Project Summary / Abstract The human microbiome plays a vital role in health and disease. However, the ways in which the bacterial guests interact with and affect the human host at a molecular level are poorly understood. One of the most concrete 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 my laboratory is to understand and control the chemistry of human-associated bacteria in order to uncover how the bacterial guests affect the human host in states of both health and disease. We are prioritizing the study of bacterially produced metabolites from bioactive compound classes. These molecules contain conserved structural elements and have potent biological activities in the human body. Although much is known about the function of these molecules in host-self and host-pathogen interactions, less is known about how production or modification of these compounds by commensal bacteria affects other bacteria and the human host. By studying bioactive compound classes through a new lens, that of the human microbiome, we will uncover crucial 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 metabolism of bile acids. These steroidal natural products constitute an important part of the molecular environment of a healthy 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 in the host by acting both as detergents that aid in digestion and as ligands for host receptors, including FXR and TGR5. These interactions suggest that modulation of bile acids represents a significant opportunity for intervention in obesity and metabolic syndrome. However, the role of specific bile acids in the regulation of host metabolism remains undefined, and as a result, the therapeutic potential of targeting bacterial bile acid metabolism remains unexplored. Previous studies involving bile acids have fallen mainly into two categories: (1) research focused on host biology and (2) research focused on bacterial biochemistry. As a result, crucial connections between bacterial biochemical transformations of bile acids and the in vivo function of these molecules have not yet been fully established. By taking a chemically guided approach to understanding both the production and in vivo functions of this class of bacterial metabolites, we will gain a more complete understanding of these molecules and their biological activities than has ever been established. This work will provide us with a deeper understanding of how gut bacterial bile acid metabolism functions on a molecular level and how this activity affects host physiology. Our research program will...