Berberine as a dual-target therapeutic for ulcerative colitis

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by a dysregulated immune response, gut microbiota imbalance, and epithelial barrier disruption. Preclinical studies using dextran sulfate sodium-induced colitis models, which mimic UC pathology, have highlighted the therapeutic potential of berberine, a bioactive isoquinoline alkaloid derived from traditional Chinese medicine. The efficacy of berberine is attributed to a dual mechanism involving microbiota remodeling and direct inhibition of gasdermin D (GSDMD), which collectively suppress pyroptosis and intestinal inflammation. Through these actions, berberine restores tight junction proteins (e.g., zonula occludens-1, claudin-1), reduces pro-inflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α), and improves disease-associated clinical outcomes. Importantly, this dual-target profile distinguishes berberine from conventional single-pathway agents, as it simultaneously modulates luminal microbial communities and epithelial inflammasome signaling, thereby targeting a critical interface linking microbial dysbiosis, epithelial cell death, and immune activation. However, current evidence is largely derived from acute experimental models and indirect modulation of GSDMD, highlighting the need for deeper mechanistic and translational validation. Thus, with further clinical optimization, berberine emerges as a promising adjunct therapeutic candidate for the inflammation- and barrier-centric treatment of UC. Therefore, this opinion-review emphasizes not only what berberine does, but why its combined targeting of microbiota, GSDMD, and pyroptosis represents a conceptually compelling strategy for UC management.

Keywords: Ulcerative colitis; Inflammatory bowel disease; Berberine; Traditional Chinese medicine; Fecal microbiota transplantation; Gasdermin D

Core Tip: Berberine ameliorates ulcerative colitis by modulating gut microbiota dysbiosis and inhibiting gasdermin D-mediated pyroptosis. It enriches beneficial taxa that produce short-chain fatty acids, suppresses proinflammatory cytokines (e.g., interleukin-1β, tumor necrosis factor-α), and restores epithelial tight junctions (zonula occludens-1, claudin-1). Preclinical dextran sulfate sodium mouse models demonstrate reduced inflammation, histological damage, and clinical scores.