@article{8498f157599542beab294b51ee20ec45,
title = "Linking bacterial enterotoxins and alpha defensin 5 expansion in the Crohn{\textquoteright}s colitis: A new insight into the etiopathogenetic and differentiation triggers driving colonic inflammatory bowel disease",
abstract = "Evidence link bacterial enterotoxins to apparent crypt-cell like cells (CCLCs), and Alpha Defensin 5 (DEFA5) expansion in the colonic mucosa of Crohn{\textquoteright}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 {\textquoteleft}the colonic ectopy ileal metaplasia formation{\textquoteright} conspicuously of pathogenic importance in CC.",
author = "Tanu Rana and Korolkova, {Olga Y.} and Girish Rachakonda and Williams, {Amanda D.} and Hawkins, {Alexander T.} and James, {Samuel D.} and Sakwe, {Amos M.} and Nian Hui and Li Wang and Chang Yu and Goodwin, {Jeffrey S.} and Izban, {Michael G.} and Offodile, {Regina S.} and Washington, {Mary K.} and Ballard, {Billy R.} and Smoot, {Duane T.} and Shi, {Xuan Zheng} and Forbes, {Digna S.} and Anil Shanker and M{\textquoteright}Koma, {Amosy E.}",
note = "Funding Information: AEM, R21DK095186, NIDDK/NIH/USA, https://grantome.com/grant/NIH/R21-DK095186-02 AEM, LPG086, Research Foundation, American Society of Colon and Rectal Surgeons, https:// fascrs.org/my-ascrs/research-foundation/grantsawards; SEA, 3U54CA091408–09S1, 5U54RR026140-03, U54RR026140, U54CA09148-08, 5U54MD007586, NCI/NIH/USA, https://projectreporter.nih.gov/reporter_ searchresults.cfm MKW, UL1 RR024975-01, 5P30 DK58404-08/RR/NCRR NIH HHS/USA, https:// grantome.com/grant/NIH/UL1-RR024975-01 RJC, P50CA095103, S21MD000104, EHDR/NIH/USA, https://projectreporter.nih.gov/reporter_ searchresults.cfm; JEKH, 5U54MD007586, RCMI Program in Health Disparities Research/NIH/USA, https://projectreporter.nih.gov/project_info_ description.cfm?aid=9449956&icde= 36184150&ddparam=&ddvalue=&ddsub=&cr= 4&csb=default&cs=ASC&pball= AS, U54 CA163069, U54 MD007593, National Cancer Institute/National Institute of Health, /National Institute of Health SC1 CA182843, CA/NCI NIH HHS/United States https://pubmed.ncbi.nlm.nih. gov/?term=SC1+CA182843%2FCA%2FNCI+NIH +HHS%2FUnited+States%5BGrant+Number%5D and R01 CA175370, https://pubmed.ncbi.nlm.nih. gov/?term=R01+CA175370%2FCA%2FNCI+NIH +HHS%2FUnited+States%5BGrant+Number%5D The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021 Rana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2021",
month = mar,
doi = "10.1371/journal.pone.0246393",
language = "English (US)",
volume = "16",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3 March",
}