$8.5M Federal Grant Aims for Big Impact from Small Molecules in the Gut

Anatomical diagram of human intestine, stomach, and liver
June 7, 2021

Yale researchers across a range of disciplines are coming together to explore the important role of microbial metabolites in our microbiota – the trillions of bacterial cells that colonize our intestines.

The collaboration brings together scientists from the Faculty of Arts and Sciences, Yale School of Medicine and Yale School of Public Health with the support from the National Institute of General Medical Sciences of the National Institutes of Health (NIH).

Modern analytical technologies have led to the realization that the vast majority of metabolites
found in any microbe or animal, including humans, remain unknown. Estimates suggest that we only understand the functions of 0.1% of all small molecules derived from the microbiota.

A new $8.5 million NIH grant will seek to answer some of the big questions of this so called “dark matter” of the metabolome, with the results expected to have profound functional consequences in human health and disease.

The initiative combines expertise from a variety of Yale programs. The Yale Institute of Biomolecular Design and Discovery (IBDD) will join forces with faculty from across Yale with research backgrounds in chemical biology, immunobiology, epidemiology, and microbial pathogenesis to illuminate novel small molecule signals from the dark matter of the host-bacteria interface that regulate host G-protein coupled receptor (GPCR) signaling programs.

“I’m excited to work alongside colleagues from across Yale toward the kind of big outcomes that are possible when we connect our laboratories,” said Jason Crawford, Maxine F. Singer ’57 Ph.D., Associate Professor of Chemistry and of Microbial Pathogenesis, principal investigator of the grant, and Director of the IBDD.

“This study represents an unprecedented exploration of the “dark matter” of the microbiota metabolome, which we hope will lead to targeted therapeutic strategies for a variety of human diseases.”

Specifically, the new program will characterize the molecular mechanisms of GPCR signaling mediated by the microbiota, discover potential signals of “orphan” GPCRs, and explore interactions between receptor-targeted medical drugs and their molecular responses that “rewire” chemical signaling at the host-microbiota interface.

The new grant provides funding for five years. In addition to Crawford, Noah Palm (Immunobiology) and Caroline Johnson (Epidemiology) are serving as co-principal investigators. Andrew Goodman (Microbial Pathogenesis) is a significant contributor to the program. Goodman is Director of the Microbial Sciences Institute, which is also on Yale’s West Campus.

For more information about the Yale IBDD, visit the institute’s website.