Intestinal permeability, non-steroidal anti-inflammatory drug enteropathy and inflammatory bowel disease: an overview.

There is recent renewed interest in the role of the intestine in the pathogenesis of the various arthritides'7. In general, it is postulated that an intestinal microbial constituent or product is absorbed by the intestinal mucosa eliciting an immunological response and tissue damage by simple or induced molecular mimicry"'. The difference between the two mechanisms can best be shown by considering the proposed pathogenesis of ankylosing spondylitis which has a strong association (96% in Europe) with HLA-B27. Proponents of simple molecular mimicry would suggest that the frequent finding of certain Klebsiella species in the stools of patients with ankylosing spondylitis implies that a Klebsiella macromolecule may have an amino acid sequence homology with a region of the HLA-B27 molecule itself so that an immunological response towards the Klebsiella antigen would cross react with the HLA B27 protein6. Such a sequence has indeed been found for 10 consecutive amino acid residues of the enzyme nitrogen reductase, which is found in 10% of Klebsiella species, and in the HLA-B27 molecule. ''" The induced molecular mimicry theory states that a putative macromolecule binds directly to the HLAB27 molecule so that it is no longer recognised as 'self'. Both theories are controversial but are susceptible to further investigation. With regard to the intestine, it is important to realise that if the simple molecular mimicry theory holds true there need not be a severe disruption of the intestinal barrier function as the antigen would only have to gain access to the lamina propria, whereas if the latter theory is operational there would have to be profound loss of intestinal integrity so as to allow a significant antigenaemia. Regardless of the precise cascade of events it is clear that the assocation between intestinal defects and the various arthritides ranges from almost certainty with Salmonella, Shigella, Yersinia, and Campylobacter infections, as well as the less specific intestinal bacterial overgrowth syndrome which may follow intestinal bypass surgery'2 16 to the speculative with rheumatoid arthritis. '718 The idea of infection and rheumatoid arthritis dates back to the last century and culminated in the theory of focal sepsis which in turn was translated into the common therapeutic practice of total tooth extraction, removal of tonsils and adenoids, and even colectomy in an attempt to cure the disease. ' After their failure, the idea was resurrected in Scandinavia and, after some sound scientific work, led to the use of sulphasalazine in rheumatoid arthritis and inflammatory bowel disease. '02" The idea has by no means fallen into obscurity and Ebringer has recently suggested a pathogenic role for Proteus mirabilis in rheumatoid arthritis after showing high antibody titres of this common pathogen in patients with rheumatoid arthritis.6 A gastroenterological approach to the problem was initiated by us five years ago and the results show that most of the intestinal abnormalities encountered in patients with rheumatoid arthritis are the result of the use of non-steroidal anti-inflammatory drugs (NSAID). Moreover, it is apparent that the small intestine is an important site of NSAID-related gastrointestinal toxicity, contributing significantly to the morbidity of patients with rheumatoid arthritis.2'25