心肠对话:肠道菌群在心血管疾病中的作用
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摘要
心血管疾病(CVD)是对人类健康构成极大威胁的一类疾病,其发生、发展往往受遗传与环境的多种因素影响。肠道菌群是人体内数目最大的菌群库,影响宿主的生理代谢,近年来肠道菌群与宿主间的相互作用逐渐受到重视。肠道微生物群在人类健康和疾病中发挥着重要作用,许多研究证实了肠道菌群及其代谢产物可从血脂异常、2型糖尿病、高血压、动脉粥样硬化、心力衰竭等多个方面影响CVD。因此,以肠道菌群作为CVD治疗靶点的方案值得探索。本文将对肠道菌群在CVD发病机制中的作用及通过调节肠道菌群治疗CVD的方法进行系统综述。
Cardiovascular disease(CVD) is a kind of disease that poses a great threat to human health. Its occurrence and development are often influenced by many factors of heredity and environment. The gut bacteria are the largest population of bacteria in the human body, affecting the physiological metabolism of the host. In recent years, the interaction between intestinal flora and host has been paid more and more attention. Intestinal microflora plays an important role in human health and disease. Many studies have confirmed that intestinal flora and its metabolites can affect CVD from dyslipidemia, type 2 diabetes mellitus, hypertension, atherosclerosis, heart failure and other aspects. Therefore, it is worth exploring the scheme of using intestinal flora as the target of CVD treatment. This article will systematically review the role of gut bacteria in the pathogenesis of CVD and the methods of regulating gut bacteria to treat CVD.
Cardiovascular disease(CVD) is a kind of disease that poses a great threat to human health. Its occurrence and development are often influenced by many factors of heredity and environment. The gut bacteria are the largest population of bacteria in the human body, affecting the physiological metabolism of the host. In recent years, the interaction between intestinal flora and host has been paid more and more attention. Intestinal microflora plays an important role in human health and disease. Many studies have confirmed that intestinal flora and its metabolites can affect CVD from dyslipidemia, type 2 diabetes mellitus, hypertension, atherosclerosis, heart failure and other aspects. Therefore, it is worth exploring the scheme of using intestinal flora as the target of CVD treatment. This article will systematically review the role of gut bacteria in the pathogenesis of CVD and the methods of regulating gut bacteria to treat CVD.
引文
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[3] Fu J,Bonder MJ,Cenit MC,et al.The gut microbiome contributes to a substantial proportion of the variation in blood lipids[J].Circ Res,2015,117(9):817-824.
[4] B?ckhed F,Ding H,Wang T,et al.The gut microbiota as an environmental factor that regulates fat storage[J].Proc Natl Acad Sci USA,2004,101(44):15718-15723.
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[19] Ma J,Li H.The role of gut microbiota in atherosclerosis and hypertension[J].Front Pharmacol,2018,9:1082-1085.
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[28] Pasini E,Aquilani R,Testa R,et al.Pathogenic gut flora in patients with chronic heart failure[J].JACC Heart Fail,2016,4(3):220-227.
[29] Sandek A,Bjarnason I,Volk HD,et al.Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure[J].Int J Cardiol,2012,157(1):80-85.
[30] Tang WH,Wang Z,Fan Y,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].J Am Coll Cardiol,2014,64(18):1908-1914.
[31] Organ CL,Otsuka H,Bhushan S,et al.Choline diet and its gut microbe-derived metabolite,trimethylamine N-oxide,exacerbate pressure overload-induced heart failure[J].Circ Heart Fail,2015,9(1):e002314.
[32] Xu Z,Knight R.Dietary effects on human gut microbiome diversity[J].Br J Nutr,2015,113(Supp l):S1-S5.
[33] Voreades N,Kozil A,Weir TL.Diet and the development of the human intestinal microbiome[J].Front Microbiol,2014,5:494.
[34] Ravussin Y,Koren O,Spor A,et al.Responses of gut microbiota to diet composition and weight loss in lean and obese mice[J].Obesity (Silver Spring),2012,20(4):738-747.
[35] David LA,Maurice CF,Carmody RN,et al.Diet rapidly and reproducibly alters the human gut microbiome[J].Nature,2014,505(7484):559-563.
