Trying to Quit Smoking? Your Gut Microbiome May Hold The Key

Trying to Quit Smoking? Your Gut Microbiome May Hold The Key

According to the U.S. Department of Health & Human Services (HHS), tobacco use remains the leading cause of morbidity and preventable death in both the United States and worldwide. According to the Centers for Disease Control and Prevention (CDC), in 2019, approximately 14 of every 100 U.S. adults aged 18 or older smoked cigarettes. This percentage equates to just about 34,000,000 adults in the U.S. who smoke cigarettes.

That number is not including the increasing number of vaping users, and unfortunately those users are in the younger demographic. As of 2018, 9% of U.S. adults said they “regularly or occasionally” vape. Furthermore, a 2019 survey found that more than 5,000,000 U.S. middle and high school students used e-cigarettes in the past 30-days, coming out to 27.5% of high school students. The Surgeon General’s advisory board found that in 2018, youth e-cigarette use increased 78% among high school students during the past year, and that 1 in 5 high school students, as well as 1 in 20 middle school students currently use e-cigarettes.

“It is no surprise that quitting smoking for most people is incredibly difficult.”

It is no surprise that quitting smoking for most people is incredibly difficult. Nicotine is one of the most addictive chemicals for our brains. Inhaling smoke delivers nicotine to the brain within 20 seconds, which makes it incredibly addictive – comparable to opioids, alcohol and cocaine. It releases the neurotransmitter dopamine in the same regions of the brain as other addictive drugs. It can cause mood-altering changes that make the user temporarily feel good.

If you or someone you know smokes cigarettes, chances are they want to quit, and have tried more than once in the past. The U.S. Food & Drug Administration (FDA) found that in 2015, nearly 70% of current smokers said they wanted to quit. They also found that in 2018, 55% of smokers had tried to quit in the past year, with only 8% of them being successful in quitting for 6-12 months. One of the reasons for this high rate of recurrence has to do with the smoking cessation-induced weight gain (SCWG), however the mechanisms underlying this weight gain are incompletely understood.

“…researchers uncovered a microbiome-dependent mechanism underlying this undesirable weight gain…”

In a study published in Nature in 2021, researchers at the Weizmann Institute of Science in Tel Aviv, under the leadership of Eran Elinav, uncovered a microbiome-dependent mechanism underlying this undesirable weight gain which could be targeted to increase smoking-cessation success and prevent the associated weight gain.

Their findings may not only have implications for the success of smoking cessation, but may also be of benefit for weight loss and normalization of metabolic disturbances in non-smoking individuals.

The study utilized a mouse model (obese mice on a high fat diet (HFD)) to demonstrate that smoking and cessation of smoking induced an imbalanced state that is driven by an influx of cigarette-smoke-related metabolites in the intestines. Acute exposure to cigarette smoke induced plasma levels of nicotine comparable to such levels seen in human smokers, and acute exposure to cigarette smoke induced a significant reduction in weight.

By contrast, mice no longer exposed to cigarette smoke, gained weight that was comparable to weight levels of those animals not exposed to smoke. The researchers found that the microbiome-induced weight gain associated with smoking cessation involved changes in the gut microbiome composition (“dysbiosis”) and function. For example, it resulted in the transformation of dietary choline to its metabolite dimethylglycine (DMG), which drives increased gut energy harvest, paired with the depletion of the weight-lowering metabolite, N-acetylglycine (ACG), as well as other abundant cigarette-smoke related metabolites. In other words, these findings suggest that microbiome-induced weight gain associated with smoking cessation depletes ACG, a weight-lowering metabolite, while promoting dietary choline conversion into DMG, a weight-promoting metabolite. Interestingly, both metabolites may also modulate weight and metabolic function under non-smoking conditions.

The researchers also found that microbiome suppression induced by antibiotic treatment prior to nicotine exposure prevented weight gain after smoking cessation, and conversely, fecal microbial transplantation from mice previously exposed to cigarette smoke into germ-free mice, never exposed to cigarette smoke, induced excessive weight gain. In other words, the animals who were exposed to cigarette smoke, had molecules in their feces which were necessary for the development of SCWG, and the metabolites, when transferred into mice without prior smoke exposure, induced weight gain. When viewed together, these findings clearly demonstrated a causal role of the microbiome in the smoking-related weight and metabolic changes.

“These intriguing results highlight the intensive cooperation that exist between the gut microbes and our gut…”

These intriguing results highlight the intensive cooperation that exist between the gut microbes and our gut in driving SCWG. Together, they contribute to an increase in conversion of dietary choline to bioactive DMG, a reduction in bioactive ACG and, possibly, to effects mediated by other cigarette-smoke-altered metabolites. A similar concept was suggested for the carnitine– tri-methylamine – trimethylamine-N-oxide pathway in the context of atherosclerosis. Earlier studies had shown a link between the microbial metabolism of L-carnitine (a nutrient contained in high concentrations in red meat and eggs), and further metabolism of this microbial product in the liver to trimethylamine N-oxide (TMAO), a compound equally as harmful to our arteries as bad cholesterol.

Based on their findings, the authors of the study hypothesized that the gradual development of dysbiosis and associated metabolite alterations during smoking, including excessive production of the weight-promoting metabolite DMG, and the simultaneous suppression of the weight-reducing metabolite ACG, may serve as a feedback loop to the anorexia (not to be confused with anorexia nervosa, the eating disorder) that characterizes active cigarette smoking, and which is not dependent on the microbiome.

Following smoking cessation, the anorexic signals generated by the body rapidly dissipate while the obesogenic ‘smoking microbiome’ configuration and accumulated metabolites are slow to reverse. This can ultimately lead to the weight gain associated with smoking cessation.

As smoking is a voluntary human behavior that is not possible to replicate in mice, the translational relevance of these interesting mouse findings remains to be determined. However, they raise the possibility that targeted dietary, microbial and postbiotic therapy may be utilized in attenuating or even preventing the undesirable weight gain and optimizing long-term abstinence success.

Several related questions remain to be addressed: Is there a relationship between cigarette smoking and SCWG and dietary habits? Is smoking cessation-related weight gain related to the consumption of foods with high carnitine content? And is this mechanism specific for nicotine, or does it apply to other forms of substance use disorders?


E. Dylan Mayer is a graduate from the University of Colorado at Boulder with both a major in Neuroscience and minor in Business. He is fascinated by the interactions of brain, gut and microbiome, and the role of nutrition in influencing the health of our microbiome, as well as our own well-being.