Research Progress in the Effects of Gut Microbiota on Atherosclerotic Cardiovascular Diseases

doi:10.12114/j.issn.1007-9572.2019.00.256

Abstract

Abstract: The morbidity and mortality of cardiovascular disease in the world has been on the rise，among which atherosclerosis cardiovascular diseases（ACVD） is its most common type with a high morbidity，disability and mortality，but current prevention and treatment measures fail to meet clinical needs for ACVD，and new therapeutic strategies are urgently need to be explored.Intestinal flora，as an indivisible "organ" of the human body，has a great influence on the physiological activities of the host.It not only affects the metabolism，neural development，energy homeostasis and immune regulation of the host，but also plays an important role on blood pressure，plasma glucose，serum lipids and the formation of atherosclerotic plaques that are risk factors for ACVD.Therefore，effective regulation of intestinal flora could be a potentially effective method for the prevention and treatment of atherosclerotic diseases.This article reviews the possible mechanisms of intestinal flora affecting atherosclerosis and the commonly used therapeutic measures to regulate dysbacteriosis，in order to provide references for the prevention and treatment of ACVD.

Key words: Gastrointestinal tract, Probiotic, Dysbacteriosis, Atherosclerosis, Cardiovascular diseases

摘要： 心血管疾病的发病率和病死率在全球一直呈上升趋势，其中动脉粥样硬化性心血管疾病（ACVD）为最常见的一种，有较高的患病率、致残率和致死率，但目前的预防和治疗措施未能满足临床需求，亟需探索新的防治策略。肠道菌群作为机体不可分割的“器官”，对宿主的生理活动有很大影响，不仅影响宿主代谢、神经发育、体内能量平衡和免疫调节，还对血压、血糖、血脂和动脉粥样斑块形成有重要作用，这些均为ACVD发病的危险因素，因此通过对肠道菌群的有效调节来预防或治疗动脉粥样硬化可能成为一种有效手段。本文对肠道菌群影响动脉粥样硬化的可能机制及目前常用的调节菌群失调的治疗措施进行综述，旨在为ACVD的防治提供参考。

关键词: 胃肠道, 有益菌种, 菌群失调, 动脉粥样硬化, 心血管疾病

ZHAO Wenyan,CHEN Xi. Research Progress in the Effects of Gut Microbiota on Atherosclerotic Cardiovascular Diseases　[J]. Chinese General Practice, 2019, 22(27): 3292-3297. DOI: 10.12114/j.issn.1007-9572.2019.00.256.
赵文艳,陈曦. 肠道菌群对动脉粥样硬化性心血管疾病影响的研究进展[J]. 中国全科医学, 2019, 22(27): 3292-3297. DOI: 10.12114/j.issn.1007-9572.2019.00.256.

