The Gut Microbiota Regulates the Metabolic Benefits Mediated by Red Raspberry Polyphenols

Abstract Objectives Red raspberry (RR) polyphenols, including ellagic acid and their gut-derived metabolites, the urolithins, reduce inflammation and improve insulin sensitivity. However, it is unknown whether the gut microbiota is responsible for these health benefits and why certain individuals do not transform ellagic acid into urolithins. Here, we determined the causative role for the microbiome in mediating the health benefits from RR polyphenols using germ-free and conventionalized mouse models of diet-induced obesity. We also tested whether Gordonibacter urolithinfaciens (G. uro), a gut microbe previously shown to metabolize ellagic acid into urolithins, could enhance metabolic benefits when administered as a synbiotic with RR polyphenols. Methods RR polyphenols were extracted using a macroporous ion-exchange resin column to remove sugars and fibers. C3H/HeN mice with (CVZ) or without a microbiota (GF) were fed either a low fat (LF), high fat (HF), or HF diet with RR polyphenols (HF + RR) for 12 weeks. For synbiotic studies, GF C57BL/6 mice were given a G. uro deficient-microbiome and then fed either a HF or HF + RR diet plus 20% fructose water with or without G. uro for 7 weeks. Results Feeding a HF diet increased body weight and fat mass for both GF and CVZ mice compared to feeding a LF diet (P < 0.05). Feeding a HF diet with RR polyphenols significantly decreased visceral adipose tissue and liver triglycerides (P < 0.05) compared to a HF control diet in CVZ but not GF mice. G. uro administration to mice receiving a HF diet and fructose water significantly reduced body weight, body fat percentage, fasting blood glucose, and subcutaneous adipose tissue mass as well as increased ileal tight junction protein gene expression (P < 0.05) compared to controls. Notably, mice supplemented with both G. uro and RR polyphenols experienced no metabolic improvements compared to controls (P < 0.05). Conclusions Our results demonstrate that the microbiome is required for mediating RR polyphenol metabolic benefits. Supplementation of G. uro improved metabolic health; however, those beneficial effects were abrogated in the presence of RR polyphenols. Together, these results highlight the importance of considering specific diet-microbiota interactions when developing foods for preventing and treating obesity-related diseases. Funding Sources USDA NIFA.