Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity

Abstract

A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota. An important next step is to elucidate a human-relevant “map’’ of microbiota-host interactions that regulate the metabolic health of the host. An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity. Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions, including cancer, neurodegeneration, and aging. The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood. Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage. Changes in the composition and function of the gut microbiota, i.e., dysbiosis, are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction. Many effects of the microbiota on the host are mediated by microbiota-derived metabolites. In this review, we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases. The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.

Keywords: Obesity; Metabolic diseases; Microbiota; Mucosal homeostasis; Gut; Microbial metabolites

Core Tip: The manner in which the gut microbiota influences obesity development remains incompletely understood. Recent studies have indicated that the changes in the gut barrier functions act as an important driver of metabolic disorders. There is currently an urgent need to define molecular and cellular modulators of intestinal mucosal barrier homeostasis. Here, we discuss the current understanding of microbiota-derived metabolites in regulating mucosal homeostasis and how they contribute to the metabolic health of the host.