A Western-style, high-fat diet promotes cardiovascular disease, in part because it is rich in choline, which is converted to trimethylamine (TMA) by the gut microbiota. However, whether diet-induced changes in intestinal physiology can alter the metabolic capacity of the microbiota remains unknown. Using a mouse model of diet-induced obesity, we show that chronic exposure to a high-fat diet escalates Escherichia coli choline catabolism by altering intestinal epithelial physiology. A high-fat diet impaired the bioenergetics of mitochondria in the colonic epithelium to increase the luminal bioavailability of oxygen and nitrate, thereby intensifying respiration-dependent choline catabolism of E. coli. In turn, E. coli choline catabolism increased levels of circulating trimethlamine N-oxide, which is a potentially harmful metabolite generated by gut microbiota.
Bibliographical noteFunding Information:
W.Y. was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) by the Ministry of Education 2020R1A6A3A03037326. Y.L. was supported by Vaadia-BARD Postdoctoral Fellowship FI-505-2014. E.E.O. was supported by Public Health Service Grant TR001861. C.S. was supported by the Dorothy Beryl and Theodore Roe Austin Pathology Research Fund and T32AI112541. N.J.F. was supported by T32DK007673-07. N.G.S. was supported by T32ES007028-46. E.G. and B.J.B. were supported by the U.S. Department of Agriculture (USDA) Project 2032-51530-025-00D. Work in A.J.B.'s laboratory was supported by USDA/NIFA award 2015-67015-22930; by Crohn's and Colitis Foundation of America Senior Investigator Award 650976; and by Public Health Service Grants AI044170, AI096528, AI112445, AI112949, AI146432, and AI153069. Work in M.X.B.'s laboratory was supported by V Scholar grant V2020-013 from The V Foundation for Cancer Research, Vanderbilt Digestive Disease Pilot and Feasibility grant P30 058404, ACS Institutional Research Grant IRG-19-139-59, VICC GI SPORE grant P50CA236733, United States-Israel Binational Science Foundation grant 2019136, and Vanderbilt Institute for Clinical and Translational Research Grant VR53102 and VR54267.
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