Influence of gut microbiota on subclinical inflammation and insulin resistance

Abstract

Obesity is the main condition that is correlated with the appearance of insulin resistance, which is the major link among its comorbidities, such as type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. Obesity affects a large number of individuals worldwide; it degrades human health and quality of life. Here, we review the role of the gut microbiota in the pathophysiology of obesity and type 2 diabetes, which is promoted by a bacterial diversity shift mediated by overnutrition. Whole bacteria, their products, and metabolites undergo increased translocation through the gut epithelium to the circulation due to degraded tight junctions and the consequent increase in intestinal permeability that culminates in inflammation and insulin resistance. Several strategies focusing on modulation of the gut microbiota (antibiotics, probiotics, and prebiotics) are being experimentally employed in metabolic derangement in order to reduce intestinal permeability, increase the production of short chain fatty acids and anorectic gut hormones, and promote insulin sensitivity to counteract the inflammatory status and insulin resistance found in obese individuals.

Figure 1

The gut microbiota is modulated by metabolic derangement, such as nutrition overload and obesity, which promote a cluster of metabolic disease-associated processes that culminate in bacterial products and whole bacteria translocation to the circulation through increased intestinal permeability caused by a reduction in tight junction expression. This triggers an immune response, inflammation, and immune cell infiltration of liver and adipose tissue. It induces insulin resistance in various tissues by diverse mechanisms and food intake deregulation in the hypothalamus promoted by the insulin and leptin resistance and also inhibited expression of gut-secreted anorectic hormones, such as GLP-1 and PYY. Additionally, there is a reduction in the intestinal Fiaf expression mediated by bacteria that deregulate the fat storage and lipid metabolism favoring the obese phenotype.

Figure 2

The advent of products (antibiotics, probiotics, and prebiotics) capable of modulating the gut microbiota profile, their products and metabolites (i.e., LPS, short-chain fatty acids), promotes a shift on the bacterial community prevalence, which favored the increase in tight junctions expression and function, reducing intestinal permeability and bacterial products circulation levels. Thus, the LPS circulating levels and inflammatory status in insulin-sensitive tissues are reduced, as well as muscle S-nitrosylation and liver and adipose tissue macrophage infiltration, promoting increased insulin sensitivity and the whole body metabolism. GLP-1 and PYY circulating levels are increased after treatment with gut microbiota modulators which together with the improvement in insulin sensitivity in the hypothalamus promoted reduction in food intake by satiety mechanisms and in conjunction with the increased Fiaf expression, contributed to reduce body weight.