[36] Appel LJ,Moore TJ,Obarzanek E,et al.A clinical trial of the effects of dietary patterns on blood pressure.Dash collaborative research group[J].N Engl J Med,1997,336(16):1117-1124.
[37] Martínez-González MA,Ros E,Estruch R,et al.Primary prevention of cardiovascular disease with a mediterranean diet supplemented extra-virgin olive or nuts[J].N Engl J Med,2018,379(14):1388-1389.
[38] Zeevi D,Korem T,Zmora N,et al.Personalized nutrition by prediction of glycemic responses[J].Cell,2015,163(5):1079-1094.
[39] Foye OT,Huang IF,Chiou CC,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.
[40] Marques FZ,Nelson EM,Chu PY,et al.High fibre diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in doca-salt hypertensive mice[J].Circulation,2017,135(10):964-977.
[41] Mirmiran P,Bahadoran Z,Khalili Moghadam S,et al.A prospective study of different types of dietary fiber and risk of cardiovascular disease:tehran lipid and glucose study[J].Nutrients,2016,8(11):E686.
[42] Kim TT,Parajuli N,Sung MM,et al.Fecal transplant from resveratrol-fed donors improves glycaemia and cardiovascular features of the metabolic syndrome in mice[J].Am J Physiol Endocrinol Metab,2018,315(4):E511-E519.
[43] Vrieze A,Van Nood E,Holleman F,et al.Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome[J].Gastroenterology,2012,143(4):913-916.
[44] Caesar R.Pharmacologic and nonpharmacologic therapies for the gut microbiota in type 2 diabetes[J].Can J Diabetes,2019,43(3):224-231.
[45] Goodrich JK,Waters JL,Poole AC,et al.Human genetics shape the gut microbiome[J].Cell,2014,159(4):789-799.
[46] Simon MC,Strassburger K,Nowotny B,et al.Intake of lactobacillus reuteri improves incretin and insulin secretion in glucose-tolerant humans:A proof of concept[J].Diabetes Care,2015,38(10):1827-1834.
[47] Furusawa Y,Obata Y,Fukuda S,et al.Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells[J].Nature,2013,504(7480):446-450.
[48] Frost G,Sleeth ML,Sahuri-Arisoylu M,et al.The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism[J].Nat Commun,2014,5:3611.
[49] Cani PD,Neyrinck AM,Fava F,et al.Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia[J].Diabetologia,2007,50(11):2374-2383.
[50] Robertson MD,Bickerton AS,Dennis AL,et al.Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism[J].Am J Clin Nutr,2005,82(3):559-567.
[51] Everard A,Lazarevic V,Derrien M,et al.Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice[J].Diabetes,2011,60(11):2775-2786.
[52] Dewulf EM,Cani PD,Claus SP,et al.Insight into the prebiotic concept:Lessons from an exploratory,double blind intervention study with inulin-type fructans in obese women[J].Gut,2013,62(8):1112-1121.
[53] Galla S,Chakraborty S,Cheng X,et al.Disparate effects of antibiotics on hypertension[J].Physiol Genomics,2018,50(10):837-845.
[54] Cho I,Yamanishi S,Cox L,et al.Antibiotics in early life alter the murine colonic microbiome and adiposity[J].Nature,2012,488(7413):621-626.
[55] Trasande L,Blustein J,Liu M,et al.Infant antibiotic exposures and early-life body mass[J].Int J Obes (Lond),2013,37(1):16-23.
[2] Turnbaugh PJ,Ley RE,Mahowald MA,et al.An obesity-associated gut microbiome with increased capacity for energy harvest[J].Nature,2006,444(7122):1027-1031.
[3] Fu J,Bonder MJ,Cenit MC,et al.The gut microbiome contributes to a substantial proportion of the variation in blood lipids[J].Circ Res,2015,117(9):817-824.
[4] B?ckhed F,Ding H,Wang T,et al.The gut microbiota as an environmental factor that regulates fat storage[J].Proc Natl Acad Sci USA,2004,101(44):15718-15723.
[5] Ridlon JM,Kang DJ,Hylemon PB,et al.Bile acids and the gut microbiome[J].Curr Opin Gastroenterol,2014,30(3):332-338.
