Mechanisms of Disease: Nicotine -- A Review of its Actions in the Context of Gastrointestinal Disease

Gareth AO Thomas; John Rhodes; John R Ingram


Nat Clin Pract Gastroenterol Hepatol. 2005;2(11):536-544. 

In This Article

Negative Effects of Nicotine on Gastrointestinal Disease

Patients with Crohn's disease are more often smokers, and smoking has a detrimental effect on the course of their disease, with improvement on cessation.[2,38] The reason for the 'opposite' association with smoking status compared with ulcerative colitis is unclear. Is it due to a negative effect of nicotine? There are no published data on the effect of nicotine in Crohn's disease; however, we have given nicotine to patients with Crohn's colitis -- as an enema to 13 patients, and as an oral formulation to five patients -- and some gained benefit and none deteriorated (GAO Thomas, J Rhodes and JR Ingram, unpublished observations). Of possible relevance to this observation is the finding that smoking is associated with a higher risk of ileal disease, and less colonic involvement.[39] Studies are needed to assess the effect of nicotine alone on Crohn's colitis.

It has been suggested that Crohn's disease could be caused by an impaired host response to luminal bacteria -- in support of this theory is the fact that mutations of the CARD15 (NOD2) gene are more frequently found in patients with Crohn's disease than in patients with ulcerative colitis or controls. These mutations seem to be associated with decreased production of antimicrobial peptides.[40] The detrimental effects of smoking in Crohn's disease could, therefore, be related to its immunosuppressive effects on macrophages,[17] which might further compound any deficiency in the host response to luminal bacteria. Other components of tobacco smoke, such as oxidizing chemicals, could also be important; these, unlike nicotine, have prothrombotic effects that might exacerbate microvasculature abnormalities and ischemia.[41,42]

Smoking increases the incidence of peptic ulcer disease. In patients with peptic ulcer disease smoking also delays healing and is associated with increased relapse rates.[43] There are a number of mechanisms through which nicotine might have a detrimental effect.[44]

The integrity of the mucosa depends on the balance between 'aggressive' and 'defensive' factors. Although some of the work discussed below is contradictory and some is inconclusive, the balance of evidence suggests that nicotine has a role in peptic ulcer disease, and acts by increasing the aggressive factors and decreasing the defensive factors.

Aggressive Factors. The aggressive factors include gastric acid, Helicobacter pylori, pepsinogen and vasopressin. The effect of nicotine on gastric acid secretion is still not entirely clear, as studies have yielded contradictory findings, with both an increase[45] and a decrease[46] in secretion being observed.

H. pylori infection is more common in smokers, and eradication therapy less effective. Nicotine potentiates the vacuolating toxin activity of H. pylori in gastric cells,[47] which might be relevant to the finding that smoking promotes atrophic gastritis and intestinal metaplasia in patients infected with H. pylori.[48]

Pepsinogen, through the action of pepsin, has powerful mucolytic properties and is probably an important factor in the development of ulcers. Nicotine stimulates nAChRs on gastric chief cells, which release pepsinogen, thus potentiating the effects of pepsin.[49]

Vasopressin is thought to have a role in ulcerogenesis through its vasoconstrictive activity, and nicotine gum is known to increase vasopressin release.[50]

Defensive Factors. Gastric mucosal blood flow, mucosal restitution, mucus secretion, prostaglandins and glutathione are all considered to be defensive factors. A healthy mucosal barrier in the stomach depends on a number of factors. Inadequate blood perfusion results in the formation of erosions and ulcers. Studies have provided conflicting results, but in some studies nicotine reduced gastric mucosal blood flow.[51]

After superficial injury the gastric mucosa repairs itself by the process of restitution. Nicotine can impair this process by inhibiting two processes that are important for tissue repair in the gastrointestinal tract -- the production of endogeneous polyamines, and expression of voltage-gated potassium ion channels.[52]

The effect of nicotine on gastric mucus depends on the duration of its administration. Acute administration of nicotine protects against ethanol-induced gastric injury by increasing mucus volume, whereas chronic administration of nicotine exacerbates the effect by decreasing mucus volume.[53]

Prostaglandins decrease gastric acid secretion and increase bicarbonate production, mucus secretion, and mucosal blood flow. Nicotine reduces the level of prostaglandin E2 in gastric mucosa, thus diminishing its protective effects.[54]

The gastric mucosa contains a high concentration of reduced glutathione, a free radical scavenger, which reduces cellular injury induced by oxidative stress. Nicotine has been shown to exacerbate stress-induced depletion of gastric reduced glutathione levels, leading to ulceration.[55]

Smoking causes some physiologic effects that could potentially worsen gastroesophageal reflux disease (GERD). It decreases the lower esophageal sphincter pressure and increases the number of reflux episodes.[56,57] As a consequence, patients with GERD are asked to stop smoking in an attempt to improve their symptoms. Nicotine might be responsible for the effects of smoking on GERD. Nicotine patches produce a decrease in distal esophageal peristalsis and sphincter pressure, resulting in reflux.[58,59] This is probably the result of nicotine-mediated release of NO at the lower esophageal sphincter.[60] As already mentioned, nicotine affects other factors that might be important in reflux, such as gastric acid secretion, pepsinogen, mucus, and prostaglandins.

With respect to the clinical relevance of these findings, it is noteworthy that several studies have been carried out in which non-smoking ulcerative colitis patients were given nicotine, some for up to 6 months.[61] Side effects were recorded during these studies -- primarily headaches, nausea, and agitation, as well any others that were new following the introduction of nicotine -- but no patients spontaneously complained of symptoms suggestive of peptic ulcer or GERD. Further work is needed in this area to establish whether the effects of nicotine that have been outlined are clinically relevant.

Smoking is a risk factor for various gastrointestinal cancers including those of the esophagus, stomach, pancreas, liver and colon.[62] Many carcinogenic agents are produced by smoking, such as tobacco-specific N-nitrosamines, which are likely to be important in this process. There has been speculation as to whether nicotine can be endogenously converted to these carcinogenic counterparts, but the evidence remains inconclusive. There is no clinical or epidemiologic evidence to suggest that nicotine itself increases cancer risk. Indeed, smokeless tobacco users are exposed to as much nicotine as cigarette smokers, but there is no documented excess cancer risk in this group. In this context, there are some theoretical considerations. In vitro, nicotine has shown mutagenic potential by forming adducts with liver DNA.[63] It has also been shown to stimulate a human colon cancer cell line, inducing proliferation and enhanced tumor growth.[64] Nicotine can suppress apoptosis, rendering a cell more likely to accumulate genetic mutational lesions.[65] Finally, nicotine might enhance angiogenesis, an important process for the growth of solid tumors -- it increases endothelial cell growth in vitro, and accelerates fibrovascular growth in vivo.[66]

Although nicotine, as an addictive substance, is linked with smoking and cancer risk, its most important effect is likely to be an actual reduction in this risk, when used as an aid to cessation of smoking.


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