An Enteric Pathogen Subverts Colonization Resistance by Evading Competition for Amino Acids in the Gut

• Published in: Cell host & microbe 2020-10, Vol.28 (4), p.526-533.e5
• Main Authors: Caballero-Flores, Gustavo, Pickard, Joseph M., Fukuda, Shinji, Inohara, Naohiro, Núñez, Gabriel
• Format: Article
• Language: English
• Subjects: amino acid biosynthesis; Amino Acids - biosynthesis; Animals; Bacteria - genetics; Citrobacter rodentium; Citrobacter rodentium - pathogenicity; colonization resistance; enteric pathogen; Female; Gastrointestinal Microbiome - genetics; Gastrointestinal Microbiome - physiology; Gastrointestinal Tract - microbiology; Gastrointestinal Tract - pathology; Gene Expression Regulation, Bacterial; Male; Mice; Mice, Inbred C57BL; microbiota; Tn-seq
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2020.06.018

The microbiota confers host protection by limiting the colonization of pathogenic bacteria in the gut, but the mechanisms by which pathogens overcome colonization resistance remain poorly understood. Using a high-density transposon screen in the enteric pathogen Citrobacter rodentium, we find that the bacterium requires amino acid biosynthesis pathways to colonize conventionally raised mice, but not germ-free or antibiotic-treated animals. These metabolic pathways are induced during infection by the presence of the gut microbiota. Reduced amounts of amino acids are found in the guts of conventionally raised mice compared with germ-free animals. Dietary administration of high protein increases amino acid levels in the gut and promotes pathogen colonization. Thus, the depletion of amino acids by the microbiota limits pathogen colonization, and in turn, the pathogen activates amino acid biosynthesis to expand in the presence of the microbiota. [Display omitted] •Tn-seq screen revealed genes required for pathogen expansion in the mouse gut•The microbiota depletes the gut of amino acids, limiting their availability•C. rodentium induces amino acid biosynthesis for its expansion in the gut•Administration of a high protein diet promotes pathogen colonization in mice The mechanisms allowing pathogens to subvert colonization resistance are poorly understood. Using a high-density mutant library, Caballero-Flores et al. identify genes required for early pathogen expansion in the presence of the gut microbiota. They find that induction of pathogen amino acid biosynthesis and increased dietary amino acids promote pathogen colonization.