Small molecules to study and manipulate human-associated bacteria in order to better understand how the microbiome affects human health and disease.
Seeley G. Mudd Building - Rm 622B
250 Longwood Ave
Harvard Medical School
Boston, MA 02115
Lab Size: Between 5 and 10
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 microbiology, biochemistry, analytical and organic chemistry, molecular and cellular biology, and germ-free mouse experiments. Project areas in the lab include:
1) Uncovering how and why bacteria metabolize host-produced molecules, including 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.
- Yao L, Seaton SC, Ndousse-Fetter S, Adhikari AA, DiBenedetto N, Mina AI, Banks AS, Bry L, Devlin AS. A selective gut bacterial bile salt hydrolase alters host metabolism. Elife.2018 Jul 17;7. doi: 10.7554/eLife.37182. PubMed PMID: 30014852; PubMed Central PMCID: PMC6078496.
- Devlin AS, Marcobal A, Dodd D, Nayfach S, Plummer N, Meyer T, Pollard KS, Sonnenburg JL, Fischbach MA. Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota. Cell Host Microbe. 2016 Dec 14;20(6):709-715. doi: 10.1016/j.chom.2016.10.021. Epub 2016 Dec 1. PubMed PMID: 27916477; PubMed Central PMCID: PMC5159218.
- Devlin AS, Fischbach MA. A biosynthetic pathway for a prominent class of microbiota-derived bile acids. Nat Chem Biol. 2015 Sep;11(9):685-90. doi: 10.1038/nchembio.1864. PubMed PMID: 26192599; PubMed Central PMCID: PMC4543561.