We 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:
1) Uncovering how and why bacteria metabolize 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 or which genes are responsible. By uncovering how and why bacteria transform these compounds, we will pave the way for the rational alteration of the human gut microbiome to treat diseases such as inflammatory bowel disease and obesity.
2) Monitoring and altering bacterial metabolism in vivo. The composition and metabolic output of the gut bacterial community changes in response to diet, lifestyle, and other environmental factors. Our ability to understand these changes is limited because we rely on excretions or post-mortem analyses to study bacterial populations and metabolic products. We are designing, synthesizing, and utilizing activity-based small molecule probes to selectively monitor and affect bacterial metabolism in vivo.
3) Developing novel synthetic methods to access antibiotic scaffolds. Researchers in the human microbiome field need better tools to differentiate between and control the levels of pathogenic and commensal bacteria in vivo. In addition, there is a pressing medical need for new antibiotics targeting pathogenic bacteria. We are developing novel methods to rapidly access oxidized core structures found in selected classes of bioactive natural products with demonstrated antibiotic activity but for which no facile method of synthesis has yet been elucidated.