[Show abstract][Hide abstract] ABSTRACT: Objective: Chronic constipation (CC) is a well recognized gastrointestinal (GI) disturb in most Parkinson’s disease (PD) patients. Nonetheless, the clinical features and the attendant enteric neuropathological / neurochemical abnormalities of CC in PD patients (CC/PD) are still largely undefined. In CC/PD patients our goals were to: (i) characterize CC by assessing colonic transit time (TT) and anorectal manometry (AM); (ii) analyze possible neurochemical abnormalities of colonic submucosal neuron.
Methods: CC and related symptoms were assessed using the Rome III criteria, while PD was established by a Unified Parkinson’s Disease Rating Scale (part III). CC was characterized in 25 PD patients (7F, 18M; age range: 64–85 years) by TT, AM and colonoscopy; 14 control
subjects (4F, 10M; age range: 33–77 years) undergoing screening colonoscopy were included. Using routine biopsies during colonoscopy, we obtained submucosal specimens with related neural network in 10 CC/PD patients and 10 controls. The submucosal plexus was studied by immunohistochemistry on whole mount preparations using a mouse monoclonal anti-HuC/D as pan-neuronal marker (Invitrogen, 1 : 50) and two rabbit polyclonal anti-VIP (vasoactive intestinal peptide-7913;
CURE/DDRC, UCLA, 1 : 2500) and anti-pChAT (peripheral choline acetyl transferase, Justus-Liebig- University Giessen, Germany; 1 : 100) antibodies.
Results: Four groups of CC/PD patients were characterized: (i) 55% with both delayed TT and altered AM; (ii) 15% only with a delayed TT; (iii) 20% only with an altered AM; (iv) the remaining 10% showing no abnormalities. Concerning quantitative immunohistochemical analysis, CC/PD patients did not show any significant differences in terms of total number of HuC/ D immunoreactive (-IR) neurons/ganglionvs. Controls (4.7 _ 0.8 and 5.5 _ 1.5, respectively); however, areduced number of HuC/D/VIP-IR neurons was found in CC/PD (73.3 _ 17.1) vs controls (86.0 _ 10.9; p < 0.05). There were no significant changes for HuC/D/ChAT neurons in both groups (85.6 _ 11.1 vs 91.2 _ 10.1).
Conclusions: Colonic motor and rectal sensory function abnormalities were detected in almost 90% of CC/PD patients. A selective reduction of VIP containing submucosal (i.e. most likely secretomotor) neurons is
suggestive of altered secretory mechanisms that accompany sensorymotor dysfunction in the pathophysiology of CC/PD patients.
Neurogastroenterology and Motility 09/2014; 26(SUPPLEMENT 1):33-34. · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: See Covering the Cover synopsis on page 1583. BACKGROUND & AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na V 1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether pa-tients with IBS have SCN5A variants that affect the function of Na V 1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na V 1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na V 1.5 had the greatest effect in reducing Na V 1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na V 1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
[Show abstract][Hide abstract] ABSTRACT: Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are classically viewed as dichotomous conditions. The former is perceived as a typical organic disease, and the latter is regarded as a disorder of gut function driven by mood. Recent research identified some shared contributing factors, which will be discussed here.
Mounting evidence shows the importance in both IBD and IBS of genetic, microbiological, epithelial, and immunological factors. In some instances, these factors overlap in the two conditions as shown by: involvement of brain-gut axis dysfunction in IBD, implication of TNFSF gene in Crohn's disease and IBS, evidence of abnormal microbiota and its impact on host functions, identification of low-grade inflammation in subsets of IBS patients, and development of IBS symptoms in patients with IBD in remission.
IBD and IBS remain separate conditions although there are some overlapping mechanisms. Both research and clinical management would benefit from considering a functional approach for certain manifestations of IBD and accepting an organic view in subsets of IBS patients.
Current opinion in gastroenterology 05/2014; · 4.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute infectious gastroenteritis increases the risk for irritable bowel syndrome (IBS) and functional dyspepsia (FD). Children are particularly vulnerable to gastroenteritis due to the immaturity of their intestinal barrier, enteric nervous system, and immune response to pathogens. We investigated whether acute gastroenteritis in early life increases the risk of IBS and FD through adulthood.
