Kardiyovasküler hastalıklarda barsak mikrobiyotasının rolü

Year 2018, Volume: 75 Issue: 2, 213 - 224, 01.06.2018

Zinnet Şevval Aksoyalp Cahit Nacitarhan

Abstract

Barsak mikrobiyotası, gastrointestinal sistemde yaşayan organizmaların tamamı olarak tanımlanmaktadır. Barsak mikrobiyotası çok komplekstir ve barsak mikrobiyotasında başlıca bakteri ve arkebakteri olmak üzere virüs, mantar ve birçok ökaryotik mikroorganizma yer almaktadır. Bu organizmaların çoğu kalın barsakta yer almakta ve yaşamın sürdürülmesinde önemli fizyolojik rol oynamaktadır. Barsak mikrobiyotası dinamiktir ve beslenme alışkanlıkları, yaşam tarzı, antibiyotikler ve genetik geçmiş ile düzenlenmektedir. Barsak mikrobiyotası besinlerden çeşitli metabolitlerin üretilmesinde önemli role sahiptir. Mikrobiyota vücuda alınan besinlere göre farklı metabolitler oluşturmaktadır. Bu metabolitlerin bazıları karbon ve enerji kaynağı olarak konak tarafından kullanılmakta ve obezite, iştah ve kolonik inflamasyonun modülasyonu üzerinde faydalı etkiler göstermekte, bazıları ise olumsuz etkiler meydana getirmektedir. Mikrobiyota ile hastalık risklerinin önceden tespit edilebileceği öngörülmektedir. Yapılan çalışmalarda, barsak mikrobiyotası bileşimi gastrointestinal sistem hastalıkları, obezite, diyabet, kanser ve depresyon, otizm, anksiyete ve Parkinson hastalığı gibi hemen hemen tüm hastalıklarla ilişkilendirilmiştir. Barsak mikrobiyotasının; barsak immunitesi ve barsak motilitesinin düzenlenmesi, besinlerin sindirilmesi, enerji üretimi, intestinal bariyerin ve barsak vasküler sistemin düzenlenmesi gibi barsakla ilgili etkileri iyi bilinmektedir fakat ekstra intestinal etkileri hakkındaki kesin bilgiler henüz sınırlıdır. Mikrobiyota ve metabolitlerin pek çok sistem üzerine ekstra intestinal etkileri araştırılıyorken özellikle kardiyovasküler sistem üzerine etkileri dikkat çekmektedir. Örneğin en sık görülen kardiyovasküler hastalıklardan kalp krizi, inme ve periferal damar hastalıkları gibi çoğunlukla tromboemboliye ikincil gelişen hastalıklarda barsak mikrobiyotasının rolü olduğu düşünülmektedir. Kardiyovasküler hastalıklarda barsak mikrobiyotasının rolü hakkında en ilginç kanıtlar, kardiyovasküler risk ile ilişkili yeni metabolitlerin ve yolakların tanımlanması ve plazma örneklerinin metabolik analizleri sonucu elde edilmesidir. Ancak bu hastalıklarda mikrobiyotanın oluşturduğu etkinin mekanizmaları hala net olarak anlaşılmış değildir. Dünya Sağlık Örgütü’ne göre batı ülkelerinde meydana gelen ölümlerin ana nedenlerinden biri kardiyovasküler hastalıklardır ve her yıl 20 milyon ölüm kardiyovasküler hastalıklardan meydana gelmektedir. Bu kadar fazla ölümün görüldüğü kardiyovasküler hastalıklarda, mikrobiyotanın rolünün gösterilmesi bu tür yaygın hastalıkların tedavisinde güncel tedavi yaklaşımlarından farklı, umut verici, yeni tedavi seçenekleri sağlayabilir. Bu nedenle, kardiyovasküler hastalıklarda terapötik strateji olarak barsak mikrobiyotasının düzenlenmesi üzerine ilgi giderek artmaktadır. Bu derlemede, barsak mikrobiyotası ile kardiyovasküler hastalıkların ilişkisi üzerine yapılmış son çalışmalara ve bu hastalıkları kontrol etmek için barsak mikrobiyotasını düzenleyecek olası yollara odaklanılmıştır

Keywords

gastrointestinal mikrobiyom, kalp ve damar hastalıkları, ateroskleroz, inflamasyon, probiyotikler, prebiyotikler, kısa zincirli yağ asitleri, kolin

