Modulation of Gut Bacteria-derived Host Metabolites

Project Summary/AbstractCrohn's disease and Ulcerative Colitis, collectively referred to as inflammatory bowel disease (IBD) aredevastating diseases that affect over one million people in the US. Current IBD therapies target the immunesystem, leaving patients susceptible to opportunistic infections. Therefore, the discovery of new therapeutics forIBD is an important priority. Recent studies have discovered several metabolites produced exclusively by gutbacteria that exert immunomodulatory effects at the mucosal interface. Indolepropionic acid (IPA) has emergedas the most exciting compound thus far in that it specifically engages host receptors and protects fromexperimental colitis in mice. This compound is produced by a discrete number of strictly anaerobic gutcommensal bacteria including Clostridium sporogenes. Strategies to modulate levels of IPA could represent anew adjunct therapy for IBD patients. Despite the broad interest in this compound, the specific biochemicalpathways involved in its synthesis are entirely unknown.Our long-term objective is to develop new therapeutic strategies aimed at controlling the metabolic output of gutbacterial communities. The goal of the current proposal is to unravel the biochemical pathway for IPAsynthesis in C. sporogenes and to establish methods for increasing its production within the gut. The specificaims are to: 1) Determine how metabolic engineering and nutrient availability influence IPA production byClostridium sporogenes in vitro, and 2) Develop strategies for ecosystem restructuring to promote therapeuticIPA production in the mouse gut. We will leverage newly developed genetic tools to understand how and whygut bacteria produce IPA. Using this information, we will assemble synthetic microbial communities in the gutdesigned to promote colonization by IPA producing bacteria. Finally, we will use these communities to reprogramIPA levels in mice and test whether we can protect against experimental colitis. The outcomes of these aims willrepresent the first steps toward controlling the metabolic output of gut bacteria for clinical benefit. This knowledgewill be broadly relevant to modulating other microbial metabolites implicated in human diseases such as uremia,liver disease, cardiovascular disease, and autism.The proposed research is part of a mentored career development plan to achieve an academic careerstudying host-microbe interactions. The principal investigator is a PhD-trained microbiologist with training inClinical Pathology. My goal as an independent scientist is to understand the microbial contribution to thebiochemical inventory within our body. The mentor for this project is Dr. Justin Sonnenburg, a pioneer in studyingthe contribution of gut bacteria to host biology. The career development plan includes a research advisory board,a career development committee, seminars in microbial physiology, formal coursework in bacterial genetics andecology, and presentations at microbiome and human metabolic conferences. These activities will provide thenecessary environment and experiences for developing an independent research career.