In 1994, we identified and monitored a single culture-proven foodborne Salmonella enteritidis outbreak that involved 1811 patients (mostly pediatric) in Bologna, Italy. Clinical data were collected and a prospective, controlled, cohort study was designed. Long-term effects were assessed by mailing a questionnaire to 757 subjects, 16 years after the outbreak (when all of children were adults). We randomly selected a cohort of 250 adults exposed to Salmonella as children, all 127 individuals exposed as adults, and a cohort of non-exposed participants matched for number, age, sex, and area of residence (controls).
Among 198 exposed participants, 64 reported FD (32.3%), compared to 51 of 188 controls (27.1%; P=.268). Among 204 exposed participants, 75 reported having IBS (36.8%), compared to 44 of 189 controls (23.3%; P=.004). The odds ratio for IBS among people exposed to the Salmonella was 1.92 (95% confidence interval 1.23-2.98). The prevalence of IBS was higher in individuals exposed Salmonella as children than in controls (35.3% vs 20.5%; P=.008), but not in individuals exposed as adults, compared with controls. After multivariate logistic regression, post-infectious IBS was independently associated with anxiety and FD.
Based on data collected from a single culture-proven foodborne Salmonella enteritidis outbreak in 1994, Salmonella-induced gastroenteritis during childhood (but not adulthood) is a risk factor for IBS.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND & AIMS:
SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5.
We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls.
Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS.
About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
[Show abstract][Hide abstract] ABSTRACT: Chronic constipation is a frequent pathological condition bearing relevant socioeconomic burdens, mainly due to uncertain management and unsatisfactory response to traditional laxatives. Prucalopride is a novel enterokinetic drug, that has been demonstrated to improve bowel functions and relieve a broad spectrum of digestive symptoms in patients with severe chronic constipation who had failed to respond to various traditional laxatives. In this paper we discussed the practical aspects of chronic constipation treatment, in particular focusing on some questions about the practical use of prucalopride. Prucalopride is a potent, selective, high-affinity agonist of the 5-HT4 receptors widely expressed in the gastrointestinal tract. Unlike other 5-HT4 agonists, such as cisapride and tegaserod, it is devoid of adverse cardiovascular effects. Furthermore, it is characterized by a low potential for interactions with other drugs, due to its pharmacokinetic characteristics. Prucalopride was approved, in 2009, by the European Medicines Agency for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief, however, there are ongoing studies to extend the use of the drug even to males.
Minerva gastroenterologica e dietologica 03/2014; 60(1):85-99.
[Show abstract][Hide abstract] ABSTRACT: Background & Aims
SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Nav1.5.
We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without (controls). Mutant forms of SCN5A were expressed in HEK-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study (GWAS) was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls.
Missense mutations were found in SCN5A in 13/584 patients (2.2%, probands). Diarrhea-predominant IBS (IBS-D) was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (IBS-C, 31%) than IBS-D (10%, P<.05). Electrophysiologic analysis showed that 10/13 detected mutations disrupted NaV1.5 function (9 reduced and 1 increased function); p.A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current; administration of mexiletine to 1 carrier of this mutation (who had IBS-C) normalized their bowel habits. In the GWAS and 4 replicated studies, the SCN5A locus was strongly associated with IBS.
About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
[Show abstract][Hide abstract] ABSTRACT: The statements produced by the Consensus Conference on Diverticular Disease promoted by GRIMAD (Gruppo Italiano Malattia Diverticolare, Italian Group on Diverticular Diseases) are reported. Topics such as epidemiology, risk factors, diagnosis, medical and surgical treatment of diverticular disease (DD) in patients with uncomplicated and complicated DD were reviewed by a scientific board of experts who proposed 55 statements graded according to level of evidence and strength of recommendation, and approved by an independent jury. Each topic was explored focusing on the more relevant clinical questions. Comparison and discussion of expert opinions, pertinent statements and replies to specific questions, were presented and approved based on a systematic literature search of the available evidence. Comments were added explaining the basis for grading the evidence, particularly for controversial areas.
United European Gastroenterology Journal. 01/2014; 1383:21-1.
[Show abstract][Hide abstract] ABSTRACT: Neuroimmune interactions and inflammation have been proposed as factors involved in sensory-motor dysfunction and symptom generation in adult irritable bowel syndrome (IBS) patients. In children with IBS and healthy controls, we measured ileocolonic mast cell infiltration and fecal calprotectin and evaluated the relationships between these parameters and abdominal pain symptoms and stooling pattern.
