Berberine as a dual-target therapeutic for ulcerative colitis

Figure 1 Berberine’s dual pathway in ulcerative colitis. In the microbiota arm, dysbiosis elevates Proteobacteria, prompting berberine intervention that boosts Lactobacillus and Bacteroidetes populations, enhancing short-chain fatty acid (SCFA) production. Elevated SCFAs upregulate tight junction proteins zonula occludens-1 and claudin-1, restoring intestinal barrier integrity. Concurrently, the gasdermin D (GSDMD) arm activates the NLRP3 inflammasome and caspase-1, cleaving GSDMD to form membrane pores that release interleukin (IL)-1β and IL-18, driving pyroptosis. Berberine directly binds GSDMD, occluding pores and curbing cytokine release. Crosstalk amplifies protection as microbial metabolites inhibit NLRP3 activation, synergistically suppressing GSDMD-mediated pyroptosis and fortifying gut homeostasis. DSS: Dextran sulfate sodium; GSDMD: Gasdermin D; IL: Interleukin; TNF: Tumor necrosis factor; ZO-1: Zonula occludens-1; SCFA: Short-chain fatty acid.

Figure 2 Schematic illustration of the multilevel mechanism through which berberine protects the gut. Berberine reshapes the luminal microbiota toward a saccharolytic, short-chain fatty acid-rich community and normalizes bile-acid metabolism. Within the epithelium, it suppresses inflammasome activation, inhibits gasdermin D-mediated pyroptosis, and reduces interleukin-1β release. At the barrier level, berberine enhances tight-junction protein expression and limits bacterial translocation. These upstream effects synergistically reduce pro-inflammatory cytokines, restore regulatory T/T helper 17 balance, and attenuate chronic intestinal inflammation. GSDMD: Gasdermin D; IL: Interleukin; TNF: Tumor necrosis factor; ZO-1: Zonula occludens-1; SCFA: Short-chain fatty acid; Th: T helper; Treg: Regulatory T cell.