Gut-on-chip models for clearing pathogens with the competitive abilities of gut strains

The increase in antimicrobial resistant (AMR) pathogens colonising the gut is associated with an increase in morbidity, mortality rates and high health care costs. It is estimated that bacterial AMR was directly responsible for 1.14 million global deaths in 2021 and contributed to 4.71 million deaths. The resident microbiota confers protective mechanisms against AMR pathogens known as colonization resistance (CR). The role of the gut resident microbiome in providing CR against AMR pathogens has been demonstrated by our group and others. These mechanisms include competitive microbial-microbial interactions but also complex microbial-host interactions. The capacity of the resident microbiota to block pathogens is partially provided by blocking their access to nutrients (nutrients-mediated competition). Much less explored in the gut microbiome is the capacity of commensals to directly kill pathogens with bacterial weapons (toxin-mediated competition). This project will address strategies to clear AMR pathogens by harnessing the competitive ability of gut strains possessing weapons (toxins-mediated competition) and the ability to starve pathogens (nutrients-mediated competition). For this, we will use an innovative technology called gut-on-a-chip built with human colonic cells from patient biopsies combined with validation via other in vitro and in vivo experiments (germ-free mice). This project aims not only to find solutions against AMR pathogens but also to better understand and predict CR. CR is modulated by host and microbial factors, making it hard to track and understand changes. A gut-on-a chip technology, will allow us to study and predict host-microbe interactions in a controllable manner; but also understand how the host modulates these microbial interactions and how the gut structure and physiology affect the CR dynamics. A human based gut-on-a-chip technology could be used as a tool to discover and develop new microbiome-derived therapeutics to fight AMR.