Amlodipine, an anti-hypertensive drug, alleviates non-alcoholic fatty liver disease by modulating gut microbiota

BACKGROUND AND PURPOSE Non-alcoholic fatty liver disease (NAFLD) represents a severe public health problem. It often coexists with hypertension in the context of metabolic syndrome. Here, we investigated the effects of amlodipine on non-alcoholic fatty liver disease combined with hypertension and the underlying mechanism. EXPERIMENTAL APPROACH mice were fed with high-fat diet and 0.05% N-Nitro-L-arginine methylester sterile water to induce NAFLD with hypertension. Gut microbiota composition and function were assessed by 16S ribosomal DNA and metagenomic sequencing. Untargeted metabolome profiles were applied to identify differential metabolites in mice cecum. KEY RESULTS Amlodipine besylate (AB) and amlodipine aspartate (AA) significantly decreased liver injury, hepatic steatosis and improved lipid metabolism with a concomitant reduction in the expression of lipogenic genes in mice with NAFLD and hypertension. Mechanistically, AA and AB have potential in restoring intestinal barrier integrity and improving antimicrobial defense along with the elevated abundances of Akkermansia, Bacteroides and Lactobacillus. Noteworthily, the gut microbiota in AB and AA-treated mice had higher abundance of functional genes involved in taurine and hypotaurine metabolism. Consistently, the strengthened taurine and hypotaurine metabolism was confirmed by the untargeted metabolome analysis. Based on the correlation and causal analysis, the altered gut microbiota composition and the enhancement of taurine and hypotaurine metabolism may synergistically decreased ALT, liver triglycerides, lipogenic genes and plasma cholesterol in HFD-fed hypertensive mice. CONCLUSION AND IMPLICATIONS Collectively, AA and AB exert multi-factorial improvements in NAFLD and hypertension by modulating gut microbiota, and may serve as a promising therapeutic agent for treating these diseases.