Gut Enterococcus faecium derived leucic acid mediates the antiobesity effect of dietary fiber

Obesity is a globally prevalent metabolic disorder closely associated with gut microbiota dysbiosis. However, the precise roles of gut microbiota and microbial metabolism in this disease remain unclear. Through fecal metagenomic data mining and clinical cohort validation, we identified a gut bacterial strain with anti-obesity potential, Enterococcus faecium ( E. faecium ). It inhibited adipocyte enlargement, dyslipidemia, and hepatic steatosis in obese mice by metabolizing leucine to produce leucic acid (LEA). Colonization with E. faecium or exogenous LEA supplementation improved obesity-associated metabolic phenotypes. Mechanistically, E. faecium metabolized leucine into LEA via putative branched-chain amino acids metabolic enzymes. The bacterium-derived LEA regulated mitochondrial oxidative phosphorylation and thus alleviated obesity. Furthermore, using a high-content screening system and an in vitro fermentation model, we found that the dietary fiber glucomannan exerted anti-obesity effects by promoting the growth of E. faecium . This study reveals the critical role of microbial metabolism and LEA production in ameliorating the onset and progression of obesity, providing a theoretical basis for dietary fiber intervention strategies targeting the gut microbiota. Graphical This study identified Enterococcus faecium as a gut bacterium with anti-obesity activity, which alleviated adipocyte hypertrophy, dyslipidemia, and hepatic steatosis by converting leucine into leucic acid (LEA) to regulate mitochondrial oxidative phosphorylation. In addition, dietary glucomannan effectively enriched this bacterium, providing a theoretical basis for developing precision dietary fiber-based anti-obesity strategies targeting the gut microbiota. Highlights Metagenomic and clinical data verified E. faecium as an anti-obesity gut bacterium. E. faecium alleviated obesity via leucine conversion to leucic acid (LEA). LEA modulated mitochondrial oxidative phosphorylation against obesity. Glucomannan inhibited obesity by enriching E. faecium for microbiota intervention.