Exploring molecular mechanisms by which microbially produced metabolites protect against or promote type 2 diabetes

Type 2 diabetes (T2D) is a common condition of diverse aetiologies diagnosed by high blood glucose levels. Over the past 20-years it has become evident that the gut microbiota is altered in patients with T2D.

One outstanding question is if the altered gut microbiota contributes to disease development or merely reflects the disease state.

We and others have shown that the gut microbiota interacts with the diet to produce bioactive metabolites that can regulate host metabolism.

Here we will explore the effects of structurally related metabolites: caffeic acid-derived metabolites and imidazole propionate (ImP), which are negatively and positively associated with T2D, respectively.

It is unclear how caffeic acid-derived metabolites are produced and thus we will use a combination of metagenomics, classical microbiology, biochemistry and bacterial genetics to identify bacterial strains with high capacity to produce these metabolites as well as the specific enzymes.

We will also investigate how these metabolites and ImP affect glucose metabolism in mice by combining hyperinsulinemic-euglycemic clamps, single cells sequencing, and gene deficient mice.

This work will extend microbiome associations to causality and mechanisms and may provide insights into how the microbiome and can be leveraged to identify novel treatment strategies for T2D.