Articles Service
Review
Unlocking Cardioprotective Potential of Gut Microbiome: Exploring Therapeutic Strategies
1Department of Internal Medicine-Cardiovascular, YanTai YuHuangDing Hospital, Yantai, Shandong, P.R. China
2Department of Internal Medicine-Cardiovascular, LinYi Central Hospital, LinYi, Shandong, P.R. China
J. Microbiol. Biotechnol. 2024; 34(12): 2413-2424
Published December 28, 2024 https://doi.org/10.4014/jmb.2405.05019
Copyright © The Korean Society for Microbiology and Biotechnology.
Abstract
Keywords
Graphical Abstract

Introduction
The term ‘microbiota’ refers to the community of microorganisms that normally reside within human colon. Although they reside in a relatively much smaller space, they are 10 times more abundant in their number as compared to the total cells of an average adult human body [1]. They are comprised of more than 2000 species with a majority of anaerobic bacteria [2]. The colonization of human gut starts right after the birth, however it gradually expands in diversity until the age of 3 years with a persistent composition that is maintained over years [2-6]. These microorganisms are well tolerated by the host immune cells and their number and special diversity greatly varies from person to person. Such diversity greatly depends on a number of factors such as age, geographical location, diet and host genetic makeup [7-9]. Although a vast majority of these microorganisms live in a commensal relationship with human body, some species develop a symbiotic relationship by producing energy though carbohydrate fermentation, synthesizing vitamins such as vitamin K and B12 [10, 11], short chain fatty acids such as acetate, propionate and butyrate [12], and releasing immune modulating molecules [4, 5, 13]. The butyrate synthesized by the microbiota not only acts as a local anti-inflammatory agent, it also serves as a pivotal energy source of gut epithelium [14, 15]. The symbiotic gut microflora also contribute in digesting the cardioprotective high fiber mediterranean diet [16].
Over the past many decades, our knowledge regarding the health benefits of gut microbiota has been merely limited to vitamin synthesis and immunomodulation. However, the tremendous advancements in molecular biology in recent years have opened new horizons in microbiome research. The number and diversity of gut flora is immensely related to an individual’s overall health and wellbeing. For instance, the microbiome derived short chain fatty acids exhibit strong immunomodulatory [17], analgesic [18], antidepressant [12] and metabolic properties [19]. The emerging scientific evidence suggests a direct link between the composition of microbiome and the pathogenesis of many different diseases. For instance, the neurodegeneration and demyelination in multiple sclerosis has been found associated with dysbiosis in gut microbiome [20]. Likewise, the deformities in the proportion of microbial species are reported to pave the way for hepatic cirrhosis and fibrosis [21], thyroid defects [22], gynecological disorders [23] and inflammatory bowel disease [24]. More importantly, the relevance of microbiota to the cardiovascular system has gained tremendous attention among researchers. Many recent studies have reported a direct relevance of microbiome dysbiosis to the progression of ischemic CADs, atherosclerosis and CAD [25, 26]. Since the composition of gut flora is not constant and is greatly influenced by geographical and diet factors, one cannot directly relate CAD with a particular composition of microbiota. Nevertheless, a deep understanding of different molecular mechanisms that the gut bacteria utilize to modulate cardiovascular function suggests novel therapeutic targets in the prevention and treatment of cardiovascular ailments. An in-depth relationship between CAD pathogenesis and microbiome dysbiosis is briefly summarized in the sections below.
Pathophysiological Basis of Microbiome Induced CAD
The complicated interrelation between CAD and microbial dysbiosis involves several molecular pathways influenced by a variety of local factors such as infections, host lipid profile, gall-bladder competencies and the regulation of bile secretions, leaky gut with associated endotoxins and microbial metabolites that exacerbate atherosclerosis. For instance, the proinflammatory cytokines are upregulated during infections. The persistently higher levels of these cytokines may compromise the integrity and stability of atherosclerotic plaques. Consequently, these plaques may rupture or decompose and thereby induce clot formation and other complications. Although the relevance of gut infections to the said atherosclerotic complications are not clear [27], the respiratory infections are strongly associated with systemic inflammation and the resultant plaque rupture [28]. The relevance of reverting dysbiosis by administering microbial preparations have been closely associated with several clinical benefits in patients with CAD, as illustrated in Fig. 1. A previous study has reported the presence of bacteria such as
-
Fig. 1. Association between therapeutics interventions to treat microbiome dysbiosis clinical goals. (A) illustrates therapeutics effects of probiotics, prebiotics, symbiotics and trimethylamine N-oxide (TMAO) inhibitors. (B) depicts various mechanisms employed by probiotics and prebiotics to impart health benefits.
The lipid metabolism is also affected by the gut flora, however the impact of microbiome dysbiosis on the expression of low density lipoprotein (LDL) is not clear yet [38]. The growing evidence suggests the involvement of peroxisome proliferator-activated receptors (PPAR) in facilitating the crosstalk between host cells and gut flora [39]. Moreover, such crosstalk between the host and microbiota involves interactions that are specific for various microbial species. For instance, the gut flora produce butyrate that further facilitates the β-oxidation process via involving PPARγ receptors. Additionally, PPARγ signaling ensures downregulation of nitric oxide synthesis to maintain anaerobic environment in colon to support the survival of anaerobic microbiota [39-42]. It is evident from the preclinical studies in mice that a high fat diet resulted into significant compositional and spatial modifications in gut microbiota with aberrant PPARγ signaling. Interestingly, the restoration of PPARγ signaling reverted all the compositional and spatial alterations back to normal, suggesting a direct involvement of these receptors in preventing microbiota dysbiosis [43].
In addition to the mechanisms mentioned above, some microbial metabolites are now believed to exhibit direct atherosclerotic properties. One important metabolic dysregulation in microbiome is the aberrant tryptophan metabolism. Under healthy conditions, the gut bacteria metabolize tryptophane to derivatives that upregulate the secretion of GLP-1, an important incretin hormone by activating aryl hydrocarbon receptors. The inability of gut microbiome to metabolize tryptophane is found associated with hyperinsulinemia that has exacerbated metabolic syndrome in both preclinical and clinical studies [44, 45]. Another important bacterial metabolite is the trimethylamine N-oxide (TMAO) that has been reported to be associated with atherosclerosis in rodents [46]. The administration of TMAO via oral route has significantly upregulated serum triglyceride and cholesterol levels in mice [47]. The Higher levels of TMAO are positively associated with the non-alcoholic fatty liver disease and CAD [48-50]. TMAO is a metabolic product of trimethylamine (TMA) which is synthesized by gut bacteria from choline. TMA is metabolized by the hepatic flavin-containing monooxygenases to synthesize TMAO. TMA is produced by many bacterial strains such as
A recent positional paper on coronary pathophysiology and microcirculation by the European Society of Cardiology working Group has outlined various clinical reports of observational nature that have been conducted with pathophysiological rationale [61, 62]. A number of such studies reported microbiome dysbiosis in patients with atherosclerosis and other cardiovascular ailments. Although a few such reports presented conflicting results due to differences in patient background and other technicalities, the alterations in gut microbial diversity has been a prominent pathological factor in most of the patients with atherosclerosis and infarction. Accordingly,
Despite of a strong scientific evidence that links microbiome dysbiosis with CAD pathogenesis, the factors that cause such dysbiosis in CAD are not known till today. Nevertheless, the findings of such studies suggest many valuable therapeutic interventions that could be used as an efficient tool to improve patient’s health and well-being. Some of the valuable associations between such therapeutic interventions and clinical success are illustrated in Fig. 2.
-
Fig. 2. Association between various interventions to revert microbial dysbiosis and clinical goals in treating cardiovascular ailments.
Contemporary Treatment Approaches
The contemporary interventions employed to inhibit microbiome dysbiosis include prebiotics, probiotics, synbiotics and TMAO inhibitors.
Prebiotics
These are the substances that are not digested by the gastrointestinal system; however they may be utilized to revert dysbiosis of gut microbiome. By promoting growth and diversity of gut bacteria, these prebiotics may add significant health benefits [66]. For example, chitosan oligosaccharides, pectin polysaccharides, fructooligosaccharides, falactans (galactooligosaccharides), inulin, betaglucan and minolest are prebiotics that are commonly used in patients with cardiovascular disorders. Their health benefits in patients with CAD are well affirmed by clinical trials. Different underlying mechanisms are suggested such as an increase in the growth of beneficial bacteria, improvement of leaky gut by enforcing gut epithelial junctions and the upregulation of short chain fatty acid synthesis in gut bacteria [67]. Prebiotics are reported to reduce the release of ghrelin from gastric mucosa with a significant upregulation in glucagon-like peptide-1 (GLP-1) release [68]. By promoting the growth of beneficial bacteria such as
The benefits of prebiotics in CAD are supported mainly by preclinical studies with only a handful clinical reports [67, 77, 78]. Different prebiotic preparations with potential cardioprotective properties include oligofructose [68], B-1,3/1,6 glucan [79], oligofructose-enriched inulin [80] and fructo-oligosaccharides [81]. The treatment with beta glycans has shown to reduce the risk of ischemia and reperfusion injury after coronary artery bypass [79]. Likewise, the growth of beneficial bacteria such as
Probiotics
The anti-thrombotic, vascular protective, antioxidant and anti-inflammatory effects are probiotics are well acclaimed [88]. Alive
The benefits of administering probiotics in cardiovascular diseases are evident from two preclinical studies. In knockout LDLr-/- mice, the administration of
In addition to
Participants who received probiotics exhibited a decrease in the abundance of
Preclinical investigations have provided valuable insights into the concurrent administration of multiple probiotics. In a study, probiotics including
Gut Health Strategies: Antibiotics, Postbiotics, Synbiotics
The attempt to target microorganisms within atherosclerotic plaque in CAD using antibiotics has not yielded any observed benefits and was recently discovered to have adverse effects on human health [107, 108]. Furthermore, this approach should be discarded due to its detrimental effects on numerous beneficial gut microorganisms. Analysis of microbial presence within atherosclerotic plaques has revealed a diverse community of over 50 bacterial species, including
The probiotics are defined as inanimate microbial preparations and/or their components that are administered to exhibit health benefits [113]. The definition however does not affirm postbiotic-associated clinical benefits in CAD patients. Although the purified metabolites of microorganisms with known health benefits do not fall within the definition of “postbiotics”, the fragments of bacterial cell-wall meet such criterion. One of such preparation, Anuc_1100 that is consisted of purified membrane proteins of
Synbiotics comprise a blend of live bacteria and their substrates designed to foster health benefits [115]. They have emerged as promising interventions in human CAD and its associated conditions such as obesity and diabetes mellitus [116]. The favorable effects of synbiotics primarily arise from the synergistic actions of their pre-and probiotic components. A thorough examination of randomized controlled trials [117], has unveiled significant enhancements in various metabolic parameters among patients with metabolic syndrome who underwent synbiotic supplementation. These enhancements encompass reduced levels of serum triglycerides, insulin, LDL cholesterol, total cholesterol, body weight, waist circumference, serum interleukin-6 and blood pressure along with upregulated HDL cholesterol. Nevertheless, determining the optimal synbiotic formulation for CAD treatment remains challenging. In a randomized controlled trial of diabetic patient with cardiovascular comorbidities [118], a synbiotic blend containing inulin,
Fecal transplantation is a clinical procedure primarily employed in treating
Expanding on this observation, a small-scale randomized controlled trial on metabolic syndrome assigned 20 male participants to undergo either autologous fecal or vegan donor transplantation [122]. While a shift towards a gut microbiota profile resembling that of vegan donors was noted in the recipients, this change did not correspond to reductions in vascular inflammation or trimethylamine-N-oxide (TMAO) as indicated by ex vivo production of pro-inflammatory cytokines by the peripheral blood monocytes or evaluated by imaging.
The intricacies of these clinical studies in human patients are complemented by pre-clinical investigations in laboratory animals. For example, the transplantation of fecal bacteria in murine model of myocarditis exhibited profound anti-inflammatory effect by modulating the
Furthermore, the findings of a recent investigation on atherosclerosis-prone C1q/TNF-related protein 9-knockout mice suggested a strong association between gut microbiota and CAD progression [125] The transplantation of fecal microbiota from wild-type mice transformed the composition of the recipient mice's gut microbiota to impede the progression of atherosclerotic lesions in the carotid artery following partial ligation. These findings underscore the potential of fecal transplantation as a therapeutic approach for mitigating atherosclerosis.
