Altered Mucus Glycosylation in Core 1 O-Glycan-Deficient Mice Affects Microbiota Composition and Intestinal Architecture

Abstract

A functional mucus layer is a key requirement for gastrointestinal health as it serves as a barrier against bacterial invasion and subsequent inflammation. Recent findings suggest that mucus composition may pose an important selection pressure on the gut microbiota and that altered mucus thickness or properties such as glycosylation lead to intestinal inflammation dependent on bacteria. Here we used TM-IEC C1galt -/- mice, which carry an inducible deficiency of core 1-derived O-glycans in intestinal epithelial cells, to investigate the effects of mucus glycosylation on susceptibility to intestinal inflammation, gut microbial ecology and host physiology. We found that TM-IEC C1galt -/- mice did not develop spontaneous colitis, but they were more susceptible to dextran sodium sulphate-induced colitis. Furthermore, loss of core 1-derived O-glycans induced inverse shifts in the abundance of the phyla Bacteroidetes and Firmicutes. We also found that mucus glycosylation impacts intestinal architecture as TM-IEC C1galt-/- mice had an elongated gastrointestinal tract with deeper ileal crypts, a small increase in the number of proliferative epithelial cells and thicker circular muscle layers in both the ileum and colon. Alterations in the length of the gastrointestinal tract were partly dependent on the microbiota. Thus, the mucus layer plays a role in the regulation of gut microbiota composition, balancing intestinal inflammation, and affects gut architecture.

Genetic and environmental control of host-gut microbiota interactions

“…This high heritability presumably results from the fine tuning of a symbiotic relationship that has co-evolved for millions of years. Among the likely contributing factors are differences in immunoglobulin and antibacterial molecules secreted into the gut lumen (Wen et al 2008;Vijay-Kumar et al 2010;Shulzhenko et al 2011), differences in the mucosal gut structure (Sommer et al 2014;Wlodarska et al 2014), and differences in bile acid metabolism (Ryan et al 2014).…”

The mucosal barrier at a glance

“…Mucus is impermeable to commensal bacteria, with the exception of that forming the outer layer in the colon (Johansson et al, , 2008(Johansson et al, , 2013. Mucins are highly glycosylated proteins produced and released by goblet cells that vary in structure, function and sites of expression (Fu et al, 2011;Johansson et al, 2013;Larsson et al, 2011;Sommer et al, 2014). For example, differences in their protein domains distinguish the transmembrane mucins anchored to the epithelial layer from the detached gel-forming mucins.…”

Microbiota-Mediated Inflammation and Antimicrobial Defense in the Intestine

“…Some pathogens and commensal bacteria can penetrate the dense mucin layer by proteolytic degradation (30, 31), and a subset of commensal bacteria can penetrate the outer mucin layer and break down and metabolize the O -linked glycans attached to Muc2 (32–34) (Figure 1). Deficient O -linked glycosylation of Muc2 by epithelial cells increases susceptibility to dextran sodium sulfate (DSS)-induced colitis and also shifts the composition of the microbiota (35, 36). DSS administration to mice is associated with increased bacterial penetration of the inner mucous layer by commensal bacteria, potentially leading to subsequent inflammation (37).…”