Linking bacterial enterotoxins and alpha defensin 5 expansion in the Crohn’s colitis: A new insight into the etiopathogenetic and differentiation triggers driving colonic inflammatory bowel disease

Tanu Rana, Olga Y. Korolkova, Girish Rachakonda, Amanda D. Williams, Alexander T. Hawkins, Samuel D. James, Amos M. Sakwe, Nian Hui, Li Wang, Chang Yu, Jeffrey S. Goodwin, Michael G. Izban, Regina S. Offodile, Mary K. Washington, Billy R. Ballard, Duane T. Smoot, Xuan Zheng Shi, Digna S. Forbes, Anil Shanker, Amosy E. M’Koma

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Evidence link bacterial enterotoxins to apparent crypt-cell like cells (CCLCs), and Alpha Defensin 5 (DEFA5) expansion in the colonic mucosa of Crohn’s colitis disease (CC) patients. These areas of ectopic ileal metaplasia, positive for Paneth cell (PC) markers are consistent with diagnosis of CC. Retrospectively, we: 1. Identified 21 patients with indeterminate colitis (IC) between 2000–2007 and were reevaluation their final clinical diagnosis in 2014 after a followed-up for mean 8.7±3.7 (range, 4–14) years. Their initial biopsies were analyzed by DEFA5 bioassay. 2. Differentiated ulcer-associated cell lineage (UACL) analysis by immunohistochemistry (IHC) of the CC patients, stained for Mucin 6 (MUC6) and DEFA5. 3. 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. 4. Treated colonoids with/without enterotoxins for 14 days and the spent medium were collected and determined by quantitative expression of DEFA5, CCLCs and other biologic signatures. The experiments were repeated twice. Three statistical methods were used: (i) Univariate analysis; (ii) LASSO; and (iii) Elastic net. DEFA5 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 DEFA5 stained in different locations indicating that DEFA5 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 DEFA5 treatment on NCM460 and colonoids cells expressed at different times, intervals, and intensity. These factors are key stem cell niche regulators leading to DEFA5 secreting CCLCs differentiation ‘the colonic ectopy ileal metaplasia formation’ conspicuously of pathogenic importance in CC.

Original languageEnglish (US)
Article numbere0246393
JournalPloS one
Volume16
Issue number3 March
DOIs
StatePublished - Mar 2021

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Linking bacterial enterotoxins and alpha defensin 5 expansion in the Crohn’s colitis: A new insight into the etiopathogenetic and differentiation triggers driving colonic inflammatory bowel disease'. Together they form a unique fingerprint.

Cite this