References

［1］陈伟伟，高润霖，刘力生，等．《中国心血管病报告2016》概要［J］．中国循环杂志，2017，32（6）：521-530．DOI：10.3969/j.issn.1000-3614.2017.06.001.
CHEN W W，GAO R L，LIU L S，et al．Summary of China Cardiovascular Disease Report 2016［J］．Chinese Circulation Journal，2017，32（6）：521-530．DOI：10.3969/j.issn.1000-3614.2017.06.001.
［2］WEN W，SHENG S H，LING Z K，et al．Summary of report on cardiovascular diseases in China，2012［J］．Biomed Environ Sci，2014，27（7）：552-558．DOI：10.3967/bes2014.085.
［3］Cholesterol Treatment Trialists'（CTT） Collaboration，BAIGENT C，BLACKWELL L，et al．Efficacy and safety of more intensive lowering of LDL cholesterol：a meta-analysis of data from 170?000 participants in 26 randomised trials［J］．Lancet，2010，376（9753）：1670-1681．DOI：10.1016/S0140-6736（10）61350-5.
［4］HAMER H M，DE PRETER V，WINDEY K，et al．Functional analysis of colonic bacterial metabolism：relevant to health?［J］．Am J Physiol Gastrointest Liver Physiol，2012，302（1）：G1-9．DOI：10.1152/ajpgi.00048.2011.
［5］HEUSCH G.Molecular basis of cardioprotection：signal transduction in ischemic pre-，post-，and remote conditioning［J］．Circ Res，2015，116（4）：674-699．DOI：10.1161/CIRCRESAHA.116.305348.
［6］CROSWELL A，AMIR E，TEGGATZ P，et al．Prolonged impact of antibiotics on intestinal microbial ecology and susceptibility to enteric Salmonella infection［J］．Infect Immun，2009，77（7）：2741-2753．DOI：10.1128/IAI.00006-09.
［7］GRIFFIN J L，WANG X Z，STANLEY E.Does our gut microbiome predict cardiovascular risk? A review of the evidence from metabolomics［J］．Circ Cardiovasc Genet，2015，8（1）：187-191．DOI：10.1161/CIRCGENETICS.114.000219.
［8］QIN J J，LI R Q，RAES J，et al．A human gut microbial gene catalogue established by metagenomic sequencing［J］．Nature，2010，464（7285）：59-65．DOI：10.1038/nature08821.
［9］MAZIDI M，REZAIE P，KENGNE A P，et al．Gut microbiome and metabolic syndrome［J］．Diabetes Metab Syndr Clinical Research & Reviews，2016，10（2）：S150-157．DOI：10.1016/j.dsx.2016.01.024.
［10］胡旭，王涛，王沥，等．肠道共生微生物与健康和疾病［J］．中国微生态学杂志，2012，24（12）：1134-1139．DOI：10.13381/j.cnki.cjm.2012.12.004.
HU X，WANG T，WANG L，et al．Relationship between human intestinal symbiotic microbes and health and disease［J］．Chinese Journal of Microecology，2012，24（12）：1134-1139．DOI：10.13381/j.cnki.cjm.2012.12.004.
［11］B?CKHED F，LEY R E，SONNENBURG J L，et al．Host-bacterial mutualism in the human intestine［J］．Science，2005，307（5717）：1915-1920．DOI：10.1126/science.1104816.
［12］LEPAGE P，LECLERC M C，JOOSSENS M，et al．A metagenomic insight into our gut's microbiome［J］．Gut，2013，62（1）：146-158．DOI：10.1136/gutjnl-2011-301805.
［13］AHMADMEHRABI S，TANG W H W.Gut microbiome and its role in cardiovascular diseases［J］．Current Opinion in Cardiology，2017，32（6）：761-766．DOI：10.1097/hco.0000000000000445.
［14］LIPPI G，DANESE E，MATTIUZZI C，et al．The intriguing Link between the intestinal microbiota and cardiovascular disease［J］．Semin Thromb Hemost，2017，43（6）：609-613．DOI：10.1055/s-0036-1597903.
［15］GóZD-BARSZCZEWSKA A，KOZIOI-MONTEWKA M，BARSZCZEWSKI P，et al．Gut microbiome as a biomarker of cardiometabolic disorders［J］．Ann Agric Environ Med，2017，24（3）：416-422．DOI：10.26444/aaem/75456.
［16］JIE Z Y，XIA H H，ZHONG S L，et al．The gut microbiome in atherosclerotic cardiovascular disease［J］．Nat Commun，
2017，8（1）：845．DOI：10.1038/s41467-017-00900-1.
［17］徐也鲁.动脉粥样硬化——一种慢性炎症过程［J］．中国动脉硬化杂志，2001，9（2）：93-95．DOI：10.3969/j.issn.1007-3949.2001.02.002.
XU Y L.Atherosclorosis——a chronic inflammatory process［J］．Chinese Journal of Arteriosclerosis，2001，9（2）：93-95．DOI：10.3969/j.issn.1007-3949.2001.02.002.
