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

Positive Effects of Nicotine on Gastrointestinal Disease

Ulcerative colitis is largely a disease of non-smokers and ex-smokers, and is uncommon amongst current smokers.^[2] There is clinical evidence to suggest that nicotine is responsible for this difference, as transdermal nicotine patches have been used with beneficial effects in patients with active disease.^[11,12]

Although nicotine appears to be the beneficial ingredient, the precise mechanism of action remains unclear. As the cause of ulcerative colitis remains unknown there is much opportunity for speculation.

Immunomodulatory Effects of Nicotine. Smoking is immunosuppressive and alters a wide range of immunologic functions, including innate and adaptive responses. Nicotine induces similar effects, and this might be how it exerts some of its actions.^[13] Animals treated chronically with nicotine show a significant loss of antibody responses and T-cell proliferation, similar to that seen in animals exposed to cigarette smoke.^[14,15] Studies that explore how nicotine suppresses the immune system indicate that in nicotine-treated animals the transmission of antigen-receptor-mediated signals is abnormal, so that T-cells do not enter the cell cycle and proliferate as expected -- a similar effect has been observed in smokers and in animals exposed to smoking.^[14,15,16] Nicotine has also been shown to affect macrophage responses directly.^[17]

Nictoine can also influence the immune system through its actions on the central nervous system, via two pathways: it activates the hypothalamus-pituitary-adrenal axis, which results in the release of glucocorticoids; and it activates the autonomic nervous system, which connects the brain directly to visceral target tissue, including lymphoid tissues, through sympathetic and parasympathetic innervations.^[13]

nAChRs as Regulators of Inflammation and Cellular Function. The parasympathetic nervous system, primarily the vagus nerve, has been called the 'cholinergic anti-inflammatory pathway'. It is one of the endogenous mechanisms that help to regulate the innate immune response, and activation of this response attenuates systemic inflammatory responses.^[18]

nAChRs composed of the α7 subunit (Sidebar) have been identified on cells that are important in the mediation of inflammation and immune reactions, including human macrophages, dendritic cells and microglial cells.^[5,6,7] Stimulation of these receptors (through vagal release of acetylcholine, or by exogenous nicotine), causes a reduction in the amount of tumor necrosis factor alpha (TNF-α) released from macrophages, when they are subsequently stimulated by lipopolysaccharide.^[5] It is unclear whether this is relevant in ulcerative colitis, but identifying α7-positive cells in the gastrointestinal tract would be of interest, and could provide a route through which nicotine might act. Nicotine also impairs the ability of dendritic cells to induce naive T-cells to differentiate into T helper 1 (T_H1) cells.^[6] This suggests that nicotine is also able to influence some of the key elements of the adaptive immune response. It is unclear whether smoking and nicotine affect the proportion of T_H1 and T_H2 cells, relative to each other, in inflammatory bowel disease. This is an interesting question, given the fact that there is some evidence that patients with Crohn's disease exhibit a T_H1 cytokine profile, and those with ulcerative colitis exhibit a T_H2 profile.

α3 nAChRs have been identified in the mucosal epithelium, enteric ganglia, nerves and lymphoid tissue of the normal small and large bowel.^[8,9] Smoking and nicotine, however, had no effect on the density or distribution of these receptors in the colon.^[9] If an action of these nAChRs is pertinent, then some functional change in the receptor that is induced by nicotine might be responsible. α3 nAChRs have been shown to mediate the function of other epidermal cells, such as keratinocytes^[3,10] and bronchial epithelial cells,^[4] resulting in cellular adhesion and differentiation. That α3 nAChRs might have a similar effect on colonic epithelial cell stability and function is an attractive hypothesis that is worthy of further investigation.

Cytokines and Eicosanoids. Nicotine affects some soluble mediators of inflammation, although the clinical relevance of these findings are unclear: in vitro, nicotine decreases interleukin (IL)-2 and TNF-α production by blood mononuclear cells;^[19]in vivo, nicotine decreases IL-1ß and TNF-α concentrations in colonic tissue from healthy mice,^[20] as well as IL-10 from human mononuclear cells,^[21] and IL-8 expression in patients with active ulcerative colitis.^[22]

Rabbits given nicotine have reduced levels of the prostaglandins F1α and F2α, and of 15-hydroxy-eicosatetraenoic acid (15-HETE) in the rectal mucosa compared with controls^[23] (but no change was observed in ferrets).^[24]

Colonic Mucus Production. Colonic mucus can be qualitatively and quantitatively abnormal in patients with ulcerative colitis. In vitro, nicotine increased mucus production by colonic mucosa in human controls.^[25]In vivo, it either increases^[23] or has no effect^[24] on colonic mucus. Transdermal nicotine has no effect on mucin gene expression in patients with ulcerative colitis.^[22] The clinical relevance of these findings is unclear.

Colonic Motility. Animal studies have shown that nicotine produces smooth-muscle relaxation at various sites in the gastrointestinal tract, largely through the release of nitric oxide (NO), which acts as a nonadrenergic noncholinergic neurotransmitter.^[26] This action of nicotine has been confirmed in the human sigmoid colon.^[27,28]In vivo, nicotine has been shown to reduce tone and muscular activity.^[27]In vitro, this effect was shown to be primarily achieved through the action of NO.^[28] This could account for the observation made by some patients given nicotine for active ulcerative colitis that they experience a dramatic and rapid relief of fecal urgency and frequency.

Endogenous Glucocorticoids. Both smoking and nicotine stimulate adrenocorticoid release.^[29] Intravenous nicotine causes the release of adrenocorticotropin,^[30] and central nAChRs are involved in the modulation of basal and stress-induced adrenocortical responses.^[31] This increase in the concentration of endogenous corticosteroids might be beneficial in patients with inflammatory conditions.

Other Potential Mechanisms. Rectal blood flow and intestinal permeability are both reduced by smoking,^[32,33] but the relevance of these findings is unclear. So far, the action of nicotine alone on rectal blood flow and intestinal permeability has not been studied to see if the effects are similar.

Primary sclerosing cholangitis is less common in smokers, a finding that is independent of whether or not the patient has underlying inflammatory bowel disease.^[34] Nicotine was of no clinical benefit in one study,^[35] however, and it might not be the relevant active moiety in this case. Smoking might also reduce the risk of pouchitis in those patients who have undergone restorative proctocolectomy for ulcerative colitis;^[36] celiac disease is also less common in smokers.^[37] The effect of nicotine alone in the context of pouchitis and celiac disease has yet to be explored. The mechanisms underlying these relationships are unclear, but might include the immunomodulatory effects of smoking and nicotine already outlined in ulcerative colitis, as well as others yet to be identified.

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

Cite this: Mechanisms of Disease: Nicotine -- A Review of its Actions in the Context of Gastrointestinal Disease - Medscape - Nov 01, 2005.