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.
Citation
Ahmed I, Roy BC, Raach R-MT, Owens
SM, Xia L, Anant S, et al. (2018) Enteric infection
coupled with chronic Notch pathway inhibition
alters colonic mucus composition leading to
dysbiosis, barrier disruption and colitis. PLoS ONE
13(11): e0206701. https://doi.org/10.1371/journal.
pone.0206701