［18］LAM V，SU J D，HSU A，et al．Intestinal microbial metabolites are linked to severity of myocardial infarction in rats［J］．PLoS One，2016，11（8）：e0160840．DOI：10.1371/journal.pone.0160840.
［19］OHASHI R，MU H，WANG X，et al．Reverse cholesterol transport and cholesterol efflux in atherosclerosis［J］．QJM，2005，98（12）：845-856．DOI：10.1093/qjmed/hci136.
［20］LAN T H，HUANG X Q，TAN H M.Vascular fibrosis in atherosclerosis［J］．Cardiovasc Pathol，2013，22（5）：401-407．DOI：10.1016/j.carpath.2013.01.003.
［21］VAN DER WAL A C，BECKER A E.Atherosclerotic plaque rupture——pathologic basis of plaque stability and instability［J］．Cardiovasc Res，1999，41（2）：334-344.
［22］TANG W H，WANG Z N，LEVISON B S，et al．Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk［J］．N Engl J Med，2013，368（17）：1575-1584．DOI：10.1056/NEJMoa1109400.
［23］KOETH R A，WANG Z N，LEVISON B S，et al．Intestinal microbiota metabolism of L-carnitine，a nutrient in red meat，promotes atherosclerosis［J］．Nat Med，2013，19（5）：576-585．DOI：10.1038/nm.3145.
［24］SELDIN M M，MENG Y.Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB［J］．J Am Heart Assoc，2016，5（2）：pii：e002767．DOI：10.1161/JAHA.115.002767.
［25］SCHUGAR R C，BROWN J M.Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis［J］．Curr Opin Lipidol，2015，26（5）：426-431．DOI：10.1097/mol.0000000000000215.
［26］MARTINEZ -DEL C A，ROMANO K A，REY F E，et al．The plot thickens：diet microbe interactions may modulate thrombosis risk［J］．Cell Metab，2016，23（4）：573-575．DOI：10.1016/j.cmet.2016.03.017.
［27］WU G D，CHEN J，HOFFMANN C，et al．Linking long-term dietary patterns with gut microbial enterotypes［J］．Science，2011，334（6052）：105-108．DOI：10.1126/science.1208344.
［28］MENZEL T，LüHRS H，ZIRLIK S，et al．Butyrate inhibits leukocyte adhesion to endothelial cells via modulation of VCAM-1
［J］．Inflamm Bowel Dis，2004，10（2）：122-128.
［29］SEGAIN J P.Butyrate inhibits inflammatory responses through NFkappa B inhibition：implications for Crohn's disease［J］．Gut，2000，47（3）：397-403．DOI：10.1136/gut.47.3.397.
［30］CHAN Y K，BRAR M S，KIRJAVAINEN P V，et al．High fat diet induced atherosclerosis is accompanied with low colonic bacterial diversity and altered abundances that correlates with plaque size，plasma A-FABP and cholesterol：a pilot study of high fat diet and its intervention with Lactobacillus rhamnosus GG （LGG） or telmisartan in ApoE-/- mice［J］．BMC Microbiol，2016，16（1）：264．DOI：10.1186/s12866-016-0883-4.
［31］VAN NOOD E，VRIEZE A，NIEUWDORP M，et al．Duodenal infusion of donor feces for recurrent Clostridium difficile［J］．N Engl J Med，2013，368（5）：407-415．DOI：10.1056/NEJMoa1205037.
［32］KARLSSON F H，TREMAROLI V，NOOKAEW I，et al．Gut metagenome in European women with normal，impaired and diabetic glucose control［J］．Nature，2013，498（7452）：99-103．DOI：10.1038/nature12198.
［33］ZHU W F，GREGORY J C，ORG E，et al．Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk［J］．Cell，2016，165（1）：111-124．DOI：10.1016/j.cell.2016.02.011
［34］ WYMORE BRAND M，WANNEMUEHLER M J，PHILLIPS G J，et al．The altered schaedler flora：continued applications of a defined murine microbial community［J］．ILARJ，2015，56（2）：169-178．DOI：10.1093/ilar/ilv012.
［35］DUNCAN S H，LOBLEY G E，HOLTROP G，et al．Human colonic microbiota associated with diet，obesity and weight loss［J］．Int J Obes （Lond），2008，32（11）：1720-1724．DOI：10.1038/ijo.2008.155.
［36］FOYE O T，HUANG I F，CHIOU C C，et al．Early administration of probiotic Lactobacillus acidophilus and/or prebiotic inulin attenuates pathogen-mediated intestinal inflammation and Smad 7 cell signaling［J］．FEMS Immunol Med Microbiol，2012，65（3）：467-480．DOI：10.1111/j.1574-695X.2012.00978.x.
