Microbial metabolites and cardiometabolic diseases

A major focus of our lab is to understand the molecular mechanisms underlying the link between the gut microbiota and cardiometabolic diseases. We hypothesize that communication between the microbiota and host is largely mediated by metabolites that are produced, or modified, by the gut microbiota. Our approach is to first identify microbial metabolites of interest by performing untargeted or targeted metabolomics in human population cohorts or mice. We then use a variety of techniques and models – including genetically modified germ-free and conventional mice, bioreactors, primary cell cultures, and gut organoids – to determine whether the metabolites are causally linked to disease.

To date, our lab has focused on two types of microbially produced metabolites: bile acids and the amino acid-derived metabolite imidazole propionate.

• Bile acids are produced in the liver from cholesterol and released into the gut where they are metabolized by bacteria and become secondary bile acids. Bile acids can signal through nuclear receptors (FXR) and membrane-bound G protein-coupled receptors (TGR5/GBAR1). We are currently investigating how different secondary bile acids are produced and how they signal, and identifying their potential role in cardiometabolic disease.
• We identified imidazole propionate as a potential diabetogenic metabolite by first performing metabolomics in portal vein blood from obese individuals with or without type 2 diabetes. We then analyzed this metabolite in peripheral plasma from an independent cohort and confirmed that it was associated with type 2 diabetes. By injecting the metabolite into mice, we showed that it could be causally linked to disease progression. We also identified a mechanism for its action by showing that it induces a novel p38γ-dependent signalling pathway.

This illustrates the mechanism by which microbial metabolites affect health and diseases.
From the review article From association to causality: the role of the gut microbiota and its functional products on host metabolism, Molecular Cell (2020).

Although our lab is focusing on the microbially produced metabolites bile acids and imidazole propionate, it is highly likely that there are other as yet unknown microbially produced, or modified, metabolites that can contribute to cardiometabolic diseases. A major challenge will be to identify them and determine their relative impact on disease progression.

Want to know more?

• Gut microbial metabolites as multi-kingdom intermediates, Nature Reviews Microbiology (2020)
• Microbially produced imidazole propionate impairs insulin signaling through mTORC1, Cell (2018) 
• From association to causality: the role of the gut microbiota and its functional products on host metabolism, Molecular Cell (2020)
• Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist, Cell Metabolism (2013)
• Microbiota-induced obesity requires farnesoid X receptor, Gut (2017)
• L-Cell Differentiation is induced by bile acids through GPBAR1 and paracrine GLP-1 and serotonin signaling, Diabetes (2020)
• Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism, Cell Metabolism (2016)