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

Sinensetin markedly impeded the development of metabolic syndrome in high-fat diet-fed mice.

• The study used an in vivo high-fat diet (HFD)-fed mouse model to assess metabolic syndrome development.
• Sinensetin administration altered hepatic transcriptomic profiles by activating alternative bile acid biosynthesis signaling cascades.
• Effects were demonstrated both in vivo and in vitro.

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).

• The increase in non-12-OH BAs was observed in HFD-fed mice treated with sinensetin.
• Sinensetin activated alternative bile acid biosynthesis signaling cascades.
• The shift in bile acid composition was identified as a key mechanism underlying the metabolic benefits of sinensetin.

Oral administration of sinensetin significantly relieved intestinal dysbiosis caused by high-fat diet by altering the composition of gut microbiota in mice.

• HFD-induced intestinal dysbiosis was ameliorated by sinensetin treatment.
• Sinensetin altered the composition of gut microbiota in HFD-fed mice.
• The gut microbiota changes were linked to enhanced non-12-OH BA synthesis.

The therapeutic efficacy of sinensetin against metabolic syndrome was microbiota-dependent.

• Antibiotic-mediated depletion of gut microbiota abolished the beneficial effects of sinensetin.
• Fecal microbiota transplantation (FMT) transmitted the metabolic improvement observed with sinensetin treatment.
• These two experimental approaches together confirmed the causal role of gut microbiota in sinensetin's therapeutic effects.

Sinensetin's mechanism of action involves reshaping gut microbiota to enhance non-12-OH bile acid synthesis as a treatment strategy for metabolic syndrome.

• The study identified a gut microbiota–bile acid metabolism axis as the mechanistic basis for sinensetin's effects.
• The findings offer 'novel mechanistic insights and promising avenues for therapeutic intervention' according to the authors.
• Sinensetin is a dietary flavonoid, situating these findings within the broader context of dietary flavonoids alleviating metabolic syndrome via gut microbiota.