Common gut microbial metabolites of dietary flavonoids exert potent protective activities in beta-cells and skeletal muscle cells

Flavonoids are dietary compounds with potential anti-diabetes activities. Many fiavonoids have poor bioavailability and thus low circulating concentrations. Unabsorbed fiavonoids are metabolized by the gut microbiota to smaller metabolites, which are more bioavailable than their precursors. The activities of these metabolites may be partly responsible for associations between flavonoids and health. However, these activities remain poorly understood. We investigated bioactivities of flavonoid microbial metabolites [hippuric acid (HA), homovanillic acid (HVA), and 5-phenylvaleric acid (5PVA)] in primary skeletal muscle and beta-cells compared to a native flavonoid [(-)-epicatechin, EC]. In muscle, EC was the most potent stimulator of glucose oxidation, while 5PVA and HA simulated glucose metabolism at 25 mu M, and all compounds preserved mitochondrial function after insult. However, EC and the metabolites did not uncouple mitochonndrial respiration, with the exception of 5PVA at 10 mu M. In beta-cells, all metabolites more potently enhanced glucose-stimulated insulin secretion (GSIS) compared to EC. Unlike EC, the metabolites appear to enhance GSIS without enhancing beta-cell mitochondria] respiration or increasing expression of mitochondrial electron transport chain components, and with varying effects on beta-cell insulin content. The present results demonstrate the activities of flavonoid microbial metabolites for preservation of beta-cell function and glucose utilization. Additionally, our data suggest that metabolites and native compounds may act by distinct mechanisms, suggesting complementary and synergistic activities in vivo which warrant further investigation. This raises the intriguing prospect that bioavailability of native dietary flavonoids may not be as critical of a limiting factor to bioactivity as previously thought. (C) 2018 Elsevier Inc. All rights reserved.