High-fat diet–induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide

Authors: YOO, WOONGJAE - Vanderbilt University Medical Center; ZIEBA, JACOB - Vanderbilt University Medical Center; FOEGEDING, NORA - Vanderbilt University Medical Center; TORRES, TERESA - Vanderbilt University Medical Center; SHELTON, CATHERINE - Vanderbilt University Medical Center; SHEALY, NICOLAS - Vanderbilt University Medical Center; BYNDLOSS, AUSTIN - University Of California, Davis; CEVALLOS, STEPHANIE - University Of California, Davis; Gertz, Erik; TIFFANY, CONNOR - University Of California, Davis; THOMAS, JULIA - Vanderbilt University Medical Center; LITVAK, YAEL - University Of California, Davis; NGUYEN, HENRY - University Of California, Davis; OLSAN, ERIN - University Of California, Davis; Bennett, Brian; RATHMELL, JEFFREY - Vanderbilt University Medical Center; MAJOR, AMY - Vanderbilt University Medical Center; BAUMLER, ANDREAS - University Of California, Davis; BYNDLOSS, MARIANA - Vanderbilt University Medical Center

Submitted to: Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/29/2020
Publication Date: 8/13/2021
Citation: Yoo, W., Zieba, J.K., Foegeding, N.J., Torres, T.P., Shelton, C.D., Shealy, N.G., Byndloss, A.J., Cevallos, S.A., Gertz, E.R., Tiffany, C.R., Thomas, J., Litvak, Y., Nguyen, H., Olsan, E.E., Bennett, B.J., Rathmell, J.C., Major, A.S., Baumler, A.J., Byndloss, M.X. 2021. High-fat diet–induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide. Science. 373(6556):813-818. https://doi.org/10.1126/science.aba3683.
DOI: https://doi.org/10.1126/science.aba3683

Interpretive Summary: The gut microbiota is a newly discovered factor mediating the biological effects of diet on a person’s health. For example, eating a high fat diet is thought to promote cardiovascular disease and one way that a high-fat diet may contribute to cardiovascular disease is through the microbiota’s metabolism of dietary choline to trimethylamine (TMA), a metabolite oxidized to atherosclerosis-promoting trimethylamine N-oxide (TMAO) in the liver. TMAO is mechanistically linked to increased cardiovascular disease in humans but the specific host-microbiota interactions altering TMA/TMAO production are largely unknown. In these studies we demonstrate that a high-fat diet triggered changes in the gut environment that escalated choline catabolism by facultative anaerobic Enterobacteriaceae, such as Escherichia coli. The alteration of the microbiota composition, to one supporting Escherichia coli, may in fact be due to increased oxygen and nitrate production by the host’s intestinal cells. These data suggest that high-fat diet alters the microenvironment of the gut lumen and thus accelerates the development of cardiovascular disease.

Technical Abstract: Western-style high-fat diet promotes cardiovascular disease, in part by enhancing microbiota-mediated conversion of dietary choline into trimethylamine (TMA), a metabolite oxidized to atherosclerosis-promoting trimethylamine N-oxide (TMAO) in the liver. Here we show that high-fat diet triggered changes in the gut environment that escalated choline catabolism by facultative anaerobic Enterobacteriaceae, such as Escherichia coli. High-fat diet elevated the bioavailability of host-derived oxygen and nitrate, two respiratory electron acceptors that drove a dysbiotic expansion of E. coli in the gut lumen. Notably, choline utilization by E. coli was nitrate respiration-dependent, thus linking a high-fat diet-induced luminal production of host-derived nitrate to an increase in TMAO levels in the circulation. These data suggest that high-fat diet enhances the cardiovascular disease-inducing activity of the microbiota by impairing habitat filters that limit the availability of host-derived respiratory electron acceptors, which in turn drives an expansion of choline-utilizing Enterobacteriaceae, while simultaneously escalating their ability to produce TMA.