Harnessing nutrient metabolism by the gut microbiota to restrict the intestinal colonisation with multidrug-resistant pathogens

The intestine is the primary colonisation site for multidrug-resistant (MDR) pathogens and acts as a reservoir of pathogens that seed difficult-to-treat invasive infections. Methods to remove the intestinal reservoir of MDR pathogens are urgently needed. The healthy gut microbiota protects against pathogen colonisation via colonisation resistance (e.g. nutrient competition and metabolite inhibition). However, antibiotics disrupt colonisation resistance and promote MDR pathogen colonisation. Our aim is to predict and restrict MDR pathogen intestinal colonisation by manipulating the nutrient- and metabolite-defined niches occupied by MDR pathogens. Our objectives are: (1) to define the nutrient utilisation abilities and metabolite inhibition susceptibilities of MDR pathogens and gut commensals, (2) to investigate how MDR pathogens occupy nutrient-enriched and metabolite-depleted intestinal niches; (3) to predict the impact of excluding microbial functional groups on MDR pathogen colonisation, and (4) to manipulate nutrient metabolism by the gut microbiota to protect against MDR pathogen colonisation. This proposal will deliver a significant shift in the field by establishing that we can predict and control MDR pathogen colonisation within the intestine by modifying nutrient- and metabolite-defined intestinal niches using synthetic bacterial consortia. This project will lay the groundwork to design effective microbiome therapeutics to prevent or restrict MDR pathogen intestinal colonisation.