Cargando…

Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms

Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic...

Descripción completa

Detalles Bibliográficos
Autores principales: Schugar, Rebecca C, Gliniak, Christy M, Osborn, Lucas J, Massey, William, Sangwan, Naseer, Horak, Anthony, Banerjee, Rakhee, Orabi, Danny, Helsley, Robert N, Brown, Amanda L, Burrows, Amy, Finney, Chelsea, Fung, Kevin K, Allen, Frederick M, Ferguson, Daniel, Gromovsky, Anthony D, Neumann, Chase, Cook, Kendall, McMillan, Amy, Buffa, Jennifer A, Anderson, James T, Mehrabian, Margarete, Goudarzi, Maryam, Willard, Belinda, Mak, Tytus D, Armstrong, Andrew R, Swanson, Garth, Keshavarzian, Ali, Garcia-Garcia, Jose Carlos, Wang, Zeneng, Lusis, Aldons J, Hazen, Stanley L, Brown, Jonathan Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8813054/
https://www.ncbi.nlm.nih.gov/pubmed/35072627
http://dx.doi.org/10.7554/eLife.63998
_version_ 1784644781170753536
author Schugar, Rebecca C
Gliniak, Christy M
Osborn, Lucas J
Massey, William
Sangwan, Naseer
Horak, Anthony
Banerjee, Rakhee
Orabi, Danny
Helsley, Robert N
Brown, Amanda L
Burrows, Amy
Finney, Chelsea
Fung, Kevin K
Allen, Frederick M
Ferguson, Daniel
Gromovsky, Anthony D
Neumann, Chase
Cook, Kendall
McMillan, Amy
Buffa, Jennifer A
Anderson, James T
Mehrabian, Margarete
Goudarzi, Maryam
Willard, Belinda
Mak, Tytus D
Armstrong, Andrew R
Swanson, Garth
Keshavarzian, Ali
Garcia-Garcia, Jose Carlos
Wang, Zeneng
Lusis, Aldons J
Hazen, Stanley L
Brown, Jonathan Mark
author_facet Schugar, Rebecca C
Gliniak, Christy M
Osborn, Lucas J
Massey, William
Sangwan, Naseer
Horak, Anthony
Banerjee, Rakhee
Orabi, Danny
Helsley, Robert N
Brown, Amanda L
Burrows, Amy
Finney, Chelsea
Fung, Kevin K
Allen, Frederick M
Ferguson, Daniel
Gromovsky, Anthony D
Neumann, Chase
Cook, Kendall
McMillan, Amy
Buffa, Jennifer A
Anderson, James T
Mehrabian, Margarete
Goudarzi, Maryam
Willard, Belinda
Mak, Tytus D
Armstrong, Andrew R
Swanson, Garth
Keshavarzian, Ali
Garcia-Garcia, Jose Carlos
Wang, Zeneng
Lusis, Aldons J
Hazen, Stanley L
Brown, Jonathan Mark
author_sort Schugar, Rebecca C
collection PubMed
description Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lep(ob/ob)). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.
format Online
Article
Text
id pubmed-8813054
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-88130542022-02-04 Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms Schugar, Rebecca C Gliniak, Christy M Osborn, Lucas J Massey, William Sangwan, Naseer Horak, Anthony Banerjee, Rakhee Orabi, Danny Helsley, Robert N Brown, Amanda L Burrows, Amy Finney, Chelsea Fung, Kevin K Allen, Frederick M Ferguson, Daniel Gromovsky, Anthony D Neumann, Chase Cook, Kendall McMillan, Amy Buffa, Jennifer A Anderson, James T Mehrabian, Margarete Goudarzi, Maryam Willard, Belinda Mak, Tytus D Armstrong, Andrew R Swanson, Garth Keshavarzian, Ali Garcia-Garcia, Jose Carlos Wang, Zeneng Lusis, Aldons J Hazen, Stanley L Brown, Jonathan Mark eLife Medicine Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lep(ob/ob)). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics. eLife Sciences Publications, Ltd 2022-01-24 /pmc/articles/PMC8813054/ /pubmed/35072627 http://dx.doi.org/10.7554/eLife.63998 Text en © 2022, Schugar et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Medicine
Schugar, Rebecca C
Gliniak, Christy M
Osborn, Lucas J
Massey, William
Sangwan, Naseer
Horak, Anthony
Banerjee, Rakhee
Orabi, Danny
Helsley, Robert N
Brown, Amanda L
Burrows, Amy
Finney, Chelsea
Fung, Kevin K
Allen, Frederick M
Ferguson, Daniel
Gromovsky, Anthony D
Neumann, Chase
Cook, Kendall
McMillan, Amy
Buffa, Jennifer A
Anderson, James T
Mehrabian, Margarete
Goudarzi, Maryam
Willard, Belinda
Mak, Tytus D
Armstrong, Andrew R
Swanson, Garth
Keshavarzian, Ali
Garcia-Garcia, Jose Carlos
Wang, Zeneng
Lusis, Aldons J
Hazen, Stanley L
Brown, Jonathan Mark
Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
title Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
title_full Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
title_fullStr Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
title_full_unstemmed Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
title_short Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
title_sort gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8813054/
https://www.ncbi.nlm.nih.gov/pubmed/35072627
http://dx.doi.org/10.7554/eLife.63998
work_keys_str_mv AT schugarrebeccac gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT gliniakchristym gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT osbornlucasj gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT masseywilliam gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT sangwannaseer gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT horakanthony gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT banerjeerakhee gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT orabidanny gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT helsleyrobertn gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT brownamandal gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT burrowsamy gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT finneychelsea gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT fungkevink gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT allenfrederickm gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT fergusondaniel gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT gromovskyanthonyd gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT neumannchase gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT cookkendall gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT mcmillanamy gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT buffajennifera gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT andersonjamest gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT mehrabianmargarete gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT goudarzimaryam gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT willardbelinda gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT maktytusd gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT armstrongandrewr gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT swansongarth gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT keshavarzianali gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT garciagarciajosecarlos gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT wangzeneng gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT lusisaldonsj gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT hazenstanleyl gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms
AT brownjonathanmark gutmicrobetargetedcholinetrimethylaminelyaseinhibitionimprovesobesityviarewiringofhostcircadianrhythms