Modulating TMAO Levels
The scientific interest in trimethylamine-N-oxide (TMAO) has sparked numerous investigations aimed at inhibiting its production and exploring associated outcomes. In an early study conducted by Wang
In a recent study, DMB was administration with either high-TMAO or high choline diet in wild type murine model of partial carotid artery ligation [131]. Compared to control groups, DMB treatment effectively mitigated adverse vascular remodeling induced by the diets, attenuating flow-induced atherosclerotic lesion formation and suppressing the expression of NLRP3 inflammasome, endoplasmic reticulum stress burden, and reactive oxygen species formation. Roberts
The pathophysiological mechanism of TMAO induced atherosclerosis is concisely presented in Fig. 3. Fluoromethylcholine demonstrated the ability to reverse TMAO-induced tissue factor expression in a mouse model of arterial injury, suggesting a potential antithrombotic role [135]. In essence, inhibiting TMAO formation may hold promise in attenuating the progression of atherosclerosis by targeting various pathological processes, including foam cell formation, inflammation, endoplasmic reticulum stress, oxidative stress, coagulation, and extracellular matrix remodeling. Flavonoids, a diverse group of polyphenolic compounds found abundantly in various foods such as tea, citrus fruits, berries, red wine, apples, and legumes, have emerged as potential inhibitors of TMAO formation, sparking interest in their role in cardiovascular health. Among these compounds, flavonoid aglycones such as baicalein, fisetin, acacetin, and myricetin have demonstrated significant binding affinity to TMA-lyase, the enzyme involved in TMAO production. Similarly, flavonoid glycosides like baicalin, naringin, and hesperidin also show promising inhibitory effects on TMA-lyase activity [136]. Thus, targeting TMA-lyase activity presents a novel approach for reducing TMAO levels, potentially contributing to the observed benefits of flavonoids in preventing CAD [137]. However, the association between dietary patterns, such as the Mediterranean diet, and TMAO levels remains under debate, with conflicting findings and potential sex-specific associations observed [138, 139]. Consequently, further investigation is necessary to clarify the role of specific dietary patterns in modulating TMAO levels.
-
Fig. 3. The pathophysiological mechanism of trimethylamine-N-oxide (TMAO) induced atherosclerosis. The dietary choline is converted into trimethylamine within gut via trimethylamine lyase. The trimethylamine is further converted into TMAO by hepatic flavin-containing monooxygenases. The synthesis of TMAO is supported by microbiome dysbiosis. By inhibiting the enzymatic activity of trimethylamine lyase, TMAO inhibitors such as 3,3-dimethyl-1-butnol, fluoromethylcholine and iodomethylcholine may exert potential antiatherosclerosis by attenuating TMAO synthesis.
In conclusion, while initial research suggests the potential of flavonoids and dietary patterns in modulating TMAO and preventing CAD, evidence in humans remains limited. Therefore, the use of TMAO inhibitors or other methods to manipulate gut microbial composition for CAD prevention purposes is currently under investigation. It is premature to recommend routine microbiota measurements or modulation strategies for this specific purpose without further substantiation through rigorous research.
Conclusion
Currently, a substantial body of evidence links disruptions in gut microbial balance, known as dysbiosis, to CAD and associated cardiovascular risks. This connection is mainly attributed to the induction of mild systemic inflammation involving activities or components of gut bacteria, representing a series of fundamental pathophysiological events. Moreover, the metabolites that are generated by the gut microbiota act as indicators of heightened cardiovascular risk among patients, although definitive causality in human populations has yet to be firmly established. While several therapeutic strategies aimed at modulating the microbiota have been proposed and tested, their effects have generally been modest. Despite some relatively robust evidence derived from small-scale randomized controlled trials and meta-analyses, the translation of microbiota manipulation into clinical practice for CAD management will likely remain a distant prospect until larger, well-designed randomized controlled trials are conducted and their outcomes assessed.
Conflict of Interest
The authors have no financial conflicts of interest to declare.
References
- Thursby E, Juge N. 2017. Introduction to the human gut microbiota.
Biochem. J. 474 : 1823-1836. - Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M,
et al . 2005. Diversity of the human intestinal microbial flora.Science 308 : 1635-1638. - Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J, Knight R,
et al . 2011. Succession of microbial consortia in the developing infant gut microbiome.Proc. Natl. Acad. Sci. USA 108 Suppl 1 1(Suppl 1) : 4578-85. - Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, Goodman AL,
et al . 2013. The long-term stability of the human gut microbiota.Science 341 : 1237439. - Guarner F, Malagelada J-R. 2003. Gut flora in health and disease.
Lancet 361 : 512-519. - Clemente JC, Ursell LK, Parfrey LW, Knight R. 2012. The impact of the gut microbiota on human health: an integrative view.
Cell 148 : 1258-1270. - David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE,
et al . 2014. Diet rapidly and reproducibly alters the human gut microbiome.Nature 505 : 559-563. - Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M,
et al . 2012. Human gut microbiome viewed across age and geography.Nature 486 : 222-227. - Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. 2009. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice.
Science Transl. Med. 1 : 6ra14-6ra14. - Pham VT, Dold S, Rehman A, Bird JK, Steinert RE. 2021. Vitamins, the gut microbiome and gastrointestinal health in humans.
Nutr. Res. 95 : 35-53. - Kang WK, Florman JT, Araya A, Fox BW, Thackeray A, Schroeder FC,
et al . 2024. Vitamin B12 produced by gut bacteria modulates cholinergic signalling.Nat. Cell Biol. 26 : 72-85. - Cheng J, Hu H, Ju Y, Liu J, Wang M, Liu B,
et al . 2024. Gut microbiota-derived short-chain fatty acids and depression: deep insight into biological mechanisms and potential applications.Gen. Psychiatr. 37 : e101374. - Wu M, Zheng W, Song X, Bao B, Wang Y, Ramanan D,
et al . 2024. Gut complement induced by the microbiota combats pathogens and spares commensals.Cell 187 : 897-913.e18. - Garcia-Mantrana I, Selma-Royo M, Collado MC. 2018. Shifts on gut microbiota associated to mediterranean diet adherence and specific dietary intakes on general adult population.
Front. Microbiol. 9 : 319919. - Salvi PS, Cowles RA. 2021. Butyrate and the intestinal epithelium: modulation of proliferation and inflammation in homeostasis and disease.
Cells 10 : 1775. - Barber TM, Kabisch S, Pfeiffer AFH, Weickert MO. 2023. The effects of the mediterranean diet on health and Gut Microbiota.
Nutrients 15 : 2150. - Jardou M, Brossier C, Marquet P, Picard N, Druilhe A, Lawson R. 2024. Solid organ transplantation and gut microbiota: a review of the potential immunomodulatory properties of short-chain fatty acids in graft maintenance.
Front. Cell Infect. Microbiol. 14 : 1342354. - Tang Y, Du J, Wu H, Wang M, Liu S, Tao F. 2024. Potential therapeutic effects of short-chain fatty acids on chronic pain.
Curr. Neuropharmacol. 22 : 191-203. - Zheng J, An Y, Du Y, Song Y, Zhao Q, Lu Y. 2024. Effects of short-chain fatty acids on blood glucose and lipid levels in mouse models of diabetes mellitus: a systematic review and network meta-analysis.
Pharmacol. Res. 199 : 107041. - Paraschiv AC, Vacaras V, Nistor C, Vacaras C, Nistor DT, Vesa SC,
et al . 2024. Dysbiosis in multiple sclerosis: can immunoglobulin Y supplements help?J. Gastrointestin. Liver Dis. 33 : 115-122. - Li O, Xu H, Kim D, Yang F, Bao Z. 2024. Roles of human gut microbiota in liver cirrhosis risk: a two-sample mendelian randomization study.
J. Nutr. 154 : 143-151. - Virili C, Stramazzo I, Bagaglini MF, Carretti AL, Capriello S, Romanelli F,
et al . 2024. The relationship between thyroid and humanassociated microbiota: a systematic review of reviews.Rev. Endocr. Metab Disord. 25 : 215-237. - Ottinger S, Robertson CM, Branthoover H, Patras KA. 2024. The human vaginal microbiota: from clinical medicine to models to mechanisms.
Curr. Opin. Microbiol. 77 : 102422. - Danne C, Skerniskyte J, Marteyn B, Sokol H. 2024. Neutrophils: from IBD to the gut microbiota.
Nat. Rev. Gastroenterol. Hepatol. 21 : 184-197. - Liu L, Kaur GI, Kumar A, Kanwal A, Singh SP. 2024. The role of gut microbiota and associated compounds in cardiovascular health and its therapeutic implications.
Cardiovasc. Hematol. Agents Med. Chem. . doi: 10.2174/0118715257273506231208045308. Online ahead of print. - Hamjane N, Mechita MB, Nourouti NG, Barakat A. 2024. Gut microbiota dysbiosis -associated obesity and its involvement in cardiovascular diseases and type 2 diabetes. A systematic review.
Microvasc. Res. 151 : 104601. - Hizo-Abes P, Clark WF, Sontrop JM, Young A, Huang A, Thiessen-Philbrook H,
et al . 2013. Cardiovascular disease afterEscherichia coli O157: H7 gastroenteritis.CMAJ. 185 : E70-E77. - Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. 2004. Risk of myocardial infarction and stroke after acute infection or vaccination.
New Engl. J. Med. 351 : 2611-2618. - Ziganshina EE, Sharifullina DM, Lozhkin AP, Khayrullin RN, Ignatyev IM, Ziganshin AM. 2016. Bacterial communities associated with atherosclerotic plaques from Russian individuals with atherosclerosis.
PLoS One 11 : e0164836. - Jonsson AL, Bäckhed F. 2017. Role of gut microbiota in atherosclerosis.
Nat. Rev. Cardiol. 14 : 79-87. - Lambert G, Amar MJ, Guo G, Brewer HB, Gonzalez FJ, Sinal CJ. 2003. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis.
J. Biol. Chem. 278 : 2563-2570. - Mori H, Svegliati Baroni G, Marzioni M, Di Nicola F, Santori P, Maroni L,
et al . 2022. Farnesoid X receptor, bile acid metabolism, and gut microbiota.Metabolites 12 : 647. - Wiedermann CJ, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F,
et al . 1999. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the bruneck study.J. Am. College Cardiol. 34 : 1975-1981. - Stoll LL, Denning GM, Weintraub NL. 2004. Potential role of endotoxin as a proinflammatory mediator of atherosclerosis.
Arterioscler. Thromb. Vasc. Biol. 24 : 2227-2236. - van den Munckhof IC, Kurilshikov A, ter Horst R, Riksen NP, Joosten L, Zhernakova A,
et al . 2018. Role of gut microbiota in chronic low‐grade inflammation as potential driver for atherosclerotic cardiovascular disease: a systematic review of human studies.Obes. Rev 19 : 1719-1734. - Huang J, Li M, Zhoua WJ, Yao ZM, Ji G, Zhang L,
et al . 2022. Integrated miRNA and mRNA analysis identified potential mechanisms and targets of qianggan extracts in preventing nonalcoholic steatohepatitis.World J. Tradit. Chinese Med. 8 : 77. - Wang X, Liu XR, Li KX, Fan X, Liu Y. 2022. Effects of ferulic acid on regulating the neurovascular unit: implications for ischemic stroke treatment.
World J. Tradit. Chin. Med. 8 : 210-217. - Dural AŞ, Ergün C, Urhan M. 2023. Investigation of the relationship between serum low-density lipoprotein cholesterol levels with genetic polymorphisms, gut microbiota, and nutrition.
Metab. Syndr. Relat. Disord. 22 : 133-140. - Hasan AU, Rahman A, Kobori H. 2019. Interactions between host PPARs and gut microbiota in health and disease.
Int. J. Mol. Sci. 20 : 387. - Byndloss MX, Olsan EE, Rivera-Chávez F, Tiffany CR, Cevallos SA, Lokken KL,
et al . 2017. Microbiota-activated PPAR-γ signaling inhibits dysbioticEnterobacter iaceae expansion.Science 357 : 570-575. - Montaigne D, Butruille L, Staels B. 2021. PPAR control of metabolism and cardiovascular functions.
