Obesity-induced hyperglycemia impairs oral tolerance induction and aggravates food allergy.

Obesity and type 2 diabetes (T2D) have been found to be associated with abnormalities in several organs, including the gut mucosal immune system. These conditions can lead to changes in gut homeostasis, compromising tolerance to luminal antigens and increasing susceptibility to food allergies. However, the underlying mechanisms for this phenomenon are not yet fully understood. In this study, we investigated changes in the intestinal mucosa of diet-induced obese mice and found that they exhibited increased gut permeability and a reduced frequency of regulatory T cells. Upon oral treatment with ovalbumin (OVA), obese mice failed to develop oral tolerance, as confirmed by their inability to suppress humoral and cellular immune responses after OVA feeding. However, hyperglycemia treatment improved intestinal permeability and oral tolerance induction in mice. Furthermore, we observed that obese mice exhibited a more severe food allergy to OVA than control lean mice when oral tolerance was broken down. However, this allergy was alleviated in diet-induced obese mice that were treated with a hypoglycemic drug. Importantly, some of our findings were translated to obese humans. Specifically, individuals with T2D had higher serum immunoglobulin E levels and downregulated genes related to gut mucosal immune regulation and homeostasis when compared to obese individuals without hyperglycemia. Taken together, our results suggest that obesity-induced hyperglycemia can lead to a failure in oral tolerance induction and an exacerbation of food allergy. These findings shed light on the mechanisms underlying the relationship among obesity, T2D, and gut mucosal immunity, which could inform the development of new therapeutic approaches for these conditions.