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

Woongjae Yoo; Jacob K. Zieba; Nora J. Foegeding; Teresa P. Torres; Catherine D. Shelton; Nicolas G. Shealy; Austin J. Byndloss; Stephanie A. Cevallos; Erik Gertz; Connor R. Tiffany; Julia D. Thomas; Yael Litvak; Henry Nguyen; Erin E. Olsan; Brian J. Bennett; Jeffrey C. Rathmell; Amy S. Major; Andreas J. Bäumler; Mariana X. Byndloss

doi:10.1126/science.aba3683

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

Woongjae Yoo, Jacob K. Zieba, Nora J. Foegeding, Teresa P. Torres, Catherine D. Shelton, Nicolas G. Shealy, Austin J. Byndloss, Stephanie A. Cevallos, Erik Gertz, Connor R. Tiffany, Julia D. Thomas, Yael Litvak, Henry Nguyen, Erin E. Olsan, Brian J. Bennett, Jeffrey C. Rathmell, Amy S. Major, Andreas J. Bäumler^*, Mariana X. Byndloss^*

^*Corresponding author for this work

Department of Biological Chemistry

Research output: Contribution to journal › Article › peer-review

94 Scopus citations

Abstract

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.

Original language	American English
Pages (from-to)	813-818
Number of pages	6
Journal	Science
Volume	373
Issue number	6556
DOIs	https://doi.org/10.1126/science.aba3683
State	Published - 13 Aug 2021

Bibliographical note

Funding 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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Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

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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., Tiffany, C. R., Thomas, J. D., Litvak, Y., Nguyen, H., Olsan, E. E., Bennett, B. J., Rathmell, J. C., Major, A. S., Bäumler, 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

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title = "High-fat diet-induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide",

abstract = "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.",

author = "Woongjae Yoo and Zieba, {Jacob K.} and Foegeding, {Nora J.} and Torres, {Teresa P.} and Shelton, {Catherine D.} and Shealy, {Nicolas G.} and Byndloss, {Austin J.} and Cevallos, {Stephanie A.} and Erik Gertz and Tiffany, {Connor R.} and Thomas, {Julia D.} and Yael Litvak and Henry Nguyen and Olsan, {Erin E.} and Bennett, {Brian J.} and Rathmell, {Jeffrey C.} and Major, {Amy S.} and B{\"a}umler, {Andreas J.} and Byndloss, {Mariana X.}",

note = "Funding 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. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2021",

month = aug,

day = "13",

doi = "10.1126/science.aba3683",

language = "American English",

volume = "373",

pages = "813--818",

journal = "Science",

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publisher = "American Association for the Advancement of Science",

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Yoo, W, Zieba, JK, Foegeding, NJ, Torres, TP, Shelton, CD, Shealy, NG, Byndloss, AJ, Cevallos, SA, Gertz, E, Tiffany, CR, Thomas, JD, Litvak, Y, Nguyen, H, Olsan, EE, Bennett, BJ, Rathmell, JC, Major, AS, Bäumler, AJ & Byndloss, MX 2021, 'High-fat diet-induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide', Science, vol. 373, no. 6556, pp. 813-818. https://doi.org/10.1126/science.aba3683

TY - JOUR

T1 - High-fat diet-induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide

AU - Yoo, Woongjae

AU - Zieba, Jacob K.

AU - Foegeding, Nora J.

AU - Torres, Teresa P.

AU - Shelton, Catherine D.

AU - Shealy, Nicolas G.

AU - Byndloss, Austin J.

AU - Cevallos, Stephanie A.

AU - Gertz, Erik

AU - Tiffany, Connor R.

AU - Thomas, Julia D.

AU - Litvak, Yael

AU - Nguyen, Henry

AU - Olsan, Erin E.

AU - Bennett, Brian J.

AU - Rathmell, Jeffrey C.

AU - Major, Amy S.

AU - Bäumler, Andreas J.

AU - Byndloss, Mariana X.

N1 - Funding 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. Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

PY - 2021/8/13

Y1 - 2021/8/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85112423896&partnerID=8YFLogxK

U2 - 10.1126/science.aba3683

DO - 10.1126/science.aba3683

M3 - Article

C2 - 34385401

AN - SCOPUS:85112423896

SN - 0036-8075

VL - 373

SP - 813

EP - 818

JO - Science

JF - Science

IS - 6556

ER -

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

Abstract

Bibliographical note

UN SDGs

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