Milk-derived casein glycomacropeptide improves colonic mucus function under Western-style diet feeding in a sialylation-dependent manner.

The colonic mucus layer is the primary interface between the host and the gut microbiota. It serves both as an ecological niche for bacteria and a barrier protecting the host from microbial exposure. Disruption of the mucus layer, particularly under Western-style diet (WSD) feeding, increases the risk of infection and inflammation. Here, we identify casein glycomacropeptide (CGMP), a milk-derived glycopeptide, as a novel dietary supplement capable of preserving mucus function under WSD consumption. Notably, we demonstrate that the sialylation level of CGMP is a key determinant of its protective effects. Supplementation of highly sialylated CGMP not only prevented WSD-induced mucus defects but also altered the gut microbiota composition, enhancing beneficial bacterial genera, particularly Bifidobacterium. Mechanistically, bacterial shifts were associated with increased production of the short-chain fatty acid propionate, which can induce mucus growth. Our findings thus reveal sialylated CGMP as a promising prebiotic supplement to counteract diet-induced mucus dysfunction, highlighting the importance of protein-bound glycan structures in modulating host-microbiota interaction.