Innovative experimental approaches to determine how the human microbiota prevents Salmonella Typhimurium infections

The gastrointestinal microbiota protects humans from many infections. It remains unknown why levels of “colonisation-resistance” vary from person-to-person. We will focus on S.Typhimurium diarrhoea, building on the unique Wellcome-funded CHANTS S.Typhimurium-human-challenge clinical study to close this knowledge gap. We will create a unique set of human-microbiota models using mice and fermenters. By combining pre-infection CHANTS stool samples with matched data on gut-colonisation by gastroenteritis-associated and bloodstream-associated S. Typhimurium strains, we aim to replicate colonisation-resistance seen in volunteers. We will measure Salmonella infection-kinetics and use multi-omics to probe mechanisms and investigate effects of dietary-composition on colonisation-resistance. Our transformative models will allow colonisation-resistance mechanisms of the human gut microbiota to be studied for first time. We will address critical unanswered questions regarding how the human gut microbiota prevents S.Typhimurium infections: 1) Do the nutrient-utilisation patterns of resident E.coli or other microbiota families determine the level of colonisation resistance? 2) Can we identify or create gut microbiotas which universally-protect against a whole range of S.Typhimurium strains with distinct colonisation properties? We will share our microbiota-communities and individual genome-sequence microbiota strains with scientists worldwide to help transform understanding of how human microbiota prevents Salmonella infections, and enable the rational design of microbiome-based preventative medicines.