CC BY
5ROL MICROBIOME IN CARDIOVASCULAR DISEASE
Sohibnazarova Kh.A., Reyimbergenova Z.A., Gulomov J.I., Abdunabiev A.M.
Urmonalieva Sh.U., Abduvohidova Y.O, Ermatova H.Y., Abrorkhujaev A.A., Dalimova D.A.
https://doi.org/10.5281/zenodo.8354266
Abstract. According to the results of the latest research in the world, the intestinal microbiome has a direct and indirect effect on human health. For example, inflammatory bowel diseases are involved in diseases such as type 2 diabetes, hypertension, cirrhosis of the liver, obesity, and rheumatoid arthritis. Year after year, ongoing research on the impact of the gut microbiome on various diseases, new discoveries and new research is required. The purpose of the analytical article is to determine the interrelationship between the intestinal microbiome and their metabolites and its importance in cardiovascular diseases.
Such knowledge will serve to pave the way for the development offurther diagnostics and therapeutics for the prevention and treatment of cardiovascular diseases.
Keywords: Microbiome, cardiovascular diseases, gut microbiota, Trimethylamine, trimethylamine-N-oxide, short chain fatty acids
Introduction
Cardiovascular diseases in Uzbekistan rank 2nd in the world ranking, including the first cause of death in Central Asia (CA) [11], and with a high incidence in the world, it is of particular importance due to this reason affecting it. Determining the relationship between intestinal microbiome and their metabolites allows early diagnosis and prevention of the disease. The human gastrointestinal tract contains several hundred trillion bacteria [1]. Including Bifidobacteria, lactobacilli, Escherichia coli, enterococci, Clostridium perfringens and Pseudomonas are colonised and permanently affected [12]. Evidence from ongoing studies suggests that the gut microbiome is involved in the pathogenesis of extra-intestinal diseases, such as obesity and allergic diseases [2] skin diseases[4,31] colorectal cancer[3] and other metabolic diseases, inflammatory bowel disease and nonalcoholic steatohepatitis and others [5,6].
Recent research and multi-omic approaches have dramatically expanded our knowledge of the microbiota. Surprisingly, cardiovascular disease (CVD) is a disease with this association [7]. The World Health Organization (WHO) stated that CVDs caused 17.7 million deaths in 2012 [8], with a high incidence and mortality rate in Uzbekistan. In 2012, its share was 61.6% [9]. The participation of the intestinal microbiome in the origin of cardiovascular diseases is largely dependent on the metabolites produced by microorganisms. Furthermore, the gut microbiota (GM) functions like an endocrine organ that produces bioactive metabolites, including trimethylamine/trimethylamine N-oxide and short-chain fatty acids which are also involved in host health and disease via numerous pathways[13].
Trimethylamine-N-oxide and CVD
Trimethylamine (TMA) is a metabolite derived from specific nutrients such as choline and L-carnitine dependent on gut microbes and converted to trimethylamine-N-oxide (TMAO) in the liver [10] (Figure-1). The conversion of choline and carnitine to TMAO depends on the balance and diversity of the gut microbiota (Figure-2).
Figure-1 Formation of trimethylamine (TMA) to trimethylamine-N-oxide (TMAO).
The homeostasis of the gut microbiota is essential for maintaining human health [15, 16]. Intestinal changes such as intestinal dysbiosis can directly lead to high plasma TMAO levels and ultimately lead to the development of various diseases and cardiovascular diseases [14]. Firmicutes and Bacteroides were found to be much higher in such development [17]. Proteobacteria including the genera Chryseomonas and Helicobacter are higher in patients with ACVD compared to healthy adults [18]. The correlation between Streptococcus spp. and Bacteroides spp. observed only in patients with CAD[27]. On the other hand, the positive correlation between Bacteroides spp. and Erysipelotrichaceae bacteria were observed only in healthy individuals (Table-1).
