Smoking-related dysbiosis and associated metabolites drive cessation-induced weight gain

Smoking cessation-associated weight gain (SCWG) constitutes a major obstacle to smoking withdrawal, yet its molecular drivers remain elusive. We demonstrate in a murine SCWG model that smoking and smoking cessation induce distinct dysbiosis states, driven by a gut influx of smoking-related metabolites such as nicotine. Importantly, smoking cessation-related dysbiosis contributes to SCWG, as antibiotics-induced microbiome depletion prevents SCWG, while microbiome transplantation from smoking-cessation mice into HFD-fed, non-smoking germ-free mice, induces excessive weight gain. Microbiome contribution to SCWG is orchestrated by a concerted host and microbiome metabolic shunting of dietary choline into the metabolite dimethylglycine (DMG), driving SCWG by enhancing gut energy harvest, coupled with depletion of a weight-lowering metabolite AcetylGlycine (ACG). Importantly, DMG and ACG may modulate weight also in non-smoking conditions. Collectively, we uncover microbiome-dependent orchestration of SCWG and highlight dietary, host and microbial candidates impacting this withdrawal-prohibitive manifestation. Exploiting these checkpoints may enable to improve smoking cessation success.