Integrative animal model and pilot clinical study reveal the therapeutic effects and mechanisms of Modified Wumei Pill against intestinal inflammation

Modified Wumei Pill (MWP) is a Chinese herbal prescription that has shown significant efficacy in ulcerative colitis (UC) patients in our previous preliminary clinical observations. However, its molecular mechanism has not yet been elucidated. The in vivo efficacy of MWP was evaluated in a DSS-induced colitis mouse model. Network pharmacology was employed to determine the main bioactive compounds and key targets of MWP for the UC treatment, and the results were validated through in vitro naïve CD4 + T-cell differentiation experiments. Subsequently, a small sample, randomized, double-blind, double-dummy controlled trial was conducted to further clarify the therapeutic effect of MWP on UC, and relevant clinical samples, including serum and colon tissues, were used to further validate the mechanisms discovered in animal experiments. Our results showed that MWP markedly attenuated disease severity, colonic damage, and pro-inflammatory cytokines expression in DSS-induced colitis mice. Network pharmacology prediction indicated Th17 cell differentiation may represent a core pathway underlying MWP’s potential effects. This was confirmed by the results from flow cytometric analysis of lymphocyte phenotypes in the spleen and mesenteric lymph nodes showing a marked decrease in the percentage of Th17 cells in MWP-treated colitis mice. Mechanistically, the human-derived CD4 + T cell experiment showed that MWP suppressed Th17 differentiation, and this effect may be partially associated with glycolytic reprogramming. Our pilot clinical study further revealed the good clinical efficacy of MWP in treating patients with active UC, with a clinical response rate of 95.65%, remission rate of 52.17%, and endoscopic response rate of 95.65%, and mucosal healing rate of 43.48%. Furthermore, similar to the results of animal experiments, the levels of Th17 cell in PBMC and key glycolytic enzymes including Glut1, HK2, PKM2, and LDHA in UC patients were significantly reduced after 8 weeks of MWP treatment. In conclusion, orally administrated MWP alleviates intestinal inflammation and promotes mucosal healing, at least partially through inhibiting Th17 cell differentiation, and holds promise as a novel immune‐based therapy for UC treatment. This clinical trial is registered with http://www.chictr.org.cn , registered at the Chinese Clinical Trial Registry (ChiCTR2200063465).