Irritable bowel syndrome patients diagnosed according to Pediatric Rome III criteria and healthy controls kept a 2-week pain/stooling diary. Ileocolonic mucosal mast cells (MC) and MC in close proximity to nerve fibers (MC-NF) were identified immunohistochemically and quantified. Fecal calprotectin concentration was measured.
21 IBS patients and 10 controls were enrolled. The MC-NF count was significantly higher in the ileum (p = 0.01), right colon (p = 0.04), and left colon (p < 0.001) of IBS patients compared with controls. No differences in fecal calprotectin concentration were noted. Abdominal pain intensity score correlated with ileal MC count (rs = 0.47, p = 0.030) and right colon MC-NF count (rs = 0.52, p = 0.015). In addition, children with IBS with >3 abdominal pain episodes/week had greater ileal (p = 0.002) and right colonic (p = 0.01) MC counts and greater ileal (p = 0.05) and right colonic (p = 0.016) MC-NF counts than children with less frequent pain. No relationship was found between MC and MC-NF and fecal calprotectin or stooling pattern.
Mast cells-nerve fibers counts are increased in the ileocolonic mucosa of children with IBS. Mast cells and MC-NF counts are related to the intensity and frequency of abdominal pain.
Neurogastroenterology and Motility 11/2013; · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gas-related symptoms represent very common complaints in children. The reduction of gas production can be considered as a valuable target in controlling symptoms. alpha-galactosidase has been shown to reduce gas production and related symptoms in adults.Aim: To evaluate the efficacy and tolerability of alpha-galactosidase in the treatment of gas-related symptoms in pediatric patients.
Single center, randomized, double-blind, placebo-controlled, parallel group study performed in tertiary care setting. Fifty-two pediatric patients (32 female, age range 4--17) with chronic or recurrent gas-related symptoms were randomized to receive placebo (n = 25) or alpha-galactosidase (n = 27). Both treatments were given as drops or tablets, according to body weight for 2 weeks. The primary endpoint was the reduction in global distress measured by the Faces Pain Scale-Revised (FPS-R) at the end of treatment compared to baseline. Secondary endpoints were the reduction in severity and frequency of gas-related symptoms as recorded by parents and/or children.
alpha-galactosidase significantly reduced global distress (p = 0.02) compared to placebo. The digestive enzyme decreased the number of days with moderate to severe bloating (p = 0.03) and the proportion of patients with flatulence (p = 0.02). No significant differences were found for abdominal spasms and abdominal distension. No adverse events were reported during treatment.
Although larger and longer trials are needed to confirm this result, alpha-galactosidase seems to be a safe, well tolerated and effective treatment for gas-related symptoms in the pediatric population.Trial registration: ClinicalTrials.gov - NCT01595932.
[Show abstract][Hide abstract] ABSTRACT: Diverticular disease (DD) and irritable bowel syndrome (IBS) share a similar symptom pattern. However, comparative studies are flawed by different age at onset of symptoms. We aimed to verify whether clinical features distinguish DD from IBS.
Patients with DD or IBS, matched for age and gender (1/1) were consecutively recruited. Data on demographic parameters, voluptuary habits, inheritance of disease and symptoms were collected. Moreover, the association between pain > 24 h, and clinical parameters were evaluated.
Ninety patients with DD and 90 patients with IBS (DD: F/M: 46/44; age: 50.9 years; IBS: 46/44; 50.4) were selected from an overall population of 1275 patients. Only nine patients with DD (10%) fulfilled the criteria for IBS diagnosis. Abdominal pain > 24 h was more prevalent in SDD than in patients with IBS (20 vs. 6 patients; P < 0·01). Furthermore, compared with IBS, patients with DD showed more episodes of pain > 24 h requiring medical attention (80% vs. 33%; P < 0·01).
Abdominal pain lasting for more than 24 h discriminates patients with DD compared with those with IBS. Identifying this symptom could be an appropriate strategy to define the diagnosis and management.
