Crohn's disease--a permeability disorder of the tight junction?

Abstract

Leading articleCrohn's disease -a permeability disorder of the tight junction?Despite extensive efforts the aetiology of Crohn's disease has yet to be established.Studies have concentrated on possible infectious or immuno- logical causes, but have not provided a clear explanation of the pathogenesis of this disease.Many infectious agents such as bacteria, viruses, myco- plasma, and mycobacteria have been considered as possibly causing Crohn's disease.1-3 So far none of the infectious agents have fulfilled Koch's postulates or been consistently confirmed as a causative agent of this disease.Possible immunological abnormalities have also been studied.4Numerous investigators have looked for either primary immunological abnormalities5 or abnormalities of immune response.6Again, none of these efforts have consistently identified immunological abnormalities as the cause of Crohn's disease.78Prostanoid metabolism has recently received extensive scrutiny in the search for the aetiology of Crohn's disease.Numerous investigators have been able to show increased PGE2 concentrations in inflamed colonic mucosa9 '° or colonic lumenal contents from patients with Crohn's disease.'1Increased elaboration of other prostanoids9 1213 and leucotrienes"`has also been reported in patients with Crohn's disease.The consensus of opinion is that changes in prostanoid metabolism in Crohn's disease are probably secondary to the inflammatory process itself and not an underlying aetio- logical factor.14While the aetiology and pathogenesis of Crohn's disease is complex, I propose that increased intestinal permeability through abnormal tight junctions could play a role.I am not proposing that increased intestinal permeability is the only aetiological factor in the development of Crohn's disease; rather, I am proposing that increased intestinal permeability could allow the penetration of antigenic or infectious agents into the intestinal wall and thus start the process which in susceptible individuals culminates in Crohn's disease.The proposal that increased intestinal permeability could be important is not new.'5Recent new clinical and experimental evidence,'"2' however, is sufficient to suggest serious consideration of this proposal as a working hypothesis.The term permeability needs clarification and definition.Normally the intestinal epithelium is able to act as a selective entry gate into the body.The intestinal epithelium which absorbs needed nutrients, fluids, and electro- lytes with a very high degree of efficiency can also selectively prevent the absorption of water soluble compounds larger than 0.4 nm in diameter.22Such size considerations do not apply to lipid soluble molecules, because they penetrate the absorptive cell membrane directly.23Strictly speaking, small water soluble charged molecules can also be absorbed by a process which is also sometimes referred to as permeability.24The penetration of the intestinal epithelium by sodium ions is an example for such a process.