MICROBIAL ECOLOGY OF THE INFLAMED INTESTINE

Project SummarySalmonellosis is one of the most significant food-borne diseases affecting humans and agriculture. Salmonellaenterica induces inflammation of the host intestinal tract, which disrupts the normal microbiota. Salmonellathen thrives on the nutrients that are not consumed by the microbiota. Salmonella nutrient sources include 1,2-propanediol, which is a product of the microbiota; ethanolamine, which is derived from damaged cells;glucarate and galactarate which are derived from Nos2-mediated oxidation of glucose and galactose; andfructose-asparagine (F-Asn) which is derived from the diet. The F-Asn utilization system provides aninteresting therapeutic target as inhibition of the FraB enzyme intoxicates the bacterium with a metabolicintermediate. Our primary objectives are to use a systems-level approach to identify the major nutrient sourcesutilized by Salmonella over time in the inflamed gut and to identify the microbes that compete for thosenutrients. We hypothesize that some of these nutrient acquisition systems will provide therapeutic targets forSalmonella and potentially other Enterobacteriaceae, including the carbapenem-resistant Enterobacteriaceae(CRE) that are classified as an ?urgent? threat by the CDC report, ?Antibiotic resistance threats in the UnitedStates?. In other cases, we hypothesize that the competing microbes could be utilized as probiotics or thenutrients utilized could be utilized as prebiotics. We propose to fulfill our objectives and test our hypotheseswith the following two aims: 1) Identify the chemical and biological indicators of Salmonella-mediatedinflammation over time; 2) characterize metabolic exchanges between Salmonella and its competitors in thegut. The fulfillment of these aims will greatly expand our understanding of the microbial ecology ofsalmonellosis and may be broadly relevant to other pathogens or related inflammatory disorders.