Nat. Rev. Cardiol. 18 : 809-823. - Xia YM, Gao H, Wang QS, Feng X, Wang YQ, Xu ZX. 2022. Characteristics of traditional Chinese medicine syndrome in patients with coronary heart disease at different disease stages.
World J. Tradit. Chin Med. 8 . DOI:10.4103/wjtcm.wjtcm_65_21. - Tomas J, Mulet C, Saffarian A, Cavin J-B, Ducroc R, Regnault B,
et al . 2016. High-fat diet modifies the PPAR-γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine.Proc. Natl. Acad. Sci. USA 113 : E5934-E5943. - Natividad JM, Agus A, Planchais J, Lamas B, Jarry AC, Martin R,
et al . 2018. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome.Cell Metab. 28 : 737-749.e4. - Peng L, Ma L, Jiang QQ, Tian X, Shao MY, Li CX,
et al . 2022. The mechanism of Panax notoginseng in the treatment of heart failure based on biological analysis.World J. Tradit. Chin. Med. 8 : 530-538. - Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B,
et al . 2011. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature 472 : 57-63. - Li XY, Yu ZL, Zhao YC, Wang DD, Xue CH, Zhang TT,
et al . 2024. Gut microbiota metabolite TMA may mediate the effects of TMAO on glucose and lipid metabolism in C57BL/6J mice.Mol. Nutr. Food Res. 68 : e2300443. - Theofilis P, Vordoni A, Kalaitzidis RG. 2022. Trimethylamine N-oxide levels in non-alcoholic fatty liver disease: a systematic review and meta-analysis.
Metabolites 12 : 1243. - Toh JZK, Pan XH, Tay PWL, Ng CH, Yong JN, Xiao J,
et al . 2022. A meta-analysis on the global prevalence, risk factors and screening of coronary heart disease in nonalcoholic fatty liver disease.Clin. Gastroenterol. Hepatol. 20 : 2462-2473.e10. - Wan SY, Hu JG, Zhang Y, Yu BY, Kou JP, Li F. 2022. Recent advances of traditional Chinese medicine in the regulation of myocardial mitochondrial function.
World J. Tradit. Chinese Med. 8 : 50-58. - Rath S, Heidrich B, Pieper DH, Vital M. 2017. Uncovering the trimethylamine-producing bacteria of the human gut microbiota.
Microbiome 5 : 54. - Romano K, Vivas E, Amador-Noguez D. FE Rey Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide., 2015, 6, p. e02481. DOI: https://doi.org/10.1128/mBio.02481-14.
- Rath S, Rud T, Pieper DH, Vital M. 2020. Potential TMA-producing bacteria are ubiquitously found in mammalia.
Front. Microbiol. 10 : 500963. - Tang WW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X,
et al . 2013. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.New Engl.J. Med. 368 : 1575-1584. - Heianza Y, Ma W, Manson JE, Rexrode KM, Qi L. 2017. 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. - Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A,
et al . 2017. 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. - Huang YX, Fan JJ, Xu LL, Yu R, Kuang Y, Chai Y,
et al . 2024. Network pharmacology-based dissection of the bioactive compounds and pharmacological mechanisms of yiqi fumai lyophilized injection for the treatment of heart failure.World J. Tradit. Chin. Med. 10 : 75-82. - Fan Y, Pedersen O. 2021. Gut microbiota in human metabolic health and disease.
Nat. Rev. Microbiol. 19 : 55-71. - Jia J, Dou P, Gao M, Kong X, Li C, Liu Z,
et al . 2019. Assessment of causal direction between gut microbiota-dependent metabolites and cardiometabolic health: a bidirectional Mendelian randomization analysis.Diabetes 68 : 1747-1755. - Wang CH, Gong B, Meng H, Wu YL, Zhao XS, Wei JH. 2023. Dalbergia odorifera essential oil protects against myocardial ischemia through upregulating nrf2 and inhibiting caspase signaling pathways in isoproterenol-induced rats.
World J. Tradit. Chin. Med. 9 : 338-347. - Tousoulis D, Guzik T, Padro T, Duncker DJ, De Luca G, Eringa E,
et al . 2022. Mechanisms, therapeutic implications, and methodological challenges of gut microbiota and cardiovascular diseases: a position paper by the ESC Working Group on Coronary Pathophysiology and Microcirculation.Cardiovasc. Res. 118 : 3171-3182. - Hu YR, Qu HY, Guo JY, Yang T, Zhou H. 2023. Jujuboside a improved energy metabolism in senescent H9c2 cells injured by ischemia, hypoxia, and reperfusion through the CD38/silent mating type information regulation 2 homolog 3 signaling pathway.
World J. Tradit. Chin. Med. 9 : 322-329. - Jie Z, Xia H, Zhong SL, Feng Q, Li S, Liang S,
et al . 2017. The gut microbiome in atherosclerotic cardiovascular disease.Nat. Commun. 8 : 845. - Yin J, Liao SX, He Y, Wang S, Xia GH, Liu FT,
et al . 2015. 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. - Zhu Q, Gao R, Zhang Y, Pan D, Zhu Y, Zhang X,
et al . 2018. Dysbiosis signatures of gut microbiota in coronary artery disease.Physiol. Genomics 50 : 893-903. - Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ,
et al . 2017. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.Nat. Rev. Gastroenterol. Hepatol. 14 : 491-502. - Wu H, Chiou J. 2021. Potential benefits of probiotics and prebiotics for coronary heart disease and stroke.
Nutrients 13 : 2878. - Parnell JA, Reimer RA. 2009. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults2.
Am. J. Clin. Nutr. 89 : 1751-1759. - Monteagudo-Mera A, Rastall RA, Gibson GR, Charalampopoulos D, Chatzifragkou A. 2019. Adhesion mechanisms mediated by probiotics and prebiotics and their potential impact on human health.
Appl.Microbiol. Biotechnol. 103 : 6463-6472. - Kendrick SFW, O'Boyle G, Mann J, Zeybel M, Palmer J, Jones DEJ,
et al . 2010. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis.Hepatology 51 : 1988-1997. - Usami M, Kishimoto K, Ohata A, Miyoshi M, Aoyama M, Fueda Y,
et al . 2008. Butyrate and trichostatin A attenuate nuclear factor κB activation and tumor necrosis factor α secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells.Nutr. Res. 28 : 321-328. - Pang XB, Zhang XL, Wang MR, Yuan Y, Zhang X. 2024. Study on the effect of ginaton on reducing cerebral vasospasm and early brain injury after hemorrhagic stroke by inhibiting inflammatory response.
World J. Tradit. Chin. Med. 10 : 33-39. - Zhang SD, Su ZH, Liu RH, Diao YY, Li SL, Ya-Ping-Hua,
et al . 2018. Exploring the pathways and targets of shexiang baoxin pill for coronary heart disease through a network pharmacology approach.World J. Tradit. Chin. Med. 4 : 137-146. - Liu X, Cao JN, Liu T, Zhong H, Liu M, Chang XR,
et al . 2023. Effect of herb-partitioned moxibustion on structure and functional prediction of gut microbiota in rats with irritable bowel syndrome with diarrhea.World J. Tradit. Chin. Med. 9 : 141-149. - Cheng D, Xu JH, Li JY, Wang SY, Wu TF, Chen QK,
et al . 2018. Butyrate ameliorated-NLRC3 protects the intestinal barrier in a GPR43-dependent manner.Exper. Cell Res. 368 : 101-110. - EFSA Panel on Dietetic Products N, Allergies. 2010. Scientific opinion on the substantiation of health claims related to various food(s)/food constituents(s) and increasing numbers of gastro-intestinal microorganisms (ID 760, 761, 779, 780, 779, 1905), and decreasing potentially pathogenic gastro-intestinal microorganisms (ID 760, 761, 779, 780, 779, 1905) pursuant to Article 13(1) of Regulation (EC) No 1924/2006.
EFSA J. 8 : 1809. - Wouk J, Dekker RFH, Queiroz EAIF, Barbosa-Dekker AM. 2021. β-Glucans as a panacea for a healthy heart? Their roles in preventing and treating cardiovascular diseases.
Int. J. Biol. Macromol. 177 : 176-203. - Sun Y, Wang M, Zhang SJ, Gao YS, Chen L, Wu MY,
et al . 2020. Effects of dachaihu decoction and Its "Prescription Elements" on intestinal flora of nonalcoholic fatty liver disease model rats.World J. Tradit. Chin. Med. 6 : 97-105. - Aarsæther E, Rydningen M, Einar Engstad R, Busund R. 2006. Cardioprotective effect of pretreatment with β-glucan in coronary artery bypass grafting.
Scand. Cardiovasc. J. 40 : 298-304. - Dehghan P, Farhangi MA, Tavakoli F, Aliasgarzadeh A, Akbari AM. 2016. Impact of prebiotic supplementation on T-cell subsets and their related cytokines, anthropometric features and blood pressure in patients with type 2 diabetes mellitus: a randomized placebo-controlled Trial.
Complement. Ther. Med. 24 : 96-102. - Merino-Aguilar H, Arrieta-Baez D, Jiménez-Estrada M, Magos-Guerrero G, Hernández-Bautista RJ, Susunaga-Notario ADC,
et al . 2014. Effect of fructooligosaccharides fraction fromPsacalium decompositum on inflammation and dyslipidemia in rats with fructose-induced obesity.Nutrients 6 : 591-604. - Jiang T, Xing X, Zhang L, Liu Z, Zhao J, Liu X. 2019. Chitosan oligosaccharides show protective effects in coronary heart disease by improving antioxidant capacity via the increase in intestinal probiotics.
Oxid. Med. Cell. Longev. 2019 : 7658052. - Santos-Marcos JA, Perez-Jimenez F, Camargo A. 2019. The role of diet and intestinal microbiota in the development of metabolic syndrome.
J. Nutr. Biochem. 70 : 1-27. - Healey G, Murphy R, Butts C, Brough L, Whelan K, Coad J. 2018. Habitual dietary fibre intake influences gut microbiota response to an inulin-type fructan prebiotic: a randomised, double-blind, placebo-controlled, cross-over, human intervention study.
Br. J. Nutr. 119 : 176-189. - Canfora EE, van der Beek CM, Hermes GDA, Goossens GH, Jocken JWE, Holst JJ,
et al . 2017. Supplementation of diet with galactooligosaccharides increases bifidobacteria, but not insulin sensitivity, in obese prediabetic individuals.Gastroenterology 153 : 87-97.e3. - Ramnani P, Costabile A, Bustillo AG, Gibson GR. 2015. A randomised, double- blind, cross-over study investigating the prebiotic effect of agave fructans in healthy human subjects.
J. Nutr. Sci. 4 : e10. - Ohashi Y, Sumitani K, Tokunaga M, Ishihara N, Okubo T, Fujisawa T. 2015. Consumption of partially hydrolysed guar gum stimulates
Bifidobacteria and butyrate-producing bacteria in the human large intestine.Benef Microbes. 6 : 451-5. - Mahdavi-Roshan M, Salari A, Kheirkhah J, Ghorbani Z. 2022. The effects of probiotics on inflammation, endothelial dysfunction, and atherosclerosis progression: a mechanistic overview.
Heart Lung Circ. 31 : e45-e71. - Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B,
et al . 2014. The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic.Nat. Rev. Gastroenterol. Hepatol. 11 : 506-514. - O'Morain VL, Ramji DP. 2020. The potential of probiotics in the prevention and treatment of atherosclerosis.
Mol. Nutr. Food Res. 64 : 1900797. - Moludi J, Kafil HS, Qaisar SA, Gholizadeh P, Alizadeh M, Vayghyan HJ. 2021. Effect of probiotic supplementation along with calorie restriction on metabolic endotoxemia, and inflammation markers in coronary artery disease patients: a double blind placebo controlled randomized clinical trial.
Nutr. J. 20 : 47. - Malik M, Suboc TM, Tyagi S, Salzman N, Wang J, Ying R,
et al . 2018.Lactobacillus plantarum 299v supplementation improves vascular endothelial function and reduces inflammatory biomarkers in men with stable coronary artery disease.Circ. Res. 123 : 1091-1102. - Koppinger MP, Lopez-Pier MA, Skaria R, Harris PR, Konhilas JP. 2020.
