Indole propionic acid modulates macrophage polarization via TGF-β1/smads to enhance E-cadherin expression in intestinal epithelium in inflammatory bowel disease

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OBJECTIVES: This study investigated the regulatory effects of Indole Propionic Acid (IPA) on macrophage polarization and its role in promoting epithelial integrity via the transforming growth factor-β1 (TGF-β1)/Smads signaling pathway in inflammatory bowel disease (IBD). METHODS: Peritoneal macrophages (PEMs) from dextran sulfate sodium (DSS)-induced colitis mice, RAW264.7 cells, and bone marrow-derived macrophages (BMDMs) were used to assess IPA's impact on macrophage polarization. Classical (M1) polarization was induced with lipopolysaccharide (LPS), followed by IPA treatment. The TGF-β1/Smads pathway was modulated using SB-431542 or TGF-β1. HCT116 human epithelial cells were co-cultured with PEMs, and epithelial cadherin (E-cadherin) expression was evaluated via histopathology, immunofluorescence, qRT-PCR, and Western blotting. DSS-induced colitis mice received IPA, and colonic tissues were assessed for inflammation, polarization, E-cadherin expression, barrier integrity, and apoptosis. RESULTS: IPA suppressed M1 and promoted alternatively activated M2 macrophages (P < 0.05), alleviated inflammation, decreased tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), and improved barrier integrity (P < 0.05). Enhanced E-cadherin expression was observed in both IPA-treated mice and HCT116 cells, indicating consistent epithelial protection. IPA inhibited TGF-β1/Smads signaling and reduced epithelial apoptosis. Co-cultures confirmed IPA enhanced proliferation and suppressed apoptosis via TGF-β1/Smads inhibition. CONCLUSION: IPA promotes anti-inflammatory macrophage polarization and enhances epithelial integrity by inhibiting the TGF-β1/Smads pathway, suggesting therapeutic potential in IBD.