Lactobacillus reuteri FN 041 Alleviates Radiation Enteritis by Regulating M 2 Macrophages Polarization Based on Gut Microbiota and Its Metabolites

ABSTRACT Radiotherapy, a common method for treating pelvic and abdominal cancer, can easily result in radiation enteritis (RE). The gut microbiota and its metabolites have a crucial role in regulating macrophage polarization and maintaining immune homeostasis. Lactobacillus reuteri FN041, derived from human milk, can promote M2 polarization while attenuating RE. After FN041 treatment, the crypt depth and goblet cell numbers were significantly improved in RE mice. The levels of Muc2, ZO‐1, and Occludin were significantly higher in the FN041 group than in the RE group. FN041 stimulated the polarization of macrophages toward M2 and inhibited the expression of IL‐6 and TNF‐α in RE mice. Mechanically, FN041 regulated the gut microbiota and metabolites, including key intermediates in phospholipid synthesis such as CDP‐DG, prostaglandins, and their phospholipid derivatives (including PI, PE, PA, and PS), which were linked to M2 macrophage polarization. Collectively, FN041 exerts a protective effect against RE by modulating macrophage polarization based on gut microbiota and its metabolites.