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Retrospectively, we: <jats:bold>1.<\/jats:bold> Identified 21 patients with indeterminate colitis (IC) between 2000\u20132007 and were reevaluation their final clinical diagnosis in 2014 after a followed-up for mean 8.7\u00b13.7 (range, 4\u201314) years. Their initial biopsies were analyzed by <jats:italic>DEFA5<\/jats:italic> bioassay. <jats:bold>2.<\/jats:bold> Differentiated ulcer-associated cell lineage (UACL) analysis by immunohistochemistry (IHC) of the CC patients, stained for Mucin 6 (MUC6) and <jats:italic>DEFA5<\/jats:italic>. <jats:bold>3<\/jats:bold>. Treated human immortalized colonic epithelial cells (NCM460) and colonoids with pure DEFA5 on the secretion of signatures after 24hr. The control colonoids were not treated. <jats:bold>4<\/jats:bold>. Treated colonoids with\/without enterotoxins for 14 days and the spent medium were collected and determined by quantitative expression of <jats:italic>DEFA5<\/jats:italic>, CCLCs and other biologic signatures. The experiments were repeated twice. Three statistical methods were used: (i) Univariate analysis; (ii) LASSO; and (iii) Elastic net. <jats:italic>DEFA5<\/jats:italic> bioassay discriminated CC and ulcerative colitis (UC) in a cohort of IC patients with accuracy. A fit logistic model with group CC and UC as the outcome and the DEFA5 as independent variable differentiator with a positive predictive value of 96 percent. IHC staining of CC for MUC6 and <jats:italic>DEFA5<\/jats:italic> stained in different locations indicating that <jats:italic>DEFA5<\/jats:italic> is not co-expressed in UACL and is therefore NOT the genesis of CC, rather a secretagogue for specific signature(s) that underlie the distinct crypt pathobiology of CC. Notably, we observed expansion of signatures after <jats:italic>DEFA5<\/jats:italic> treatment on NCM460 and colonoids cells expressed at different times, intervals, and intensity. These factors are key stem cell niche regulators leading to <jats:italic>DEFA5<\/jats:italic> secreting CCLCs differentiation \u2018the colonic ectopy ileal metaplasia formation\u2019 conspicuously of pathogenic importance in CC.<\/jats:p>","DOI":"10.1371\/journal.pone.0246393","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T18:31:13Z","timestamp":1615314673000},"page":"e0246393","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Linking bacterial enterotoxins and alpha defensin 5 expansion in the Crohn\u2019s colitis: A new insight into the etiopathogenetic and differentiation triggers driving colonic inflammatory bowel disease"],"prefix":"10.1371","volume":"16","author":[{"given":"Tanu","family":"Rana","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga 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