Hypothesis about mechanisms through which nicotine might exert its effect on the interdependence of inflammation and gut barrier function in ulcerative colitis

Abstract

Ulcerative colitis (UC) is characterized by impairment of the epithelial barrier and the formation of ulcer-type lesions, which result in local leaks and generalized alterations of mucosal tight junctions. Ultimately, this results in increased basal permeability. Although disruption of the epithelial barrier in the gut is a hallmark of inflammatory bowel disease and intestinal infections, it remains unclear whether barrier breakdown is an initiating event of UC or rather a consequence of an underlying inflammation, evidenced by increased production of proinflammatory cytokines. UC is less common in smokers, suggesting that the nicotine in cigarettes may ameliorate disease severity. The mechanism behind this therapeutic effect is still not fully understood, and indeed it remains unclear if nicotine is the true protective agent in cigarettes. Nicotine is metabolized in the body into a variety of metabolites and can also be degraded to form various breakdown products. It is possible these metabolites or degradation products may be the true protective or curative agents. A greater understanding of the pharmacodynamics and kinetics of nicotine in relation to the immune system and enhanced knowledge of gut permeability defects in UC are required to establish the exact protective nature of nicotine and its metabolites in UC. This review suggests possible hypotheses for the protective mechanism of nicotine in UC, highlighting the relationship between gut permeability and inflammation, and indicates where in the pathogenesis of the disease nicotine may mediate its effect.

Review article: ulcerative colitis, smoking and nicotine therapy

“…4 Intermittent smokers have often been reported to experience symptomatic exacerbation during periods of nonsmoking and alleviation of symptoms on recommencement of smoking. 2,5,6,15,20 The observation that heavier smokers who quit smoking are more susceptible to the rebound effect of developing UC, compared to lighter smokers, also corroborates the notion of a dose-dependent relationship. 6,9,10,16 Current smokers with UC have been found to have less relapses, 33 require fewer hospitalisations 1,6,24,34,35 and demonstrate a reduced need for oral corticosteroid and immunosuppressant therapy for their disease, compared to ex-smokers and nonsmokers with UC.…”

“…6,35 Those patients who quit smoking after diagnosis of UC often experience an exacerbation in their disease course, and have been uniformly shown to have increased hospitalisation rates and need for oral corticosteroids and immunosuppressants. 1,2,6,24,34,36 It remains divided as to whether smoking reduces the rate of surgery required in UC, particularly colectomy. Fraga et al 11 found that nonsmokers and especially exsmokers underwent surgery for their UC more frequently than current smokers.…”

“…70 Nicotine may act on the MAP kinase family and affect TNF-a through inhibition of nuclear factor kappa B signalling. 2 Loss of the intestinal mucosal barrier function may underlie the pathogenesis of IBD. Smoking has been proposed to help maintain normal intestinal permeability.…”

“…[1][2][3][4] Paradoxically, UC appears to be predominantly a disease of ex-smokers and nonsmokers. 2, First noted by Samuelsson in 1976 25 and confirmed by Harries, Baird and Rhodes in 1982, 26 it was observed that there was a distinct lack of current smokers in a cohort of UC patients, compared with that of a group of matched control subjects. Since then, numerous studies of the relationship between smoking and UC have confirmed this observation and demonstrated that smoking not only appears to protect against the development of UC, but in fact ameliorates the clinical course of the disease.…”

“…Since then, numerous studies of the relationship between smoking and UC have confirmed this observation and demonstrated that smoking not only appears to protect against the development of UC, but in fact ameliorates the clinical course of the disease. [1][2][3][4][5][6]24 Subjectively, in a cohort of smokers with UC, over half-indicated smoking improved their disease and none felt smoking had a detrimental effect on their UC. 27 Similarly, in a group of ex-smokers with refractory UC, 14 out of 15 achieved prolonged clinical remission without steroids, following resumption of low-dose smoking.…”