Dietary resveratrol intervention improves lipid homeostasis via attenuating HFD-induced fecal chenodeoxycholic acid and jejunum SR-B1 elevation

Abstract Two common features of dietary polyphenols have hampered our mechanistic understanding of their metabolic beneficial effects for decades: targeting multiple organs and extremely low bioavailability. We show here that resveratrol intervention (REV-I) in high fat diet (HFD)-challenged mice inhibited chylomicron secretion, associated with reduced jejunal but not hepatic SR-B1 expression. Intestinal-mucosa-specific SR-B1-/- mice on HFD challenge exhibited improved lipid homeostasis but showed virtually no further response to REV-I. The SR-B1 inhibitor BLT-1 and REV-I generated no additive effect on improving lipid homeostasis. SR-B1 expression in the Caco-2 cell line cannot be repressed by pure resveratrol while fecal-microbiota transplantation from mice on REV-I suppressed jejunal SR-B1 in recipient mice. REV-I reduced fecal levels of bile acids including chenodeoxycholic acid (CDCA), while CDCA stimulated FXR, NF-κB and SR-B1 in Caco-2 cells. We conclude that gut microbiome is the primary target of REV-I, and REV-I improves lipid homeostasis at least partially via attenuating CDCA-stimulated gut SR-B1 elevation.