Enteric infection coupled with chronic Notch pathway inhibition alters colonic mucus composition leading to dysbiosis, barrier disruption and colitis

Ahmed, Ishfaq; Roy, Badal C.; Raach, Rita-Marie T.; Owens, Sarah M.; Xia, Lijun; Anant, Shrikant; Sampath, Venkatesh; Umar, Shahid; Han, Xiaonan

doi:10.1371/journal.pone.0206701

Title: Enteric infection coupled with chronic Notch pathway inhibition alters colonic mucus composition leading to dysbiosis, barrier disruption and colitis

Journal Article · 31 October 2018 · PLoS ONE

DOI: https://doi.org/10.1371/journal.pone.0206701 · OSTI ID:1569278

Ahmed, Ishfaq ^[1]; Roy, Badal C. ^[1]; Raach, Rita-Marie T. ^[2]; Owens, Sarah M. ^[3]; Xia, Lijun ^[4]; Anant, Shrikant ^[1]; Sampath, Venkatesh ^[5];

^[1]; Han, Xiaonan ^[6]

Univ. of Kansas Medical Center, Kansas City, KS (United States). Dept. of Surgery
Univ. of Kansas, Lawrence, KS (United States). Dept. of Molecular Biosciences
Argonne National Lab. (ANL), Argonne, IL (United States). Biosciences Division
Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK (United States). Oklahoma Medical Research Foundation
Children's Mercy Hospital, Kansas City, MO (United States). Division of Neonatology
Cincinnati Children's Hospital Medical Center, Cincinnati, OH (United States)

Intestinal mucus layer disruption and gut microflora modification in conjunction with tight junction (TJ) changes can increase colonic permeability that allows bacterial dissemination and intestinal and systemic disease. In a previous study, we showed that Citrobacter rodentium (CR)-induced colonic crypt hyperplasia and/or colitis is regulated by a functional cross-talk between the Notch and Wnt/β-catenin pathways. In the current study, mucus analysis in the colons of CR-infected (10⁸ CFUs) and Notch blocker Dibenzazepine (DBZ, i.p.; 10μmol/Kg b.w.)-treated mice revealed significant alterations in the composition of trace O-glycans and complex type and hybrid N-glycans, compared to CR-infected mice alone that preceded/ accompanied alterations in 16S rDNA microbial community structure and elevated EUB338 staining. While mucin-degrading bacterium, Akkermansia muciniphila (A. muciniphila) along with Enterobacteriaceae belonging to Proteobacteria phyla increased in the feces, antimi- crobial peptides Angiogenin-4, Intelectin-1 and Intelectin-2, and ISC marker Dclk1, exhibited dramatic decreases in the colons of CR-infected/DBZ-treated mice. Also evident was a loss of TJ and adherens junction protein immuno-staining within the colonic crypts that negatively impacted paracellular barrier. These changes coincided with the loss of Notch signaling and exacerbation of mucosal injury. In response to a cocktail of antibiotics (Metro- nidazole/ciprofloxacin) for 10 days, there was increased survival that coincided with: i) decreased levels of Proteobacteria, ii) elevated Dclk1 levels in the crypt and, iii) reduced paracellular permeability. Thus, enteric infections that interfere with Notch activity may pro- mote mucosal dysbiosis that is preceded by changes in mucus composition. Controlled use of antibiotics seems to alleviate gut dysbiosis but may be insufficient to promote colonic crypt regeneration.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); University of Kansas Medical Center, Kansas City, KS (United States)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1569278

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 11 Vol. 13; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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