The intestinal immune system, which is influenced by diet and intestinal microbiota and their metabolites, modulates glucose homeostasis and obesity-associated insulin resistance. The intestinal immune system affects processes such as intestinal permeability, immune cell trafficking, and intestinal hormone availability, affecting systemic insulin resistance.

Khan et al. have highlighted how understanding intestinal immune system pathways might identify mechanisms underlying treatments for insulin resistance, such as metformin and bariatric surgery, or aid in developing new therapies and vaccination approaches and, in their recent paper, they discuss the main advances in intestinal immunometabolism and microbiology in obesity and associated metabolic condition.

According to Khan and colleagues, early life factor-induced microbial dysbiosis can extend to adult life and potentiate the microbiome towards an obesogenic phenotype. Consumption of a Western diet (rich in saturated fats, red meat, and sugars, poor in dietary fibers and vegetables) results in a trigger that further produces pro-obesity intestinal microbial dysbiosis and a variation in the intestinal immune landscape towards a pro-inflammatory condition. This low-grade inflammation promotes intestinal permeability and facilitates the leakage of microbial ligands systemically. Penetration of microbial antigens and colonization of microbes at metabolic sites, such as the liver and visceral adipose tissue, affects tissue-specific metabolic processes and tissue-specific immune cell functionality.

Interactions between the host environment and genetics consistently affects these processes, ultimately resulting in the development of metabolic complications such as insulin resistance and non-alcoholic fatty liver disease.

In the prospective vision of the authors, it is essential to incorporate large-scale analyses that better dissect the immune cell-microbiota axis, to visualize the immune landscape paired with single-cell RNA sequencing to achieve transcriptional profiles and facilitate the discovery of diet-induced metabolic changes to intestinal immune phenotypes, activation pathways, antigen receptor diversity, and even predict developmental lineages and cellular dynamics within the intestines of individuals who are obese.

Similarly, studies should further conduct unbiased large-scale omics analyses on the intestinal bacteria and their metabolome to identify important target microbes and metabolites to improve metabolic syndrome.

Also, they propose avenues of research that might yield new insight into immune cell-microbiota crosstalk and the development of therapeutic modalities. With future research adding to our understanding of obesity-associated intestinal dysfunction and uncovering mechanisms of immune cell pathogenicity, the goal of developing safe therapies with improved effectiveness in obesity-related metabolic disease will be closer.