HUMAN MICROBIOME METABOLITES IN HEALTH AND DISEASE

Project Summary / AbstractThe human microbiome plays a vital role in health and disease. However, the ways in which the bacterialguests interact with and affect the human host at a molecular level are poorly understood. One of the mostconcrete effects that human-associated bacteria have on the host is to produce small molecule metabolites,some of which accumulate in the body to levels higher than that of a typical drug. The long-term goal of mylaboratory is to understand and control the chemistry of human-associated bacteria in order to uncover how thebacterial guests affect the human host in states of both health and disease. We are prioritizing the study ofbacterially produced metabolites from bioactive compound classes. These molecules contain conservedstructural elements and have potent biological activities in the human body. Although much is known about thefunction of these molecules in host-self and host-pathogen interactions, less is known about how production ormodification of these compounds by commensal bacteria affects other bacteria and the human host. Bystudying bioactive compound classes through a new lens, that of the human microbiome, we will uncovercrucial small molecule-mediated interactions underlying host health and disease.Over the next five years, one major focus area of my laboratory will be to investigate the bacterial metabolismof bile acids. These steroidal natural products constitute an important part of the molecular environment of ahealthy human gut. In the colon, bile acids are modified by the resident bacteria in near-quantitative fashion,forming a class of roughly 50 different metabolites called secondary bile acids. Bile acids play crucial roles inthe host by acting both as detergents that aid in digestion and as ligands for host receptors, including FXR andTGR5. These interactions suggest that modulation of bile acids represents a significant opportunity forintervention in obesity and metabolic syndrome. However, the role of specific bile acids in the regulation of hostmetabolism remains undefined, and as a result, the therapeutic potential of targeting bacterial bile acidmetabolism remains unexplored.Previous studies involving bile acids have fallen mainly into two categories: (1) research focused on hostbiology and (2) research focused on bacterial biochemistry. As a result, crucial connections between bacterialbiochemical transformations of bile acids and the in vivo function of these molecules have not yet been fullyestablished. By taking a chemically guided approach to understanding both the production and in vivofunctions of this class of bacterial metabolites, we will gain a more complete understanding of these moleculesand their biological activities than has ever been established. This work will provide us with a deeperunderstanding of how gut bacterial bile acid metabolism functions on a molecular level and how this activityaffects host physiology. Our research program will also lay the groundwork for the rational manipulation of themicrobiome in a clinical context to treat disease and improve health.