SRP409802 PRJNA904807 Mouse gut microbiota after acute high fat diet and intestinal damage Chronic exposure to high-fat diets (HFD) worsens intestinal disease pathology, but acute effects of HFD in tissue damage remain unclear. Here, we used short-term HFD feeding in a model of intestinal injury and found sustained damage with increased accumulation of dead neutrophils in the cecum, where we find dietary lipid accumulation. Neutrophil depletion rescued enhanced pathology. Macrophages from HFD treated mice showed reduced capacity to engulf dead neutrophils. Macrophage clearance of dead neutrophils is one upstream activator of critical barrier repair and anti-inflammatory pathways including IL-10, which was lost after acute HFD feeding and intestinal injury. IL-10 overexpression was sufficient to restore intestinal repair after HFD feeding and intestinal injury. Macrophage exposure to lipids from the HFD prevented tethering and uptake of apoptotic cells and IL-10 induction. Our findings demonstrate that HFD promotes intestinal pathology by interfering with macrophage clearance of dead neutrophils, leading to an unresolved tissue damage. mouse gut metagenome