Berberine treatment increases Akkermansia in the gut and improves high-fat diet-induced atherosclerosis in Apoe−/− mice


      • Berberine markedly increases Akkermansia spp. abundance in HFD-fed Apoe−/− mice.
      • Berberine decreases HFD-induced inflammation and restores the gut barrier integrity.
      • Modulation of the gut microbiota may contribute to the antiatherosclerotic effect of berberine.


      Background and aims

      Gut microbiota plays a major role in metabolic disorders. Berberine is used to treat obesity, diabetes and atherosclerosis. The mechanism underlying the role of berberine in modulating metabolic disorders is not fully clear because berberine has poor oral bioavailability. Thus, we evaluated whether the antiatherosclerotic effect of berberine is related to alterations in gut microbial structure and if so, whether specific bacterial taxa contribute to the beneficial effects of berberine.


      Apoe−/− mice were fed either a normal-chow diet or a high-fat diet (HFD). Berberine was administered to mice in drinking water (0.5 g/L) for 14 weeks. Gut microbiota profiles were established by high throughput sequencing of the V3–V4 region of the bacterial 16S ribosomal RNA gene. The effects of berberine on metabolic endotoxemia, tissue inflammation and gut barrier integrity were also investigated.


      Berberine treatment significantly reduced atherosclerosis in HFD-fed mice. Akkermansia spp. abundance was markedly increased in HFD-fed mice treated with berberine. Moreover, berberine decreased HFD-induced metabolic endotoxemia and lowered arterial and intestinal expression of proinflammatory cytokines and chemokines. Berberine treatment increased intestinal expression of tight junction proteins and the thickness of the colonic mucus layer, which are related to restoration of gut barrier integrity in HFD-fed mice.


      Modulation of gut microbiota, specifically an increase in the abundance of Akkermansia, may contribute to the antiatherosclerotic and metabolic protective effects of berberine, which is poorly absorbed orally. Our findings therefore support the therapeutic value of gut microbiota manipulation in treating atherosclerosis.


