Dual roles of complement in ulcerative colitis: insights from clinical studies and animal research

Ulcerative colitis (UC), a major form of inflammatory bowel disease (IBD), is marked by chronic mucosal inflammation and epithelial barrier disruption. The complement system, a central component of the immune system, is a key modulator of UC pathogenesis. Recent studies from clinical observations and dextran sulfate sodium (DSS)-induced murine colitis models reveal that complement activation plays a context-dependent role in UC. Complement components such as C3a, C5a, and the membrane attack complex (MAC) exacerbate mucosal inflammation and epithelial injury by promoting neutrophil recruitment and cytokine storms, while initiator molecules C1q and mannose-binding lectin (MBL) support protective functions, including immune regulation, apoptotic cell clearance, and tissue repair. This review synthesizes current clinical and experimental evidence on the bidirectional roles of the complement system in UC, with emphasis on the regulatory balance between protective and pathogenic pathways. Emerging therapeutics, ranging from C5aR antagonists to colon-targeted complement inhibitors, highlight the translational potential of modulating complement activity in UC. Understanding these mechanisms provides a framework for developing complement-targeted therapies and precision treatment strategies in IBD.