Lactobacillus reuteri attenuates cardiac injury without lowering cholesterol in low-density lipoprotein receptor-deficient mice fed standard chow.Am. J. Physiol. Heart Circ. Physiol. 319 : H32-H41. - Sun B, Ma T, Li Y, Yang N, Li B, Zhou X,
et al . 2022. Bifidobacterium lactis Probio-M8 adjuvant treatment confers added benefits to patients with coronary artery disease via target modulation of the gut-heart/-brain axes.mSystems 7 : e00100-22. - Yoshida N, Emoto T, Yamashita T, Watanabe H, Hayashi T, Tabata T,
et al . 2018.Bacteroides vulgatus and bcteroides dorei reduce gut microbial lipopolysaccharide production and inhibit atherosclerosis.Circulation 138 : 2486-2498. - O'Morain VL, Chan Y-H, Williams JO, Alotibi R, Alahmadi A, Rodrigues NP,
et al . 2021. The Lab4P consortium of probiotics attenuates atherosclerosis in LDL receptor deficient mice fed a high fat diet and causes plaque stabilization by inhibiting inflammation and several pro-atherogenic processes.Mol. Nutr. Food Res. 65 : 2100214. - Gan XT, Ettinger G, Huang CX, Burton JP, Haist JV, Rajapurohitam V,
et al . 2014. Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat.Circ. Heart Fail. 7 : 491-499. - Aboulgheit A, Karbasiafshar C, Zhang Z, Sabra M, Shi G, Tucker A,
et al . 2021.Lactobacillus plantarum probiotic induces Nrf2-mediated antioxidant signaling and eNOS expression resulting in improvement of myocardial diastolic function.Am. J. Physiol. Heart Circ. Physiol. 321 : H839-h849. - Neverovskyi A, Chernyavskyi V, Shypulin V, Hvozdetska L, Tishchenko V, Nechypurenko T,
et al . 2021. ProbioticLactobacillus plantarum may reduce cardiovascular risk: an experimental study.ARYA Atheroscler. 17 : 1-10. - Hofeld BC, Puppala VK, Tyagi S, Ahn KW, Anger A, Jia S,
et al . 2021.Lactobacillus plantarum 299v probiotic supplementation in men with stable coronary artery disease suppresses systemic inflammation.Sci. Rep. 11 : 3972. - Tarrah A, dos Santos Cruz BC, Sousa Dias R, da Silva Duarte V, Pakroo S, Licursi de Oliveira L,
et al . 2021.Lactobacillus paracasei DTA81, a cholesterol‐lowering strain having immunomodulatory activity, reveals gut microbiota regulation capability in BALB/c mice receiving high‐fat diet.J. Appl.Microbiol. 131 : 1942-1957. - Sun J, Buys N. 2015. Effects of probiotics consumption on lowering lipids and CVD risk factors: a systematic review and metaanalysis of randomized controlled trials.
Annal. Med. 47 : 430-440. - de Araújo Henriques Ferreira G, Magnani M, Cabral L, Brandão LR, Noronha MF, de Campos Cruz J,
et al . 2022. Potentially probioticLimosilactobacillus fermentum fruit-derived strains alleviate cardiometabolic disorders and gut microbiota impairment in male rats fed a high-fat diet.Probiotics Antimicrob. Proteins 14 : 349-359. - de Luna Freire MO, do Nascimento LCP, de Oliveira KÁR, de Oliveira AM, dos Santos Lima M, Napoleão TH,
et al . 2023.Limosilactobacillus fermentum strains with claimed probiotic properties exert anti-oxidant and anti-inflammatory properties and prevent cardiometabolic disorder in female rats fed a high-fat diet.Probiotics Antimicrob. Proteins 15 : 601-613. - Zafar H, Ain Nu, Alshammari A, Alghamdi S, Raja H, Ali A,
et al . 2022.Lacticaseibacillus rhamnosus FM9 andLimosilactobacillus fermentum Y57 Are as effective as statins at improving blood lipid profile in high cholesterol, high-fat diet model in male wistar rats.Nutrients 14 : 1654. - Romão da Silva LdF, de Oliveira Y, de Souza EL, de Luna Freire MO, Braga VdA, Magnani M,
et al . 2020. Effects of probiotic therapy on cardio-metabolic parameters and autonomic modulation in hypertensive women: a randomized, triple-blind, placebocontrolled trial.Food Funct. 11 : 7152-7163. - Sethi NJ, Safi S, Korang SK, Hróbjartsson A, Skoog M, Gluud C,
et al . 2017. Antibiotics for secondary prevention of coronary heart disease.Cochrane Database Syst. Rev. 7 . - Taylor-Robinson D, Boman J. 2005. The failure of antibiotics to prevent heart attacks.
BMJ. 331 : 361-362. - Ott SJ, Mokhtari NEE, Musfeldt M, Hellmig S, Freitag S, Rehman A,
et al . 2006. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease.Circulation 113 : 929-937. - Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. 1997. Elevated
Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction.Circulation 96 : 404-407. - Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP,
et al . 2005. Antibiotic treatment ofChlamydia pneumoniae after acute coronary syndrome.N. Engl. J. Med. 352 : 1646-1654. - Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD,
et al . 2005. Azithromycin for the secondary prevention of coronary events.N. Engl. J. Med. 352 : 1637-1645. - Salminen S, Collado MC, Endo A, Hill C, Lebeer S, Quigley EMM,
et al . 2021. 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. - Plovier H, Everard A, Druart C, Depommier C, Van Hul M, Geurts L,
et al . 2017. A purified membrane protein fromAkkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.Nat. Med. 23 : 107-113. - Swanson KS, Gibson GR, Hutkins R, Reimer RA, Reid G, Verbeke K,
et al . 2020. The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics.Nat. Rev. Gastroenterol. Hepatol. 17 : 687-701. - Sáez-Lara MJ, Robles-Sanchez C, Ruiz-Ojeda FJ, Plaza-Diaz J, Gil A. 2016. Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: a review of human clinical trials.
Int. J. Mol. Sci. 17 : 928. - Arabi SM, Bahrami LS, Rahnama I, Sahebkar A. 2022. Impact of synbiotic supplementation on cardiometabolic and anthropometric indices in patients with metabolic syndrome: a systematic review and meta-analysis of randomized controlled trials.
Pharmacol. Res. 176 : 106061. - Tajabadi-Ebrahimi M, Sharifi N, Farrokhian A, Raygan F, Karamali F, Razzaghi R,
et al . 2016. A Randomized controlled clinical trial investigating the effect of synbiotic administration on markers of insulin metabolism and lipid profiles in overweight type 2 diabetic patients with coronary heart disease.Exp. Clin. Endocrinol. Diabetes 125 : 21-27. - Shakeri H, Hadaegh H, Abedi F, Tajabadi-Ebrahimi M, Mazroii N, Ghandi Y,
et al . 2014. Consumption of synbiotic bread decreases triacylglycerol and VLDL levels while increasing HDL levels in serum from patients with type-2 diabetes.Lipids 49 : 695-701. - Moayyedi P, Yuan Y, Baharith H, Ford AC. 2017. Faecal microbiota transplantation for Clostridium difficile-associated diarrhoea: a systematic review of randomised controlled trials.
Med. J. Australia 207 : 166-172. - Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JFWM,
et al . 2012. Transfer of iIntestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.Gastroenterology 143 : 913-916.e7. - Smits LP, Kootte RS, Levin E, Prodan A, Fuentes S, Zoetendal EG,
et al . 2018. 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. - Hu XF, Zhang WY, Wen Q, Chen WJ, Wang ZM, Chen J,
et al . 2019. Fecal microbiota transplantation alleviates myocardial damage in myocarditis by restoring the microbiota composition.Pharmacol. Res. 139 : 412-421. - Brandsma E, Kloosterhuis NJ, Koster M, Dekker DC, Gijbels MJJ, Velden Svd,
et al . 2019. A Proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis.Circ. Res. 124 : 94-100. - Kim ES, Yoon BH, Lee SM, Choi M, Kim EH, Lee BW,
et al . 2022. Fecal microbiota transplantation ameliorates atherosclerosis in mice with C1q/TNF-related protein 9 genetic deficiency.Exper. Mol. Med. 54 : 103-114. - Wang Z, Roberts Adam B, Buffa Jennifer A, Levison Bruce S, Zhu W, Org E,
et al . 2015. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis.Cell 163 : 1585-1595. - Chen K, Zheng X, Feng M, Li D, Zhang H. 2017. Gut microbiota-dependent metabolite trimethylamine N-oxide contributes to cardiac dysfunction in western diet-induced obese mice.
Front. Physiol. 8 : 139. - Zou D, Li Y, Sun G. 2021. Attenuation of circulating trimethylamine N-oxide prevents the progression of cardiac and renal dysfunction in a rat model of chronic cardiorenal syndrome.
Front. Pharmacol. 12 : 751380. - Brunt VE, Gioscia-Ryan RA, Casso AG, VanDongen NS, Ziemba BP, Sapinsley ZJ,
et al . 2020. Trimethylamine-N-oxide promotes age-related vascular oxidative stress and endothelial dysfunction in mice and healthy humans.Hypertension 76 : 101-112. - Li T, Chen Y, Gua C, Li X. 2017. Elevated circulating trimethylamine N-oxide levels contribute to endothelial dysfunction in aged rats through vascular inflammation and oxidative stress.
Front. Physiol. 8 : 350. - Chen CY, Leu HB, Wang SC, Tsai SH, Chou RH, Lu YW,
et al . 2022. Inhibition of trimethylamine N-oxide attenuates neointimal formation through reduction of inflammasome and oxidative stress in a mouse model of carotid artery ligation.Antioxid. Redox Signal. 38 : 215-233. - Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W,
et al . 2018. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential.Nat. Med. 24 : 1407-1417. - Organ CL, Li Z, Sharp TE, Polhemus DJ, Gupta N, Goodchild TT,
et al . 2020. Nonlethal inhibition of gut microbial trimethylamine N‐oxide production improves cardiac function and remodeling in a murine model of heart failure.J. Am. Heart Assoc. 9 : e016223. - Pathak P, Helsley RN, Brown AL, Buffa JA, Choucair I, Nemet I,
et al . 2020. Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism.Am. J. Physiol. Heart Circ. Physiol. 318 : H1474-h1486. - Witkowski M, Witkowski M, Friebel J, Buffa JA, Li XS, Wang Z,
et al . 2021. Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis.Cardiovasc. Res. 118 : 2367-2384. - Zhou P, Zhao XN, Ma YY, Tang TJ, Wang SS, Wang L,
et al . 2022. Virtual screening analysis of natural flavonoids as trimethylamine (TMA)-lyase inhibitors for coronary heart disease.J. Food Biochem. 46 : e14376. - Micek A, Godos J, Del Rio D, Galvano F, Grosso G. 2021. Dietary flavonoids and cardiovascular disease: a comprehensive doseresponse meta-analysis.
Mol. Nutr. Food Res. 65 : e2001019. - Barrea L, Annunziata G, Muscogiuri G, Laudisio D, Di Somma C, Maisto M,
et al . 2019. Trimethylamine N-oxide, mediterranean diet, and nutrition in healthy, normal-weight adults: also a matter of sex?Nutrition 62 : 7-17. - Pignanelli M, Just C, Bogiatzi C, Dinculescu V, Gloor GB, Allen-Vercoe E,
et al . 2018. Mediterranean diet score: associations with metabolic products of the intestinal microbiome, carotid plaque burden, and renal function.Nutrients 10 : 779.
Related articles in JMB

Article
Review
J. Microbiol. Biotechnol. 2024; 34(12): 2413-2424
Published online December 28, 2024 https://doi.org/10.4014/jmb.2405.05019
Copyright © The Korean Society for Microbiology and Biotechnology.
Unlocking Cardioprotective Potential of Gut Microbiome: Exploring Therapeutic Strategies
Jun Qu1†, Fantao Meng2†, Zhen Wang1, and Wenhao Xu1*
1Department of Internal Medicine-Cardiovascular, YanTai YuHuangDing Hospital, Yantai, Shandong, P.R. China
2Department of Internal Medicine-Cardiovascular, LinYi Central Hospital, LinYi, Shandong, P.R. China
Correspondence to:Wenhao Xu, xwhchangdao@sina.com
†These authors contributed equally to this work.
