Microbiome Catabolites as Novel Modulators of Cellular Glucose and Energy Metabolism

Abstract

The gut microbiome supplies bioactive metabolites such as butyrate from dietary fiber to enhance the function of skeletal muscle mitochondria, and influences metabolism during exercise. Trained athletes have a distinctly different microbiome compared to sedentary individuals, since the composition and activity of the microbiota is in turn affected by muscle fitness.The gut microbiota regulate mitochondrial biogenesis through modulation of PGC‐1α, SIRT1 and AMPK, and the mitochondria regulate the gut microbiota by modulating mucosal immune responses and intestinal barrier function. Skeletal muscle is the main site of postprandial glucose disposal; the glucose transporter GLUT4 is activated by insulin by translocation to the plasma membrane from internal vesicles. In diabetic and pre‐diabetic insulin‐resistant tissues, this GLUT4 translocation is compromised. Therapeutic strategies against insulin resistance, including exercise and diet‐related interventions, aim to lower postprandial glycemia at least partly by restoring skeletal muscle glucose uptake and enhancing metabolism.Dietary phenolics can be considered as prebiotic‐type molecules, including precursors present in the unbound form as well as covalently‐attached to dietary fiber such as in cereal brans. After microbial action, many potentially bioactive phenolics are released and absorbed in the colon. These microbial products, once absorbed, interact with other tissues, including muscle and adipose cells, and stimulate the uptake of glucose by several mechanisms. For example, the microbial metabolite isovanillic acid sulfate (IVAS) stimulated a dose‐dependent increase in glucose transport in human LHCN‐M2 muscle cells through a GLUT4‐ and PI3K‐dependent mechanism. IVAS also upregulated GLUT1, GLUT4 and PI3K p85α protein, and increased phosphorylation of Akt.The stimulation of glucose uptake and metabolism provides a novel link between the diet, gut microbiota and skeletal muscle energy utilization.