Metaorganismal Endocrinology in Cardiometabolic Disease

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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, cardiovascular disease, and cancer. However, mechanisms by which gut microbial-derived factors signal to the host to promote these diseases are largely unknown. We have recently discovered a metaorganismal pathway where nutrients present in high fat foods (phosphatidylcholine, choline, and L-carnitine) can be metabolized by the gut microbial enzymes to generate trimethylamine (TMA), which is then further metabolized by the host enzyme flavin-containing monooxygenase 3 (FMO3) to produce trimethylamine-N-oxide (TMAO). Here we show that pharmacologic inhibition of the gut microbial choline TMA lyase enzyme CutC/D protects mice against the metabolic disturbances associated with a high fat diet. Unexpectedly, this protection is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. These studies described in this proposal will be significant because they have the potential to uncover the first ever described diet-microbe-derived zeitgeber. Successful completion of this project will be transformative by providing proof of concept that a non-antibiotic drug targeting a specific microbial enzyme can serve as a therapeutic strategy for diseases associated with circadian disruption.