Gut microbiota-derived metabolites are novel targets for improving insulin resistance

Abstract

The gut microbiota plays a key role in metabolic diseases. Gut-microbiota-derived metabolites are found in different dietary sources, including: Carbohydrate (acetate, propionate, butyrate, also known as short-chain fatty acids, as well as succinate); protein (hydrogen sulfide, indole, and phenylacetic acid); and lipids (resveratrol-, ferulic acid-, linoleic acid-, catechin- and berry-derived metabolites). Insulin resistance, which is a global pandemic metabolic disease that progresses to type 2 diabetes mellitus, can be directly targeted by these metabolites. Gut-microbiota-derived metabolites have broad effects locally and in distinct organs, in particular skeletal muscle, adipose tissue, and liver. These metabolites can modulate glucose metabolism, including the increase in glucose uptake and lipid oxidation in skeletal muscle, and decrease in lipogenesis and gluconeogenesis associated with lipid oxidation in the liver through activation of phosphatidylinositol 3-kinase - serine/threonine-protein kinase B and AMP-activated protein kinase. In adipose tissue, gut-microbiota-derived metabolites stimulate adipogenesis and thermogenesis, inhibit lipolysis, and attenuate inflammation. Importantly, an increase in energy expenditure and fat oxidation occurs in the whole body. Therefore, the therapeutic potential of current pharmacological and non-pharmacological approaches used to treat diabetes mellitus can be tested to target specific metabolites derived from intestinal bacteria, which may ultimately ameliorate the hyperglycemic burden.

Keywords: Insulin resistance; Gut microbiota; Metabolites; Host metabolism; Metabolic organs; Novel targets

Core Tip: The gut-microbiota-derived metabolites play a key role in metabolic diseases. Insulin signaling pathways are directly targeted by these metabolites, as they promote an increase in glucose uptake and lipid oxidation in skeletal muscle; a decrease in lipogenesis and gluconeogenesis associated with an increase in lipid oxidation in the liver; and an improvement in thermogenesis and inflammation in the adipose tissue. Collectively, these findings pave the way for the development of novel drugs or for investigation of the therapeutic potential of drugs currently used to treat insulin resistance, targeting the gut-microbiota-derived metabolites.