Gut microbiome, obesity, and metabolic dysfunction

Abstract

The prevalence of obesity and related disorders such as metabolic syndrome has vastly increased throughout the world. Recent insights have generated an entirely new perspective suggesting that our microbiota might be involved in the development of these disorders. Studies have demonstrated that obesity and metabolic syndrome may be associated with profound microbiotal changes, and the induction of a metabolic syndrome phenotype through fecal transplants corroborates the important role of the microbiota in this disease. Dietary composition and caloric intake appear to swiftly regulate intestinal microbial composition and function. As most findings in this field of research are based on mouse studies, the relevance to human biology requires further investigation.

Figure 1. Microbiota regulates host metabolic functions.

The microbiota controls host physiology at multiple levels. Microbial metabolic products such as SCFAs bind to GPCRs on intestinal epithelial cells (for example, Gpr41 and Gpr43) to control energy balance, partly via the gut-derived hormone Pyy, and also to control the inflammatory responsiveness of the host. Tlr5 activation (e.g., through bacterial flagellin) presumably on epithelial or myeloid cells profoundly affects the structural composition of the intestinal microbiota, which in turn regulates appetite, weight gain, and insulin sensitivity through unknown mechanisms. Microbial signals also regulate Fiaf release from intestinal epithelial cells, which acts as an inhibitor of Lpl and thereby regulates peripheral fat storage. Through another unknown mechanism, the microbiota also regulates the energy gauge in the liver and muscle through the phosphorylation of Ampk. Glp2 ascertains epithelial barrier function, and a leaky barrier leads to exposure and activation of myeloid cells in response to microbial signals such as the Tlr4 ligand endotoxin. Fiaf, fasting-induced adipose factor; Glp2, glucagon-like peptide-2; Gpr41/43, G-protein coupled receptor; Lpl, lipoprotein lipase; Pyy, peptide YY; SCFA, short chain fatty acids.