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Benson J.R.,Queens University | Xu J.,Queens University | Moynes D.M.,Queens University | Lapointe T.K.,University of Calgary | And 4 more authors.
Cell and Tissue Research | Year: 2014

Sensitization of dorsal root ganglia (DRG) neurons is an important mechanism underlying the expression of chronic abdominal pain caused by intestinal inflammation. Most studies have focused on changes in the peripheral terminals of DRG neurons in the inflamed intestine but recent evidence suggests that the sprouting of central nerve terminals in the dorsal horn is also important. Therefore, we examine the time course and reversibility of changes in the distribution of immunoreactivity for substance P (SP), a marker of the central terminals of DRG neurons, in the spinal cord during and following dextran sulphate sodium (DSS)-induced colitis in mice. Acute and chronic treatment with DSS significantly increased SP immunoreactivity in thoracic and lumbosacral spinal cord segments. This increase developed over several weeks and was evident in both the superficial laminae of the dorsal horn and in lamina X. These increases persisted for 5 weeks following cessation of both the acute and chronic models. The increase in SP immunoreactivity was not observed in segments of the cervical spinal cord, which were not innervated by the axons of colonic afferent neurons. DRG neurons dissociated following acute DSS-colitis exhibited increased neurite sprouting compared with neurons dissociated from control mice. These data suggest significant colitis-induced enhancements in neuropeptide expression in DRG neuron central terminals. Such neurotransmitter plasticity persists beyond the period of active inflammation and might contribute to a sustained increase in nociceptive signaling following the resolution of inflammation. © 2014 Springer-Verlag.


Vanner S.J.,Gastrointestinal Diseases Research Unit | Greenwood-Van Meerveld B.,The University of Oklahoma Health Sciences Center | Mawe G.M.,University of Vermont | Shea-Donohue T.,University of Maryland Baltimore County | And 3 more authors.
Gastroenterology | Year: 2016

This review examines the fundamentals of neurogastroenterology that may underlie the pathophysiology of functional GI disorders (FGIDs). It was prepared by an invited committee of international experts and represents an abbreviated version of their consensus document that will be published in its entirety in the forthcoming book and online version entitled Rome IV. It emphasizes recent advances in our understanding of the enteric nervous system, sensory physiology underlying pain, and stress signaling pathways. There is also a focus on neuroimmmune signaling and intestinal barrier function, given the recent evidence implicating the microbiome, diet, and mucosal immune activation in FGIDs. Together, these advances provide a host of exciting new targets to identify and treat FGIDs, and new areas for future research into their pathophysiology. © 2016 by the AGA Institute.


Lourenssen S.,Queens University | Houpt E.R.,University of Virginia | Chadee K.,University of Calgary | Blennerhassett M.G.,Queens University | Blennerhassett M.G.,Gastrointestinal Diseases Research Unit
Infection and Immunity | Year: 2010

The enteric protozoan parasite Entamoeba histolytica causes amebic colitis through disruption of the mucus layer, followed by binding to and destruction of epithelial cells. However, it is not known whether ameba infections or ameba components can directly affect the enteric nervous system. Analysis of mucosal innervations in the mouse model of cecal amebiasis showed that axon density was diminished to less than 25% of control. To determine whether amebas directly contributed to axon loss, we tested the effect of either E. histolytica secreted products (Eh-SEC) or soluble components (Eh-SOL) to an established coculture model of myenteric neurons, glia, and smooth muscle cells. Neuronal survival and axonal degeneration were measured after 48 h of exposure to graded doses of Eh-SEC or Eh-SOL (10 to 80 μg/ml). The addition of 80 μg of either component/ml decreased the neuron number by 30%, whereas the axon number was decreased by 50%. Cytotoxicity was specific to the neuronal population, since the glial and smooth muscle cell number remained similar to that of the control, and was completely abrogated by prior heat denaturation. Neuronal damage was partially prevented by the cysteine protease inhibitor E-64, showing that a heat-labile protease was involved. E. histolytica lysates derived from amebas deficient in the major secreted protease EhCP5 caused a neurotoxicity similar to that of wild-type amebas. We conclude that E. histolytica infection and ameba protease activity can cause selective damage to enteric neurons. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Muinuddin A.,Queens University | Aslahi R.,Queens University | Hopman W.M.,Queens University | Paterson W.G.,Queens University | Paterson W.G.,Gastrointestinal Diseases Research Unit
Canadian Journal of Gastroenterology | Year: 2013

