Abstract
Elucidating the role of metabolites and signaling molecules used by the microbiota and pathogens is critical to develop strategies to support intestinal homeostasis and to prevent pathogenic infection. Utilization of the nutrient ethanolamine (EA) by commensal bacteria and enteric pathogens remains incompletely understood and has important implications for human health. The dogma of the EA utilization field had been that pathogens metabolize EA as a noncompetitive metabolite, based on one study that examined expression of EA utilization (eut) genes by bovine commensal Escherichia coli. The view of EA as a metabolite that is specifically used by pathogens as a way to overcome commensal nutritional competition has broad implications for our understanding of EA use in the intestinal tract. However, limitations of the aforementioned study led us to re-examine EA utilization by human commensal E. coli. We hypothesized that commensal E. coli, which encode conserved eut loci with pathogenic Enterobacteriaceae, would respond to EA to promote eut gene expression and growth using EA. In Chapter 2, we demonstrate that EA supports human commensal E. coli gene expression and growth, resulting in outgrowth compared to the enteric pathogen enterohemorrhagic E. coli O157:H7 (EHEC) in co-culture. Additionally, commensal E. coli sense EA to alter fimbrial gene expression, which may impact host colonization. Therefore, our data challenge the dogma that pathogens preferentially utilize EA and demonstrate that commensal E. coli sense EA to alter gene expression and promote metabolism. Unlike commensal E. coli, EHEC is a foodborne pathogen with significant morbidity and mortality, and an extremely low infectious dose is sufficient to cause disease. Without therapeutic options to treat EHEC infection, better understanding of EHEC pathogenesis is critical. Before this work, the role of the eut operon transcriptional regulator EutR in EHEC intestinal pathogenesis remained to be elucidated. In Chapter 3, we use the murine model of EHEC infection, Citrobacter rodentium, to show that EutR impacts virulence and colonization in the intestinal tract. Additionally, a critically important but understudied area of enteric pathogenesis is the ability to transmit to naïve hosts. We demonstrate that EutR-dependent gene expression promotes effective transmission to naïve hosts to contribute to pathogen propagation in a host population. Together, these studies expand our understanding of intestinal metabolism and signaling in host-pathogen-microbiota interactions.
