Interactions between host metabolism, immune regulation, and the gut microbiota in diet-associated obesity and metabolic dysfunction

Abstract

The increase in the prevalence of obesity and obesity-associated complications such as the metabolic syndrome is becoming a global challenge. Dietary habits and nutrient consumption modulates host homeostasis, which manifests in various diet-induced complications marked by changes in host metabolism and immune regulation, which are intricately linked. In addition, diet effectively shapes the gut microbiota composition and activity, which in turn interacts with the host to modulate host metabolism and immune regulation. In the three studies included in this PhD thesis, we have explored the impact of specific dietary components on host metabolic function, immune regulation and gut microbiota composition and activity. In the first study, we have characterized the effect of a combined high-fat and gliadin-rich diet, since dietary gliadin has been reported to be associated with intestinal inflammation and permeability. The combination of gliadin with an obesogenic diet allowed us to investigate the long-term effects of a single dietary component on host function of obese mice, resulting in identification of notable changes in host metabolic and immune function, as well as in the gut microbiota composition. In the second study, the effect of a safflower-based high-fat diet on host homeostasis is evaluated, and we show that intake of this n-6 polyunsaturated fatty acid-rich diet exerts only minor host metabolic and inflammatory changes even after 40 weeks intake. Although potentially proinflammatory n-6 polyunsaturated fatty acids are effectively contributing to the liver phospholipids and glucose intolerance manifested after 5 weeks intake, body weight gain, insulin resistance and adipose tissue inflammation are delayed and detectable only after 40 weeks feeding. In the last study, we evaluated the effect of short-term fasting of obese mice. By applying a coabundance cluster analysis that identifies fasting-induced changes in urine metabolites, gut microbiome and liver lipid composition; we identified defining factors that integrate with the host response to propagate a fasting-induced metabolic shift. The use of multivariate analyses allows for a better understanding of the interplay between diet, host metabolic regulation, immune function and gut microbiota composition and activity. These studies indicate new directions in which to focus further studies to increase our knowledge of hostdiet-microbiome interactions.