Table-1 TMA production bacteria
Phyla Species TMA production
Firmicutes Anaerococcus hydrogenalis + [24],[29]
Clostridium asparagiforme + [24],[30]
Clostridium hathewayi +
Clostridium sporogenes +
Clostridium asparagiforme +
Proteobacteria Edwardsiella tarda + [23]
Escherichia fergusonii + [29]
Proteus penneri + [23]
Providencia rettger + [28]
Proteobacteria phyla + [23]
Figure-2 Interaction between gut microbiome and cardiovascular disease An example of a bacterium with beneficial effects on atherosclerosis is Akkermansia muciniphila, which is part of the normal microbiota and is important in protecting the intestinal
barrier in diet-induced obesity [20]. Probiotic Lactobacillus has been proven helpful in controlling blood pressure by reducing vascular inflammation and protecting endothelial function [21,22].
Elevated blood TMAO levels are directly associated with poor outcomes in patients with CVD, such as coronary artery disease and acute and chronic heart failure [11,16]. In addition, higher TMAO levels were observed in patients with stable heart failure compared to healthy individuals [11]. This result suggests that the gut microbiome may play a role in the development and progression of heart failure.
Because different gut microbial compositions produce different levels of TMAO [18], elevated blood TMAO levels and increased risk of cardiovascular disease may be associated with a TMA-producing microbiome containing TMA lyases. These results support the idea that cardiovascular disease prevention may be mediated by gut microbial modulation. However, the area under the receiver operating characteristic curve based on TMA lyases was insufficient to predict CAD (area under the curve = 0.63). In addition, recent clinical studies have shown that fish consumption increases circulating TMAO levels, highlighting serious limitations in our current understanding of the relationship between our diet and gut microbial TMAO production [18]. In addition, all existing clinical studies are cross-sectional studies or cohort studies rather than interventional studies. To determine whether TMAO directly contributes to the development of cardiovascular disease or reflects the presence of harmful colonic microbial metabolism, dietary habits, or renal tubular dysfunction additional research is required. In addition, the prevalence of TMAO levels in the general population is unknown and standard reference values are not currently available [19].
A recent metagenomic-wide association study characterised the microbial community of coronary artery disease (CAD) patients and showed that TMA-producing gut microbial enzymes were enriched in CAD patients compared with healthy controls.
SCFA and their relationship to CVD
Short-chain fatty acids (SCFAs), produced by colonic bacterial fermentation of dietary fiber, play an important role in making up a significant part of the human daily cardiac energy requirement [21], as well as in regulating the immunity of the intestinal tract. SCFAs produced by gut bacteria, especially butyrate and propionate, are important in regulatory T cell differentiation and immune system function. SCFA end products (including acetate, propionate, and butyrate) interact with CVD by maintaining intestinal integrity, anti-inflammatory, glycolipid metabolism, blood pressure, and activation of the gut-brain axis. The molar ratio of acetate, propionate, and butyrate in the colon is approximately 60:20:20, respectively.
Fatty acids as the main energy source for the adult heart can be divided into three types, including short-chain fatty acids (SCFAs, <6 carbons), medium-chain fatty acids (MCFAs, 6-12 carbons) and long. -chain fatty acids (LCFAs, >12 carbons). [33] LCFA is involved in P-oxidation in cardiac energy metabolism. MCFAs are also considered a metabolic therapy in heart disease[32] SCFAs, with chain lengths of one to six carbon atoms, are mainly derived from the fermentation of dietary fiber in the large intestine. Total SCFA concentrations can reach 50-150 mM in the colon [34]. Recently, it has been shown that SCFAs may also play an important role in cardiac energy metabolism.
In addition, SCFAs have the ability to modulate CVD risk factors, including lowering blood pressure and regulating glucose and lipid homeostasis [ 35 ]. Lactobacillusfermentum 296 strain in mice was found to increase microbiological production of propionic acid in colonic
reactors, as well as reduce harmful LDL and increase HDL levels in a mouse model [36]. As a result, the ability to improve altered cardiovascular and biochemical parameters in cardiometabolic diseases was determined[37].
