Tshikudi, Diane Malu2025-08-072025-08-072025-07-242025-07-252025-08-07http://hdl.handle.net/1993/39207Ulcerative colitis (UC), an acute inflammation of the colon, is characterized by long-term care and carries an increased risk of complications, including surgery, sepsis, and cancer. Epidemiological studies have shown that UC affects more men than women, underscoring the need to consider sex as a biological variable in UC therapeutic research. Defective immune response and compromised colonic mucosa integrity and function appear central in UC etiology and pathophysiology. Growing evidence suggests that complete regeneration of the colonic mucosa in UC patients predicts long-term remission, reduced risk of complications, and improved quality of life. However, 80-85% of UC patients fail to achieve complete mucosal healing, highlighting the need to develop effective therapeutic strategies that offer complete mucosal healing for individuals with UC. Chromogranin A (CHGA), a marker for enteroendocrine cells, can undergo proteolytic cleavage and generate Pancreastatin (PST). High levels of colonic CHGA and PST in patients with UC correlate with UC severity, and mediators of inflammation and apoptosis are all known to disrupt the mucosal barrier functions. However, the effects of CHGA and PST depletion on colonic epithelial integrity and mucosal functions are not understood. Here, we characterized the influence of CHGA ablation and PST inhibition with the Pancreastatin inhibitor 8 (PSTi8) on colonic epithelial integrity, mucosal barrier functions, and healing under homeostatic and colitic conditions between sexes. Males and females CHGA knockout or C57BL/6 mice treated with PSTi8, or PBS for six days were treated with 5% dextran sodium sulfate (DSS) to induce colitis or water (control) for five days. We tested markers specific to intestinal mucosa proliferation and differentiation, epithelial cell lineages, and mucosal mediators. These studies demonstrated that female mice are protected against DSS-induced colitis due to higher healing potential, correlating with enhanced epithelial cell proliferation and differentiation and increased mucosal barrier function. Moreover, we reported distinct immune cells and cytokines spatial patterns across colon segments between sexes during experimental colitis, suggesting a link between biological sex, the compartmentalization of immune responses in the colon, and the potential susceptibility of males to colitis. However, the deletion of CHGA correlated with increased production of TGF-β, which likely reduces the abundance of hematopoietic cells, dampens mucosal inflammation and limits intestinal mucosal damage in males. However, the same process promotes a loss of intestinal integrity and mucosal barrier function in females. Similarly, PST inhibition with PSTi8 correlates with reduced epithelial cell differentiation, likely mediated by lower Atoh1 in females and BMP4 in males under homeostatic conditions. Furthermore, treatment with PSTi8 correlated with increased susceptibility to colitis in females while offering a protective effect in males. This research highlights notable sex-based differences in colonic mucosal integrity and barrier functions under steady state and colitic conditions. These differences were associated with variations in immune responses along the large intestine and distinct reactions to CHGA deletion and neutralization of PST between males and females.engInflammatory bowel diseaseUlcerative colitisChromogranin AIntestinal epitheliumpancreastatin inhibitionMucosal immunitySex-related differences