Abstract
The microbial community inhabiting the human gut resembles a bustling metropolis, wherein beneficial bacteria play pivotal roles in regulating our bodily functions. These microorganisms adeptly break down resilient dietary fibers to fuel our energy, synthesize essential vitamins crucial for our well-being, and maintain the delicate balance of our immune system. Recent research indicates a potential correlation between alterations in the composition and activities of these gut microbes and the development of coronary artery disease (CAD). Consequently, scientists are delving into the intriguing realm of manipulating these gut inhabitants to potentially mitigate disease risks. Various promising strategies have emerged in this endeavor. Studies have evidenced that probiotics can mitigate inflammation and enhance the endothelial health of our blood vessels. Notably, strains such as Lactobacilli and Bifidobacteria have garnered substantial attention in both laboratory settings and clinical trials. Conversely, prebiotics exhibit anti-inflammatory properties and hold potential in managing conditions like hypertension and hypercholesterolemia. Synbiotics, which synergistically combine probiotics and prebiotics, show promise in regulating glucose metabolism and abnormal lipid profiles. However, uncertainties persist regarding postbiotics, while antibiotics are deemed unsuitable due to their potential adverse effects. On the other hand, TMAO blockers, such as 3,3-dimethyl-1-butanol, demonstrate encouraging outcomes in laboratory experiments owing to their anti-inflammatory and tissue-protective properties. Moreover, fecal transplantation, despite yielding mixed results, warrants further exploration and refinement. In this comprehensive review, we delve into the intricate interplay between the gut microbiota and CAD, shedding light on the multifaceted approaches researchers are employing to leverage this understanding for therapeutic advancements.
Keywords: Microbiome dysbiosis, probiotics, prebiotics, synbiotics, TMAO inhibitors, atherosclerosis
Introduction
The term ‘microbiota’ refers to the community of microorganisms that normally reside within human colon. Although they reside in a relatively much smaller space, they are 10 times more abundant in their number as compared to the total cells of an average adult human body [1]. They are comprised of more than 2000 species with a majority of anaerobic bacteria [2]. The colonization of human gut starts right after the birth, however it gradually expands in diversity until the age of 3 years with a persistent composition that is maintained over years [2-6]. These microorganisms are well tolerated by the host immune cells and their number and special diversity greatly varies from person to person. Such diversity greatly depends on a number of factors such as age, geographical location, diet and host genetic makeup [7-9]. Although a vast majority of these microorganisms live in a commensal relationship with human body, some species develop a symbiotic relationship by producing energy though carbohydrate fermentation, synthesizing vitamins such as vitamin K and B12 [10, 11], short chain fatty acids such as acetate, propionate and butyrate [12], and releasing immune modulating molecules [4, 5, 13]. The butyrate synthesized by the microbiota not only acts as a local anti-inflammatory agent, it also serves as a pivotal energy source of gut epithelium [14, 15]. The symbiotic gut microflora also contribute in digesting the cardioprotective high fiber mediterranean diet [16].
Over the past many decades, our knowledge regarding the health benefits of gut microbiota has been merely limited to vitamin synthesis and immunomodulation. However, the tremendous advancements in molecular biology in recent years have opened new horizons in microbiome research. The number and diversity of gut flora is immensely related to an individual’s overall health and wellbeing. For instance, the microbiome derived short chain fatty acids exhibit strong immunomodulatory [17], analgesic [18], antidepressant [12] and metabolic properties [19]. The emerging scientific evidence suggests a direct link between the composition of microbiome and the pathogenesis of many different diseases. For instance, the neurodegeneration and demyelination in multiple sclerosis has been found associated with dysbiosis in gut microbiome [20]. Likewise, the deformities in the proportion of microbial species are reported to pave the way for hepatic cirrhosis and fibrosis [21], thyroid defects [22], gynecological disorders [23] and inflammatory bowel disease [24]. More importantly, the relevance of microbiota to the cardiovascular system has gained tremendous attention among researchers. Many recent studies have reported a direct relevance of microbiome dysbiosis to the progression of ischemic CADs, atherosclerosis and CAD [25, 26]. Since the composition of gut flora is not constant and is greatly influenced by geographical and diet factors, one cannot directly relate CAD with a particular composition of microbiota. Nevertheless, a deep understanding of different molecular mechanisms that the gut bacteria utilize to modulate cardiovascular function suggests novel therapeutic targets in the prevention and treatment of cardiovascular ailments. An in-depth relationship between CAD pathogenesis and microbiome dysbiosis is briefly summarized in the sections below.
Pathophysiological Basis of Microbiome Induced CAD
The complicated interrelation between CAD and microbial dysbiosis involves several molecular pathways influenced by a variety of local factors such as infections, host lipid profile, gall-bladder competencies and the regulation of bile secretions, leaky gut with associated endotoxins and microbial metabolites that exacerbate atherosclerosis. For instance, the proinflammatory cytokines are upregulated during infections. The persistently higher levels of these cytokines may compromise the integrity and stability of atherosclerotic plaques. Consequently, these plaques may rupture or decompose and thereby induce clot formation and other complications. Although the relevance of gut infections to the said atherosclerotic complications are not clear [27], the respiratory infections are strongly associated with systemic inflammation and the resultant plaque rupture [28]. The relevance of reverting dysbiosis by administering microbial preparations have been closely associated with several clinical benefits in patients with CAD, as illustrated in Fig. 1. A previous study has reported the presence of bacteria such as
-
Figure 1. Association between therapeutics interventions to treat microbiome dysbiosis clinical goals. (A) illustrates therapeutics effects of probiotics, prebiotics, symbiotics and trimethylamine N-oxide (TMAO) inhibitors. (B) depicts various mechanisms employed by probiotics and prebiotics to impart health benefits.
The lipid metabolism is also affected by the gut flora, however the impact of microbiome dysbiosis on the expression of low density lipoprotein (LDL) is not clear yet [38]. The growing evidence suggests the involvement of peroxisome proliferator-activated receptors (PPAR) in facilitating the crosstalk between host cells and gut flora [39]. Moreover, such crosstalk between the host and microbiota involves interactions that are specific for various microbial species. For instance, the gut flora produce butyrate that further facilitates the β-oxidation process via involving PPARγ receptors. Additionally, PPARγ signaling ensures downregulation of nitric oxide synthesis to maintain anaerobic environment in colon to support the survival of anaerobic microbiota [39-42]. It is evident from the preclinical studies in mice that a high fat diet resulted into significant compositional and spatial modifications in gut microbiota with aberrant PPARγ signaling. Interestingly, the restoration of PPARγ signaling reverted all the compositional and spatial alterations back to normal, suggesting a direct involvement of these receptors in preventing microbiota dysbiosis [43].
In addition to the mechanisms mentioned above, some microbial metabolites are now believed to exhibit direct atherosclerotic properties. One important metabolic dysregulation in microbiome is the aberrant tryptophan metabolism. Under healthy conditions, the gut bacteria metabolize tryptophane to derivatives that upregulate the secretion of GLP-1, an important incretin hormone by activating aryl hydrocarbon receptors. The inability of gut microbiome to metabolize tryptophane is found associated with hyperinsulinemia that has exacerbated metabolic syndrome in both preclinical and clinical studies [44, 45]. Another important bacterial metabolite is the trimethylamine N-oxide (TMAO) that has been reported to be associated with atherosclerosis in rodents [46]. The administration of TMAO via oral route has significantly upregulated serum triglyceride and cholesterol levels in mice [47]. The Higher levels of TMAO are positively associated with the non-alcoholic fatty liver disease and CAD [48-50]. TMAO is a metabolic product of trimethylamine (TMA) which is synthesized by gut bacteria from choline. TMA is metabolized by the hepatic flavin-containing monooxygenases to synthesize TMAO. TMA is produced by many bacterial strains such as
A recent positional paper on coronary pathophysiology and microcirculation by the European Society of Cardiology working Group has outlined various clinical reports of observational nature that have been conducted with pathophysiological rationale [61, 62]. A number of such studies reported microbiome dysbiosis in patients with atherosclerosis and other cardiovascular ailments. Although a few such reports presented conflicting results due to differences in patient background and other technicalities, the alterations in gut microbial diversity has been a prominent pathological factor in most of the patients with atherosclerosis and infarction. Accordingly,
Despite of a strong scientific evidence that links microbiome dysbiosis with CAD pathogenesis, the factors that cause such dysbiosis in CAD are not known till today. Nevertheless, the findings of such studies suggest many valuable therapeutic interventions that could be used as an efficient tool to improve patient’s health and well-being. Some of the valuable associations between such therapeutic interventions and clinical success are illustrated in Fig. 2.
-
Figure 2. Association between various interventions to revert microbial dysbiosis and clinical goals in treating cardiovascular ailments.
Contemporary Treatment Approaches
The contemporary interventions employed to inhibit microbiome dysbiosis include prebiotics, probiotics, synbiotics and TMAO inhibitors.
Prebiotics
These are the substances that are not digested by the gastrointestinal system; however they may be utilized to revert dysbiosis of gut microbiome. By promoting growth and diversity of gut bacteria, these prebiotics may add significant health benefits [66]. For example, chitosan oligosaccharides, pectin polysaccharides, fructooligosaccharides, falactans (galactooligosaccharides), inulin, betaglucan and minolest are prebiotics that are commonly used in patients with cardiovascular disorders. Their health benefits in patients with CAD are well affirmed by clinical trials. Different underlying mechanisms are suggested such as an increase in the growth of beneficial bacteria, improvement of leaky gut by enforcing gut epithelial junctions and the upregulation of short chain fatty acid synthesis in gut bacteria [67]. Prebiotics are reported to reduce the release of ghrelin from gastric mucosa with a significant upregulation in glucagon-like peptide-1 (GLP-1) release [68]. By promoting the growth of beneficial bacteria such as
The benefits of prebiotics in CAD are supported mainly by preclinical studies with only a handful clinical reports [67, 77, 78]. Different prebiotic preparations with potential cardioprotective properties include oligofructose [68], B-1,3/1,6 glucan [79], oligofructose-enriched inulin [80] and fructo-oligosaccharides [81]. The treatment with beta glycans has shown to reduce the risk of ischemia and reperfusion injury after coronary artery bypass [79]. Likewise, the growth of beneficial bacteria such as
Probiotics
The anti-thrombotic, vascular protective, antioxidant and anti-inflammatory effects are probiotics are well acclaimed [88]. Alive
The benefits of administering probiotics in cardiovascular diseases are evident from two preclinical studies. In knockout LDLr-/- mice, the administration of
In addition to
Participants who received probiotics exhibited a decrease in the abundance of
Preclinical investigations have provided valuable insights into the concurrent administration of multiple probiotics. In a study, probiotics including
Gut Health Strategies: Antibiotics, Postbiotics, Synbiotics
The attempt to target microorganisms within atherosclerotic plaque in CAD using antibiotics has not yielded any observed benefits and was recently discovered to have adverse effects on human health [107, 108]. Furthermore, this approach should be discarded due to its detrimental effects on numerous beneficial gut microorganisms. Analysis of microbial presence within atherosclerotic plaques has revealed a diverse community of over 50 bacterial species, including
The probiotics are defined as inanimate microbial preparations and/or their components that are administered to exhibit health benefits [113]. The definition however does not affirm postbiotic-associated clinical benefits in CAD patients. Although the purified metabolites of microorganisms with known health benefits do not fall within the definition of “postbiotics”, the fragments of bacterial cell-wall meet such criterion. One of such preparation, Anuc_1100 that is consisted of purified membrane proteins of
Synbiotics comprise a blend of live bacteria and their substrates designed to foster health benefits [115]. They have emerged as promising interventions in human CAD and its associated conditions such as obesity and diabetes mellitus [116]. The favorable effects of synbiotics primarily arise from the synergistic actions of their pre-and probiotic components. A thorough examination of randomized controlled trials [117], has unveiled significant enhancements in various metabolic parameters among patients with metabolic syndrome who underwent synbiotic supplementation. These enhancements encompass reduced levels of serum triglycerides, insulin, LDL cholesterol, total cholesterol, body weight, waist circumference, serum interleukin-6 and blood pressure along with upregulated HDL cholesterol. Nevertheless, determining the optimal synbiotic formulation for CAD treatment remains challenging. In a randomized controlled trial of diabetic patient with cardiovascular comorbidities [118], a synbiotic blend containing inulin,
Fecal transplantation is a clinical procedure primarily employed in treating
Expanding on this observation, a small-scale randomized controlled trial on metabolic syndrome assigned 20 male participants to undergo either autologous fecal or vegan donor transplantation [122]. While a shift towards a gut microbiota profile resembling that of vegan donors was noted in the recipients, this change did not correspond to reductions in vascular inflammation or trimethylamine-N-oxide (TMAO) as indicated by ex vivo production of pro-inflammatory cytokines by the peripheral blood monocytes or evaluated by imaging.
