While smoking tobacco is a major risk factor for Crohn’s disease, the exact opposite is true for ulcerative colitis. Smoking not only reduces relapse rates and hospitalization but is currently the epidemiological factor most associated with a lower incidence of UC.
This protective factor has posed a great mystery to researchers, who have struggled to clarify why smoking has such opposite effects on UC and CD.
Nicotine in Traditional Medicine: A Brief & Disappointing History
Tobacco is traditionally held as a sacred herb to indigenous people throughout North America, used both recreationally and medicinally for several illnesses. Records from the late 1400s also report its use in Cuba, where it was burned in a torch to ward off infection and disease, and in Mexico, where it was applied topically to heal wounds and burns.
When tobacco arrived on European shores, it quickly acquired a reputation as a cure-all remedy and was featured in pharmacopeias throughout the 16th century for catarrh, colds, and fevers, and as an antidiarrhoeal agent. But by the late 1700s, physicians began to doubt its medicinal value and it was shortly excluded from medical guidelines.
By the early 1900s, researchers had noted an increase in lung cancer associated with smoking tobacco, and in the 1950s it was officially identified as a serious health hazard. Still, modern researchers could not deny the protective association of nicotine seen in clinical trials on UC patients and began a series of trials to test its therapeutic potential.
Clinical Studies on Nicotine for UC: An Even Shorter & More Disappointing History
In therapeutic studies for UC, nicotine has been applied in the form of chewing gum, enemas, and transdermal patches. A 1994 clinical trial showed that nicotine patches could control mild-to-moderate colitis symptoms in certain cases. However, efficacy was limited and the treatment caused a range of side effects, from headaches and nausea to acute pancreatitis.
The side effects could be decreased by topical application of nicotine to the colon via enema or delayed-release capsules, and a few trials showed mildly promising results. However, human trials on nicotine for UC subsided during the 1990s, with research turning instead to its proposed mechanism as a potential target for therapy. Here’s what they found:
Does Smoking Help Ulcerative Colitis?
Nicotine activates nicotinic receptors α7 (α7-nAChR) in immune cells, initiating the anti-inflammatory “cholinergic pathway”. This pathway refers to a system of acetylcholine (ACh) neurotransmitters, which play a chief role in the parasympathetic nervous system.
The cholinergic anti-inflammatory pathway modulates the parasympathetic nervous system through vagus nerve signaling, which alone can attenuate intestinal epithelial tight junction disruption, a main feature of IBD. But it also leads to a decrease of pro-inflammatory signals and cytokines, including the NF-κB pathway, which is heavily increased in the mucosal immune cells of IBD patients.
Moreover, when nicotine stimulates acetylcholine receptors, it enhances acetylcholine (ACh) release. ACh is vital for the healthy movement of food through the digestive tract and is an important regulator of inflammation. It’s made up of choline and acetate which must be readily available to neurons so that ACh can be synthesized whenever needed. Studies show that insufficient dietary choline intake plays a role in the development of IBD, aggravates the severity of colitis, and that administration of ACh “remarkably ameliorated intestinal inflammation”.
But nicotine is hardly the only natural compound that activates the cholinergic pathway, nor the most beneficial.
As it turns out, curcumin not only acts as an indirect agonist of α7-nACh receptors but reduces desensitization over time to preserve its biological activity over long durations. In fact, trials on curcumin for UC show a higher rate of remission than nicotine. For instance, a 2015 RCT on curcumin reported a 38% rate of endoscopic remission, whereas one of the few trials on nicotine (administered through enema) only induced remission in 27% of cases.
What About Crohn’s Disease?
It must be noted that although CD and UC have a cross-over of symptoms, they impact different locations of the intestinal tract, with their own immune expression and interactions between genetics and environmental factors, and so will have varied responses to agonists.
For example, the anti-inflammatory aryl hydrocarbon receptor (AhR), which is stimulated by dioxin (a by-product of tobacco smoke), has a downregulated response in inflamed Crohn’s disease tissue compared with UC tissue.
Takeaway
Essentially, what we see is that some smokers who stop smoking and experience a flare of ulcerative colitis may improve if they go back to a little smoking. On the other hand, a non-smoker who experiences a flare will probably have little to no improvement if they start smoking. The reason for this phenomenon is unclear, but it may be due to an interaction between the host immunity and one of the compounds inhaled during smoking.
The above research in no way suggests one should try to control their disease or hesitate to quit smoking for fear of a flare-up. There are emerging treatments for UC that work through similar pathways and can offer greater efficacy, more long-term benefits, and a much higher safety profile.
Tessa Eskin
