7,857 research outputs found

    Enteric dysfunctions in experimental Parkinson's disease: alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats

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    Parkinson's disease (PD) is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiological assay. Electrically and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, while acetylcholine levels were assayed in their incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors. As compared with control rats, at week 4 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate; impaired electrically evoked neurogenic cholinergic contractions; enhanced carbachol-induced contractions; decreased basal and electrically stimulated acetylcholine release from colonic tissues; decreased ChAT immunopositivity in the neuromuscular layer; unchanged density of HuC/D immunoreactive myenteric neurons; increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were detected also at week 8 post-6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate

    Gastrointestinal neuromuscular apparatus: An underestimated target of gut microbiota

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    Over the last few years, the importance of the resident intestinal microbiota in the pathogenesis of several gastro- intestinal diseases has been largely investigated. Growing evidence suggest that microbiota can influence gastro- intestinal motility. The current working hypothesis is that dysbiosis-driven mucosal alterations induce the production of several inflammatory/immune mediators which affect gut neuro-muscular functions. Besides these indirect mucosal-mediated effects, the present review highlights that recent evidence suggests that microbiota can directly affect enteric nerves and smooth muscle cells functions through its metabolic products or bacterial molecular components translocated from the intestinal lumen. Toll- like receptors, the bacterial recognition receptors, are expressed both on enteric nerves and smooth muscle and are emerging as potential mediators between microbiota and the enteric neuromuscular apparatus. Furthermore, the ongoing studies on probiotics support the hypothesis that the neuromuscular apparatus may represent a target of intervention, thus opening new physiopathological and therapeutic scenarios

    Alteration of colonic excitatory tachykininergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration

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    Background: Parkinson's disease (PD) is frequently associated with gastrointestinal (GI) symptoms, including constipation and defecatory dysfunctions. The mechanisms underlying such disorders are still largely unknown, although the occurrence of a bowel inflammatory condition has been hypothesized. This study examined the impact of central dopaminergic degeneration, induced by intranigral injection of 6-hydroxydopamine (6-OHDA), on distal colonic excitatory tachykininergic motility in rats. Methods: Animals were euthanized 4 and 8 weeks after 6-OHDA injection. Tachykininergic contractions, elicited by electrical stimulation or exogenous substance P (SP), were recorded in vitro from longitudinal muscle colonic preparations. SP, tachykininergic NK1 receptor, and glial fibrillary acidic protein (GFAP) expression, as well as the density of eosinophils and mast cells in the colonic wall, were examined by immunohistochemical analysis. Malondialdehyde (MDA, colorimetric assay), TNF, and IL-1 beta (ELISA assay) levels were also examined. The polarization of peritoneal macrophages was evaluated by real-time PCR. Results: In colonic preparations, electrically and SP-evoked tachykininergic contractions were increased in 6-OHDA rats. Immunohistochemistry displayed an increase in SP and GFAP levels in the myenteric plexus, as well as NK1 receptor expression in the colonic muscle layer of 6-OHDA rats. MDA, TNF, and IL-1 beta levels were increased also in colonic tissues from 6-OHDA rats. In 6-OHDA rats, the number of eosinophils and mast cells was increased as compared with control animals, and peritoneal macrophages polarized towards a pro-inflammatory phenotype. Conclusions: The results indicate that the induction of central nigrostriatal dopaminergic degeneration is followed by bowel inflammation associated with increased oxidative stress, increase in pro-inflammatory cytokine levels, activation of enteric glia and inflammatory cells, and enhancement of colonic excitatory tachykininergic motility

    Functional bowel disease : a challenging frontier in gastroenterology

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    The last 30 years have seen incredible advances in the science and practice of gastroenterology and hepatology. In the 1970s, the fiberoptic endoscopic revolution facilitated the visualization of the mucosa of a large segment of the gastrointestinal tract and afforded the opportunity for specialized studies using histological and biochemical analyses. The impact of fiberoptic endoscopy on surveillance or screening for cancer of the colon will be more apparent in the next millennium. Novel pharmacological approaches have had a dramatic impact on gastroenterology.peer-reviewe

    Saccharomyces boulardii CNCM I-745 supplementation reduces gastrointestinal dysfunction in an animal model of IBS

