Short-term canagliflozin treatment remodels the gut microbiota and plasma bile acids in high-fat diet-fed mice

Abstract The sodium–glucose cotransporter 2 inhibitor canagliflozin exerts rapid cardiovascular and renal protective effects; however, its underlying mechanisms remain incompletely understood. Considering the emerging role of gut microbiota as pivotal mediators of drug efficacy, this study aimed to elucidate the short-term impact of canagliflozin on gut microbiota and bile acid metabolism. We administered canagliflozin for 1 week to C57BL/6 J mice previously fed a high-fat diet (HFD) for 4 weeks. We then performed 16S ribosomal RNA gene sequencing of the colonic contents and measured plasma bile acid profiles. Although canagliflozin did not alter alpha diversity, it induced a distinct shift in the overall gut microbial structure (beta diversity). Notably, canagliflozin selectively enriched Turicibacter , coinciding with the preservation of plasma bile acids, including cholic acid and deoxycholic acid, which were suppressed following HFD feeding. These findings suggest that canagliflozin rapidly remodels the gut microbiota and is associated with maintained bile acid homeostasis. This gut-mediated action, which we hypothesize may involve intestinal SGLT1 inhibition, provides new insights into the distinct, early metabolic benefits of canagliflozin.