Genetic variation in glucosamine metabolism contributes to the colonization resistance of Bacteroides to Salmonella.

The gut microbiota contributes to variation in susceptibility to enteric infection, but the underlying mechanisms remain poorly defined. Here, we leverage a natural model of disease resistance comparing Salmonella-resistant indigenous Tibetan chickens with susceptible commercial broilers to uncover conserved mechanisms of colonization resistance relevant to human health. We find that enrichment of Bacteroides, particularly B. salanitronis, is associated with resistance, and supplementation with B. salanitronis significantly reduces S. Enteritidis colonization in susceptible hosts. Mechanistically, Bacteroides species competitively deplete N-acetyl-D-glucosamine (GlcNAc), a growth-limiting carbohydrate for S. Enteritidis, through highly efficient glucosamine-6-phosphate deaminase (GNPDA) activity. Enzymatic assays, structural modeling, and mutational analysis identify Ile138 as critical for the catalytic advantage of Bacteroides GNPDA over S. Enteritidis GNPDA. Replacing this residue abolishes the competitive advantage, confirming its role in nutrient-mediated colonization resistance. These findings show how genetic variation in microbial nutrient-metabolizing enzymes shapes interspecies competition and suggests microbiome-based strategies for controlling enteric pathogens.