Metaorganismal Endocrinology 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, 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.

Grant Number: 5R01DK130227-04
NIH Institute/Center: NIH
Principal Investigator: Jonathan Brown