The long-term goal of the Devlin lab is to understand and control the chemistry of human-associated bacteria in order to uncover 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 bacteria metabolize host-produced molecules, including bile acids, steroids, and vitamins, and the effects of these compounds on host physiology. Host-produced compounds such as steroids and vitamins act as crucial signaling molecules and regulators of host biology, but their chemical transformations by gut bacteria have been relatively unexplored. We hypothesize that chemical modifications of host-produced molecules by gut bacteria produce metabolites with altered functions compared to the parent compounds. We aim to uncover both the ways in which bacteria make these molecules (that is, what bacterial genes and proteins are responsible) and the biological roles of these bacterially modified metabolites. 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, obesity, and depression.
2. Controlling bacterial metabolism in vivo using small molecule inhibitors and probes of gut bacterial enzymes. There is currently growing interest in targeting the gut microbiome for the betterment of human health and the treatment of disease. However, there are very few examples of interventions that selectively target the microbiome in vivo. Most treatments are like sledgehammers – they are either non-selective (e.g., antibiotics) or target a wide variety of bacterial metabolites (e.g., resins like cholestyramine). Moreover, from the point of view of discovery-based science, our ability to control the levels of bacterially produced small molecules in vivo in hosts containing a complete microbiome is currently limited. While germ-free animals are a useful tool, in order to investigate the effects of bacteria on the host in the context of the full complement of bacterial and mammalian processes, it is necessary to perform experiments in conventionally raised animals. In order to address the challenge of controlling bacterial metabolism in vivo and to pave the way for new therapeutic strategies to improve human health and treat disease, we are designing, synthesizing, and utilizing small molecule probes of gut bacterial enzymes. This work has implications for the prevention or treatment of a range of human diseases, including inflammatory bowel disease, liver disease, type 1 and type 2 diabetes, and cardiovascular disease.
A biosynthetic pathway for the selective sulfonation of steroidal metabolites by human gut bacteria
Yao L, D’Agostino GD, Park J, Hang S, Adhikari AA, Zhang Y, Li W, Avila-Pacheco J, Bae S, Clish CB, Franzosa EA, Huttenhower C, Huh JR, Devlin AS.
Nature Microbiology 2022, 7 (9), 1404–1418. DOI
Human gut bacteria produce TH17-modulating bile acid metabolites
Paik D, Yao L, Zhang Y, Bae S, D’Agostino GD, Kim E, Franzosa EA, Avila-Pacheco J, Bisanz JE, Rakowski CK, Vlamakis H, Xavier RJ, Turnbaugh PJ, Longman RS, Krout MK, Clish CB, Huttenhower C, Huh JR, Devlin AS.
Nature 2022, 603 (7903), 907–912. DOI
Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects
Chaudhari SN, Harris DA, Aliakbarian H, Luo JN, Henke MT, Subramaniam R, Vernon AH, Tavakkoli A, Sheu EG, Devlin AS.
Nature Chemical Biology 2021, 17 (1), 20–29. DOI
Development of a covalent inhibitor of gut bacterial bile salt hydrolases
Adhikari AA, Seegar TCM, Ficarro SB, McCurry MD, Ramachandran D, Yao L, Chaudhari SN, Ndousse-Fetter S, Banks AS, Marto JA, Blacklow SC, Devlin AS.
Nature Chemical Biology 2020, 16 (3), 318–326. DOI