Correction: 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.

[This corrects the article DOI: 10.1371/journal.pone.0246393.].

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.

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.

Adenocarcinoma at the Ileostomy Site After a Proctocolectomy for Ulcerative Colitis and/or Familial Adenomatous Polyposis: An Overview.

Adenocarcinoma that occurs at the ileostomy site after proctocolectomy (TPC) with an end ileostomy for ulcerative colitis (UC) and/or familial adenomatous polyposis (FAP) is a late and uncommon complication. To ascertain the rate of adenocarcinoma at the empirical ileostomy site following TPC, a review of the literature was conducted. PubMed, MEDLINE, the Cumulative Index of Nursing and Allied Health Literature, EMBASE, Google search engine, and the Cochrane Database were investigated for research published between January 1975 and December 2016. Search criteria included English language and human-only publications; broad search terms related to UC, FAP, ileostomy procedures, and dysplasias were used. Abstracts were eliminated if they were foreign language and nonhuman studies; editorials also were excluded. Secondary and hand/manual searches of reference lists, other studies cross-indexed by authors, reviews, commentaries, books, and meeting abstracts also were performed. Data extracted included age at diagnosis, operation technique, interval to ileostomy cancer, age when cancer was diagnosed, histology for both UC and FAP patients, and subsequent treatment. Papers were included on the basis of available evidence for each specific point of interest. Final and conclusive agreement was assessed with the k statistics during the title review and abstract review. Studies that did not report original data also were excluded. A total of 5753 publications were identified; 5697 publications did not conform to inclusion criteria and were eliminated. Among the reviewed publications (all case studies), 57 patients were diagnosed with ileostomy adenocarcinoma after TPC; 42 had UC, and 15 had FAP. The interval between TPC operation and ileostomy cancer diagnosis ranged from 3 to 51 years for UC and from 9 to 40 years for FAP, with a mean interval of 30 and 26 years, respectively. Biopsies were performed of all polypoid lesions found at the stoma site. Patients were treated with wide excision and refashioning (diversion) of the stoma. While adenocarcinoma arising at the mucocutaneous junction at the ileostomy site with adjacent skin invasion after TPC for UC and FAP appears to be rare, patients and clinicians need to be aware of this potential complication even years after surgery and regular screening is recommended.

Correction: Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease.

[This corrects the article DOI: 10.1371/journal.pone.0179710.].

Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease.

Inability to distinguish Crohn's colitis from ulcerative colitis leads to the diagnosis of indeterminate colitis. This greatly effects medical and surgical care of the patient because treatments for the two diseases vary. Approximately 30 percent of inflammatory bowel disease patients cannot be accurately diagnosed, increasing their risk of inappropriate treatment. We sought to determine whether transcriptomic patterns could be used to develop diagnostic biomarker(s) to delineate inflammatory bowel disease more accurately. Four patients groups were assessed via whole-transcriptome microarray, qPCR, Western blot, and immunohistochemistry for differential expression of Human α-Defensin-5. In addition, immunohistochemistry for Paneth cells and Lysozyme, a Paneth cell marker, was also performed. Aberrant expression of Human α-Defensin-5 levels using transcript, Western blot, and immunohistochemistry staining levels was significantly upregulated in Crohn's colitis, p< 0.0001. Among patients with indeterminate colitis, Human α-Defensin-5 is a reliable differentiator with a positive predictive value of 96 percent. We also observed abundant ectopic crypt Paneth cells in all colectomy tissue samples of Crohn's colitis patients. In a retrospective study, we show that Human α-Defensin-5 could be used in indeterminate colitis patients to determine if they have either ulcerative colitis (low levels of Human α-Defensin-5) or Crohn's colitis (high levels of Human α-Defensin-5). Twenty of 67 patients (30 percent) who underwent restorative proctocolectomy for definitive ulcerative colitis were clinically changed to de novo Crohn's disease. These patients were profiled by Human α-Defensin-5 immunohistochemistry. All patients tested strongly positive. In addition, we observed by both hematoxylin and eosin and Lysozyme staining, a large number of ectopic Paneth cells in the colonic crypt of Crohn's colitis patient samples. Our experiments are the first to show that Human α-Defensin-5 is a potential candidate biomarker to molecularly differentiate Crohn's colitis from ulcerative colitis, to our knowledge. These data give us both a potential diagnostic marker in Human α-Defensin-5 and insight to develop future mechanistic studies to better understand crypt biology in Crohn's colitis.

Identification of pathologic features associated with "ulcerative colitis-like" Crohn's disease.

AIM: To identify pathologic features associated with this "ulcerative colitis (UC)-like" subgroup of Crohn's disease (CD). METHODS: Seventeen subjects diagnosed as having UC who underwent proctocolectomy (RPC) from 2003-2007 and subsequently developed CD of the ileal pouch were identified. UC was diagnosed based on pre-operative clinical, endoscopic, and pathologic studies. Eighteen patients who underwent RPC for UC within the same time period without subsequently developing CD were randomly selected and used as controls. Pathology reports and histological slides were reviewed for a wide range of gross and microscopic pathological features, as well as extent of disease. The demographics, gross description and histopathology of the resection specimens were reviewed and compared between the two groups. RESULTS: Patients with "UC-like" CD were on average 13 years younger than those with "true" UC (P < 0.01). More severe disease in the proximal involved region and active ileitis with/without architectural distortion were observed in 6 of 17 (35%) and 7 of 17 (41%) "UC-like" CD cases, respectively, but in none of the "true" UC cases (P < 0.05). Active appendicitis occurred in 8 of 16 (50%) "UC-like" CD cases but in only two (11%) "true" UC cases (P < 0.05). Conspicuous lamina propria neutrophils were more specific for "UC-like" CD (76% vs 22%, P < 0.05). In addition, prominent lymphoid aggregates tended to be more common in "UC-like" CD (P = 0.07). The "true" UC group contained a greater number of cases with severe activity (78% vs 47%). Therefore, the features more commonly seen in "UC-like" CD were not due to a more severe disease process. Crohn's granulomas and transmural inflammation in non-ulcerated areas were absent in both groups. CONCLUSION: More severe disease in the proximal involved region, terminal ileum involvement, active appendicitis, and prominent lamina propria neutrophils may be morphological factors associated with "UC-like" CD.