High-Fat Diet Causes Rapid Loss of Intestinal Group 3 Innate Lymphoid Cells Through Microbiota-Driven Inflammation

Group 3 innate lymphoid cells (ILC3s) are critical sensory hubs to maintain intestinal immunity while adapting to environmental changes, including food intake and microbiota composition. Nutritional stress such as feeding on a high-fat diet (HFD) impairs ILC3s homeostasis, but the drivers underlying this phenotype remain elusive. Here, we found that intestinal ILC3s are depleted in overweight and obese humans, similarly to HFD-induced obese mice. However, we identified that ILC3s loss is not dependent on excessive calorie intake, weight gain, or glucose intolerance. Instead, we found that ILC3s impairment starts upon hours of HFD consumption, inducing microbial efflux. As a result, tissue-resident mononuclear phagocytes (MNPs) become proinflammatory, driving ILC3 cell death. We determined that the microbiota-driven stimulation overrides lipid-laden ILC3s ability to perform fatty acid oxidation, causing mitochondrial damage due to the accumulation of lipid peroxides. Collectively, our findings define the mechanism driving ILC3s maladaptation to fat-microbiota crosstalk and raise new considerations for understanding intestinal homeostasis and inflammation.