The intricacies of these clinical studies in human patients are complemented by pre-clinical investigations in laboratory animals. For example, the transplantation of fecal bacteria in murine model of myocarditis exhibited profound anti-inflammatory effect by modulating the
Furthermore, the findings of a recent investigation on atherosclerosis-prone C1q/TNF-related protein 9-knockout mice suggested a strong association between gut microbiota and CAD progression [125] The transplantation of fecal microbiota from wild-type mice transformed the composition of the recipient mice's gut microbiota to impede the progression of atherosclerotic lesions in the carotid artery following partial ligation. These findings underscore the potential of fecal transplantation as a therapeutic approach for mitigating atherosclerosis.
Modulating TMAO Levels
The scientific interest in trimethylamine-N-oxide (TMAO) has sparked numerous investigations aimed at inhibiting its production and exploring associated outcomes. In an early study conducted by Wang
In a recent study, DMB was administration with either high-TMAO or high choline diet in wild type murine model of partial carotid artery ligation [131]. Compared to control groups, DMB treatment effectively mitigated adverse vascular remodeling induced by the diets, attenuating flow-induced atherosclerotic lesion formation and suppressing the expression of NLRP3 inflammasome, endoplasmic reticulum stress burden, and reactive oxygen species formation. Roberts
The pathophysiological mechanism of TMAO induced atherosclerosis is concisely presented in Fig. 3. Fluoromethylcholine demonstrated the ability to reverse TMAO-induced tissue factor expression in a mouse model of arterial injury, suggesting a potential antithrombotic role [135]. In essence, inhibiting TMAO formation may hold promise in attenuating the progression of atherosclerosis by targeting various pathological processes, including foam cell formation, inflammation, endoplasmic reticulum stress, oxidative stress, coagulation, and extracellular matrix remodeling. Flavonoids, a diverse group of polyphenolic compounds found abundantly in various foods such as tea, citrus fruits, berries, red wine, apples, and legumes, have emerged as potential inhibitors of TMAO formation, sparking interest in their role in cardiovascular health. Among these compounds, flavonoid aglycones such as baicalein, fisetin, acacetin, and myricetin have demonstrated significant binding affinity to TMA-lyase, the enzyme involved in TMAO production. Similarly, flavonoid glycosides like baicalin, naringin, and hesperidin also show promising inhibitory effects on TMA-lyase activity [136]. Thus, targeting TMA-lyase activity presents a novel approach for reducing TMAO levels, potentially contributing to the observed benefits of flavonoids in preventing CAD [137]. However, the association between dietary patterns, such as the Mediterranean diet, and TMAO levels remains under debate, with conflicting findings and potential sex-specific associations observed [138, 139]. Consequently, further investigation is necessary to clarify the role of specific dietary patterns in modulating TMAO levels.
-
Figure 3. The pathophysiological mechanism of trimethylamine-N-oxide (TMAO) induced atherosclerosis. The dietary choline is converted into trimethylamine within gut via trimethylamine lyase. The trimethylamine is further converted into TMAO by hepatic flavin-containing monooxygenases. The synthesis of TMAO is supported by microbiome dysbiosis. By inhibiting the enzymatic activity of trimethylamine lyase, TMAO inhibitors such as 3,3-dimethyl-1-butnol, fluoromethylcholine and iodomethylcholine may exert potential antiatherosclerosis by attenuating TMAO synthesis.
In conclusion, while initial research suggests the potential of flavonoids and dietary patterns in modulating TMAO and preventing CAD, evidence in humans remains limited. Therefore, the use of TMAO inhibitors or other methods to manipulate gut microbial composition for CAD prevention purposes is currently under investigation. It is premature to recommend routine microbiota measurements or modulation strategies for this specific purpose without further substantiation through rigorous research.
Conclusion
Currently, a substantial body of evidence links disruptions in gut microbial balance, known as dysbiosis, to CAD and associated cardiovascular risks. This connection is mainly attributed to the induction of mild systemic inflammation involving activities or components of gut bacteria, representing a series of fundamental pathophysiological events. Moreover, the metabolites that are generated by the gut microbiota act as indicators of heightened cardiovascular risk among patients, although definitive causality in human populations has yet to be firmly established. While several therapeutic strategies aimed at modulating the microbiota have been proposed and tested, their effects have generally been modest. Despite some relatively robust evidence derived from small-scale randomized controlled trials and meta-analyses, the translation of microbiota manipulation into clinical practice for CAD management will likely remain a distant prospect until larger, well-designed randomized controlled trials are conducted and their outcomes assessed.
Conflict of Interest
The authors have no financial conflicts of interest to declare.
Fig 1.

Fig 2.

Fig 3.

References
- Thursby E, Juge N. 2017. Introduction to the human gut microbiota.
Biochem. J. 474 : 1823-1836. - Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M,
et al . 2005. Diversity of the human intestinal microbial flora.Science 308 : 1635-1638. - Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J, Knight R,
et al . 2011. Succession of microbial consortia in the developing infant gut microbiome.Proc. Natl. Acad. Sci. USA 108 Suppl 1 1(Suppl 1) : 4578-85. - Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, Goodman AL,
et al . 2013. The long-term stability of the human gut microbiota.Science 341 : 1237439. - Guarner F, Malagelada J-R. 2003. Gut flora in health and disease.
Lancet 361 : 512-519. - Clemente JC, Ursell LK, Parfrey LW, Knight R. 2012. The impact of the gut microbiota on human health: an integrative view.
Cell 148 : 1258-1270. - David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE,
et al . 2014. Diet rapidly and reproducibly alters the human gut microbiome.Nature 505 : 559-563. - Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M,
et al . 2012. Human gut microbiome viewed across age and geography.Nature 486 : 222-227. - Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. 2009. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice.
Science Transl. Med. 1 : 6ra14-6ra14. - Pham VT, Dold S, Rehman A, Bird JK, Steinert RE. 2021. Vitamins, the gut microbiome and gastrointestinal health in humans.
Nutr. Res. 95 : 35-53. - Kang WK, Florman JT, Araya A, Fox BW, Thackeray A, Schroeder FC,
et al . 2024. Vitamin B12 produced by gut bacteria modulates cholinergic signalling.Nat. Cell Biol. 26 : 72-85. - Cheng J, Hu H, Ju Y, Liu J, Wang M, Liu B,
et al . 2024. Gut microbiota-derived short-chain fatty acids and depression: deep insight into biological mechanisms and potential applications.Gen. Psychiatr. 37 : e101374. - Wu M, Zheng W, Song X, Bao B, Wang Y, Ramanan D,
et al . 2024. Gut complement induced by the microbiota combats pathogens and spares commensals.Cell 187 : 897-913.e18. - Garcia-Mantrana I, Selma-Royo M, Collado MC. 2018. Shifts on gut microbiota associated to mediterranean diet adherence and specific dietary intakes on general adult population.
Front. Microbiol. 9 : 319919. - Salvi PS, Cowles RA. 2021. Butyrate and the intestinal epithelium: modulation of proliferation and inflammation in homeostasis and disease.
Cells 10 : 1775. - Barber TM, Kabisch S, Pfeiffer AFH, Weickert MO. 2023. The effects of the mediterranean diet on health and Gut Microbiota.
Nutrients 15 : 2150. - Jardou M, Brossier C, Marquet P, Picard N, Druilhe A, Lawson R. 2024. Solid organ transplantation and gut microbiota: a review of the potential immunomodulatory properties of short-chain fatty acids in graft maintenance.
Front. Cell Infect. Microbiol. 14 : 1342354. - Tang Y, Du J, Wu H, Wang M, Liu S, Tao F. 2024. Potential therapeutic effects of short-chain fatty acids on chronic pain.
Curr. Neuropharmacol. 22 : 191-203. - Zheng J, An Y, Du Y, Song Y, Zhao Q, Lu Y. 2024. Effects of short-chain fatty acids on blood glucose and lipid levels in mouse models of diabetes mellitus: a systematic review and network meta-analysis.
Pharmacol. Res. 199 : 107041. - Paraschiv AC, Vacaras V, Nistor C, Vacaras C, Nistor DT, Vesa SC,
et al . 2024. Dysbiosis in multiple sclerosis: can immunoglobulin Y supplements help?J. Gastrointestin. Liver Dis. 33 : 115-122. - Li O, Xu H, Kim D, Yang F, Bao Z. 2024. Roles of human gut microbiota in liver cirrhosis risk: a two-sample mendelian randomization study.
J. Nutr. 154 : 143-151. - Virili C, Stramazzo I, Bagaglini MF, Carretti AL, Capriello S, Romanelli F,
et al . 2024. The relationship between thyroid and humanassociated microbiota: a systematic review of reviews.Rev. Endocr. Metab Disord. 25 : 215-237. - Ottinger S, Robertson CM, Branthoover H, Patras KA. 2024. The human vaginal microbiota: from clinical medicine to models to mechanisms.
Curr. Opin. Microbiol. 77 : 102422. - Danne C, Skerniskyte J, Marteyn B, Sokol H. 2024. Neutrophils: from IBD to the gut microbiota.
Nat. Rev. Gastroenterol. Hepatol. 21 : 184-197. - Liu L, Kaur GI, Kumar A, Kanwal A, Singh SP. 2024. The role of gut microbiota and associated compounds in cardiovascular health and its therapeutic implications.
Cardiovasc. Hematol. Agents Med. Chem. . doi: 10.2174/0118715257273506231208045308. Online ahead of print. - Hamjane N, Mechita MB, Nourouti NG, Barakat A. 2024. Gut microbiota dysbiosis -associated obesity and its involvement in cardiovascular diseases and type 2 diabetes. A systematic review.
Microvasc. Res. 151 : 104601. - Hizo-Abes P, Clark WF, Sontrop JM, Young A, Huang A, Thiessen-Philbrook H,
et al . 2013. Cardiovascular disease afterEscherichia coli O157: H7 gastroenteritis.CMAJ. 185 : E70-E77. - Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. 2004. Risk of myocardial infarction and stroke after acute infection or vaccination.
New Engl. J. Med. 351 : 2611-2618. - Ziganshina EE, Sharifullina DM, Lozhkin AP, Khayrullin RN, Ignatyev IM, Ziganshin AM. 2016. Bacterial communities associated with atherosclerotic plaques from Russian individuals with atherosclerosis.
PLoS One 11 : e0164836. - Jonsson AL, Bäckhed F. 2017. Role of gut microbiota in atherosclerosis.
Nat. Rev. Cardiol. 14 : 79-87. - Lambert G, Amar MJ, Guo G, Brewer HB, Gonzalez FJ, Sinal CJ. 2003. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis.
J. Biol. Chem. 278 : 2563-2570. - Mori H, Svegliati Baroni G, Marzioni M, Di Nicola F, Santori P, Maroni L,
et al . 2022. Farnesoid X receptor, bile acid metabolism, and gut microbiota.Metabolites 12 : 647. - Wiedermann CJ, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F,
et al . 1999. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the bruneck study.J. Am. College Cardiol. 34 : 1975-1981. - Stoll LL, Denning GM, Weintraub NL. 2004. Potential role of endotoxin as a proinflammatory mediator of atherosclerosis.
Arterioscler. Thromb. Vasc. Biol. 24 : 2227-2236. - van den Munckhof IC, Kurilshikov A, ter Horst R, Riksen NP, Joosten L, Zhernakova A,
et al . 2018. Role of gut microbiota in chronic low‐grade inflammation as potential driver for atherosclerotic cardiovascular disease: a systematic review of human studies.Obes. Rev 19 : 1719-1734. - Huang J, Li M, Zhoua WJ, Yao ZM, Ji G, Zhang L,
et al . 2022. Integrated miRNA and mRNA analysis identified potential mechanisms and targets of qianggan extracts in preventing nonalcoholic steatohepatitis.World J. Tradit. Chinese Med. 8 : 77. - Wang X, Liu XR, Li KX, Fan X, Liu Y. 2022. Effects of ferulic acid on regulating the neurovascular unit: implications for ischemic stroke treatment.
