Gut microbiota modulates weight gain in mice after discontinued smoke exposure

Leviel Fluhr, Uria Mor, Aleksandra A. Kolodziejczyk, Mally Dori-Bachash, Avner Leshem, Shlomik Itav, Yotam Cohen, Jotham Suez, Niv Zmora, Claudia Moresi, Shahar Molina, Niv Ayalon, Rafael Valdés-Mas, Shanni Hornstein, Hodaya Karbi, Denise Kviatcovsky, Adi Livne, Aurelie Bukimer, Shimrit Eliyahu-Miller, Alona Metz, Alexander Brandis, Tevie Mehlman, Yael Kuperman, Michael Tsoory, Noa Stettner, Alon Harmelin, Hagit Shapiro () and Eran Elinav ()
Additional contact information
Leviel Fluhr: Weizmann Institute of Science
Uria Mor: Weizmann Institute of Science
Aleksandra A. Kolodziejczyk: Weizmann Institute of Science
Mally Dori-Bachash: Weizmann Institute of Science
Avner Leshem: Weizmann Institute of Science
Shlomik Itav: Weizmann Institute of Science
Yotam Cohen: Weizmann Institute of Science
Jotham Suez: Weizmann Institute of Science
Niv Zmora: Weizmann Institute of Science
Claudia Moresi: Weizmann Institute of Science
Shahar Molina: Weizmann Institute of Science
Niv Ayalon: Weizmann Institute of Science
Rafael Valdés-Mas: Weizmann Institute of Science
Shanni Hornstein: Weizmann Institute of Science
Hodaya Karbi: Weizmann Institute of Science
Denise Kviatcovsky: Weizmann Institute of Science
Adi Livne: Weizmann Institute of Science
Aurelie Bukimer: Weizmann Institute of Science
Shimrit Eliyahu-Miller: Weizmann Institute of Science
Alona Metz: Weizmann Institute of Science
Alexander Brandis: Weizmann Institute of Science
Tevie Mehlman: Weizmann Institute of Science
Yael Kuperman: Weizmann Institute of Science
Michael Tsoory: Weizmann Institute of Science
Noa Stettner: Weizmann Institute of Science
Alon Harmelin: Weizmann Institute of Science
Hagit Shapiro: Weizmann Institute of Science
Eran Elinav: Weizmann Institute of Science

Nature, 2021, vol. 600, issue 7890, 713-719

Abstract: Abstract Cigarette smoking constitutes a leading global cause of morbidity and preventable death1, and most active smokers report a desire or recent attempt to quit2. Smoking-cessation-induced weight gain (SCWG; 4.5 kg reported to be gained on average per 6–12 months, >10 kg year–1 in 13% of those who stopped smoking3) constitutes a major obstacle to smoking abstinence4, even under stable5,6 or restricted7 caloric intake. Here we use a mouse model to demonstrate that smoking and cessation induce a dysbiotic state that is driven by an intestinal influx of cigarette-smoke-related metabolites. Microbiome depletion induced by treatment with antibiotics prevents SCWG. Conversely, fecal microbiome transplantation from mice previously exposed to cigarette smoke into germ-free mice naive to smoke exposure induces excessive weight gain across diets and mouse strains. Metabolically, microbiome-induced SCWG involves a concerted host and microbiome shunting of dietary choline to dimethylglycine driving increased gut energy harvest, coupled with the depletion of a cross-regulated weight-lowering metabolite, N-acetylglycine, and possibly by the effects of other differentially abundant cigarette-smoke-related metabolites. Dimethylglycine and N-acetylglycine may also modulate weight and associated adipose-tissue immunity under non-smoking conditions. Preliminary observations in a small cross-sectional human cohort support these findings, which calls for larger human trials to establish the relevance of this mechanism in active smokers. Collectively, we uncover a microbiome-dependent orchestration of SCWG that may be exploitable to improve smoking-cessation success and to correct metabolic perturbations even in non-smoking settings.

Date: 2021
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DOI: 10.1038/s41586-021-04194-8

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