The microbial community inhabiting the large intestine confers protection against enteric pathogens, a property known as colonization resistance. A disruption of the microbial community by antibiotic treatment is accompanied with increased susceptibility to infections with enteric pathogens, such as Salmonella enterica. However, the mechanisms lowering colonization resistance after antibiotic treatment remain poorly understood, which represents a key gap in knowledge that will be addressed in this application. Our central hypothesis is that antibiotic treatment induces a mild inflammatory response associated with the generation of reactive oxygen and nitrogen species, which in turn react with carbohydrates to generate inflammation-derived nutrients that fuel luminal growth of S. enterica. We will test key aspects of our hypothesis by determining whether oxidized carbohydrates reduce colonization resistance against S. Typhimurium after antibiotic treatment (Aim 1). It is our expectation that successful completion of the proposed experiments will establish the innovative new concept that the local inflammatory response creates a unique nutritional environment that is conducive to a bloom of enteric pathogens capable of utilizing inflammation-derived nutrients. Successful completion will be significant because results from this work will have broad relevance for understanding the mechanisms underlying colonization resistance against enteric pathogens, changes in microbial communities during conditions of intestinal inflammation (e.g. inflammatory bowel disease), and the pathogenesis of antibiotic-related intestinal disorders (e.g. irritable bowel syndrome).
Salmonella is a leading food borne pathogen worldwide. Susceptibility to infection is increased after antibiotic treatment through unknown mechanisms. Here we will investigate the biochemistry of bacterial-host interaction leading to multiplication and growth of S. enterica after disturbance of the indigenous microbiota by antibiotic treatment using animal models of infectious disease. By elucidating the molecular mechanisms underlying ecological forces that control the balance between the pathogen, the host and its microbiota, the proposed experiments will usher in important conceptual advances that have a strong potential to exert a high impact on this field of science.
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| Faber, Franziska; Tran, Lisa; Byndloss, Mariana X et al. (2016) Host-mediated sugar oxidation promotes post-antibiotic pathogen expansion. Nature 534:697-9 |
