Gut microbiota specifically mediates the anti-hypercholesterolemic effect of berberine (BBR) and facilitates to predict BBR’s cholesterol-decreasing efficacy in patients

• Published in: Journal of advanced research Vol. 37; pp. 197 - 208
• Main Authors: Wu, Chongming, Zhao, Ying, Zhang, Yingying, Yang, Yanan, Su, Wenquan, Yang, Yuanyuan, Sun, Le, Zhang, Fang, Yu, Jiaqi, Wang, Yaoxian, Guo, Peng, Zhu, Baoli, Wu, Shengxian
• Format: Journal Article
• Language: English
• Published: Egypt Elsevier B.V 01.03.2022; Elsevier
• Subjects: Alistipes; Animals; Bacteria; Berberine (BBR); Berberine - pharmacology; Berberine - therapeutic use; Blautia; Cholesterol - pharmacology; Gastrointestinal Microbiome; Gut microbiota; Humans; Hypercholesterolemia; Hyperlipidemia; Hyperlipidemias - drug therapy; Inter-individual response variation; Medicine; Mice; Gut microbiota; PS; Hyperlipidemia; LDL-c; H&E; InsR; HFD; ROC; Alistipes; Berberine (BBR); TC; NPS; Hypercholesterolemia; BBR; TG; Inter-individual response variation; AMPK; SCFAs; Blautia; RF analysis; LDLR; AMPK, AMP-activated protein kinase; InsR, insulin receptor; NPS, the non-responsive subjects; SCFAs, short-chain fatty acids; BBR, berberine; H&E, Hematoxylin and Eosin; TG, triglycerides; HFD, high-fat diet; ROC, receiving operating characteristic; LDL-c, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptors; RF analysis, Random forest analysis; PS, the responsive subjects; TC, total cholesterol
• ISSN: 2090-1232; 2090-1224
• DOI: 10.1016/j.jare.2021.07.011

[Display omitted] •The gut microbiota is necessary for the lipid-lowering effect of BBR.•The BBR-conditioned gut microbes effectively ameliorate hyperlipidemia.•Blautia is indispensable for the hypercholesterolemia-alleviating effect of BBR.•The cholesterol-lowering effect of BBR was closely related to the gut microbiota in human beings.•The baseline abundance of Alistipes and Blautia is effective to predict the cholesterol-lowering efficiency of BBR. Gut microbiota has been implicated in the pharmacological activities of many natural products. As an effective hypolipidemic agent, berberine (BBR)’s clinical application is greatly impeded by the obvious inter-individual response variation. To date, little evidence exists on the causality between gut microbes and its therapeutic effects, and the linkage of bacteria alterations to the inter-individual response variation. This study aims to confirm the causal role of the gut microbiota in BBR’s anti-hyperlipidemic effect and identify key bacteria that can predict its effectiveness. The correlation between gut microbiota and BBR’s inter-individual response variation was studied in hyperlipidemic patients. The causal role of gut microbes in BBR’s anti-hyperlipidemic effects was subsequently assessed by altered administration routes, co-treatment with antibiotics, fecal microbiota transplantation, and metagenomic analysis. Three-month clinical study showed that BBR was effectively to decrease serum lipids but displayed an obvious response variation. The cholesterol-lowering but not triglyceride-decreasing effect of BBR was closely related to its modulation on gut microbiota. Interestingly, the baseline levels of Alistipes and Blautia could accurately predict its anti-hypercholesterolemic efficiency in the following treatment. Causality experiments in mice further confirmed that the gut microbiome is both necessary and sufficient to mediate the lipid-lowering effect of BBR. The absence of Blautia substantially abolished BBR's cholesterol-decreasing efficacy. The gut microbiota is necessary and sufficient for BBR’s hyperlipidemia-ameliorating effect. The baseline composition of gut microbes can be an effective predictor for its pharmacotherapeutic efficacy, providing a novel way to achieve personalized therapy.