Gut Microbe-Derived Lipids Shape Chronic Inflammation in Cardiometabolic Disease

ABSTRACT Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible environmental factor contributing to a number of human diseases including obesity, diabetes, atherosclerotic cardiovascular disease. However, mechanisms by which gut microbial- derived factors signal to the host to promote these common cardiometabolic diseases are largely unknown. Here, we have discovered that the circulating level of select gut microbe-derived lipids called N-acyl amides are markedly reduced in the circulation of humans with obesity-driven heart failure. We also show that gut bacterially-derived N-acyl amides can signal through the host G protein-coupled receptor GPR119 to reorganize inflammatory and metabolic pathways in the host. To follow up here we propose the following central hypothesis: The microbial metabolite N-oleoyl serinol is a meal-related “lipokine” that signals via the host receptor GPR119 to suppress metainflammation in cardiometabolic disease. To test this, we have created several innovative methods to increase circulating levels of bacterially-derived N-acyl amides, and will now leverage these in preclinical mouse models of obesity, diabetes, and atherosclerosis. Successful completion of this project will advance the concept that metaorganismal endocrinology (i.e. microbial metabolite – host receptor crosstalk) can impact obesity and atherosclerosis, and will demonstrate that the host N-acyl amide receptor GRP119 may hold untapped therapeutic potential in cardiometabolic disease.