European Journal of Clinical Investigation 08/2013; · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The debate about the ethical and scientific issues regarding the use of animals in research is mainly focused on these questions: a) whether preclinical studies in animals are still ethically acceptable; b) whether it is possible to establish more soundly their predictivity; c) what measures should be taken to reduce the clinical attrition often due to biased preclinical assessment of potential efficacy of new drugs. This review aims at a critical revision of animal models of chemically induced intestinal inflammation in drug development. These models, notwithstanding differences among species, still represent a major source of information about biological systems and can have undisputable translational value, provided that appropriate measures are taken to ensure that experiments are both scientifically and ethically justified. These measures include: a) more stringent application to preclinical experiments of standards used in clinical studies (such as sample size, randomization, inclusion/exclusion criteria, blinding); b) selection of the animal model after careful pathophysiological scrutiny bearing in mind inherent limitations of each model (e.g. acute self-limiting vs chronic disease, animal species, role of the intestinal immune system and microbiome); and c) experimental design duly considering the specific pharmacological profile of each agent to be screened (such as bioavailability, route of administration, full consideration of the pharmacological spectrum). In this perspective, the new European legislation is an opportunity to fully apply these standards so that in vivo animal models can provide an invaluable mean to study complex physiological and biochemical interactions, which cannot be completely simulated in silico and/or in vitro.
[Show abstract][Hide abstract] ABSTRACT: Taste signalling molecules are found in the gastrointestinal (GI) tract suggesting that they participate to chemosensing. We tested whether fasting and refeeding affect the expression of the taste signalling molecule, α-transducin (G(αtran) ), throughout the pig GI tract and the peptide content of G(αtran) cells. The highest density of G(αtran) -immunoreactive (IR) cells was in the pylorus, followed by the cardiac mucosa, duodenum, rectum, descending colon, jejunum, caecum, ascending colon and ileum. Most G(αtran) -IR cells contained chromogranin A. In the stomach, many G(αtran) -IR cells contained ghrelin, whereas in the upper small intestine many were gastrin/cholecystokinin-IR and a few somatostatin-IR. G(αtran) -IR and G(αgust) -IR colocalized in some cells. Fasting (24 h) resulted in a significant decrease in G(αtran) -IR cells in the cardiac mucosa (29.3 ± 0.8 versus 64.8 ± 1.3, P < 0.05), pylorus (98.8 ± 1.7 versus 190.8 ± 1.9, P < 0.0 l), caecum (8 ± 0.01 versus 15.5 ± 0.5, P < 0.01), descending colon (17.8 ± 0.3 versus 23 ± 0.6, P < 0.05) and rectum (15.3 ± 0.3 versus 27.5 ± 0.7, P < 0.05). Refeeding restored the control level of G(αtran) -IR cells in the cardiac mucosa. In contrast, in the duodenum and jejunum, G(αtran) -IR cells were significantly reduced after refeeding, whereas G(αtran) -IR cells density in the ileum was not changed by fasting/refeeding. These findings provide further support to the concept that taste receptors contribute to luminal chemosensing in the GI tract and suggest they are involved in modulation of food intake and GI function induced by feeding and fasting.
Journal of Cellular and Molecular Medicine 02/2013; · 4.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diarrhea is defined as reduced stool consistency, increased water content and number of evacuations per day. A wide array of causes and pathophysiological mechanisms underlie acute and chronic forms of diarrhea. This review focuses on the major clinical aspects which should aid clinicians to diagnose chronic diarrhea. Clinical history, physical examination and stool evaluation and the predominant stool characteristic, i.e., bloody, watery, and fatty diarrhea, may narrow the differential diagnosis. Although mainly involved in acute diarrhea, many different infectious agents, including bacteria, viruses and protozoa, can be identified in chronic bloody/inflammatory diarrhea by appropriate microbiological tests and colonoscopic biopsy analysis. Osmotic diarrhea can be the result of malabsorption or maldigestion, with a subsequent passage of fat in the stool leading to steatorrhea. Secretory diarrhea is due to an increase of fluid secretion in the small bowel lumen, a mechanism often identified in gastroenteropancreatic neuroendocrine tumors. The evaluation of the fecal osmotic gap may help to characterize whether a chronic diarrhea is osmotic or secretory. Fatty diarrhea (steatorrhea) occurs if fecal fat output exceeds the absorptive/digestive capacity of the intestine. Steatorrhea results from malabsorption or maldigestion states and tests should differentiate between these two conditions. Individualized diagnostic work ups tailored on pathophysiological and clinical features are expected to reduce costs for patients with chronic diarrhea.
