18β-Glycyrrhetinic acid from Glycyrrhiza Uralensis protects colonic epithelium in ulcerative colitis by activating Wnt/β-catenin pathway to restore tight junction.

BACKGROUND

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon. Glycyrrhiza uralensis extract (ULE), a traditional medicinal plant extract, is globally recognized for its anti-inflammatory and gastrointestinal therapeutic effects. However, the precise mechanisms underlying the therapeutic benefits of ULE in UC management remain poorly understood.

PURPOSE: This study aimed to elucidate the pharmacological effects of ULE and its primary active constituent, 18β-glycyrrhetinic acid (18β-GA), on the colonic epithelium in UC rat models.

STUDY DESIGN AND

METHODS

We employed a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced UC rat model and a TNBS-LPS-induced UC Caco-2 cell model to explore the protective mechanisms of ULE and 18β-GA. The methodologies included UPLC-Q/TOF-MS chemical analysis in chemico, network pharmacological screening in silico, histopathological and flow cytometry evaluations in vivo, and molecular biological validation in vitro.

RESULTS

ULE significantly alleviated UC symptoms in rats, including weight loss, diarrhea, and rectal bleeding, particularly at a dosage of 100 mg/kg. Network pharmacology and transcriptomic analyses identified the Wnt pathway as a pivotal hub linking inflammation, epithelial proliferation, and tight junction integrity. ULE treatment reduced apoptosis (from 13.24% to 8.34%), CD3+ T cells (from 13% to 6.04%), and CD45RA+ B cells (from 7.23% to 1.67%) in colonic tissues. Furthermore, ULE restored tight junction protein expression, notably increasing Occludin (2.5×) and ZO-1 (5.3×). Similarly, 18β-GA activated the Wnt/β-catenin signaling pathway and elevated tight junction protein expression, thereby protecting against UC-like damage in the Caco-2 cell model. These protective effects were potentiated by the Wnt pathway agonist SKL2001 and diminished by the antagonist IWR-1.

CONCLUSION

ULE and its active constituent, 18β-GA, exhibit protective effects against TNBS-induced colonic epithelial injury and tight junction protein disruption by upregulating the Wnt/β-catenin signaling pathway, making them promising therapeutic candidates for UC management.