Project 463076

The gastrointestinal tract is home to a complex community of microorganisms, called the microbiota. The microbiota benefits the host by digesting complex fibers, regulating inflammatory responses, and inhibiting the expansion of harmful bacteria. Unfortunately, antibiotics or inflammation disrupt the microbiota. As a result, many patients with inflammatory conditions, such as inflammatory bowel disease, have a disrupted microbial community where some members of the microbiota, including the Proteobacteria group, that are usually present in very low numbers, significantly expand and can become dominant. In healthy states, Proteobacteria are inhibited by beneficial microbes through their production of short-chain fatty acids (SCFA), which are small molecules produced by fermentation of complex fibers. When the microbiota is disrupted, SCFA levels decrease and Proteobacteria expand using strategies to rapidly replicate and outcompete the beneficial members of the microbiota. For example, some Proteobacteria use an enzyme called urease to break down host-derived urea providing them with a source of nitrogen, an essential resource for bacterial replication. Importantly, these alterations in the microbiota contribute to inflammation and can increase the risk of systemic infections. Therefore, the ability to correct this microbial imbalance would improve health outcomes for many individuals. Unexpectedly, we have found that some beneficial microbes also encode urease, and that urease is predictive of high SCFA production. Currently, little is known about urease in beneficial microbes. The goal of this project is to elucidate the role of urease in beneficial microbes, its impact on healthy community structure, and its contribution to preventing or reversing dangerous Proteobacteria expansion. Overall, this project will contribute to the development of a new class of therapeutics that are designed to restore the microbiota's beneficial function.