Suppression of the gut microbiota-bile acid-FGF19 axis in patients with atrial fibrillation.

Abstract

This study aimed to investigate the role of the gut microbiota (GM)-bile acid (BA)-fibroblast growth factor (FGF) 19 axis in patients with atrial fibrillation (AF). Gut bacterial metabolisms of BAs were determined in an AF metagenomic dataset. The composition of faecal BAs pools was characterized by targeted metabolomics in an independent AF cross-sectional cohort. Circulating levels of FGF19 were measured by ELISA. In vitro cell experiments were conducted to validate the regulatory role of FGF19 in atrial cardiomyocytes stimulated with palmitic acid. First, metagenomic profiling revealed that gut microbial biotransformation from primary to secondary BAs was dysregulated in AF patients. Second, the proportion of secondary BAs decreased in the faeces of patients with AF. Also, eight BAs were identified as AF-associated BAs, including seven AF-enriched BAs (ursodeoxycholic acid, chenodeoxycholic acid, etc.), and AF-decreased dehydrolithocholic acid. Third, reduced levels of circulating FGF19 were observed in patients with AF. Subsequently, FGF19 was found to protect against palmitic acid-induced lipid accumulation and dysregulated signalling in atrial cardiomyocytes, including attenuated phosphorylation of YAP and Ca2+ /calmodulin-dependent protein kinases II and secretion of interleukin-1β, mediated via peroxisome proliferator-activated receptor α. Our data found decreased levels of secondary BAs and circulating FGF19, resulting in the impaired protective function of FGF19 against lipid accumulation in atrial cardiomyocytes.