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The small intestinal mucosa has the delicate task of allowing absorption of nutrients and limiting microbial colonization at the mucosal surface through production of antimicrobial peptides and proteins (AMPs). However, while environmental factors, including different diets, have been shown to alter AMP expression, the results from the literature are conflicting on their specific impact. Moreover, the interdependence between diet, AMPs, and metabolic health is largely unexplored. The aim of this study was thus to investigate the effect of obesogenic diets, obesity itself, and other variables, including mouse vendor, microbiota composition, and sex, on intestinal AMP expression. By using different dietary interventions in mice, we here show that prolonged intake of an obesogenic Western-style diet had a stronger impact on AMP expression than diet-independent obesity. Additionally, when comparing AMP expression under different diets in mice of both sexes from different vendors, the combined contribution of these factors had the strongest impact on absolute AMP transcript numbers, but also on the variability in small intestinal microbiota composition at the mucosa and content. Finally, we identified a novel host–microbe interaction, in which the gut commensal Faecalibaculum bloomed upon WSD-feeding and specifically induced the expression of the AMP Reg3g. Our findings thus reveal that the experimental setup, defined by mouse vendor, sex, and diet type, has a major influence on small-intestinal AMP expression. These findings could partly explain the discrepancy in the literature regarding the effect of diets on AMP expression, preventing any accurate generalization about the impact of diet on the antimicrobial response.

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.

Beneficial gut bacteria are indispensable for developing colonic mucus and fully establishing its protective function against intestinal microorganisms. Low-fiber diet consumption alters the gut bacterial configuration and disturbs this microbe-mucus interaction, but the specific bacteria and microbial metabolites responsible for maintaining mucus function remain poorly understood. By using human-to-mouse microbiota transplantation and ex vivo analysis of colonic mucus function, we here show as a proof-of-concept that individuals who increase their daily dietary fiber intake can improve the capacity of their gut microbiota to prevent diet-mediated mucus defects. Mucus growth, a critical feature of intact colonic mucus, correlated with the abundance of the gut commensal Blautia, and supplementation of Blautia coccoides to mice confirmed its mucus-stimulating capacity. Mechanistically, B. coccoides stimulated mucus growth through the production of the short-chain fatty acids propionate and acetate via activation of the short-chain fatty acid receptor Ffar2, which could serve as a new target to restore mucus growth during mucus-associated lifestyle diseases.