Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity

Abstract

Obesity is associated with metabolic alterations related to glucose homeostasis and cardiovascular risk factors. These metabolic alterations are associated with low-grade inflammation that contributes to the onset of these diseases. We and others have provided evidence that gut microbiota participates in whole-body metabolism by affecting energy balance, glucose metabolism, and low-grade inflammation associated with obesity and related metabolic disorders. Recently, we defined gut microbiota-derived lipopolysaccharide (LPS) (and metabolic endotoxemia) as a factor involved in the onset and progression of inflammation and metabolic diseases. In this review, we discuss mechanisms involved in the development of metabolic endotoxemia such as the gut permeability. We also discuss our latest discoveries demonstrating a link between the gut microbiota, endocannabinoid system tone, leptin resistance, gut peptides (glucagon-like peptide-1 and -2), and metabolic features. Finally, we will introduce the role of the gut microbiota in specific dietary treatments (prebiotics and probiotics) and surgical interventions (gastric bypass).

Figures

Figure 1. The gut microbiota controls gut barrier function and the onset of metabolic endotoxemia. Diet-induced obesity and genetic (ob/ob or db/db mice) obesity are associated with changes in gut microbiota composition. This leads to gut barrier function alteration through several mechanisms, including an altered distribution of the tight junction proteins ZO-1 and Occludin and an increased eCB system tone with a higher expression of anandamide and CB1R. These phenomena promote metabolic endotoxemia and initiate the development of low-grade inflammation and insulin resistance in the liver, muscles and adipose tissue.

Figure 2. Prebiotic-induced changes in the gut microbiota affect enteroendocrine function and leptin sensitivity. Prebiotics profoundly affect gut microbiota composition in a complex way in response to a high-fat diet or genetic obesity (e.g., increased Bifidobacterium spp. and Akkermansia muciniphila). Prebiotic treatment decreases gut permeability and metabolic endotoxemia and improves insulin sensitivity, steatosis and low-grade inflammation via several mechanisms, including the following: 1) an increased L-cell number and endogenous GLP-1 and GLP-2 production and 2) an increased leptin sensitivity, which controls energy homeostasis and GLP-1 production.