Wenyang Decoction Ameliorates DSS-Induced Ulcerative Colitis by Regulating Macrophage Polarization and the PI3K/AKT/mTOR/HIF-1α Signaling Pathway.

AIM: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by intestinal inflammation and epithelial damage. This study aims to investigate the therapeutic effects of Wenyang decoction (WYD) in a dextran sulfate sodium (DSS)-induced UC model and its underlying mechanisms, with a focus on macrophage polarization and the regulation of the PI3K/AKT/mTOR/HIF-1α signaling pathway. METHODS: A DSS-induced UC model was established in C57BL/6 mice. Treatment groups received WYD at low (8.25 g/kg/day), medium (16.50 g/kg/day), or high (33.00 g/kg/day) doses, with 5-aminosalicylic acid (5-ASA, 200 mg/kg) as a positive control. Assessments included disease activity index (DAI), colon length, histopathology, and levels of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and oxidative stress markers (SOD, CAT, and MDA). Mechanisms were probed using western blot, qPCR, immunofluorescence, and flow cytometry to analyze macrophage phenotypes (M1/M2) and key signaling pathway proteins. RESULTS: WYD administration dose-dependently alleviated UC symptoms, significantly mitigating body weight loss, reducing DAI scores, and restoring colon length. Histological analysis revealed improved mucosal integrity and reduced inflammatory infiltration. Quantitatively, WYD significantly suppressed pro-inflammatory cytokines (e.g, IL-1β, IL-6, and TNF-α) and attenuated oxidative stress by enhancing antioxidant enzyme activities (SOD and CAT) and decreasing MDA content. Mechanistically, WYD inhibited M1 macrophage polarization (evidenced by downregulation of inducible nitric oxide synthase [iNOS] and CD16/32) and promoted M2 polarization (upregulation of Arg-1 and CD206). Furthermore, WYD treatment significantly inhibited the activation of the PI3K/AKT/mTOR pathway and its downstream target, HIF-1α, both in vivo and in LPS-stimulated RAW264.7 cells. CONCLUSION: In summary, our findings indicate that WYD exerts significant therapeutic effects in DSS-induced UC. WYD alleviates intestinal inflammation and injury by reshaping macrophage polarization, attenuating oxidative stress, and modulating the PI3K/AKT/mTOR/HIF-1α signaling pathway. This study provides a potential therapeutic strategy for UC in the future.