Distinct roles of the mucus layer and microbiota in conferring innate host defense and susceptibility to disease
Date
2018-05-09
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
The intestinal epithelium is covered with a thick viscous MUC2 mucin bilayer that acts as a protective barrier and is the habitat for 1014 microorganisms that form the microbiota. Even though disruption of colonic mucus and alterations in microbial composition are intimately linked to gastrointestinal health and disease, their distinct contribution in the pathogenesis of colonic injury is not well understood. In this thesis, I interrogated the impact of alterations in the microbial composition in animals with and without Muc2 mucus in colonic epithelial barrier dysfunction and inflammation, using chemical and pathogen-induced colitis models. For all studies Muc2+/+ and Muc2+/+ littermates were used to normalize the microbiota. To induce dysbiosis (alterations in microbial composition) and reduce bacterial numbers, mice were treated with a broad-spectrum cocktail of antibiotics. Basally, Muc2-/- littermates showed low-grade ongoing inflammation, gastrointestinal permeability and alterations in tight junction proteins that were restored after antibiotic treatment. Muc2+/+ microbiota had a protective innate role against DSS-induced colitis, while microbiota from Muc2 deficient animals did not. Muc2+/+littermates that received Muc2-/- microbiota exhibited a shift in bacteria families and increased susceptibility to DSS and Citrobacter rodentium-induced colitis, demonstrating a critical role for Muc2 mucus in shaping a healthy microbiota in intestinal homeostasis. I also investigated the interdependent relationship between the mucus layer and colonic microbiota in Entamoeba histolytica (Eh)-induced secretory and inflammatory responses, using Muc2-/- and Muc2+/+ littermates and germ-free mice. Following microbial disruption with antibiotics, Eh elicited increased water and mucus secretions and enhanced pro-inflammatory responses. Eh also dysregulated the transcription factor for secretory goblet cells, Math1, which was microbiota dependent. Germ-free mice showed decrease pro-inflammatory and mucus secretagogue responses towards Eh, demonstrating that commensal microbiota plays an important role in mediating host protection against Eh and that dysbiosis can render the colonic epithelium susceptible to Eh-induced pro-inflammatory responses and tissue injury. These findings unravel the interconnected role of a healthy Muc2 barrier and commensal microbiota in maintaining intestinal innate host defense against colonic injury.
Description
Keywords
Microbiota, Mucus layer, Entamoeba histolytica, inflammatory bowel disease
Citation
Leon Coria, A. (2018). Distinct roles of the mucus layer and microbiota in conferring innate host defense and susceptibility to disease (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/31921