Nitric oxide : A suurogate marker of bowel inflammation
Abstract: The gas nitric oxide (NO) is a pluripotent biological messenger involved in numerous physiological and pathological processes in the gastrointestinal (GI) tract. In the intestinal mucosa NO is synthesized from the amino acid L-arginine via a reaction catalyzed by NO synthase (NOS). During inflammation, mucosal NO generation is increased and NO gas is released in the gut lumen. We have developed a procedure for direct measurement of gaseous NO in the GI tract. Employing this procedure, the present thesis was designed to evaluate further the potential usefulness of measurements of rectal levels of NO in diagnosing inflammatory bowel disease (IBD) and monitoring the response of this disease to treatment. Altogether, 89 patients with IBD, 39 with irritable bowel syndrome (IBS) and 28 with collagenous colitis (CC), were examined. Rectal NO levels were measured employing a tonometric method using a silicon catheter equipped with an inflatable balloon and compared to clinical indices of disease activity. We also characterized the effect of systemic inhibition of NOS (by LNMMA) on rectal levels of NO in patients with collagenous colitis to further pinpoint the source of rectal NO. Finally, we investigated the possibility that commensal gut bacteria can produce NO. In healthy subjects rectal levels of NO were low and varied little with time. Slightly and highly elevated levels were observed in patients with IBS and IBD respectively. This parameter demonstrated a sensitivity of 95 % and specificity of 91 % in discriminating between IBS and active IBD. Rectal levels of NO were correlated to disease activity in patients with IBD or CC and were reduced markedly in IBD patients who responded to treatment. Surprisingly, rectal levels of NO were not correlated to fecal calprotectin levels, another marker of IBD. Intravenous administration of L-NMMA reduced rectal NO levels in only half of the patients with CC examined, despite clear evidence of effective systemic inhibition of NOS. This could indicate the existence of alternative, NOS-independent sources of intestinal NO in this disorder. Human feces and certain isolated strains of bacteria were capable of generating NO in the presence of nitrate andlor nitrite in vitro. In addition, NO generation was observed in the gut lumen of conventional rats, but not of germ-free rats or rats colonized by lactobacilli. Thus, bacteria can be a significant source of NO in the gut. We conclude that measurements of rectal levels of NO could be clinically useful as a rapid and minimally invasive procedure for discriminating between active bowel disease and IBS, as well as a possible source of useful supplemental information when monitoring the treatment of patients with IBD. Future studies will reveal the biological significance of NO generation by GI bacteria with regards to the regulation of GI integrity and the clinical usefulness of fecal calprotectin and rectal NO as surrogate markers for bowel inflammation, as well as the exact role played by these substances in the pathogenesis of this disorder.
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