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    We evaluated the effect of Saccharomyces boulardii CNCM I-745 on intestinal neuromuscular anomalies in an IBS-type mouse model of gastrointestinal motor dysfunctions elicited by Herpes Simplex Virus type 1 (HSV-1) exposure.Mice were inoculated intranasally with HSV-1 (102 PFU) or vehicle at time 0 and 4 weeks later by the intragastric (IG) route (108 PFU). Six weeks after IG inoculum, mice were randomly allocated to receive oral gavage with either S. boulardii (107 CFU/day) or vehicle. After 4 weeks the following were determined: a) intestinal motility using fluorescein-isothiocyanate dextran distribution in the gut, fecal pellet expulsion, stool water content, and distal colonic transit of glass beads; b) integrity of the enteric nervous system (ENS) by immunohistochemistry on ileal whole-mount preparations and western blot of protein lysates from ileal longitudinal muscle and myenteric plexus; c) isometric muscle tension with electric field and pharmacological (carbachol) stimulation of ileal segments; and d) intestinal inflammation by levels of tumor necrosis factor α, interleukin(IL)-1β, IL-10 and IL-4.S. boulardii CNCM I-745 improved HSV-1 induced intestinal dysmotility and alteration of intestinal transit observed ten weeks after IG inoculum of the virus. Also, the probiotic yeast ameliorated the structural alterations of the ENS induced by HSV-1 (i.e., reduced peripherin immunoreactivity and expression, increased glial S100β protein immunoreactivity and neuronal nitric oxide synthase level, reduced substance P-positive fibers). Moreover, S. boulardii CNCM I-745 diminished the production of HSV-1 associated pro-inflammatory cytokines in the myenteric plexus and increased levels of anti-inflammatory interleukins.S. boulardii CNCM I-745 ameliorated gastrointestinal neuromuscular anomalies in a mouse model of gut dysfunctions typically observed with irritable bowel syndrome

    Stress-related alterations of visceral sensation: animal models for irritable bowel syndrome study.

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    Stressors of different psychological, physical or immune origin play a critical role in the pathophysiology of irritable bowel syndrome participating in symptoms onset, clinical presentation as well as treatment outcome. Experimental stress models applying a variety of acute and chronic exteroceptive or interoceptive stressors have been developed to target different periods throughout the lifespan of animals to assess the vulnerability, the trigger and perpetuating factors determining stress influence on visceral sensitivity and interactions within the brain-gut axis. Recent evidence points towards adequate construct and face validity of experimental models developed with respect to animals' age, sex, strain differences and specific methodological aspects such as non-invasive monitoring of visceromotor response to colorectal distension as being essential in successful identification and evaluation of novel therapeutic targets aimed at reducing stress-related alterations in visceral sensitivity. Underlying mechanisms of stress-induced modulation of visceral pain involve a combination of peripheral, spinal and supraspinal sensitization based on the nature of the stressors and dysregulation of descending pathways that modulate nociceptive transmission or stress-related analgesic response

    Endocannabinoid-related compounds in gastrointestinal diseases

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    The endocannabinoid system (ECS) is an endogenous signalling pathway involved in the control of several gastrointestinal (GI) functions at both peripheral and central levels. In recent years, it has become apparent that the ECS is pivotal in the regulation of GI motility, secretion and sensitivity, but endocannabinoids (ECs) are also involved in the regulation of intestinal inflammation and mucosal barrier permeability, suggesting their role in the pathophysiology of both functional and organic GI disorders. Genetic studies in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease have indeed shown significant associations with polymorphisms or mutation in genes encoding for cannabinoid receptor or enzyme responsible for their catabolism, respectively. Furthermore, ongoing clinical trials are testing EC agonists/antagonists in the achievement of symptomatic relief from a number of GI symptoms. Despite this evidence, there is a lack of supportive RCTs and relevant data in human beings, and hence, the possible therapeutic application of these compounds is raising ethical, political and economic concerns. More recently, the identification of several EC-like compounds able to modulate ECS function without the typical central side effects of cannabinomimetics has paved the way for emerging peripherally acting drugs. This review summarizes the possible mechanisms linking the ECS to GI disorders and describes the most recent advances in the manipulation of the ECS in the treatment of GI diseases

    Relationship between psychological state and level of activity of extrinsic gut innervation in patients with a functional gut disorder

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    Background: Anxiety and depression are known to be associated with alterations in central autonomic activity, and this may manifest as a functional gut disturbance. However, the final expression of motility disturbance is non-specific and non-quantifiable. This study examines the relationship between psychological state and psychosocial functioning with a new direct measure of the level of activity of extrinsic autonomic gut innervation, rectal mucosal Doppler blood flow. Materials and methods: Thirty four female patients (mean age 36 years, range 19-45) with constipation for greater than five years and 19 healthy women (mean age 38 years, range 21-60) were studied. They completed the general health questionnaire28 point scale (GHQ-28; psychosocial functioning) and the Bem sex role inventory (BSRI; an index of women's psychological feelings about their own femininity). On the same day they underwent measurement of rectal mucosal Doppler blood flow, a new validated measure of the activity of gut extrinsic nerve innervation. Measurements were made during the follicular phase and in the fasted state. Results: Women with constipation scored higher on the total GHQ-28 score and the somatisation (p=0.05) and anxiety (p=0.05) subscales of the GHQ-28. There was a negative correlation between mucosal blood flow and GHQ somatisation subscale (r=0.45, p<0.005), anxiety (r=0.38, p<0.05), and depression (r=0.40, p<0.01) scores in women with constipation. Although constipated women scored no higher than controls on the BSRI, there was a significant negative correlation between blood flow and BSRI score (r=0.49, p<0.005) for constipated women. Conclusions: General psychosocial function, somatisation, anxiety, depression, and feelings about female role are impaired in women with constipation and associated with altered rectal mucosal blood flow, a measure of extrinsic gut innervation. These findings suggest that psychological factors are likely to influence gut function via autonomic efferent neural pathways
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