World J. Tradit. Chin. Med. 8 : 210-217. - Dural AŞ, Ergün C, Urhan M. 2023. Investigation of the relationship between serum low-density lipoprotein cholesterol levels with genetic polymorphisms, gut microbiota, and nutrition.
Metab. Syndr. Relat. Disord. 22 : 133-140. - Hasan AU, Rahman A, Kobori H. 2019. Interactions between host PPARs and gut microbiota in health and disease.
Int. J. Mol. Sci. 20 : 387. - Byndloss MX, Olsan EE, Rivera-Chávez F, Tiffany CR, Cevallos SA, Lokken KL,
et al . 2017. Microbiota-activated PPAR-γ signaling inhibits dysbioticEnterobacter iaceae expansion.Science 357 : 570-575. - Montaigne D, Butruille L, Staels B. 2021. PPAR control of metabolism and cardiovascular functions.
Nat. Rev. Cardiol. 18 : 809-823. - Xia YM, Gao H, Wang QS, Feng X, Wang YQ, Xu ZX. 2022. Characteristics of traditional Chinese medicine syndrome in patients with coronary heart disease at different disease stages.
World J. Tradit. Chin Med. 8 . DOI:10.4103/wjtcm.wjtcm_65_21. - Tomas J, Mulet C, Saffarian A, Cavin J-B, Ducroc R, Regnault B,
et al . 2016. High-fat diet modifies the PPAR-γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine.Proc. Natl. Acad. Sci. USA 113 : E5934-E5943. - Natividad JM, Agus A, Planchais J, Lamas B, Jarry AC, Martin R,
et al . 2018. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome.Cell Metab. 28 : 737-749.e4. - Peng L, Ma L, Jiang QQ, Tian X, Shao MY, Li CX,
et al . 2022. The mechanism of Panax notoginseng in the treatment of heart failure based on biological analysis.World J. Tradit. Chin. Med. 8 : 530-538. - Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B,
et al . 2011. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature 472 : 57-63. - Li XY, Yu ZL, Zhao YC, Wang DD, Xue CH, Zhang TT,
et al . 2024. Gut microbiota metabolite TMA may mediate the effects of TMAO on glucose and lipid metabolism in C57BL/6J mice.Mol. Nutr. Food Res. 68 : e2300443. - Theofilis P, Vordoni A, Kalaitzidis RG. 2022. Trimethylamine N-oxide levels in non-alcoholic fatty liver disease: a systematic review and meta-analysis.
Metabolites 12 : 1243. - Toh JZK, Pan XH, Tay PWL, Ng CH, Yong JN, Xiao J,
et al . 2022. A meta-analysis on the global prevalence, risk factors and screening of coronary heart disease in nonalcoholic fatty liver disease.Clin. Gastroenterol. Hepatol. 20 : 2462-2473.e10. - Wan SY, Hu JG, Zhang Y, Yu BY, Kou JP, Li F. 2022. Recent advances of traditional Chinese medicine in the regulation of myocardial mitochondrial function.
World J. Tradit. Chinese Med. 8 : 50-58. - Rath S, Heidrich B, Pieper DH, Vital M. 2017. Uncovering the trimethylamine-producing bacteria of the human gut microbiota.
Microbiome 5 : 54. - Romano K, Vivas E, Amador-Noguez D. FE Rey Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide., 2015, 6, p. e02481. DOI: https://doi.org/10.1128/mBio.02481-14.
- Rath S, Rud T, Pieper DH, Vital M. 2020. Potential TMA-producing bacteria are ubiquitously found in mammalia.
Front. Microbiol. 10 : 500963. - Tang WW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X,
et al . 2013. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.New Engl.J. Med. 368 : 1575-1584. - Heianza Y, Ma W, Manson JE, Rexrode KM, Qi L. 2017. 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. - Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A,
et al . 2017. 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. - Huang YX, Fan JJ, Xu LL, Yu R, Kuang Y, Chai Y,
et al . 2024. Network pharmacology-based dissection of the bioactive compounds and pharmacological mechanisms of yiqi fumai lyophilized injection for the treatment of heart failure.World J. Tradit. Chin. Med. 10 : 75-82. - Fan Y, Pedersen O. 2021. Gut microbiota in human metabolic health and disease.
Nat. Rev. Microbiol. 19 : 55-71. - Jia J, Dou P, Gao M, Kong X, Li C, Liu Z,
et al . 2019. Assessment of causal direction between gut microbiota-dependent metabolites and cardiometabolic health: a bidirectional Mendelian randomization analysis.Diabetes 68 : 1747-1755. - Wang CH, Gong B, Meng H, Wu YL, Zhao XS, Wei JH. 2023. Dalbergia odorifera essential oil protects against myocardial ischemia through upregulating nrf2 and inhibiting caspase signaling pathways in isoproterenol-induced rats.
World J. Tradit. Chin. Med. 9 : 338-347. - Tousoulis D, Guzik T, Padro T, Duncker DJ, De Luca G, Eringa E,
et al . 2022. Mechanisms, therapeutic implications, and methodological challenges of gut microbiota and cardiovascular diseases: a position paper by the ESC Working Group on Coronary Pathophysiology and Microcirculation.Cardiovasc. Res. 118 : 3171-3182. - Hu YR, Qu HY, Guo JY, Yang T, Zhou H. 2023. Jujuboside a improved energy metabolism in senescent H9c2 cells injured by ischemia, hypoxia, and reperfusion through the CD38/silent mating type information regulation 2 homolog 3 signaling pathway.
World J. Tradit. Chin. Med. 9 : 322-329. - Jie Z, Xia H, Zhong SL, Feng Q, Li S, Liang S,
et al . 2017. The gut microbiome in atherosclerotic cardiovascular disease.Nat. Commun. 8 : 845. - Yin J, Liao SX, He Y, Wang S, Xia GH, Liu FT,
et al . 2015. 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. - Zhu Q, Gao R, Zhang Y, Pan D, Zhu Y, Zhang X,
et al . 2018. Dysbiosis signatures of gut microbiota in coronary artery disease.Physiol. Genomics 50 : 893-903. - Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ,
et al . 2017. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.Nat. Rev. Gastroenterol. Hepatol. 14 : 491-502. - Wu H, Chiou J. 2021. Potential benefits of probiotics and prebiotics for coronary heart disease and stroke.
Nutrients 13 : 2878. - Parnell JA, Reimer RA. 2009. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults2.
Am. J. Clin. Nutr. 89 : 1751-1759. - Monteagudo-Mera A, Rastall RA, Gibson GR, Charalampopoulos D, Chatzifragkou A. 2019. Adhesion mechanisms mediated by probiotics and prebiotics and their potential impact on human health.
Appl.Microbiol. Biotechnol. 103 : 6463-6472. - Kendrick SFW, O'Boyle G, Mann J, Zeybel M, Palmer J, Jones DEJ,
et al . 2010. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis.Hepatology 51 : 1988-1997. - Usami M, Kishimoto K, Ohata A, Miyoshi M, Aoyama M, Fueda Y,
et al . 2008. Butyrate and trichostatin A attenuate nuclear factor κB activation and tumor necrosis factor α secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells.Nutr. Res. 28 : 321-328. - Pang XB, Zhang XL, Wang MR, Yuan Y, Zhang X. 2024. Study on the effect of ginaton on reducing cerebral vasospasm and early brain injury after hemorrhagic stroke by inhibiting inflammatory response.
World J. Tradit. Chin. Med. 10 : 33-39. - Zhang SD, Su ZH, Liu RH, Diao YY, Li SL, Ya-Ping-Hua,
et al . 2018. Exploring the pathways and targets of shexiang baoxin pill for coronary heart disease through a network pharmacology approach.World J. Tradit. Chin. Med. 4 : 137-146. - Liu X, Cao JN, Liu T, Zhong H, Liu M, Chang XR,
et al . 2023. Effect of herb-partitioned moxibustion on structure and functional prediction of gut microbiota in rats with irritable bowel syndrome with diarrhea.World J. Tradit. Chin. Med. 9 : 141-149. - Cheng D, Xu JH, Li JY, Wang SY, Wu TF, Chen QK,
et al . 2018. Butyrate ameliorated-NLRC3 protects the intestinal barrier in a GPR43-dependent manner.Exper. Cell Res. 368 : 101-110. - EFSA Panel on Dietetic Products N, Allergies. 2010. Scientific opinion on the substantiation of health claims related to various food(s)/food constituents(s) and increasing numbers of gastro-intestinal microorganisms (ID 760, 761, 779, 780, 779, 1905), and decreasing potentially pathogenic gastro-intestinal microorganisms (ID 760, 761, 779, 780, 779, 1905) pursuant to Article 13(1) of Regulation (EC) No 1924/2006.
EFSA J. 8 : 1809. - Wouk J, Dekker RFH, Queiroz EAIF, Barbosa-Dekker AM. 2021. β-Glucans as a panacea for a healthy heart? Their roles in preventing and treating cardiovascular diseases.
Int. J. Biol. Macromol. 177 : 176-203. - Sun Y, Wang M, Zhang SJ, Gao YS, Chen L, Wu MY,
et al . 2020. Effects of dachaihu decoction and Its "Prescription Elements" on intestinal flora of nonalcoholic fatty liver disease model rats.World J. Tradit. Chin. Med. 6 : 97-105. - Aarsæther E, Rydningen M, Einar Engstad R, Busund R. 2006. Cardioprotective effect of pretreatment with β-glucan in coronary artery bypass grafting.
Scand. Cardiovasc. J. 40 : 298-304. - Dehghan P, Farhangi MA, Tavakoli F, Aliasgarzadeh A, Akbari AM. 2016. Impact of prebiotic supplementation on T-cell subsets and their related cytokines, anthropometric features and blood pressure in patients with type 2 diabetes mellitus: a randomized placebo-controlled Trial.
Complement. Ther. Med. 24 : 96-102. - Merino-Aguilar H, Arrieta-Baez D, Jiménez-Estrada M, Magos-Guerrero G, Hernández-Bautista RJ, Susunaga-Notario ADC,
et al . 2014. Effect of fructooligosaccharides fraction fromPsacalium decompositum on inflammation and dyslipidemia in rats with fructose-induced obesity.Nutrients 6 : 591-604. - Jiang T, Xing X, Zhang L, Liu Z, Zhao J, Liu X. 2019. Chitosan oligosaccharides show protective effects in coronary heart disease by improving antioxidant capacity via the increase in intestinal probiotics.
Oxid. Med. Cell. Longev. 2019 : 7658052. - Santos-Marcos JA, Perez-Jimenez F, Camargo A. 2019. The role of diet and intestinal microbiota in the development of metabolic syndrome.
J. Nutr. Biochem. 70 : 1-27. - Healey G, Murphy R, Butts C, Brough L, Whelan K, Coad J. 2018. Habitual dietary fibre intake influences gut microbiota response to an inulin-type fructan prebiotic: a randomised, double-blind, placebo-controlled, cross-over, human intervention study.
Br. J. Nutr. 119 : 176-189. - Canfora EE, van der Beek CM, Hermes GDA, Goossens GH, Jocken JWE, Holst JJ,
et al . 2017. Supplementation of diet with galactooligosaccharides increases bifidobacteria, but not insulin sensitivity, in obese prediabetic individuals.Gastroenterology 153 : 87-97.e3. - Ramnani P, Costabile A, Bustillo AG, Gibson GR. 2015. A randomised, double- blind, cross-over study investigating the prebiotic effect of agave fructans in healthy human subjects.
J. Nutr. Sci. 4 : e10. - Ohashi Y, Sumitani K, Tokunaga M, Ishihara N, Okubo T, Fujisawa T. 2015. Consumption of partially hydrolysed guar gum stimulates
Bifidobacteria and butyrate-producing bacteria in the human large intestine.Benef Microbes. 6 : 451-5. - Mahdavi-Roshan M, Salari A, Kheirkhah J, Ghorbani Z. 2022. The effects of probiotics on inflammation, endothelial dysfunction, and atherosclerosis progression: a mechanistic overview.
Heart Lung Circ. 31 : e45-e71. - Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B,
et al . 2014. The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic.Nat. Rev. Gastroenterol. Hepatol. 11 : 506-514. - O'Morain VL, Ramji DP. 2020. The potential of probiotics in the prevention and treatment of atherosclerosis.
