Supplementation of a propionate-producing consortium improves markers of insulin resistance in an in vitro model of gut-liver axis

Abstract

Gut-liver cross talk is an important determinant of human health with profound effects on energy homeostasis. While gut microbes produce a huge range of metabolites, specific compounds such as short-chain fatty acids (SCFAs) can enter the portal circulation and reach the liver (Brandl K, Schnabl B. Curr Opin Gastroenterol 33: 128–133, 2017), a central organ involved in glucose homeostasis and diabetes control. Propionate is a major SCFA involved in activation of intestinal gluconeogenesis (IGN), thereby regulating food intake, enhancing insulin sensitivity, and leading to metabolic homeostasis. Although microbiome-modulating strategies may target the increased microbial production of propionate, it is not clear whether such an effect spreads through to the hepatic cellular level. Here, we designed a propionate-producing consortium using a selection of commensal gut bacteria, and we investigated how their delivered metabolites impact an in vitro enterohepatic model of insulin resistance. Glycogen storage on hepatocyte-like cells and inflammatory markers associated with insulin resistance were evaluated to understand the role of gut metabolites on gut-liver cross talk in a simulated scenario of insulin resistance. The metabolites produced by our consortium increased glycogen synthesis by ~57% and decreased proinflammatory markers such as IL-8 by 12%, thus elucidating the positive effect of our consortium on metabolic function and low-grade inflammation. Our results suggest that microbiota-derived products can be a promising multipurpose strategy to modulate energy homeostasis, with the potential ability to assist in managing metabolic diseases due to their adaptability.