Limitation of amino acid availability by bacterial populations during enhanced colitis in IBD mouse model

Abstract

ABSTRACT Members of the Enterobacteriaceae and Enterococcus are associated with persistent gut inflammation due to rapid colonization combined with pathogenic tendencies. Here, we investigated the functions of gut microbial populations resulting in persistent gut inflammation. In this study, we utilized the IL-10 knockout mouse model and induced colitis using dextran sulfate sodium (2%) after development. Dams during gestation were provided cefoperazone to induce vertically transmitted dysbiosis in the pups that were monitored in this study. We characterized the dysbiotic gut microbial community and potential crosstalk of these microbes, and host gene expression changes to identify bacterial populations and potential functions that were involved in gut inflammation. We isolated Enterobacteriaceae populations from mice to validate the utilization of sulfur-containing amino acids. Members of Enterobacteriaceae and Enterococcus were highly detected in inflamed mice. Enterobacteriaceae populations containing L-cysteine dioxygenase were strongly correlated with the upregulation of host gene CSAD, responsible for cysteine breakdown. We observed that bacterial isolates from dysbiotic mice displayed increased growth rates when supplemented with L-cysteine, highlighting the use of sulfur metabolism. Our results show that microbial populations use alternate metabolisms and sequester host nutrients for growth, associated with inflammation in the gut.IMPORTANCEInflammatory bowel disease is associated with an increase in Enterobacteriaceae and Enterococcus species; however, the specific mechanisms are unclear. Previous research has reported the associations between microbiota and inflammation, here we investigate potential pathways that specific bacteria populations use to drive gut inflammation. Richie et al. show that these bacterial populations utilize an alternate sulfur metabolism and are tolerant of host-derived immune-response products. These metabolic pathways drive host gut inflammation and fuel over colonization of these pathobionts in the dysbiotic colon. Cultured isolates from dysbiotic mice indicated faster growth supplemented with L-cysteine, showing these microbes can utilize essential host nutrients.

Keywords

• fecal microbiota transplantation
• inflammatory bowel disease
• microbial-host interactions
• amino acid uptake
• RNA sequencing
• shotgun metagenomics