CONCLUSION
In summary, recent evidence regarding a potential interaction between the gut microbiome and cardiovascular disease is intriguing. As our awareness of the relationship between the gut microbiome and cardiovascular disease increases, we have high hopes for the clinical application of gut microbiome modulation. Further research aimed at a more precise and mechanistic understanding of TMAO formation and mechanism by the gut microbiome in the pathogenesis of CVD will allow the development of new diagnostic and therapeutic strategies for cardiovascular diseases. In addition, all existing clinical studies are cross-sectional studies or cohort studies rather than interventional studies. To determine whether TMAO directly contributes to the development of cardiovascular disease or reflects the presence of harmful colonic microbial metabolism, dietary habits, or renal tubular dysfunction additional research is required. In addition, the prevalence of TMAO levels in the general population is unknown and standard reference values are not currently available [19]. Although various metabolites produced by probiotics have been implicated in various causes and immunomodulatory effects of ACVD, researchers believe that the mechanisms of action of probiotic metabolites still need further study. The use of probiotic microorganisms for the prevention and treatment of intestinal dysbiosis leading to increased SCFAs in the colon appears to be an important area for further research.
Thus, a complete understanding of the autochthonous component of the intestinal microbiota is expected to provide important information not only for the development of therapeutic methods for various diseases of the gastrointestinal tract, but also for how to select the next generation of probiotic bacteria as part of new functional food products. However, it is unclear whether changes in the gut microbiome contribute to or cause the development of CVD.
REFERENCES
1. Marco Ventura, Francesca Turroni, Carlos Canchaya, Elaine E. Vaughan, Paul W. O'Toole, Douwe van Sinderen. Microbial diversity in the human intestine and novel insights from metagenomics. Front. Biosci. (Landmark Ed) 2009, 14(9), 3214-3221. https://doi.org/10.2741/3445
2. Ipci, K., Altintoprak, N., Muluk, N.B. et al. The possible mechanisms of the human microbiome in allergic diseases. Eur Arch Otorhinolaryngol 274, 617-626 (2017). https://doi.org/10.1007/s00405-016-4058-6
3. Mingyang Song, Andrew T. Chan, Jun Sun, Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer, Gastroenterology, Volume 158, Issue 2, 2020, Pages 322-340, ISSN 0016-5085, https://doi.org/10.1053/j.gastro.2019.06.048.
4. Daniel K. Hsu, Maxwell A. Fung, Hung-Lin Chen,Role of skin and gut microbiota in the pathogenesis of psoriasis, an inflammatory skin disease,Medicine in Microecology,Volume 4, 2020, 100016, ISSN 2590-0978, https://doi.org/10.1016/j.medmic.2020.100016.
5. Zhao, L. The gut microbiota and obesity: From correlation to causality. Nat. Rev. Microbiol. 2013, 11, 639-647.
6. Gevers, D.; Kugathasan, S.; Denson, L.A.; Vâzquez-Baeza, Y.; Van Treuren, W.; Ren, B.; Schwager, E.; Knights, D.; Song, S.J.; Yassour, M.; et al. The treatment-naïve microbiome in new-onset Crohn's disease. Cell Host Microbe 2014, 15, 382-392.
7. Tang, W.H.W.; Kitai, T.; Hazen, S.L. Gut Microbiota in Cardiovascular Health and Disease. Circ. Res. 2017,120, 1183-1196.
8. Global status report on noncommunicable diseases 2014. Global status report on noncommunicable diseases 2014 (who.int)
9. Aringazina A, Kuandikov T, Arkhipov V. Burden of the Cardiovascular Diseases in Central Asia. Cent Asian J Glob Health. 2018 Aug 8;7(1):321. doi: 10.5195/cajgh.2018.321. PMID: 30863664; PMCID: PMC6393056.
