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These conditions share overlapping symptoms but differ significantly in etiology and pathology, making accurate differentiation essential for appropriate management. This pilot study investigated protease activity in stool samples using a custom panel of fluorogenic peptide substrates across varying pH conditions to uncover disease-specific enzymatic signatures. Samples from IBD patients revealed broad protease activation involving both serine and cysteine classes, while the small IBS cohort showed a tendency toward a pattern enriched in furin-like serine proteases pattern dominated by furin-like serine proteases, especially at alkaline pH. Notably, one substrate, Ac-RSVL-AMC, showed higher activity in UC than in CD at acidic pH and moderate discriminatory ability in this pilot cohort. Inhibition assays confirmed the enzymatic contribution of furin-like proteases, and follow-up analysis in remission-phase IBD patients indicated persistent dysregulation, suggesting potential biomarker utility beyond active inflammation. The observed substrate-specific activity profiles highlight the importance of sequence context in proteolytic cleavage and underscore the complexity of protease involvement in gastrointestinal pathology. These findings support fecal protease profiling as a promising, rapid and low-cost approach that could contribute to distinguishing IBD from IBS and differentiating IBD subtypes, providing a foundation for future minimally invasive diagnostic strategies that require validation in larger cohorts.<\/jats:p>","DOI":"10.1038\/s41598-025-32301-6","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T18:45:04Z","timestamp":1765997104000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Protease profiling in fecal samples: a novel non-invasive diagnostic tool for gastrointestinal disorders"],"prefix":"10.1038","volume":"16","author":[{"given":"Laura","family":"Baldassar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Cendron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Facchin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Redavid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigida","family":"Barberio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Jorkesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Dettin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Pasquato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo Vincenzo","family":"Savarino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"32301_CR1","doi-asserted-by":"publisher","first-page":"2769","DOI":"10.1016\/S0140-6736(17)32448-0","volume":"390","author":"SC Ng","year":"2017","unstructured":"Ng, S. 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