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Intestinal homeostasis and host defense as promoted by commensal bacteria and the colonic mucus layer

University of British Columbia

The intestinal tract harbours the largest population of microbes in the human body where they play an important role in promoting the health of their host. If the composition of these microbes is altered, this may lead to dysbiosis that triggers or exacerbates intestinal and extra-intestinal diseases. Probiotics have been investigated as a complementary therapy in dysbiosis-related diseases. However, their effectiveness in treating severe conditions such as Inflammatory Bowel Disease (IBD) is quite variable and have shown controversial results. To address the importance of a personalized probiotic approach to treat intestinal inflammation, we first examined the effect of personalized bacteria using a model of chemical induced colitis. The animals that received commensals isolated from their own feces were more protected against inflammation as they showed reduced signs of colitis, less histological damage and lower levels of inflammatory markers as compared to mice given a commercial probiotic strain. Next, the role of the intestinal mucin Muc2 and the Core-1 enzyme that glycosylates it were explored using the Citrobacter rodentium model of infectious colitis. The intestinal mucus layer is the first line of defense in the intestine and is largely composed of the secreted mucin Muc2. Since almost all enteric bacteria must cross the overlying mucus layer to infect the host, the mucus-enteric bacterial interactions provide fundamental knowledge about infectious diseases as well as inflammatory conditions linked to dysbiosis (e.g. IBD). Specifically, we compared C. rodentium susceptibility by infecting WT, Muc2 -/-, core 3 (C3GnT) -/-, core -1 (C1galt1) -/-, and C1galt1 f/f mice. While C3GnT -/- mice showed a very similar phenotype to WT mice with only mild inflammation, complete absence of Muc2 or just core 1 derived O-glycans resulted in significantly higher histological damage, barrier disruption, and increased pathogen burdens. Interestingly, the supplementation of tributyrin protected mice against infection resulting in less histological damage and lower C. rodentium colonization as compared to control groups. These studies highlight a novel personalized therapy that may be considered relevant to diseases affected by dysbiosis as well as the key role of Muc2 and its core 1 glycosylation in host defense against enteric infections.

Text

2019-11-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/68002

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/