10. He, S., Jiang, H., Zhuo, C. et al. Trimethylamine/Trimethylamine-N-Oxide as a Key Between Diet and Cardiovascular Diseases. Cardiovasc Toxicol 21, 593-604 (2021). https://doi.org/10.1007/s12012-021-09656-z
11. Aringazina A, Kuandikov T, Arkhipov V. Burden of the Cardiovascular Diseases in Central Asia. Cent Asian J Glob Health. 2018 Aug 8;7(1):321. doi: 10.5195/cajgh.2018.321. PMID: 30863664; PMCID: PMC6393056.
12. Zhou, B., Yuan, Y., Zhang, S., Guo, C., Li, X., Li, G., ... Zeng, Z. (2020). Intestinal Flora and Disease Mutually Shape the Regional Immune System in the Intestinal Tract. Frontiers in Immunology, 11. doi:10.3389/fimmu.2020.00575
13. Xu H, Wang X, Feng W, Liu Q, Zhou S, Liu Q, Cai L. The gut microbiota and its interactions with cardiovascular disease. Microb Biotechnol. 2020 May;13(3):637-656. doi: 10.1111/1751-7915.13524. Epub 2020 Jan 26. PMID: 31984651; PMCID: PMC7111081.
14. Chhibber-Goel J., Singhal V., Parakh N., Bhargava B., Sharma A. The metabolite trimethylamine-N-oxide is an emergent biomarker of human health. Current Medicinal Chemistry. 2017;24(36):3942-3953. doi: 10.2174/0929867323666160830104025. [PubMed] [CrossRef] [Google Scholar]
15. Kamo T., Akazawa H., Suda W., et al. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PLoS One. 2017; 12(3, article e0174099) doi: 10.1371/journal.pone.0174099.
16. Tang W. H., Kitai T., Hazen S. L. Gut microbiota in cardiovascular health and disease. Circulation Research. 2017;120(7):1183-1196. doi: 10.1161/CIRCRESAHA.117.309715. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
17. Liu Z., Li J., Liu H., et al. The intestinal microbiota associated with cardiac valve calcification differs from that of coronary artery disease. Atherosclerosis. 2019;284:121-128. doi: 10.1016/j.atherosclerosis.2018.11.038.
18. Jie Z., Xia H., Zhong S. L., et al. The gut microbiome in atherosclerotic cardiovascular disease. Nature Communications. 2017;8(1, article 845) doi: 10.1038/s41467-017-00900-1.
19. Karlsson F. H., Fâk F., Nookaew I., et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nature Communications. 2012;3(1, article 1245) doi: 10.1038/ncomms2266.
20. Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl Acad. Sci. USA 110, 9066-9071 (2013).
21. Robles-Vera, M. Toral, M. Romero, R. Jimenez, M. Sanchez, F. Perez-Vizcaino, et al., Antihypertensive effects of probiotics, Curr. Hypertens. Rep. 19 (2017) 26
22. Y.K. Chan, H. El-Nezami, Y. Chen, K. Kinnunen, P.V. Kirjavainen, Probiotic mixture VSL#3 reduce high fat diet induced vascular inflammation and atherosclerosis in ApoE(-/-) mice, AMB Express 6 (2016) 61.
23. Oellgaard J, Winther SA, Hansen TS, Rossing P, von Scholten BJ. Trimethylamine N-oxide (TMAO) as a New Potential Therapeutic Target for Insulin Resistance and Cancer. Curr Pharm Des. 2017;23(25):3699-3712. doi: 10.2174/1381612823666170622095324. PMID: 28641532.
24. Romano KA, Vivas EI, Amador-Noguez D, Rey FE. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio. 2015 Mar 17;6(2):e02481. doi: 10.1128/mBio.02481-14. PMID: 25784704; PMCID: PMC4453578.
25. Hue T, Nowinski A, Drapala A, Konopelski P, Ufnal M. Indole and indoxyl sulfate, gut bacteria metabolites of tryptophan, change arterial blood pressure via peripheral and central mechanisms in rats. Pharmacol Res. 2018 Apr;130:172-179. doi: 10.1016/j.phrs.2017.12.025.
