Abstract
INTRODUCTION: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.