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

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.