26. Yingdong Lu, Yang Zhang,Xin Zhao, Chang Shang, Mi Xiang, Li Li, Xiangning Cui. Microbiota-derived short-chain fatty acids: Implications for cardiovascular and metabolic disease Front. Cardiovasc. Med., 11 August 2022 Sec. General Cardiovascular Medicine Volume 9 - 2022 | https://doi.org/10.3389/fcvm.2022.900381
27. Naofumi Y,Tomoya Y,Ken-ichi H Gut Microbiome and Cardiovascular Diseases. Diseases 6(3):56 June 2018 D0I:10.3390/diseases6030056
28. Kalnins G., Sevostjanovs E., Hartmane D., Grinberga S., Tars K. CntA oxygenase substrate profile comparison and oxygen dependency of TMA production in Providencia rettgeri. J. Basic Microbiol. 2018;58(1):52-59.
29. Lu, M.; Yang, Y.; Xu, Y.; Wang, X.; Li, B.; Le, G.; Xie, Y. Dietary Methionine Restriction Alleviates Choline-Induced Tri-Methylamine-N-Oxide (TMAO) Elevation by Manipulating Gut Microbiota in Mice. Nutrients 2023, 15, 206. https://doi.org/10.3390/nu15010206
30. Cai, YY., Huang, FQ., Lao, X. et al. Integrated metagenomics identifies a crucial role for trimethylamine-producing Lachnoclostridium in promoting atherosclerosis. npj Biofilms Microbiomes 8, 11 (2022). https://doi.org/10.1038/s41522-022-00273-4
31. Sohibnazarova Kh.A, Muminov M. I,Miralimova Sh M Anti-staphylococcal and anti-pseudomonas activity of lactobacillusplantarum mal Black Sea scientific journal of academic research. Vol 55, p 43-49, 2020
32. Nisha Panth, Cintia B. Dias, Katie Wynne, Harjinder Singh, Manohar L. Garg, Medium-chain fatty acids lower postprandial lipemia: A randomized crossover trial,Clinical Nutriti on,Volum e 39, Issue 1,2020,Pages 90-96,ISSN 0261-5614,https://doi.org/10.1016/j.clnu.2019.02.008.
33. Jeske H. J. Hageman; Jaap Keijer; Trine Kastrup Dalsgaard; Lara W. Zeper; Frédéric Carrière; Anouk L. Feitsma; Arie G. Nieuwenhuizen Free fatty acid release from vegetable and bovine milk fat-based infant formulas and human milk during two-phase in vitro digestion Food & Function2019 | Journal articleDOI: 10.1039/C8FQ01940A
34. Martin-Gallausiaux C, Marinelli L, Blottière HM, Larraufie P, Lapaque N. SCFA: mechanisms and functional importance in the gut. Proc Nutr Soc. 2021 Feb;80(1):37-49. doi: 10.1017/S0029665120006916. Epub 2020 Apr 2. PMID: 32238208.
35. Edwards, C.A.; Havlik, J.; Cong, W.; Mullen, W.; Preston, T.; Morrison, D.J.; Combet, E. Polyphenols and health: Interactions between fibre, plant polyphenols and the gut microbiota. Nutr. Bull. 2017, 42, 356-360.
36. Ichim, T.E.; Patel, A.N.; Shafer, K.A. Experimental support for the effects of a probiotic/digestive enzyme suplement on serum cholesterol concentrations and the intestinal microbiome. J. Transl. Med. 2016, 14, 1-9
37. Cavalcante, R.G.S.; de Albuquerque, T.M.R.; de Luna Freire, M.O.; Ferreira, G.A.H.; Carneiro dos Santos, L.A.; Magnani, M.; Cruz, J.C.; Braga, V.A.; de Souza, E.L.; de Brito Alves, J.L. The probiotic Lactobacillus fermentum 296 attenuates cardiometabolic disorders in high fat diet-treated rats. Nutr. Metab. Cardiovasc. Dis. 2019, 29, 1408-1417. [Google Scholar! rCrossRef] [PubMed!
