Document Type
Article
Publication Date
11-1-2018
Identifier
DOI: 10.1371/journal.pone.0206701; PMCID: PMC6211731
Abstract
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. We showed previously 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, antimicrobial 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 (Metronidazole/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 promote 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.
Journal Title
PLoS One
Volume
13
Issue
11
First Page
0206701
Last Page
0206701
MeSH Keywords
Animals; Animals, Outbred Strains; Citrobacter rodentium; Colitis; Colon; Dibenzazepines; Disease Models, Animal; Dysbiosis; Enterobacteriaceae Infections; Enzyme Inhibitors; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mucus; Receptors, Notch; Signal Transduction; Tight Junctions
Keywords
Outbred Strains; Citrobacter rodentium; Colitis; Colon; Dibenzazepines; Disease Models, Animal; Dysbiosis; Enterobacteriaceae Infections; Enzyme Inhibitors; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mucus; Receptors, Notch; Signal Transduction; Tight Junctions
Recommended Citation
Ahmed I, Roy BC, Raach RT, et al. Enteric infection coupled with chronic Notch pathway inhibition alters colonic mucus composition leading to dysbiosis, barrier disruption and colitis. PLoS One. 2018;13(11):e0206701. Published 2018 Nov 1. doi:10.1371/journal.pone.0206701
Comments
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.
Publisher's Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206701
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