Background: In 2007, Ontario launched a colon cancer screening program for average-risk individuals based on biennial fecal occult blood tests (FOBTs) on three fecal samples, followed by colonoscopy for individuals who tested positive. objective: To determine whether >1 positive screening FOBT was predictive of finding advanced neoplasia at colonoscopy. METHODS: A retrospective chart review of outpatient colonoscopic procedures performed at Hotel Dieu Hospital (Kingston, Ontario) in the first two years of the colon cancer screening program was conducted, focusing on endoscopic and pathological findings. RESULTS: Of 5556 individuals undergoing colonoscopy, 346 were referred for positive FOBT. Overall, 41 (11.8%) patients with a positive FOBT had colon cancer. In 16 (4.6%) cases, the number of positive FOBTs was not reported. For the 330 individuals in whom the number of positive tests was specified, 198, 71 and 61 cases had one, two and three positive results, respectively. Cancer was found at colonoscopy in 11 (5.6%), 11 (15.5%) and 18 (29.5%) of individuals with one, two and three positive FOBT results, respectively (OR 3.0 [95% CI 1.2 to 7.3] and 6.5 [95% CI 2.8 to 15.0] for two or three positive FOBTs compared with one; P=0.015 and P<0.001, respectively). High-risk adenomas (>1 cm in diameter, villous component and/or high-grade dysplasia) were found in 41 (20.8%), 29 (42.0%) and 25 (41.0%) individuals with one, two and three positive FOBTs, respectively (OR 2.8 [95% CI 1.5 to 5.0] and 2.4 [95% CI 1.3 to 4.5] for two or three positive FOBTs compared with one; P=0.001 and P=0.006, respectively). CONCLUSIONS: The diagnostic yield of colonoscopy varied directly with the number of positive FOBTs. This information may be useful in assigning scheduling priority for patients with positive FOBTs. © 2013 Pulsus Group Inc. All rights reserved.


Lukewich M.K.,Gastrointestinal Diseases Research Unit | Lomax A.E.,Gastrointestinal Diseases Research Unit | Lomax A.E.,Queens University
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2011

The sympathetic nervous system regulates visceral function through the release of catecholamines and cotransmitters from postganglionic sympathetic neurons and adrenal chromaffin cells (ACCs). Previous studies have shown that norepinephrine secretion is decreased during experimental colitis due to the inhibition of voltage-gated Ca2+ current (ICa) in postganglionic sympathetic neurons. The present study examined whether colonic inflammation causes a similar impairment in depolarization-induced Ca2+ influx in ACCs using the dextran sulfate sodium (DSS) model of acute colitis in mice. Alterations in ACC function during colitis were assessed using fura 2-acetoxymethyl ester Ca2+ imaging techniques and perforated patch-clamp electrophysiology. In ACCs isolated from mice with DSS-induced acute colitis, the high-K+-stimulated increase in intracellular Ca2+ concentration ([Ca2+]i) was significantly reduced to 74% of the response of ACCs from control mice. Acute colitis caused a 10-mV hyperpolarization of ACC resting membrane potential, without a significant effect on cellular excitability. Delayedrectifier K+ and voltage-gated Na+ current densities were significantly enhanced in ACCs from mice with DSS-induced acute colitis, with peak current densities of 154 and 144% that of controls, respectively. Importantly, acute colitis significantly inhibited ICa in ACCs between -25 and +20 mV. Peak ICa density in ACCs from mice with DSS-induced acute colitis was 61% that of controls. High-K+-induced increases in [Ca2+]i were also reduced in ACCs from mice with 2,4,6-trinitrobenzene sulfonic acid-induced acute colitis and DSSinduced chronic colitis to 68 and 78% of the control responses, respectively. Our results suggest that, during colitis, voltage-dependent Ca2+ influx is impaired in ACCs. Given the importance of Ca2+ signaling in exocytosis, these alterations may decrease systemic catecholamine levels, which could play an important role in inflammatory bowel disease. This is the first demonstration of aberrant ACC function during experimental colitis.© 2011 by the American Physiological Society.

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