Camostat mesylate restores intestinal barrier integrity and attenuated protein loss in experimental protein-losing enteropathy.

Protein-losing enteropathy (PLE) is a serious complication following the Fontan operation for single-ventricle congenital heart disease, characterized by excessive gastrointestinal protein loss, intestinal lymphangiectasia, and impaired epithelial barrier function. Dysregulated protease activity has been implicated in the pathogenesis of intestinal barrier disruption, suggesting protease inhibition as a potential therapeutic strategy. Here, we established a dextran sulfate sodium (DSS)-induced colitis mouse model that recapitulates key characteristics of PLE, including hypoalbuminemia, elevated fecal alpha-1 antitrypsin (A1AT), lymphangiectasia, and reduced EpCAM/claudin-7 expression. Oral administration of camostat mesylate (CM) significantly attenuated weight loss, colon shortening damage, and lymphangiectasia. In DSS-challenged Caco-2 monolayers, CM also restored DSS-induced reductions in ZO-1 expression and transepithelial electrical resistance. In a patient with Fontan-associated PLE, fecal A1AT decreased from 370.80 mg/dL to 254.90 mg/dL over 6 months of CM treatment, and serum albumin in a patient with Fontan-associated PLE increased from 1.9 g/dL to 4.2 g/dL over 21 months. These findings demonstrated that camostat mesylate improved intestinal barrier function and clinical outcomes, highlighting its potential for managing PLE following the Fontan operation.