[ 1 ] World Health Organization. Global status report on noncommunicable diseases 2014. Geneva: WHO Press; 2014. link1

[ 2 ] National Cardiovascular Disease Center. Annual report on cardiovascular health and diseases in China 2018. Beijing: Encyclopedia of China Publishing House; 2019. link1

[ 3 ] Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 2016;164(3):337–40. link1

[ 4 ] Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464(7285):59–65. link1

[ 5 ] Goodrich J, Waters J, Poole A, Sutter J, Koren O, Blekhman R, et al. Human genetics shape the gut microbiome. Cell 2014;159(4):789–99. link1

[ 6 ] Lederberg J. Infectious history. Science 2000;288(5464):287–93. link1

[ 7 ] Shen J, Obin MS, Zhao L. The gut microbiota, obesity and insulin resistance. Mol Aspects Med 2013;34(1):39–58. link1

[ 8 ] Tang WHW, Kitai T, Hazen SL. Gut microbiota in cardiovascular health and disease. Circ Res 2017;120(7):1183–96. link1

[ 9 ] Wang Q, Luo Y, Chaudhuri KR, Reynolds R, Tan EK, Pettersson S. The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options. Brain 2021;144(9):2571–93. link1

[10] Liu S, Gao J, Zhu M, Liu K, Zhang HL. Gut microbiota and dysbiosis in Alzheimer’s disease: implications for pathogenesis and treatment. Mol Neurobiol 2020;57(12):5026–43. link1

[11] Wang Z, Zhao Y. Gut microbiota derived metabolites in cardiovascular health and disease. Protein Cell 2018;9(5):416–31. link1

[12] Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JFWM, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012;143(4):913–6.e7. link1

[13] Aguilar EC, Leonel AJ, Teixeira LG, Silva AR, Silva JF, Pelaez JMN, et al. Butyrate impairs atherogenesis by reducing plaque inflammation and vulnerability and decreasing NFjB activation. Nutr Metab Cardiovasc Dis 2014;24 (6):606–13. link1

[14] Wang L, Zhu Q, Lu A, Liu X, Zhang L, Xu C, et al. Sodium butyrate suppresses angiotensin II-induced hypertension by inhibition of renal (pro)renin receptor and intrarenal renin–angiotensin system. J Hypertens 2017;35 (9):1899–908. link1

[15] Canfora EE, Meex RCR, Venema K, Blaak EE. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat Rev Endocrinol 2019;15(5):261–73. link1

[16] Du Y, Li X, Su C, Xi M, Zhang X, Jiang Z, et al. Butyrate protects against high-fat diet-induced atherosclerosis via up-regulating ABCA1 expression in apolipoprotein E-deficiency mice. Br J Pharmacol 2020;177(8):1754–72. link1

[17] Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 2003;278 (13):11312–9. link1

[18] Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the Gprotein-coupled receptor FFAR2. Diabetes 2012;61(2):364–71. link1

[19] Pluznick J. A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes 2014;5(2):202–7. link1

[20] den Besten G, Bleeker A, Gerding A, van Eunen K, Havinga R, van Dijk TH, et al. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARc-dependent switch from lipogenesis to fat oxidation. Diabetes 2015;64 (7):2398–408. link1

[21] Li Z, Yi CX, Katiraei S, Kooijman S, Zhou E, Chung CK, et al. Butyrate reduces appetite and activates brown adipose tissue via the gut–brain neural circuit. Gut 2018;67(7):1269–79. link1

[22] Bennett B, Vallim TD, Wang Z, Shih D, Meng Y, Gregory J, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 2013;17 (1):49–60. link1

[23] Nagata C, Wada K, Tamura T, Konishi K, Kawachi T, Tsuji M, et al. Choline and betaine intakes are not associated with cardiovascular disease mortality risk in Japanese men and women. J Nutr 2015;145(8):1787–92. link1

[24] Collins HL, Drazul-Schrader D, Sulpizio AC, Koster PD, Williamson Y, Adelman SJ, et al. L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE–/– transgenic mice expressing CETP. Atherosclerosis 2016;244:29–37. link1

[25] Lindskog Jonsson A, Caesar R, Akrami R, Reinhardt C, Fåk Hållenius F, Borén J, et al. Impact of gut microbiota and diet on the development of atherosclerosis in ApoE–/– mice. Arterioscler Thromb Vasc Biol 2018;38 (10):2318–26. link1

[26] 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. link1

[27] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472(7341):57–63. link1

[28] Shan Z, Sun T, Huang H, Chen S, Chen L, Luo C, et al. Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. Am J Clin Nutr 2017;106(3):888–94. link1

