Abstract
Under normal physiological conditions, the colonic mucus layer functions as part of the initial innate defence system, providing a critical protective barrier that shields the underlying epithelium from pathogenic invasion. This essential barrier, primarily composed of MUC2 mucins, forms a bi-layered structure consisting of an inner dense layer devoid of bacteria and an outer loose layer colonised by commensal microorganisms that work in synergy with the host to maintain colonic homeostasis.
Environmental factors, particularly the host diet, have the potential to significantly shape the composition and function of the colonic mucus barrier, thereby influencing its protective capacity. In recent decades, the global transition towards Western-style diets high in saturated fats and added sugars has been associated with a loss of colonic barrier function and a subsequent rise in the incidence of colonic diseases such as colorectal cancer (CRC). While extensive research has been conducted on the effects of high-fat diets on colonic dysbiosis and barrier function, there remains a paucity of information regarding the direct impact of high-sugar diets on colonic function, particularly concerning the mucus barrier.
To investigate the impact of prolonged high-glucose exposure on the colonic mucus barrier, a simplified in vitro model of the colonic epithelium was employed, consisting of differentiated and mucus-secreting HT29 MTX-E12 cells. This model aimed to simulate the effects of a high-sugar diet on the structure, composition, and integrity of the colonic mucus layer. Under both low and high glucose concentrations, HT29 MTX-E12 cells produced an adherent mucus barrier with similar structural characteristics. However, exposure to elevated glucose levels led to significant alterations in mucin protein expression and subsequent modifications to the mucus layer composition. Specifically, high glucose conditions induced a significant reduction in MUC2 production while simultaneously upregulating MUC5AC production, a mucin subtype frequently associated with colonic disease.
In co-culture experiments, Bacteroides fragilis, a mucin-degrading colonic commensal, demonstrated an enhanced ability to modulate mucin dynamics under high glucose conditions. Exposure of cells to both enterotoxigenic (ETBF) and non-toxigenic (NTBF) strains of B. fragilis resulted in a decrease in both MUC2 gene expression and MUC2 protein abundance, which was not observed under low glucose conditions. However, despite these glucose-mediated changes, the mucus barrier maintained its protective function against the toxigenic effects of ETBF under both high and low glucose conditions, as evidenced by the absence of toxin-induced cell damage reported in other studies using non-mucus-producing cell lines.
While the current study did not demonstrate a direct causal relationship between a high glucose environment and ETBF-mediated colorectal carcinogenesis, the findings suggest a potential dietary-related mechanism by which commensal bacterial strains with mucin-degrading abilities may exhibit an enhanced capacity to modulate the dynamics of the colonic mucus barrier. This was reinforced by the positive effect that butyrate (a dietary-related bacterial metabolite) had on MUC2 expression in cells grown under low (but not high) glucose conditions. These alterations in mucin dynamics serve to highlight the complex interplay between an individual’s diet and gut microbiota in maintaining colonic barrier function.