Characterization of myenteric neuropathy in the jejunum of spontaneously diabetic BB-rats

Abstract  Decreased gastric expression and function of neuronal nitric oxide synthase (nNOS) has been proposed as a potential mechanism underlying diabetic gastroparesis. As gastric nNOS expression is vagally controlled, these changes might occur secondarily to vagal neuropathy. In addition, it is unclear whether other inhibitory neurotransmitters are also involved. We used the type 1 diabetic BioBreeding (BB)-rat model to study jejunal motor control and nNOS expression, which is independent of the vagus. Jejunal segments were used for in vitro contractility studies, and measurement of nNOS expression after 8 or 16 weeks of diabetes compared with age- and sex-matched controls. Unlike electrical field stimulation and acetylcholine (ACh)-induced contractions, non-adrenergic non-cholinergic (NANC) relaxations were significantly reduced in diabetic rats. In contrast to control rats, NANC relaxations in diabetic rats were N _ω-nitro- l -arginine methyl ester ( l -NAME) insensitive. Jejunal nNOS expression was significantly decreased in diabetic rats. Both in diabetic and in control animals, l -NAME resistant relaxations were sensitive to P₂-receptor antagonists. In the jejunum of spontaneously diabetic rats, decreased nitric oxide responsiveness and decreased nNOS protein expression occur while purinergic transmission is unaffected. These findings indicate that nitrergic enteric neuropathy may be a primary dysfunction in diabetes, independent from vagal dysfunction.     

Intestinal immune activation in presumed post-infectious functional dyspepsia

Abstract  Functional dyspepsia (FD) symptoms may develop after an acute gastroenteritis. In post-infectious (PI) irritable bowel syndrome, persisting low-grade colonic inflammation and increased enterochromaffine cells (EC) counts have been reported. The aim was to compare signs of inflammation and EC hyperplasia on duodenal biopsies in presumed PI-FD and unspecified-onset (U-)FD. Duodenal biopsies were obtained in 12 U-FD and 12 PI-FD (on average 13 months after the acute event) patients. The presence of intra-epithelial, intravillar, and the number of CD3, CD4, CD8 and CD68+ cells per crypts, and the mean number of Chromogranine A (CA) positive cells per villus were compared. We also measured gastric emptying and assessed proximal stomach function with a barostat. Data are shown as mean ± SEM. Focal aggregates of T cells and focal CD8+ aggregates, were found in PI-FD but not in U-FD patients (respectively 5/12 vs 0/12, P  = 0.02 and 5/9 vs 0/11, P  < 0.01). In patients with focal aggregates, gastric emptying was delayed (189 ± 37 min vs 98 ± 11 min, P  = 0.002). The number of CD4+ cells per crypt (0.52 ± 1.6 vs 1.22 ± 2.18, P  = 0.04), and the number of intravillar CD4+ cells (0.5 ± 0.2 vs 2.7 ± 0.7, P  = 0.01) were reduced, while the number of CD68+ cells per crypt was increased (0.64 ± 0.13 vs 0.40 ± 0.05, P  = 0.03) in PI-FD. The number of EC and CA were comparable. PI-FD is associated with persisting focal T-cell aggregates, decreased CD4+ cells and increased macrophage counts surrounding the crypts. This may indicate impaired ability of the immune system to terminate the inflammatory response after acute insult.     

Neural mechanisms of early postinflammatory dysmotility in rat small intestine

Although human postinflammatory dysmotility is known, so far animal studies have primarily investigated changes during inflammation. Here, we focused on postinflammatory changes in rat jejunal myenteric plexus and jejunal motility. Evolution of ethanol/2,4,6-tri-nitrobenzene sulphonic acid (TNBS)-induced inflammation was assessed histologically and by measuring myeloperoxidase activity (MPO). Electromyography and immunohistochemistry were performed 1 week after ethanol/TNBS and also after N(G)-nitro-L-arginine methyl ester (L-NAME) administration. Ethanol/TNBS induced a transient inflammation, with normalization of MPO and histological signs of an early phase of recovery after 1 week. The number of cholinergic neurones was not altered, but myenteric neuronal nitric oxide synthase (nNOS)-immunoreactivity was significantly lower in the early phase of recovery after TNBS compared with water (1.8 +/- 0.2 vs 3.5 +/- 0.2 neurones ganglion(-1), P < 0.001). Interdigestive motility was disrupted with a loss of phase 1 quiescence, an increase of migrating myoelectric complex cycle length, a higher number of non-propagated activity fronts and a decrease of adequately propagated phase 3 s after TNBS. Administration of L-NAME resulted in a similar disruption of interdigestive motility patterns. In the early phase of recovery after ethanol/TNBS-induced jejunal inflammation, a loss of motor inhibition occurs due to a decrease of myenteric nNOS activity. These observations may provide a model for early postinflammatory dysmotility syndromes.     

Chronic intestinal pseudo-obstruction caused by an intestinal inflammatory myopathy: case report and review of the literature

Abstract  Chronic intestinal pseudo-obstruction (CIP) is an uncommon disorder that may be of primary or secondary origin. We report a case of a 37-year-old woman with CIP due to inflammatory disorder of unknown origin involving the skin (eosinophilic fasciitis), the lungs (decreased diffusion capacity) and the gastrointestinal tract. History, clinical examination, plain abdominal film, barium X-ray and colonoscopy established a diagnosis of recurrent pseudo-obstruction. A full-thickness biopsy was performed during explorative laparotomy, and histological examination revealed findings compatible with an inflammatory myopathy due to a dense lymphoid infiltrate and extensive loss of the muscularis propriae layers. Immunosuppressive therapy with cyclosporin was initiated, with significant clinical improvement. This case illustrates another form of CIP, characterized by an inflammatory myopathy, which is histologically distinct from other known visceral myopathies and neuropathies.     

Enteric nervous system abnormalities in inflammatory bowel diseases

Abstract  Various studies have described abnormalities of the enteric nervous system (ENS) in tissue samples from patients with chronic idiopathic inflammatory bowel diseases (IBD). The distribution of density of the different cell types of the ENS was however not studied in a systematic way. The aim of this study was to examine the density of neurons, enteroglial cells and interstitial cells of Cajal (ICC) in the different plexuses of the ENS in samples from patients with Crohn's disease (CD), ulcerative colitis (UC) and controls. Tissue samples from 16 patients with CD (ileum) and 16 patients with UC obtained in involved and non-involved areas were studied using immunohistochemistry with antibodies directed against neuron-specific enolase, S100, C-Kit and CD3. Sections were analysed blindly by two pathologists and the number of positive cells was counted for each type. Overall, an increase was noted for neuronal cell bodies, enteroglia and ICC in the deep muscular plexus in CD. In uninvolved areas of CD patients, the number of enteroglial cells was decreased. In UC, an increase of ICC in the muscularis propria and enteroglial cells was observed in diseased tissue. The study confirms the presence of abnormalities of the different cells of the ENS in IBD. The presence of lesions in samples from uninvolved areas, such as a reduction of enteroglia, supports a pathogenetic role of the ENS.