The rapid global rise in obesity and high-fat diet (HFD) consumption is a major driver of inflammatory disorders, including inflammatory bowel disease (IBD). While chronic HFD exposure promotes dysbiosis, systemic inflammation, and metabolic dysfunction, its early impact on gut immune homeostasis remains poorly understood.
Here, we investigated the acute immunological effects of short-term HFD exposure on the intestinal immune landscape. Using multiparameter flow cytometry and single-cell transcriptomics, we found that HFD rapidly impairs the function of group 3 innate lymphoid cells (ILC3s), key producers of interleukin-22 (IL-22), which is essential for epithelial barrier maintenance. This early loss of IL-22 was associated with increased intestinal permeability, dysbiosis, and reduced expression of antimicrobial peptides, mucins, and tight junction proteins.
Mechanistically, we show that the type of dietary fat dictates ILC3 function. Saturated fatty acids, metabolized through mitochondrial β-oxidation, suppressed IL-22 production and heightened susceptibility to gut injury. In contrast, unsaturated fatty acids preserved ILC3 activity by promoting lipid droplet formation via DGAT-dependent pathways, thereby sustaining IL-22 secretion and mucosal protection.
Our findings reveal that dietary fats rapidly reprogram mucosal immune responses, with implications for how specific nutrients shape intestinal inflammation and susceptibility to disease. This work uncovers new mechanistic links between nutrient metabolism, innate immunity, and barrier function.