Nicotine and gut permeability: the smoking/PSC link clarified

[Guest guest]

Cullen and Chapman (2001) have proposed that " PSC may be triggered in

genetically susceptible individuals by toxic or infectious agents

gaining access to the liver via a diseased and permeable colon "

(Cullen S, Chapman R 2001 Aetiopathogenesis of primary sclerosing

cholangitis. Best Pract. Res. Clin. Gastroenterol. 15: 577-589).

Smoking seems to be protective against both UC and PSC ( " PSC, like

UC, is a disease of non-smokers as the odds of having PSC was

significantly decreased among current and former smokers " [

SA, Thyssen M, Orchard TR, Jewell DP, Fleming KA, Chapman RW 2002

Cigarette smoking, appendectomy, and tonsillectomy as risk factors

for the development of primary sclerosing cholangitis: a case control

study. Gut 51: 567-573]).

Does this imply that smoking somehow reduces the permeability of the

colon? A recent study now sheds some light on this question ... it

seems that nicotine does indeed reduce gut permeability by increasing

expression of tight junction proteins:

Food Chem Toxicol. 2007 Feb 24; [Epub ahead of print]

The effect of nicotine in vitro on the integrity of tight junctions

in Caco-2 cell monolayers.

McGilligan VE, Wallace JM, Heavey PM, Ridley DL, Rowland IR

Northern Ireland Centre for Food and Health (NICHE), Biomedical

Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland,

UK.

Ulcerative colitis is characterised by impairment of the epithelial

barrier and tight junction alterations resulting in increased

intestinal permeability. UC is less common in smokers with smoking

reported to decrease paracellular permeability. The aim of this study

was thus to determine the effect of nicotine, the major constituent

in cigarettes and its metabolites on the integrity of tight junctions

in Caco-2 cell monolayers. The integrity of Caco-2 tight junctions

was analysed by measuring the transepithelial electrical resistance

(TER) and by tracing the flux of the fluorescent marker fluorescein,

after treatment with various concentrations of nicotine or nicotine

metabolites over 48h. TER was significantly higher compared to the

control for all concentrations of nicotine 0.01-10muM at 48h

(p<0.001), and for 0.01muM (p<0.001) and 0.1muM and 10muM nicotine

(p<0.01) at 12 and 24h. The fluorescein flux results supported those

of the TER assay. TER readings for all nicotine metabolites tested

were also higher at 24 and 48h only (p0.01). Western blot analysis

demonstrated that nicotine up-regulated the expression of the tight

junction proteins occludin and claudin-1 (p0.01). Overall, it appears

that nicotine and its metabolites, at concentrations corresponding to

those reported in the blood of smokers, can significantly improve

tight junction integrity, and thus, decrease epithelial gut

permeability. We have shown that in vitro, nicotine appears more

potent than its metabolites in decreasing epithelial gut

permeability. We speculate that this enhanced gut barrier may be the

result of increased expression of claudin-1 and occludin proteins,

which are associated with the formation of tight junctions. These

findings may help explain the mechanism of action of nicotine

treatment and indeed smoking in reducing epithelial gut permeability.

PMID: 17399881.

This seems to be a good explanation for the protective effect of

smoking/nicotine on UC and PSC, and begins to clear up one mystery

about UC/PSC.

Dave

(father of (21); PSC 07/03; UC 08/03)