Research

Bacteria_holding_tubesWe are not alone. The human body harbors more bacterial cells than human cells, and approximately one kilogram of bacteria reside in the human gut. From the moment we are born, bacteria begin training our immune system to fight disease, and bacteria in our intestinal tract aid in digestion, releasing nutrients and vitamins for our use. Microbial imbalance has been linked do a wide range of disease states, including inflammatory bowel disease, colon and liver cancers, diabetes, autism, and obesity. However, the molecular mechanisms by which the microbiota affects human health are largely unknown.

Our lab uses small molecules to study and manipulate human-associated bacteria in order to better understand how the microbiome affects human health and disease. The lab leverages expertise from different fields, including synthetic organic chemistry, molecular biology, microbiology, analytical chemistry, and bioinformatics. Project areas in the lab include:

Investigating bacterial metabolism of bile acids. Bacteria in the large intestine transform human-derived primary bile acids into secondary bile acids in near-quantitative fashion. Secondary bile acids exert wide-ranging biological effects, from acting as causative agents in colon and liver cancer to binding nuclear receptors and initiating downstream metabolic cascades. Despite their important role in human health, we know very little about which bacteria metabolize bile acids and even less about which genes are responsible. By pairing bioinformatics with biochemical techniques, we are identifying novel bacterial bile acid metabolizers and the corresponding genetic machinery responsible for these transformations. Discovery of bile acid-metabolizing genes will enable the discovery of other metabolizers using bioinformatics and may aid in the prediction of disease risk. Using in vitro and in vivo assays, we are investigating the hypotheses that bacteria either derive energy from bile acid modifications or alter the toxicity of these compounds in order to obtain a competitive growth advantage. We are also investigating how these molecules affect the host using both cell culture assays and germ-free and conventional mouse experiments. In particular, we aim to uncover how bile acids affect host metabolism and immune response by acting as ligands for host receptors, including nuclear receptors and G-protein coupled receptors. By uncovering new biosynthetic pathways and biological roles for bacterially modified bile acids, we will pave the way for the rational alteration of the human gut microbiome to treat diseases such as inflammatory bowel disease and obesity.

Developing small molecule probes of in vivo bacterial metabolism. We know that bacteria produce small molecules, some at levels comparable to or exceeding those of typical drugs. What effect do these molecules have on the host? We are limited in our ability to control the levels of these compounds in conventional animals, i.e., animals that possess a full complement of microorganisms from birth, so that we can determine their biological effects. In addition, we often rely on excretions or post-mortem analyses to study bacterial populations and their metabolic products. In the Devlin lab, we are designing, synthesizing, and utilizing activity-based small molecule probes to selectively monitor and affect bacterial metabolism in vivo.