The role of gut microbiota in cardiovascular diseases

Abstract

The gut microbiota is defined as the all of the organism living in the gastrointestinal tract. The gut microbiota is very complex, and contains mainly bacteria and archebacteria, viruses, fungi and many eukaryotic microorganisms. Many of these organisms located in the large intestine and plays an important physiological role in the maintaining of life. Gut microbiota is dynamic and is regulated by dietary habits, lifestyle, antibiotics and genetic background. The gut microbiota has an important role in the production of various metabolites from nutrients. Microbiota produces different metabolites according to the nutrients. Some of these metabolites are used by the host as a source of carbon and energy and have beneficial effects on the modulation of obesity, appetite and colonic inflammation, while others cause adverse effects. It is predicted that disease risks can be estimated with microbiota. Gut microbiota was associated with almost all diseases such as gastrointestinal tract diseases, obesity, diabetes, cancer and depression, autism, anxiety and Parkinson’s disease. Intestine-related effects of gut microbiota such as intestine immunity and intestinal motility regulation, digestion of nutrients, energy production, intestinal barrier and regulation of the intestinal vascular system are well known, but exact information about extra intestinal effects is still limited. While microbiota and its metabolites are being investigated for extra intestinal effects on many systems, the effects on the cardiovascular system are noteworthy. For example, it is thought that gut microbiota plays a role in diseases that are secondary to thromboembolism such as heart attack, stroke and peripheral vascular diseases. The most interesting evidence about the role of gut microbiota in cardiovascular diseases is the identification of new metabolites and pathways associated with cardiovascular risk and the metabolic analysis of plasma samples. However, the mechanism of action of microbiota in these diseases is still unclear. According to the World Health Organization, cardiovascular diseases are one of the main cause of deaths in Western countries. Every year, 20 million deaths occur in cardiovascular diseases. The demonstration of the role of microbiotia in cardiovascular diseases where mortalite is high may provide new, promising, and different treatment options than current treatment approaches. Therefore, interest in regulation of gut microbiota as a therapeutic strategy in cardiovascular diseases is increasing. This review focuses on recent studies on the relationship between gut microbiota and cardiovascular disease and possible ways to regulate gut microbiota to control of these diseases.

Keywords

gastrointestinal microbiome, cardiovascular diseases, atherosclerosis, inflammation, probiotics, prebiotics, volatile fatty acids, choline