[6] Kasahara K,Tanoue T,Yamashita T,et al.Commensal bacteria at the crossroad between cholesterol homeostasis and chronic inflammation in atherosclerosis[J].J Lipid Res,2017,58(3):519-528.
[7] Li DY,Tang WHW.Gut microbiota and atherosclerosis[J].Curr Atheroscler Rep,2017,19(10):39.
[8] Qin J,Li Y,Cai Z,et al.A metagenome-wide association study of gut microbiota in type 2 diabetes[J].Nature,2012,490(7418):55-60.
[9] Karlsson FH,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.
[10] Forslund K,Hildebrand F,Nielsen T,et al.Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota[J].Nature,2015,528(7581):262-266.
[11] Richards EM,Pepine CJ,Raizada MK,et al.The gut,its microbiome,and hypertension[J].Curr Hypertens Rep,2017,19(4):36.
[12] Patterson E,Ryan PM,Cryan JF,et al.Gut microbiota,obesity and diabetes[J].Postgrad Med J,2016,92(1087):286-300.
[13] Yang T,Santisteban MM,Rodriguez V,et al.Gut dysbiosis is linked to hypertension[J].Hypertension,2015,65(6):1331-1340.
[14] Li J,Zhao F,Wang Y,et al.Gut microbiota dysbiosis contributes to the development of hypertension[J].Microbiome,2017,5(1):14.
[15] Natarajan N,Hori D,Flavahan S,et al.Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41[J].Physiol Genomics,2016,48(11):826-834.
[16] Pluznick JL.Microbial short-chain fatty acids and blood pressure regulation[J].Curr Hypertens Rep,2017,19(4):25.
[17] Ufnal M,Jazwiec R,Dadlez M,et al.Trimethylamine-N-oxide:a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats[J].Can J Cardiol,2014,30(12):1700-1705.
[18] Santisteban MM,Qi Y,Zubcevic J,et al.Hypertension-linked pathophysiological alterations in the gut[J].Circ Res,2016,120(2):312-323.
[19] Ma J,Li H.The role of gut microbiota in atherosclerosis and hypertension[J].Front Pharmacol,2018,9:1082-1085.
[20] Jie Z,Xia H,Zhong SL,et al.The gut microbiome in atherosclerotic cardiovascular disease[J].Nat Commun,2017,8(1):845.
[21] Chacon MR,Lozano-Bartolome J,Portero-Otin M,et al.The gut mycobiome composition is linked to carotid atherosclerosis[J].Benef Microbes,2018,9(2):185-198.
[22] Wang Z,Klipfell E,Bennett BJ,et al.Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease[J].Nature,2011,472(7341):57-63.
[23] Koeth RA,Wang Z,Levison BS,et al.Intestinal microbiota metabolism of L-carnitine,a nutrient in red meat,promotes atherosclerosis[J].Nat Med,2013,19(5):576-585.
[24] Ma G,Pan B,Chen Y,et al.Trimethylamine N-oxide in atherogenesis:impairing endothelial self-repair capacity and enhancing monocyte adhesion[J].Biosci Rep,2017,37(2):BSR20160244.
[25] Aguilar EC,Leonel AJ,Teixeira LG,et al.Butyrate impairs atherogenesis by reducing plaque inflammation and vulnerability and decreasing NF-κB activation[J].Nutr Metab Cardiovasc Dis,2014,24(6):606-613.
[26] Lam V,Su J,Koprowski S,et al.Intestinal microbiota determine severity of myocardial infarction in rats[J].FASEB J,2012,26(4):1727-1735.
[27] Lam V,Su J,Hsu A,et al.Intestinal microbial metabolites are linked to severity of myocardial infarction in rats[J].PLoS One,2016,11(8):e0160840.
[28] Pasini E,Aquilani R,Testa R,et al.Pathogenic gut flora in patients with chronic heart failure[J].JACC Heart Fail,2016,4(3):220-227.
[29] Sandek A,Bjarnason I,Volk HD,et al.Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure[J].Int J Cardiol,2012,157(1):80-85.
[30] Tang WH,Wang Z,Fan Y,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].J Am Coll Cardiol,2014,64(18):1908-1914.
