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Intestinal barrier restoration is the most important determinant of remission in IBD, yet there are very few existing therapies that protect IECs from damage or support epithelial repair. The goal of this study was to develop a model system and tools that can be used to identify therapeutics that promote IEC survival in IBD. We developed a Beclin-1 cleavage reporter (BICR) that detects calpain-mediated Beclin-1 cleavage and the switch from autophagy to programmed cell death. We modified BICR with the HIV Tat peptide (BICR-Tat) and tested it in a model of live bacterial stress using commensal E. coli and IEC. BICR sensitively and specifically detected calpain activity in cell-free assays, and BICR-Tat successfully detected Beclin-1 cleavage and autophagy failure in IEC. Achieving IEC survival in the microbe-challenged IBD gut would be an important advance toward intestinal barrier restoration in this intractable disease. The BICR-Tat reporter coupled with the model of microbial stress developed in this study could enable high-throughput screening approaches to identify therapeutics with the potential to achieve barrier healing and sustained remission in IBD.<\/jats:p>","DOI":"10.3390\/cells15100917","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"917","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Detection of Calpain-Mediated Beclin-1 Cleavage for Drug Discovery in Inflammatory Bowel Diseases"],"prefix":"10.3390","volume":"15","author":[{"given":"Kylee A.","family":"Hunter","sequence":"first","affiliation":[{"name":"Department of Microbial Sciences in Health, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6701-1640","authenticated-orcid":false,"given":"Anne-Marie C.","family":"Overstreet","sequence":"additional","affiliation":[{"name":"Department of Microbial Sciences in Health, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryon Benjamin","family":"Koff","sequence":"additional","affiliation":[{"name":"Department of Microbial Sciences in Health, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hridai","family":"Dharan","sequence":"additional","affiliation":[{"name":"Department of Microbial Sciences in Health, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3171-9244","authenticated-orcid":false,"given":"Steven","family":"Overend","sequence":"additional","affiliation":[{"name":"Department of Microbial Sciences in Health, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannette S.","family":"Messer","sequence":"additional","affiliation":[{"name":"Department of Microbial Sciences in Health, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Center for Microbiome and Human Health, Cleveland Clinic Research, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7247238","DOI":"10.1155\/2019\/7247238","article-title":"A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease","volume":"2019","author":"Guan","year":"2019","journal-title":"J. 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