Internal and Emergency Medicine 10/2012; 7 Suppl 3:255-62. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is increasingly convincing evidence supporting the participation of the gut microenvironment in the pathophysiology of irritable bowel syndrome (IBS). Studies particularly suggest an interplay between luminal factors (eg, foods and bacteria residing in the intestine), the epithelial barrier, and the mucosal immune system. Decreased expression and structural rearrangement of tight junction proteins in the small bowel and colon leading to increased intestinal permeability have been observed, particularly in postinfectious IBS and in IBS with diarrhea. These abnormalities are thought to contribute to the outflow of antigens through the leaky epithelium, causing overstimulation of the mucosal immune system. Accordingly, subsets of patients with IBS show higher numbers and an increased activation of mucosal immunocytes, particularly mast cells. Immune factors, released by these cells, including proteases, histamine, and prostanoids, participate in the perpetuation of the permeability dysfunction and contribute to the activation of abnormal neural responses involved in abdominal pain perception and changes in bowel habits. All these mechanisms represent new targets for therapeutic approaches in IBS. Probiotics are an attractive therapeutic option in IBS given their recognized safety and by virtue of positive biological effects they can exert on the host. Of importance for the IBS pathophysiology is that preclinical studies have shown that selective probiotic strains exhibit potentially useful properties including anti-inflammatory effects, improvement of mucosal barrier homeostasis, beneficial effects on intestinal microbiota, and a reduction of visceral hypersensitivity. The effect of probiotics on IBS is positive in most randomized, controlled studies, although the gain over the placebo is small. Identifying tailored probiotic approaches for subgroups of IBS patients represents a challenge for the future.
[Show abstract][Hide abstract] ABSTRACT: Background We previously showed that colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS) activate neurons of the human submucous plexus, an area with densely packed immune cells. Based on the concept that mucosa-nerve signaling is altered in IBS, we tested in this study whether the nerve sensitizing effect of IBS mucosal biopsy supernatants is more prominent in the submucous than myenteric plexus. Methods Fast neuroimaging with the voltage-sensitive dye Di-8-ANEPPS was used to record activity of guinea-pig submucous and myenteric neurons after application of constipation (C)- and diarrhea (D)-IBS supernatants (three each) and four supernatants from healthy control subjects. Results are based on recordings from 4731 neurons. Key Results Control supernatants did not evoke significant responses in submucous or myenteric neurons. In contrast, all IBS supernatants evoked a significant spike discharge (median 3.6 Hz) in 46% of submucous neurons. This activation was significantly stronger than in the myenteric plexus where even twice the amount of supernatants evoked a lower spike frequency (median 2.1 Hz) in only 8.5% of neurons. Pharmacological studies revealed serotonin, histamine, and proteases as components mediating neuronal activation. Individual application of these components revealed that only serotonin evoked a significantly stronger activation of submucous compared with myenteric neurons. Conclusions & Inferences Direct neuronal activation by IBS mucosal biopsy supernatants is primarily a feature of submucous rather than myenteric neurons. This is associated with a stronger excitation of submucous neurons by serotonin. The plexus-specific effects support the concept that altered mucosa-nerve signaling underlies disturbances in IBS.
Neurogastroenterology and Motility 09/2012; · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled. Methods Mucosal biopsies were obtained from the descending colon of patients with IBS and controls. Mucosal mast cells were identified immunohistochemically. The impact of spontaneously released mucosal mediators on guinea pig electrically stimulated longitudinal muscle myenteric plexus (LMMP) preparations was assessed in vitro by means of selective receptor antagonists and inhibitors. Key Results Patients with IBS showed an increased mast cell count compared with controls. Application of mucosal mediators of IBS to LMMPs potentiated cholinergic twitch contractions, an effect directly correlated with mast cell counts. Enhanced contractions were inhibited by 50.3% with the prostaglandin D2 antagonist BW A868C, by 31.3% and 39% with the TRPV1 antagonists capsazepine and HC-030031, respectively, and by 60.5% with purinergic P2X antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid. Conversely, the serotonin1-4, histamine1-3, tachykinin1-3 receptor blockade, and serine protease inhibition had no significant effect. Conclusions & Inferences Colonic mucosal mediators from patients with IBS excite myenteric cholinergic motor neurons. These effects were correlated with mast cell counts and mediated by activation of prostanoid receptors, TRPV1, and P2X receptors. These results support the role of mucosal inflammatory mediators and mast cell activation in altered motor function of IBS.
Neurogastroenterology and Motility 09/2012; · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is increasingly perceived that gut host–microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS. However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated. The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID. Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS. Investigators are also starting to measure host–microbial interactions in IBS. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. While we await important insights in this field, the microbiota is already a therapeutic target. Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size. In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions. The authors also provide clinical guidance on modulation of gut microbiota in IBS.