GUT-CHECK · Deciphering commensal-host-pathogen metabolic interactions to combat intestinal infections

Our intestinal tract offers an attractive environment for bacteria. The beneficial bacteria of our microbiota feast on undigested foods and provide numerous health benefits. Enteric pathogens see this environment as an entry point for infection. Both groups influence each other, creating a tripartite interaction with us, the host. Understanding this interaction represents an emerging research area to combat infections poised to improve human health. Bacteroides are key commensals in these triangular interactions, as they produce diffusible intermediates as part of their metabolism that are utilized by pathogens and the host. These metabolites arise from the action of ~100 polysaccharide utilization loci (PUL) that have been a major focus, from biochemistry to gene regulation. While the field has focused mostly on transcriptional PUL control, recent work from my group and others demonstrated that Bacteroides employ noncoding RNAs to regulate metabolic genes. These insights raise the questions: what is the mechanism by which noncoding RNAs regulate PUL, and how do these mechanisms fit within the tripartite interaction between Bacteroides, the host, and pathogens? In GUT-CHECK, I hypothesize that PUL regulation integrates transcriptional and RNA-mediated post-transcriptional control, which in turn shape the outcome of host-pathogen interactions. To test this hypothesis, I will answer three specific questions: 1) How is PUL expression regulated?2) How does PUL regulation impact interactions with pathogens and the host? 3) To what extent can PUL regulation be manipulated to thwart pathogen invasion? The proposed work will incorporate a three-way model for Bacteroides, host tissue, and a pathogen along with modern techniques such as CRISPR-based screens and Triple RNA-seq. The functional insights gained will establish fundamental understanding of host-microbiota-pathogen interaction and may lead to novel RNA-based treatments for intestinal infections.