Mol. Nutr. Food Res. 64 : 1900797. - Moludi J, Kafil HS, Qaisar SA, Gholizadeh P, Alizadeh M, Vayghyan HJ. 2021. Effect of probiotic supplementation along with calorie restriction on metabolic endotoxemia, and inflammation markers in coronary artery disease patients: a double blind placebo controlled randomized clinical trial.
Nutr. J. 20 : 47. - Malik M, Suboc TM, Tyagi S, Salzman N, Wang J, Ying R,
et al . 2018.Lactobacillus plantarum 299v supplementation improves vascular endothelial function and reduces inflammatory biomarkers in men with stable coronary artery disease.Circ. Res. 123 : 1091-1102. - Koppinger MP, Lopez-Pier MA, Skaria R, Harris PR, Konhilas JP. 2020.
Lactobacillus reuteri attenuates cardiac injury without lowering cholesterol in low-density lipoprotein receptor-deficient mice fed standard chow.Am. J. Physiol. Heart Circ. Physiol. 319 : H32-H41. - Sun B, Ma T, Li Y, Yang N, Li B, Zhou X,
et al . 2022. Bifidobacterium lactis Probio-M8 adjuvant treatment confers added benefits to patients with coronary artery disease via target modulation of the gut-heart/-brain axes.mSystems 7 : e00100-22. - Yoshida N, Emoto T, Yamashita T, Watanabe H, Hayashi T, Tabata T,
et al . 2018.Bacteroides vulgatus and bcteroides dorei reduce gut microbial lipopolysaccharide production and inhibit atherosclerosis.Circulation 138 : 2486-2498. - O'Morain VL, Chan Y-H, Williams JO, Alotibi R, Alahmadi A, Rodrigues NP,
et al . 2021. The Lab4P consortium of probiotics attenuates atherosclerosis in LDL receptor deficient mice fed a high fat diet and causes plaque stabilization by inhibiting inflammation and several pro-atherogenic processes.Mol. Nutr. Food Res. 65 : 2100214. - Gan XT, Ettinger G, Huang CX, Burton JP, Haist JV, Rajapurohitam V,
et al . 2014. Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat.Circ. Heart Fail. 7 : 491-499. - Aboulgheit A, Karbasiafshar C, Zhang Z, Sabra M, Shi G, Tucker A,
et al . 2021.Lactobacillus plantarum probiotic induces Nrf2-mediated antioxidant signaling and eNOS expression resulting in improvement of myocardial diastolic function.Am. J. Physiol. Heart Circ. Physiol. 321 : H839-h849. - Neverovskyi A, Chernyavskyi V, Shypulin V, Hvozdetska L, Tishchenko V, Nechypurenko T,
et al . 2021. ProbioticLactobacillus plantarum may reduce cardiovascular risk: an experimental study.ARYA Atheroscler. 17 : 1-10. - Hofeld BC, Puppala VK, Tyagi S, Ahn KW, Anger A, Jia S,
et al . 2021.Lactobacillus plantarum 299v probiotic supplementation in men with stable coronary artery disease suppresses systemic inflammation.Sci. Rep. 11 : 3972. - Tarrah A, dos Santos Cruz BC, Sousa Dias R, da Silva Duarte V, Pakroo S, Licursi de Oliveira L,
et al . 2021.Lactobacillus paracasei DTA81, a cholesterol‐lowering strain having immunomodulatory activity, reveals gut microbiota regulation capability in BALB/c mice receiving high‐fat diet.J. Appl.Microbiol. 131 : 1942-1957. - Sun J, Buys N. 2015. Effects of probiotics consumption on lowering lipids and CVD risk factors: a systematic review and metaanalysis of randomized controlled trials.
Annal. Med. 47 : 430-440. - de Araújo Henriques Ferreira G, Magnani M, Cabral L, Brandão LR, Noronha MF, de Campos Cruz J,
et al . 2022. Potentially probioticLimosilactobacillus fermentum fruit-derived strains alleviate cardiometabolic disorders and gut microbiota impairment in male rats fed a high-fat diet.Probiotics Antimicrob. Proteins 14 : 349-359. - de Luna Freire MO, do Nascimento LCP, de Oliveira KÁR, de Oliveira AM, dos Santos Lima M, Napoleão TH,
et al . 2023.Limosilactobacillus fermentum strains with claimed probiotic properties exert anti-oxidant and anti-inflammatory properties and prevent cardiometabolic disorder in female rats fed a high-fat diet.Probiotics Antimicrob. Proteins 15 : 601-613. - Zafar H, Ain Nu, Alshammari A, Alghamdi S, Raja H, Ali A,
et al . 2022.Lacticaseibacillus rhamnosus FM9 andLimosilactobacillus fermentum Y57 Are as effective as statins at improving blood lipid profile in high cholesterol, high-fat diet model in male wistar rats.Nutrients 14 : 1654. - Romão da Silva LdF, de Oliveira Y, de Souza EL, de Luna Freire MO, Braga VdA, Magnani M,
et al . 2020. Effects of probiotic therapy on cardio-metabolic parameters and autonomic modulation in hypertensive women: a randomized, triple-blind, placebocontrolled trial.Food Funct. 11 : 7152-7163. - Sethi NJ, Safi S, Korang SK, Hróbjartsson A, Skoog M, Gluud C,
et al . 2017. Antibiotics for secondary prevention of coronary heart disease.Cochrane Database Syst. Rev. 7 . - Taylor-Robinson D, Boman J. 2005. The failure of antibiotics to prevent heart attacks.
BMJ. 331 : 361-362. - Ott SJ, Mokhtari NEE, Musfeldt M, Hellmig S, Freitag S, Rehman A,
et al . 2006. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease.Circulation 113 : 929-937. - Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. 1997. Elevated
Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction.Circulation 96 : 404-407. - Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP,
et al . 2005. Antibiotic treatment ofChlamydia pneumoniae after acute coronary syndrome.N. Engl. J. Med. 352 : 1646-1654. - Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD,
et al . 2005. Azithromycin for the secondary prevention of coronary events.N. Engl. J. Med. 352 : 1637-1645. - Salminen S, Collado MC, Endo A, Hill C, Lebeer S, Quigley EMM,
et al . 2021. 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. - Plovier H, Everard A, Druart C, Depommier C, Van Hul M, Geurts L,
et al . 2017. A purified membrane protein fromAkkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.Nat. Med. 23 : 107-113. - Swanson KS, Gibson GR, Hutkins R, Reimer RA, Reid G, Verbeke K,
et al . 2020. The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics.Nat. Rev. Gastroenterol. Hepatol. 17 : 687-701. - Sáez-Lara MJ, Robles-Sanchez C, Ruiz-Ojeda FJ, Plaza-Diaz J, Gil A. 2016. Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: a review of human clinical trials.
Int. J. Mol. Sci. 17 : 928. - Arabi SM, Bahrami LS, Rahnama I, Sahebkar A. 2022. Impact of synbiotic supplementation on cardiometabolic and anthropometric indices in patients with metabolic syndrome: a systematic review and meta-analysis of randomized controlled trials.
Pharmacol. Res. 176 : 106061. - Tajabadi-Ebrahimi M, Sharifi N, Farrokhian A, Raygan F, Karamali F, Razzaghi R,
et al . 2016. A Randomized controlled clinical trial investigating the effect of synbiotic administration on markers of insulin metabolism and lipid profiles in overweight type 2 diabetic patients with coronary heart disease.Exp. Clin. Endocrinol. Diabetes 125 : 21-27. - Shakeri H, Hadaegh H, Abedi F, Tajabadi-Ebrahimi M, Mazroii N, Ghandi Y,
et al . 2014. Consumption of synbiotic bread decreases triacylglycerol and VLDL levels while increasing HDL levels in serum from patients with type-2 diabetes.Lipids 49 : 695-701. - Moayyedi P, Yuan Y, Baharith H, Ford AC. 2017. Faecal microbiota transplantation for Clostridium difficile-associated diarrhoea: a systematic review of randomised controlled trials.
Med. J. Australia 207 : 166-172. - Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JFWM,
et al . 2012. Transfer of iIntestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.Gastroenterology 143 : 913-916.e7. - Smits LP, Kootte RS, Levin E, Prodan A, Fuentes S, Zoetendal EG,
et al . 2018. 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. - Hu XF, Zhang WY, Wen Q, Chen WJ, Wang ZM, Chen J,
et al . 2019. Fecal microbiota transplantation alleviates myocardial damage in myocarditis by restoring the microbiota composition.Pharmacol. Res. 139 : 412-421. - Brandsma E, Kloosterhuis NJ, Koster M, Dekker DC, Gijbels MJJ, Velden Svd,
et al . 2019. A Proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis.Circ. Res. 124 : 94-100. - Kim ES, Yoon BH, Lee SM, Choi M, Kim EH, Lee BW,
et al . 2022. Fecal microbiota transplantation ameliorates atherosclerosis in mice with C1q/TNF-related protein 9 genetic deficiency.Exper. Mol. Med. 54 : 103-114. - Wang Z, Roberts Adam B, Buffa Jennifer A, Levison Bruce S, Zhu W, Org E,
et al . 2015. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis.Cell 163 : 1585-1595. - Chen K, Zheng X, Feng M, Li D, Zhang H. 2017. Gut microbiota-dependent metabolite trimethylamine N-oxide contributes to cardiac dysfunction in western diet-induced obese mice.
Front. Physiol. 8 : 139. - Zou D, Li Y, Sun G. 2021. Attenuation of circulating trimethylamine N-oxide prevents the progression of cardiac and renal dysfunction in a rat model of chronic cardiorenal syndrome.
Front. Pharmacol. 12 : 751380. - Brunt VE, Gioscia-Ryan RA, Casso AG, VanDongen NS, Ziemba BP, Sapinsley ZJ,
et al . 2020. Trimethylamine-N-oxide promotes age-related vascular oxidative stress and endothelial dysfunction in mice and healthy humans.Hypertension 76 : 101-112. - Li T, Chen Y, Gua C, Li X. 2017. Elevated circulating trimethylamine N-oxide levels contribute to endothelial dysfunction in aged rats through vascular inflammation and oxidative stress.
Front. Physiol. 8 : 350. - Chen CY, Leu HB, Wang SC, Tsai SH, Chou RH, Lu YW,
et al . 2022. Inhibition of trimethylamine N-oxide attenuates neointimal formation through reduction of inflammasome and oxidative stress in a mouse model of carotid artery ligation.Antioxid. Redox Signal. 38 : 215-233. - Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W,
et al . 2018. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential.Nat. Med. 24 : 1407-1417. - Organ CL, Li Z, Sharp TE, Polhemus DJ, Gupta N, Goodchild TT,
et al . 2020. Nonlethal inhibition of gut microbial trimethylamine N‐oxide production improves cardiac function and remodeling in a murine model of heart failure.J. Am. Heart Assoc. 9 : e016223. - Pathak P, Helsley RN, Brown AL, Buffa JA, Choucair I, Nemet I,
et al . 2020. Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism.Am. J. Physiol. Heart Circ. Physiol. 318 : H1474-h1486. - Witkowski M, Witkowski M, Friebel J, Buffa JA, Li XS, Wang Z,
et al . 2021. Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis.Cardiovasc. Res. 118 : 2367-2384. - Zhou P, Zhao XN, Ma YY, Tang TJ, Wang SS, Wang L,
et al . 2022. Virtual screening analysis of natural flavonoids as trimethylamine (TMA)-lyase inhibitors for coronary heart disease.J. Food Biochem. 46 : e14376. - Micek A, Godos J, Del Rio D, Galvano F, Grosso G. 2021. Dietary flavonoids and cardiovascular disease: a comprehensive doseresponse meta-analysis.
Mol. Nutr. Food Res. 65 : e2001019. - Barrea L, Annunziata G, Muscogiuri G, Laudisio D, Di Somma C, Maisto M,
et al . 2019. Trimethylamine N-oxide, mediterranean diet, and nutrition in healthy, normal-weight adults: also a matter of sex?Nutrition 62 : 7-17. - Pignanelli M, Just C, Bogiatzi C, Dinculescu V, Gloor GB, Allen-Vercoe E,
et al . 2018. Mediterranean diet score: associations with metabolic products of the intestinal microbiome, carotid plaque burden, and renal function.Nutrients 10 : 779.