Pathogenetic mechanisms in irritable bowel syndrome

Abstract

Aims of the thesis: To study new pathogenetic mechanisms in IBS; to find out if IBS is a neuromuscular disease affecting the small bowel; to study humoral factors in gut dysmotility associated with visceral neuropathy; and to study the natural history of post-infectious gastro-intestinal (GI) symptoms and risk factors for their development.

Material and methods: In studies I and II, full-thickness jejunum biopsies from patients with severe IBS were investigated with immunohistochemistry. A control group that was operated on because of morbid obesity was used in study II to test the validity of reported findings in study I. The control group had no symptoms compatible with a functional GI disorder (FGID) and the pathologist was blinded with respect to diagnosis. In study III, sera from patients with different gut dysmotility diagnoses associated with visceral neuropathy, with and without ganglionitis, were investigated by immunoassays for the presence of neuronal autoantibodies. In study IV, a large cohort of patients who had suffered an acute gastroenteritis was re-investigated for persistence of GI symptoms 5 years later using mailed questionnaires. Clinical data were scrutinized in order to find risk factors for persistence of GI symptoms.

Results: A total of 17 patients with severe IBS were included in studies I and II. In both studies, signs of either visceral degenerative neuropathy (4) or a low-grade inflammatory neuropathy (13) affecting the myenteric plexus (ganglionitis) were reported. Seven of 10 controls also had this type of finding, 6 of them with ganglionitis. A peculiar longitudinal muscle hypertrophy in muscularis propria was seen in study I, but could not be confirmed in study II. An attempt to judge density of the interstitial cell of Cajal (ICC) in a standardised way suggests that this cell-population was decreased in 2 patients in study II. After testing sera from 33 patients with gut dysmotility in study III, one patient with IBS was found to have a low titre of antivoltage-gated potassium-channel antibodies and another patient with IBS had anti-alpha3 acetylcholine-receptor antibodies. Both cases were associated with a histopathologic diagnosis of ganglionitis. In study IV, 41 of 333 (12%) previously healthy patients reported GI symptoms for 3 months or more after an acute episode of gastroenteritis. Female gender and antibiotic treatment were identified as risk factors for persisting GI symptoms. No specific infectious agent was found to be a risk factor.

Conclusions: Study I introduces the novel concept of ENS pathology (visceral neuropathy and low-grade lymphocyte infiltration) being present in patients with severe IBS. Study II modulates the results of study I by showing that such findings may exist without provoking GI symptoms of FGID character. ICC pathology may be involved in IBS pathogenesis. A humoral factor may be a rare cause for symptom generation associated with ganglionitis. Finally, study IV confirms previous studies regarding the prevalence of persisting post-infectious GI symptoms. Host factors may be more important than specific infectious etiology when assessing this risk.