［37］MARQUES F Z，NELSON E，CHU P Y，et al．High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice［J］．Circulation，2017，135（10）：964-977．DOI：10.1161/circulationaha.116.024545.
［38］XIAO S M，FEI N，PANG X Y，et al．A gut microbiota-targeted dietary intervention for amelioration of chronic inflammation underlying metabolic syndrome［J］．FEMS Microbiol Ecol，2014，87（2）：357-367．DOI：10.1111/1574-6941.12228.
［39］TRACY S W.Something new under the sun? The Mediterranean diet and cardiovascular health［J］．N Engl J Med，2013，368（14）：1274-1276．DOI：10.1056/NEJMp1302616.
［40］LOPEZ-GARCIA E，RODRIGUEZ-ARTALEJO F，LI T Y，et al．The Mediterranean-style dietary pattern and mortality among men and women with cardiovascular disease［J］．Am J Clin Nutr，2014，99（1）：172-180．DOI：10.3945/ajcn.113.068106.
［41］KIM B，PARK K Y，JI Y，et al．Protective effects of Lactobacillus rhamnosus GG against dyslipidemia in high-fat diet-induced obese mice［J］．Biochem Biophys Res Commun，2016，473（2）：530-536．DOI：10.1016/j.bbrc.2016.03.107.
［42］HAFEZ M，HAYES K，GOLDRICK M，et al．The K5 capsule of Escherichia coli strain Nissle 1917 is important in stimulating expression of Toll-like receptor 5，CD14，MyD88，and TRIF together with the induction of interleukin-8 expression via the mitogen-activated protein kinase pathway in epithelial cells［J］．Infect Immun，2010，78（5）：2153-2162．DOI：10.1128/IAI.01406-09.
［43］CHEN Z Y，GUO L L，ZHANG Y Q，et al．Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity［J］．J Clin Invest，2014，124（8）：3391-3406．DOI：10.1172/JCI72517.
［44］SIMON M C，STRASSBURGER K，NOWOTNY B，et al．Intake of lactobacillus reuteri improves incretin and insulinsecretion in glucose-tolerant humans：a proof of concept［J］．Diabetes Care，2015，38（10）：1827-1834．DOI：10.2337/dc14-2690.
［45］SIMENHOFF M L，DUNN S R，ZOLLNER G P，et al．Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus［J］．Miner Electrolyte Metab，1996，22（1/3）：92-96．DOI：10.1016/S0026-0495（96）90211-5.
［46］KARLSSON C，AHRNE S，MOLIN G，et al．Probiotic therapy to men with incipient arteriosclerosis initiates increased bacterial diversity in colon：a randomized controlled trial［J］．Atherosclerosis，2010，208（1）：228-233．DOI：10.1016/j.atherosclerosis.2009.06.019.
［47］GIBSON G R，ROBERFROID M B.Dietary modulation of the human colonic microbiota：introducing the concept of prebiotics［J］．J Nutr，1995，125（6）：1401-1412．DOI：10.1093/jn/125.6.1401.
［48］PARNELL J A，REIMER R A.Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults［J］．Am J Clin Nutr，2009，89（6）：1751-1759．DOI：10.3945/ajcn.2009.27465.
［49］LIONG M T，DUNSHEA F R，SHAH N P.Effects of a synbiotic containing Lactobacillus acidophilus ATCC 4962 on plasma lipid profiles and morphology of erythrocytes in hypercholesterolaemic pigs on high- and low-fat diets［J］．Br J Nutr，2007，98（4）：736-744．DOI：10.1017/S0007114507747803.
［50］ATAIE-JAFARI A，LARIJANI B，ALAVI MAJD H，et al．Cholesterol-lowering effect of probiotic yogurt in comparison with ordinary yogurt in mildly to moderately hypercholesterolemic subjects［J］．Ann Nutr Metab，2009，54（1）：22-27．DOI：10.1159/000203284.
［51］WANG Z N，ROBERTS A B，BUFFA J A，et al．Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis［J］．Cell，2015，163（7）：1585-1595．DOI：10.1016/j.cell.2015.11.055.
［52］ZUNUNI VAHED S，BARZEGARI A，ZULUAGA M，et al．
Myocardial infarction and gut microbiota：an incidental connection［J］．Pharmacol Res，2018，129：308-317．DOI：10.1016/j.phrs.2017.11.008.

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