Background: The intestinal mucus layer is comprised of heavily glycosylated mucins, including mucin 2 (MUC2), that serve as a nutrient source for certain bacterial members of the gut microbiota. Only a subset of gut commensals encode the glycoside hydrolases required to degrade mucin glycans. However, mucin-degrading microbes can release glycans and generate compounds that can cross-fed non-mucin degrading microbes, creating complex microbial networks. While pairwise studies have shown that mucin degradation drives cross-feeding and metabolite exchange, the broader impact of mucins on community structure and metabolic output remains poorly understood.

Objective: In this study, we sought to identify how a defined microbial consortium of human commensals with varied mucin-degrading capacities responds to MUC2 to shape community composition and metabolic output.

Methods: A defined consortium of human gut commensals with varied mucin-degrading capacities was cultivated in anaerobic bioreactors in the presence or absence of porcine MUC2. Community composition was assessed, and extracellular metabolites were quantified using targeted and untargeted metabolomic profiling.

Results: MUC2 supplementation significantly altered community structure, promoting the expansion of Akkermansia muciniphila while reducing Prevotella. MUC2 also reshaped microbial metabolism, decreasing acetate levels while increasing propionate, butyrate, and formate. In addition, MUC2 supplementation altered amino acid utilization and vitamin metabolism and reduced several neuroactive compounds, including glutamate, γ-aminobutyric acid (GABA), and anthranilic acid, while increasing tryptamine levels.

Conclusion: These findings demonstrate that mucins exert broad effects on microbial community structure and metabolic output. Collectively, this work highlights the central role of bacterial cross-feeding in shaping gut ecosystem function.