[31] Organ CL,Otsuka H,Bhushan S,et al.Choline diet and its gut microbe-derived metabolite,trimethylamine N-oxide,exacerbate pressure overload-induced heart failure[J].Circ Heart Fail,2015,9(1):e002314.
[32] Xu Z,Knight R.Dietary effects on human gut microbiome diversity[J].Br J Nutr,2015,113(Supp l):S1-S5.
[33] Voreades N,Kozil A,Weir TL.Diet and the development of the human intestinal microbiome[J].Front Microbiol,2014,5:494.
[34] Ravussin Y,Koren O,Spor A,et al.Responses of gut microbiota to diet composition and weight loss in lean and obese mice[J].Obesity (Silver Spring),2012,20(4):738-747.
[35] David LA,Maurice CF,Carmody RN,et al.Diet rapidly and reproducibly alters the human gut microbiome[J].Nature,2014,505(7484):559-563.
[36] Appel LJ,Moore TJ,Obarzanek E,et al.A clinical trial of the effects of dietary patterns on blood pressure.Dash collaborative research group[J].N Engl J Med,1997,336(16):1117-1124.
[37] Martínez-González MA,Ros E,Estruch R,et al.Primary prevention of cardiovascular disease with a mediterranean diet supplemented extra-virgin olive or nuts[J].N Engl J Med,2018,379(14):1388-1389.
[38] Zeevi D,Korem T,Zmora N,et al.Personalized nutrition by prediction of glycemic responses[J].Cell,2015,163(5):1079-1094.
[39] Foye OT,Huang IF,Chiou CC,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.
[40] Marques FZ,Nelson EM,Chu PY,et al.High fibre diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in doca-salt hypertensive mice[J].Circulation,2017,135(10):964-977.
[41] Mirmiran P,Bahadoran Z,Khalili Moghadam S,et al.A prospective study of different types of dietary fiber and risk of cardiovascular disease:tehran lipid and glucose study[J].Nutrients,2016,8(11):E686.
[42] Kim TT,Parajuli N,Sung MM,et al.Fecal transplant from resveratrol-fed donors improves glycaemia and cardiovascular features of the metabolic syndrome in mice[J].Am J Physiol Endocrinol Metab,2018,315(4):E511-E519.
[43] Vrieze A,Van Nood E,Holleman F,et al.Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome[J].Gastroenterology,2012,143(4):913-916.
[44] Caesar R.Pharmacologic and nonpharmacologic therapies for the gut microbiota in type 2 diabetes[J].Can J Diabetes,2019,43(3):224-231.
[45] Goodrich JK,Waters JL,Poole AC,et al.Human genetics shape the gut microbiome[J].Cell,2014,159(4):789-799.
[46] Simon MC,Strassburger K,Nowotny B,et al.Intake of lactobacillus reuteri improves incretin and insulin secretion in glucose-tolerant humans:A proof of concept[J].Diabetes Care,2015,38(10):1827-1834.
[47] Furusawa Y,Obata Y,Fukuda S,et al.Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells[J].Nature,2013,504(7480):446-450.
[48] Frost G,Sleeth ML,Sahuri-Arisoylu M,et al.The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism[J].Nat Commun,2014,5:3611.
[49] Cani PD,Neyrinck AM,Fava F,et al.Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia[J].Diabetologia,2007,50(11):2374-2383.
[50] Robertson MD,Bickerton AS,Dennis AL,et al.Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism[J].Am J Clin Nutr,2005,82(3):559-567.
[51] Everard A,Lazarevic V,Derrien M,et al.Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice[J].Diabetes,2011,60(11):2775-2786.
[52] Dewulf EM,Cani PD,Claus SP,et al.Insight into the prebiotic concept:Lessons from an exploratory,double blind intervention study with inulin-type fructans in obese women[J].Gut,2013,62(8):1112-1121.
[53] Galla S,Chakraborty S,Cheng X,et al.Disparate effects of antibiotics on hypertension[J].Physiol Genomics,2018,50(10):837-845.
[54] Cho I,Yamanishi S,Cox L,et al.Antibiotics in early life alter the murine colonic microbiome and adiposity[J].Nature,2012,488(7413):621-626.
[55] Trasande L,Blustein J,Liu M,et al.Infant antibiotic exposures and early-life body mass[J].Int J Obes (Lond),2013,37(1):16-23.