Sinensetin Ameliorates Metabolic Syndrome via Regulating Gut Microbiota and Bile Acid Metabolism

The exact mechanism through which dietary flavonoids alleviate metabolic syndrome (MetS) via the gut microbiota remains fully unclear. This study demonstrates that sinensetin markedly impeded the development of MetS and altered hepatic transcriptomic profiles by activating alternative bile acid biosynthesis signaling cascades both <i>in vivo</i> and <i>in vitro</i>. Importantly, sinensetin administration induced significant shifts in hepatic bile acid composition, notably increasing the relative abundance of non-12-hydroxy bile acids (non-12-OH BAs) in high-fat diet (HFD)-fed mice. Additionally, oral administration of sinensetin significantly relieved intestinal dysbiosis caused by HFD by altering the composition of gut microbiota in mice. The therapeutic efficacy of sinensetin against MetS was microbiota-dependent, as antibiotic-mediated depletion of gut microbiota abolished its beneficial effects, and fecal microbiota transplantation transmited this metabolic improvement. These findings suggest that sinensetin alleviated MetS by reshaping the gut microbiota to enhance non-12-OH BAs synthesis, offering novel mechanistic insights and promising avenues for therapeutic intervention.