basic ecological principles and the factors that modulate the human microbiome composition and functions are crucial for basic biological discovery, translational research and prevention of communicable as well as noncommunicable diseases. Early identification of microbial signature associated with specific health disorders is important for both diagnostic and therapeutic intervention. Two major orientations of current human microbiome research are (i) diagnostic development and (ii) therapeutic intervention. The major questions asked by both basic and clinical scientists are (i) does composition of microbiota or their functional repertoires forecast human disease onset, progression, or outcome? (ii) can wild-type or genetically engineered individual microbe or microbial consortia be used to prevent or cure health disorders? The recent identification of elevated levels of plasma metabolites (TMAO) that predict risk of CVD in individuals, its association with intestinal microbiota and atherosclerosis, and the pathways that lead to the metabolite production reflect the importance of understanding the basic biology for diagnostic and translational research. Compared to understanding the human genome, the microbiome research has tremendous potential in both diagnostic and therapeutic intervention. Human genetic defects could be used for diagnostic/prediction of health disorders but difficult to rectify the defect. On the other hand, microbiome signature is both measurable and plastic. Resistant starch (prebiotics), probiotics, narrow-spectrum antimicrobials, environmental exposure, and good lifestyle can modulate microbial composition and may promise for beneficial microbiome modulation and improve human health as well as prevent/reduce communicable and noncommunicable disease development.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest 2014;124:4204-11.
Bäumler AJ, Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature 2016;535:85-93.
Hsiao A, Ahmed AM, Subramanian S, Griffin NW, Drewry LL, Petri WA Jr., et al.
Members of the human gut microbiota involved in recovery from vibrio cholerae infection. Nature 2014;515:423-6.
Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM, Troy EB, et al.
Gut immune maturation depends on colonization with a host-specific microbiota. Cell 2012;149:1578-93.
Brennan CA, Garrett WS. Gut microbiota, inflammation, and colorectal cancer. Annu Rev Microbiol 2016;70:395-411.
Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016;535:75-84.
Eloe-Fadrosh EA, Rasko DA. The human microbiome: From symbiosis to pathogenesis. Annu Rev Med 2013;64:145-63.
Ghosh TS, Gupta SS, Bhattacharya T, Yadav D, Barik A, Chowdhury A, et al.
Gut microbiomes of Indian children of varying nutritional status. PLoS One 2014;9:e95547.
Brodala N, Merricks EP, Bellinger DA, Damrongsri D, Offenbacher S, Beck J, et al. Porphyromonas gingivalis
bacteremia induces coronary and aortic atherosclerosis in normocholesterolemic and hypercholesterolemic pigs. Arterioscler Thromb Vasc Biol 2005;25:1446-51.
Ordovas JM, Mooser V. Metagenomics: The role of the microbiome in cardiovascular diseases. Curr Opin Lipidol 2006;17:157-61.
Brown JM, Hazen SL. Microbial modulation of cardiovascular disease. Nat Rev Microbiol 2018;16:171-81.
Tang WH, Hazen SL. The gut microbiome and its role in cardiovascular diseases. Circulation 2017;135:1008-10.
Trøseid M, Ueland T, Hov JR, Svardal A, Gregersen I, Dahl CP, et al.
Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med 2015;277:717-26.
Cai TQ, Ren N, Jin L, Cheng K, Kash S, Chen R, et al.
Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun 2008;377:987-91.
Shen Z, Jiang L, Yuan Y, Deng T, Zheng YR, Zhao YY, et al.
Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury. CNS Neurosci Ther 2015;21:271-9.
De Vadder F, Kovatcheva-Datchary P, Zitoun C, Duchampt A, Bäckhed F, Mithieux G, et al.
Microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis. Cell Metab 2016;24:151-7.
He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, et al.
Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 2004;429:188-93.
Heni M, Wagner R, Ketterer C, Böhm A, Linder K, Machicao F, et al.
Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans. J Clin Endocrinol Metab 2013;98:E1224-9.
Zhang Y, Wang X, Vales C, Lee FY, Lee H, Lusis AJ, et al.
FXR deficiency causes reduced atherosclerosis in Ldlr-/-mice. Arterioscler Thromb Vasc Biol 2006;26:2316-21.
Wahlström A, Kovatcheva-Datchary P, Ståhlman M, Khan MT, Bäckhed F, Marschall HU, et al.
Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota. J Lipid Res 2017;58:412-9.
Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al.
Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439:484-9.
Sui Y, Xu J, Rios-Pilier J, Zhou C. Deficiency of PXR decreases atherosclerosis in apoE-deficient mice. J Lipid Res 2011;52:1652-9.
Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, et al.
Vitamin D receptor as an intestinal bile acid sensor. Science 2002;296:1313-6.
Szeto FL, Reardon CA, Yoon D, Wang Y, Wong KE, Chen Y, et al.
Vitamin D receptor signaling inhibits atherosclerosis in mice. Mol Endocrinol 2012;26:1091-101.
Raufman JP, Cheng K, Zimniak P. Activation of muscarinic receptor signaling by bile acids: Physiological and medical implications. Dig Dis Sci 2003;48:1431-44.
Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, et al.
Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 2015;163:1585-95.
[Figure 1], [Figure 2]