Fig. 4. A working model of intestinal-driven metabolic disease.

We propose that early life factors induce microbial dysbiosis, which can extend to adult life and potentiate the microbiome towards an obesogenic phenotype. Consumption of a Western diet results in a dietary trigger that further establishes pro-obesity intestinal microbial dysbiosis and a shift in the intestinal immune landscape towards a pro-inflammatory phenotype with limited intestinal IgA responses. Intestinal immune changes are also poised to alter intestinal hormone bioavailability. Low-grade inflammation coupled with dietary factors promotes intestinal permeability and facilitates the leakage of microbial ligands systemically. Consequently, penetration of microbial antigens and colonization of microbes at metabolic sites, such as the liver and visceral adipose tissue (VAT), affects tissue-specific metabolic processes and tissue-specific immune cell functionality. These processes are consistently affected by interactions between the host environment and genetics, ultimately resulting in the development of metabolic complications such as insulin resistance and non-alcoholic fatty liver disease.