[29] Seldin MM, Meng Y, Qi H, Zhu W, Wang Z, Hazen SL, et al. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogenactivated protein kinase and nuclear factor-jB. J Am Heart Assoc 2016;5(2): e002767. link1

[30] Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016;165(1):111–24. link1

[31] Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med 2017;56:54–65. link1

[32] Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, et al. Identification of a nuclear receptor for bile acids. Science 1999;284 (5418):1362–5. link1

[33] Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439(7075):484–9. link1

[34] Watanabe M, Houten SM, Wang Li, Moschetta A, Mangelsdorf DJ, Heyman RA, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004;113(10):1408–18. link1

[35] Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-bmuricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013;17 (2):225–35. link1

[36] Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med 2018;24 (12):1919–29. link1

[37] Du Y, Li X, Su C, Wang L, Jiang J, Hong B. The human gut microbiome—a new and exciting avenue in cardiovascular drug discovery. Expert Opin Drug Discov 2019;14(10):1037–52. link1

[38] Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004;10(12):1344–51. link1

[39] Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab 2008;93(7):2559–65. link1

[40] Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ, et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism 2010;59(2):285–92. link1

[41] Dong SF, Hong Y, Liu M, Hao YZ, Yu HS, Liu Y, et al. Berberine attenuates cardiac dysfunction in hyperglycemic and hypercholesterolemic rats. Eur J Pharmacol 2011;660(2–3):368–74. link1

[42] Yao J, Kong W, Jiang J. Learning from berberine: treating chronic diseases through multiple targets. Sci China Life Sci 2015;58(9):854–9. link1

[43] Zuo F, Nakamura N, Akao T, Hattori M. Pharmacokinetics of berberine and its main metabolites in conventional and pseudo germ-free rats determined by liquid chromatography/ion trap mass spectrometry. Drug Metab Dispos 2006;34(12):2064–72. link1

[44] Habtemariam S. Berberine pharmacology and the gut microbiota: a hidden therapeutic link. Pharmacol Res 2020;155:104722. link1

[45] Zhang X, Zhao Y, Zhang M, Pang X, Xu J, Kang C, et al. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS ONE 2012;7(8):e42529. link1

[46] Wang Y, Shou JW, Li XY, Zhao ZX, Fu J, He CY, et al. Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism. Metabolism 2017;70:72–84. link1

[47] Li X, Su C, Jiang Z, Yang Y, Zhang Y, Yang M, et al. Berberine attenuates cholineinduced atherosclerosis by inhibiting trimethylamine and trimethylamine-Noxide production via manipulating the gut microbiome. NPJ Biofilms Microbiomes 2021;7(1):36. link1

[48] Sun R, Yang N, Kong B, Cao B, Feng D, Yu X, et al. Orally administered berberine modulates hepatic lipid metabolism by altering microbial bile acid metabolism and the intestinal FXR signaling pathway. Mol Pharmacol 2017;91 (2):110–22. link1

[49] Feng R, Shou JW, Zhao ZX, He CY, Ma C, Huang M, et al. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci Rep 2015;5 (1):12155. link1

[50] Wang Y, Tong Q, Shou JW, Zhao ZX, Li XY, Zhang XF, et al. Gut microbiotamediated personalized treatment of hyperlipidemia using berberine. Theranostics 2017;7(9):2443–51. link1

[51] Wang Y, Tong Q, Ma SR, Zhao ZX, Pan LB, Cong L, et al. Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota. Signal Transduct Target Ther 2021;6(1):77. link1

[52] Zhao ZX, Fu J, Ma SR, Peng R, Yu JB, Cong L, et al. Gut–brain axis metabolic pathway regulates antidepressant efficacy of albiflorin. Theranostics 2018;8 (21):5945–59. link1

[53] Kong WJ, Vernieri C, Foiani M, Jiang JD. Berberine in the treatment of metabolism-related chronic diseases: a drug cloud (dCloud) effect to target multifactorial disorders. Pharmacol Ther 2020;209:107496. link1

[54] Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med 2017;23(7):850–8. link1

[55] Liu Y, Song X, Zhou H, Zhou X, Xia Y, Dong X, et al. Gut microbiome associates with lipid-lowering effect of rosuvastatin in vivo. Front Microbiol 2018;9:530. link1

[56] Pryor R, Norvaisas P, Marinos G, Best L, Thingholm LB, Quintaneiro LM, et al. Host–microbe–drug–nutrient screen identifies bacterial effectors of metformin therapy. Cell 2019;178(6):1299–312. link1

[57] Vieira-Silva S, Falony G, Belda E, Nielsen T, Aron-Wisnewsky J, Chakaroun R, et al. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis. Nature 2020;581(7808):310–5. link1