Prioritization and Bioactivity Characterization of Novel Bile Acids Produced by the Microbiome - Project Summary – Through 170 years of bile acid (BA) chemistry research, our knowledge of mammalian BA conjugation was limited to the amino acids glycine and taurine. Our group recently discovered that the gut microbiome can also conjugate BAs with a wide variety of amino acids, which has changed our fundamental understanding of BA biochemistry. These compounds are called ‘microbially conjugated bile acids’ (MCBAs), they are common in humans, particularly those with inflammatory bowel disease, and are at similar concentrations to other host-produced BAs making them physiologically relevant. Furthermore, we recently discovered they are made by unrecognized transferase activity of the bacterial enzyme bile salt hydrolase (BSH/T), which itself has been studied for decades. Here we will explore how MCBAs are made by the microbiome and how their signaling properties can alter disease outcomes in a mouse model of gut inflammation. In our preliminary data, we show myriad gut bacteria produce MCBAs and we have evidence that there is selective pressure on the BSH/T for its acyl-transfer properties. In controlled murine and cell culture experiments, we show that MCBAs agonize gut BA receptors such as FXR and TGR5, which can alter inflammatory signaling properties in gut epithelial cells. Analysis of human samples shows that MCBAs are at physiologically relevant concentrations in the gut and can enter circulation. Therefore, we believe MCBAs contribute to host-microbiome crosstalk with potential implications for gut health. We also show that BA conjugation by the host is important for overall health in the mouse DSS-model of gut inflammation. This proposal will therefore test the hypothesis that MCBAs alter can alter disease outcomes in the DSS-model due to their bioactivity which is dependent on the specific amino acid conjugated. We will use a diverse approach including microbiology, cell receptor assays, and a knockout mouse model that lacks host-BA conjugation to understand the role of these compounds in GI health. We have three principle aims: 1) Define the microbiology of MCBA production and their resistance to subsequent hydrolysis, 2) Determine their agonist activity on the ileal receptor FXR in vitro and in vivo, and 3) Show that MCBAs affect outcomes in the DSS-model of GI inflammation using BA conjugation knockout and wildtype mice. Michigan State provides all the resources needed to complete the project and the PI has assembled an integrative team with broad expertise. This project will explore the basic science of MCBAs creating a platform for research on their impacts on human health. If we can better understand the signaling and physiological role of MCBAs they could be developed as drugs to treat myriad GI diseases. Results from this project will further emphasize the importance of the chemical crosstalk between us and our microbiome for maintaining human health.
