Metabolic protection by the dietary flavonoid 7,8-dihydroxyflavone requires an intact gut microbiome.

Background: 7,8-dihydroxyflavone (DHF) is a naturally occurring flavonoid found in Objective: To investigate a causal association between the gut microbiome and the metabolic effects of DHF using a model of antibiotic-induced gut microbiome ablation. Materials and methods: Age-matched male and female C57Bl6/J mice were given Results: Metabolic protection conferred by DHF in female HFD-fed mice was only apparent in the presence of an intact gut microbiome. Abx-treated mice were not protected from HFD-induced obesity by DHF administration. Further, tissue activation of the tropomyosin-related kinase receptor B (TrkB) receptor, which has been attributed to the biological activity of DHF, was lost upon gut microbiome ablation, indicating a requirement for microbial "activation" of DHF for its systemic effects. In addition, we report for the first time that DHF supplementation significantly activates TrkB in BAT of female, but not male, mice uncovering a novel target tissue of DHF. DHF supplementation also increased uncoupling protein 1 (UCP1) and AMP-activated protein kinase (AMPK) protein in BAT, consistent with protection from diet-induced obesity. Conclusion: These results establish for the first time a requirement for the gut microbiome in mediating the metabolic effects of DHF in female mice and uncover a novel target tissue that may mediate these sexually-dimorphic protective effects.