References

• Miele L, Giorgio V, Alberelli MA, De Candia E, Gasbarrini A, Grieco A. Impact of gut microbiota on obesity, diabetes, and cardiovascular disease risk. Curr Cardiol Rep, 2015; 17(12): 120.
• Baothman OA, Zamzami MA, Taher I, Abubaker J, Abu-FarhaM. The role of gut microbiota in the development of obesity and diabetes. Lipids Health Dis, 2016; 15: 108.
• Tlaskalová-Hogenová H, Stěpánková R, Kozáková H, Hudcovic T, Vannucci L, Tučková L, et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell Mol Immunol, 2011; 8(2):110-20.
• Ji B, Nielsen J. From next-generation sequencing to systematic modeling of the gut microbiome. Front Genet, 2015; 6: 219.
• Makino H, Kushiro A, Ishikawa E, Kubota H, Gawad A, Sakai T, et al. Mother-to-infant transmission of intestinal bifidobacterial strains has an impact on the early development of vaginally delivered infant’s microbiota. PLoS One, 2013; 8(11): e78331.
• Shin NR, Whon TW, Bae JW. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol, 2015; 33(9): 496-503. 7.Munyaka PM, Khafipour of establishment of gutmicrobiota and subsequent health implications. Front Pediatr, 2014; 2: 109. childhood early
• Patterson E, Ryan PM, Cryan JF, Dinan TG, Ross RP, Fitzgerald GF, et al. Gut microbiota, obesity and diabetes. Postgrad Med J, 2016; 92(1087): 286-300.
• Pacheco AR, Sperandio V. Enteric pathogens exploit the microbiota-generated nutritional environment of the gut. Microbiol Spectr, 2015; 3(3): doi: 10.1128/microbiolspec.MBP-0001- 2014.
• Marietta E, Rishi A, Taneja V. Immunogenetic control of the intestinal microbiota. Immunology, 2015; 145(3): 313-22.
• Zhang M, Chekan JR, Dodd D, Hong PY, Radlinski L, Revindran V, et al. Xylan utilization in human gut commensal bacteria is orchestrated by unique modular organization of polysaccharide degrading enzymes. Proc Natl Acad Sci U S A, 2014; 111(35): E3708-17.
• Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells. Gastroenterology, 2013; 145(2): 396-406 e1-10.
• Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short chain fatty acid receptor GPR43. Nat Commun, 2013; 4: 1829.
• Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I. Dietary gut microbial metabolites, short-chain fatty acids, and hostmetabolic regulation. Nutrients, 2015; 7(4): 2839-49. Li T, Chiang JY. Bile acids as metabolic egulators. Curr Opin Gastroenterol, 2015. 31(2): 159-65.
• Balmer ML, Slack E, de Gottardi A, Lawson MA, Hapfelmeier S, Miele L, et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci Transl Med, 2014; 6(237): 237ra66.
• Thuny F, Richet H, Casalta JP, Angelakis E, Habib G, Raoult D. Vancomycin treatment of infective endocarditis is linked with recently acquired obesity. PLoS One, 2010; 5(2): e9074.
• Saari A, Virta LJ, Sankilampi U, Dunkel L, Saxen H. Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life. Pediatrics, 2015; 135(4): 617-26.
• Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest, 2014; 124(10): 4212-8.
• Jones ML, Martoni CJ, Prakash S. Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial. Eur J Clin Nutr, 2012; 66(11): 1234-41.
• Gibson GR, Probert HM, Loo JV, Rastall RA, Roberfroid MB. Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev, 2004; 17(2): 259-75.
• Rabiei S, Shakerhosseini R, Saadat N. The effects of symbiotic therapy on anthropometric measures, body composition and blood pressure in patient with metabolic syndrome: a triple blind RCT. Med J Islam Repub Iran, 2015; 29: 213.
• Wu GD, Bushmanc FD, Lewis JD. Diet, the human gut microbiota, and IBD. Anaerobe, 2013; 24: 117-20.
• Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI.T he effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med, 2009; 1(6): p. 6ra14.
• De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A, 2010; 107 (33): 14691-6.
• Karlsson FH, Fåk F, Nookaew I, Tremaroli V, Fagerberg B, Petranovic D, et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun, 2012; 3: 1245.
• Andraws R, Berger JS, Brown DL. Effects of antibiotic therapy on outcomes of patients with coronary artery disease: a meta-analysis of randomized controlled trials. JAMA, 2005; 293(21): 2641-7.
• Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med, 2005; 352(16): 1637-45.
• Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A, 2006; 103(33): 12511-6.
• Wang Z, Tang WH, Buffa JA, Fu X, Britt EB, Koeth RA, et al. Prognostic value of choline and betaine depends on intestinal microbiotagenerated metabolite trimethylamine-N-oxide. Eur Heart J, 2014; 35(14): 904-10.
• Tang WH, Wang Z, Fan Y, Levison B, Hazen JE, Donahue LM, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol, 2014; 64(18): 1908-14.
• Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med, 2013; 368(17): 1575-84.
• Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med, 2013; 19(5): 576-85.
• Singh V, Chassaing B, Zhang L, San Yeoh B, Xiao X, Kumar M, et al. Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5- Deficient Mice. Cell Metab, 2015; 22(6): 983-96.
• Organ CL, Otsuka H, Bhushan S, Wang Z, Bradley J, Trivedi R, et al. Choline diet and its gut microbe-derived metabolite, trimethylamine n-oxide, exacerbate pressure overload-induced heart failure. Circ Heart Fail, 2016; 9(1):e002314.
• Suzuki T, Heaney LM, Bhandari SS, Jones DJ, Ng LL. Trimethylamine N-oxide and prognosis in acute heart failure. Heart, 2016; 102(11): 841-8.
• Sandek A, Bauditz J, Swidsinski A, Buhner S, Weber-Eibel J, von Haehling S, et al. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol, 2007; 50(16): 1561-9.
• Tang WW, Hazen SL. Dietary metabolism, gut microbiota and acute heart failure. Heart, 2016; 102(11): 813-4.
• Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, et al. Non-lethal inhibition of gut microbial trimethylamine production for the - treatment of atherosclerosis. Cell, 2015; 163(7): 1585-95.
• Kuka J, Liepinsh E, Makrecka-Kuka M, Liepins J, Cirule H, Gustina D, et al. Suppression of intestinal microbiota-dependent production of proatherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. Life Sci, 2014; 117(2): 84-92.
• Brugère JF, Borrel G, Gaci N, Tottey W, O’Toole PW, proposed therapeutic use of archaea to prevent trimethylaminuria and cardiovascular disease.
• Trasande L, Blustein J, Liu M, Corwin E, Cox LM, Blaser MJ. Infant antibiotic exposures and early life body mass. Int J Obes (Lond), 2013; 37(1): 16-23.
• Stepankova R, Tonar Z, Bartova J, Nedorost L, Rossman P, Poledne R, et al. Absence of microbiota (germ-free conditions) accelerates the atherosclerosis in ApoE-deficient mice fed standard low cholesterol diet. J Atheroscler Thromb, 2010; 17(8): 796-804.
• Singh V, Yeoh BS, Vijay-Kumar M. Gut microbiome as a novel cardiovascular therapeutic target. Curr Opin Pharmacol, 2016; 27: 8-12.
• Alang N, Kelly CR. Weight gain after fecal microbiota transplantation. Open Forum Infect Dis, 2015; 2(1): ofv004.