High-fat diet causes rapid microbiota-dependent intestinal ILC3 loss and impairs tolerance and immunity

Abstract

Abstract Innate lymphoid cells (ILCs) are increasingly appreciated to play a critical role in tissue homeostasis, immunity, and tolerance. At steady state, intestinal ILC3 are the main source of IL-22, ensuring epithelial barrier integrity and defense against pathogenic bacteria. In addition, ILC3 support intestinal tolerance to commensal bacteria and dietary antigens. ILC3 can also sense changes in dietary nutrients, such as vitamin A and aryl hydrocarbon receptor ligands that affect their development, function and ultimately intestinal health. Here we show that ILC3 are severely depleted from the small and large intestine of obese mice fed high-fat diet (HFD) but not in leptin or leptin receptor-deficient obese mice. Notably, consumption of HFD for only 24 hours is sufficient to trigger ILC3 cell death. Total loss of ILC3 is reached after one week of HFD without significant weight gain. We found that this short-term consumption of HFD increases host susceptibility to Citrobacter rodentium infection and impairs tolerance to dietary antigens. Unexpectedly, we found that ILC3 were maintained in germ-free mice fed HFD. However, ILC3 were depleted when HFD-fed GF mice were inoculated with either living, heat-killed bacteria or with LPS. Furthermore, HFD-fed TLR4 deficient mice are protected from intestinal ILC3 loss. TNFα blockade is sufficient to prevent HFD-induced ILC3 loss. Collectively, our findings show that short term consumption of HFD, rather than obesity potentiates rapid loss of ILC3 in presence of microbiota that leads to early impairment of gut integrity, tolerance, and protection against pathogens.