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        • Mozaffarian D.
        • Benjamin E.J.
        • Go A.S.
        • et al.
        Heart disease and stroke statistics-2016 update: a report from the american heart association.
        Circulation. 2016; 133: e38-360
        • Backhed F.
        • Ding H.
        • Wang T.
        • et al.
        The gut microbiota as an environmental factor that regulates fat storage.
        Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 15718-15723
        • Hooper L.V.
        • Gordon J.I.
        Commensal host-bacterial relationships in the gut.
        Science. 2001; 292: 1115-1118
        • Tremaroli V.
        • Backhed F.
        Functional interactions between the gut microbiota and host metabolism.
        Nature. 2012; 489: 242-249
        • Yang J.Y.
        • Lee Y.S.
        • Kim Y.
        • et al.
        Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice.
        Mucosal. Immunol. 2017; 10: 104-116
        • De Vadder F.
        • Kovatcheva-Datchary P.
        • Zitoun C.
        • et al.
        Microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis.
        Cell Metab. 2016; 24: 151-157
        • Larsen N.
        • Vogensen F.K.
        • van den Berg F.W.
        • et al.
        Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults.
        PLoS One. 2010; 5: e9085
        • Martinez I.
        • Wallace G.
        • Zhang C.
        • et al.
        Diet-induced metabolic improvements in a hamster model of hypercholesterolemia are strongly linked to alterations of the gut microbiota.
        Appl. Environ. Microbiol. 2009; 75: 4175-4184
        • Vijay-Kumar M.
        • Aitken J.D.
        • Carvalho F.A.
        • et al.
        Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5.
        Science. 2010; 328: 228-231
        • Perry R.J.
        • Peng L.
        • Barry N.A.
        • et al.
        Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome.
        Nature. 2016; 534: 213-217
        • Roopchand D.E.
        • Carmody R.N.
        • Kuhn P.
        • et al.
        Dietary polyphenols promote growth of the gut bacterium akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome.
        Diabetes. 2015; 64: 2847-2858
        • Wang Z.
        • Klipfell E.
        • Bennett B.J.
        • R
        • et al.
        Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
        Nature. 2011; 472: 57-63
        • Koeth R.A.
        • Wang Z.
        • Levison B.S.
        • et al.
        Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.
        Nat. Med. 2013; 19: 576-585
        • Tang W.H.
        • Wang Z.
        • Levison B.S.
        • et al.
        Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
        N. Engl. J. Med. 2013; 368: 1575-1584
        • Libby P.
        Inflammation and atherosclerosis.
        Circulation. 2002; 105: 1135-1143
        • Hansson G.K.
        Inflammation, atherosclerosis, and coronary artery disease.
        N. Engl. J. Med. 2005; 352: 1685-1695
        • Cani P.D.
        • Bibiloni R.
        • Knauf C.
        • et al.
        Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.
        Diabetes. 2008; 57: 1470-1481
        • Pendyala S.
        • Walker J.M.
        • Holt P.R.
        A high-fat diet is associated with endotoxemia that originates from the gut.
        Gastroenterology. 2012; 142 (e1102): 1100-1101
        • Cani P.D.
        • Possemiers S.
        • Van de Wiele T.
        • et al.
        Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability.
        Gut. 2009; 58: 1091-1103
        • Beutler B.
        • Hoebe K.
        • Du X.
        • et al.
        How we detect microbes and respond to them: the Toll-like receptors and their transducers.
        J. Leukoc. Biol. 2003; 74: 479-485
        • Lu Z.
        • Li Y.
        • Jin J.
        • et al.
        Toll-like receptor 4 activation in microvascular endothelial cells triggers a robust inflammatory response and cross talk with mononuclear cells via interleukin-6.
        Arterioscler. Thromb. Vasc. Biol. 2012; 32: 1696-1706
        • Cani P.D.
        • Amar J.
        • Iglesias M.A.
        • et al.
        Metabolic endotoxemia initiates obesity and insulin resistance.
        Diabetes. 2007; 56: 1761-1772
        • Lee Y.S.
        • Kim W.S.
        • Kim K.H.
        • et al.
        Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states.
        Diabetes. 2006; 55: 2256-2264
        • Guo T.
        • Woo S.L.
        • Guo X.
        • et al.
        Berberine ameliorates hepatic steatosis and suppresses liver and adipose tissue inflammation in mice with diet-induced obesity.
        Sci. Rep. 2016; 6: 22612
        • Chang X.
        • Yan H.
        • Fei J.
        • et al.
        Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats.
        J. Lipid Res. 2010; 51: 2504-2515
        • Wang Q.
        • Zhang M.
        • Liang B.
        • et al.
        Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2.
        PLoS One. 2011; 6: e25436
        • Lee T.S.
        • Pan C.C.
        • Peng C.C.
        • et al.
        Anti-atherogenic effect of berberine on LXRalpha-ABCA1-dependent cholesterol efflux in macrophages.
        J. Cell Biochem. 2010; 111: 104-110
        • Zhang Z.
        • Zhang H.
        • Li B.
        • et al.
        Berberine activates thermogenesis in white and brown adipose tissue.
        Nat. Commun. 2014; 5: 5493
        • Kong W.
        • Wei J.
        • Abidi P.
        • et al.
        Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins.
        Nat. Med. 2004; 10: 1344-1351
        • Zhang X.
        • Zhao Y.
        • Zhang M.
        • 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: e42529
        • Hua W.
        • Ding L.
        • Chen Y.
        • et al.
        Determination of berberine in human plasma by liquid chromatography-electrospray ionization-mass spectrometry.
        J. Pharm. Biomed. Anal. 2007; 44: 931-937
        • Zhang X.
        • Zhao Y.
        • Xu J.
        • et al.
        Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats.
        Sci. Rep. 2015; 5: 14405
        • Quast C.
        • Pruesse E.
        • Yilmaz P.
        • et al.
        The SILVA ribosomal RNA gene database project: improved data processing and web-based tools.
        Nucleic Acids Res. 2013; 41: D590-D596
        • Segata N.
        • Izard J.
        • Waldron L.
        • et al.
        Metagenomic biomarker discovery and explanation.
        Genome Biol. 2011; 12: R60
        • Kim K.A.
        • Gu W.
        • Lee I.A.
        • et al.
        High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway.
        PLoS One. 2012; 7: e47713
        • Pasterkamp G.
        • Schoneveld A.H.
        • Hijnen D.J.
        • et al.
        Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human coronary artery.
        Atherosclerosis. 2000; 150: 245-253
        • Park J.G.
        • Ryu S.Y.
        • Jung I.H.
        • et al.
        Evaluation of VCAM-1 antibodies as therapeutic agent for atherosclerosis in apolipoprotein E-deficient mice.
        Atherosclerosis. 2013; 226: 356-363
        • Derrien M.
        • Vaughan E.E.
        • Plugge C.M.
        • et al.
        Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium.
        Int. J. Syst. Evol. Microbiol. 2004; 54: 1469-1476
        • Koren O.
        • Spor A.
        • Felin J.
        • et al.
        Human oral, gut, and plaque microbiota in patients with atherosclerosis.
        Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 4592-4598
        • Chen J.
        • Cao J.
        • Fang L.
        • et al.
        Berberine derivatives reduce atherosclerotic plaque size and vulnerability in apoE−/− mice.
        J. Transl. Med. 2014; 12: 326
        • Zhang Q.
        • Piao X.L.
        • Piao X.S.
        • et al.
        Preventive effect of Coptis chinensis and berberine on intestinal injury in rats challenged with lipopolysaccharides.
        Food Chem. Toxicol. 2011; 49: 61-69
        • Lehr H.A.
        • Sagban T.A.
        • Ihling C.
        • et al.
        Immunopathogenesis of atherosclerosis: endotoxin accelerates atherosclerosis in rabbits on hypercholesterolemic diet.
        Circulation. 2001; 104: 914-920
        • Zhang C.
        • Zhang M.
        • Wang S.
        • et al.
        Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice.
        ISME J. 2010; 4: 232-241
        • Belzer C.
        • de Vos W.M.
        Microbes inside–from diversity to function: the case of Akkermansia.
        ISME J. 2012; 2012: 1449-1458
        • Everard A.
        • Belzer C.
        • Geurts L.
        • et al.
        Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.
        Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 9066-9071
        • Dao M.C.
        • Everard A.
        • Aron-Wisnewsky J.
        • et al.
        Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology.
        Gut. 2016; 65: 426-436
        • Shin N.R.
        • Lee J.C.
        • Lee H.Y.
        • et al.
        An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice.
        Gut. 2014; 63: 727-735
        • Li J.
        • Lin S.
        • Vanhoutte P.M.
        • et al.
        Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe−/− mice.
        Circulation. 2016; 133: 2434-2446
        • Johansson M.E.
        • Gustafsson J.K.
        • Holmen-Larsson J.
        • et al.
        Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis.
        Gut. 2014; 63: 281-291