Muscularis Macrophage‐Derived ApoE is Dispensable for Maintaining Gut Motility in Mice

ABSTRACT Introduction Gastrointestinal (GI) motility is controlled by the coordinated activity of enteric neurons, glial cells, and resident muscularis macrophages (mMφs). Apolipoprotein E (ApoE) is highly expressed in mMφs, but its functional role in the gut remains unclear. We hypothesized that mMφ‐derived ApoE regulates intestinal motility under physiological and stress conditions. Methods Global ApoE knockout mice, bone marrow chimeras, and macrophage‐specific ApoE‐deficient mice were used to assess the impact of ApoE loss on gut transit, immune response, and neuromuscular integrity in both homeostatic and postoperative ileus (POI) settings. Results (1) Single‐cell RNA sequencing revealed that muscularis macrophages highly express ApoE, with further upregulation after intestinal manipulation. (2) Bone marrow chimera experiments showed that hematopoietic‐derived ApoE only partially contribute to the maintenance of gut motility. (3) Global ApoE deficiency led to mild impairment of intestinal transit and increased glial activation, accompanied by an expansion of the macrophage population and elevated gene expression of inflammatory cytokines. (4) Macrophage‐specific deletion of ApoE did not affect gastrointestinal transit or tissue morphology under normal conditions. Conclusion Although highly expressed and dynamically regulated in muscularis macrophages, ApoE is largely dispensable for intestinal neuromuscular function at baseline and during postoperative ileus.