Intestinal epithelial cell EphB4 deficiency on high fat diet-induced obesity

High-fat diets (HFD) exacerbate excessive lipid absorption by compelling the small intestine (SI) to take in redundant calories, yet host-encoded mechanisms are not fully explored. Previous research demonstrated that intestinal group 3 innate lymphoid cell (ILC3)–interleukin-22 (IL-22)–phosphorylated signal transducer and activator of transcription 3 (pSTAT3) axis fluctuates with feeding rhythms and engages in nutrient absorption. We found that prolonged HFD feeding enhances this axis in the proximal SI, leading to adaptively increased lipid absorption. Notably, we identified Eph receptor B4 (EphB4), an intestinal epithelial regulator that interacts with ILC3s microbiota-independently, thereby boosting pre-meal IL-22 secretion and subsequent lipid absorption, elucidating its crucial role in the interplay between diet, immune axis, and metabolism. In HFD-induced obesed mice, deleting EphB4 in intestinal epithelial cells (IECs) reduced proximal intestinal lipid absorption, improved obesity and metabolic disorders.