675.5 - Sexually dimorphic metabolic effects of a naturally occurring flavonoid are mediated by changes in the gut microbiome

Priyanka Sharma (Department of Nutritional Sciences and Rutgers Center for Lipid Research), Camila Silva (Department of Nutritional Sciences and Rutgers Center for Lipid Research), Hong Ye (Department of Nutritional Sciences and Rutgers Center for Lipid Research), Harini Sampath (Department of Nutritional Sciences and Rutgers Center for Lipid Research)

It is increasingly understood that dietary flavonoids modulate the gut microbiome which influences host metabolism. However, sex-dependent effects of flavonoids on the gut microbiome composition and metabolic health have not been studied. In this regard, we have previously shown that an oral flavonoid 7,8-Dihydroxyflavone (DHF), exerts sexually-dimorphic effects on body weight and metabolic health. Specifically, oral DHF supplementation prevents HFD-induced obesity and inflammation in female but not male mice. Interestingly, this metabolic protection was associated with early and stable changes in the composition of the female, but not male, gut microbiome. The remodeled female microbiome contributed to increased formation of the short chain fatty acid acetate, while male mice did not display a similar effect. While a causal association between the gut microbiome and metabolic protection in female mice was not previously studied, we now demonstrate using a model of antibiotic-induced gut microbiome ablation, that an intact microbiome is required to mediate metabolic protection due to DHF in female mice. Upon ablation of the gut microbiome DHF supplementation not only did not prevent HFD-induced obesity in female mice, it also failed to activate the TrkB receptor, whose activity has been previously ascribed to metabolic signaling by DHF. Mechanistically, we report that metabolic protection in female mice is mediated by increased thermogenic markers including UCP1, AMPK, SIRT1, and PGF-1α in brown adipose tissue in females, but not males. This thermogenic activation also required an intact gut microbiome. These results reveal complex and novel interactions between dietary flavonoids, sex, and the gut microbiome that have important implications both to understanding the etiology of metabolic diseases and for the development of personalized nutrition strategies for their prevention.

NIH grant DK100640 and a Botanical Dietary Supplements Research Center (BDSRC) Pilot grant.