Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome.

Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.

The 2018 ISDE achalasia guidelines.

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

Postoperative Ileus: Pathophysiology, Current Therapeutic Approaches.

Postoperative ileus, which develops after each abdominal surgical procedure, is an iatrogenic disorder characterized by a transient inhibition of gastrointestinal motility. Its pathophysiology is complex involving pharmacological (opioids, anesthetics), neural, and immune-mediated mechanisms. The early neural phase, triggered by activation of afferent nerves during the surgical procedure, is short lasting compared to the later inflammatory phase. The latter starts after 3-6 h and lasts several days, making it a more interesting target for treatment. Insight into the triggers and immune cells involved is of great importance for the development of new therapeutic strategies. In this chapter, the pathogenesis and the current therapeutic approaches to treat postoperative ileus are discussed.

The pig as preclinical model for laparoscopic vagus nerve stimulation.

PURPOSE: Cervical vagus nerve stimulation (VNS) prevents manipulation-induced intestinal inflammation and improves intestinal transit in a mouse model of postoperative ileus (POI). Cervical VNS, however, is accompanied by cardiovascular and respiratory side effects. In view of potential clinical application, we therefore evaluated the safety and feasibility of abdominal VNS via laparoscopic approach in a porcine model. METHODS: Six pigs were used in a non-survival study for both cervical and abdominal VNS. Two cardiac pacing electrodes were positioned around the right cervical and posterior abdominal vagus nerve and connected to an external stimulator. VNS was performed using four different settings (5 and 20 Hz, 0.5 and 1 ms pulse width) during 2 min with ECG recording. Laparoscopic VNS was timed and videotaped, and technical difficulties were noted. A validated National Aeronautics and Space Administration Task Load Index (NASA-TLX) questionnaire was used to evaluate the task and workload. RESULTS: The procedure was completed in all pigs with 4-port laparoscopic technique. Cervical and abdominal VNS were performed after correct identification and isolation of the nerve, and positioning of the electrodes around the nerve. Median laparoscopic operating time was 16 min (range 8-33 min), and median NASA-TLX was 31 (range 11-74). No major complications were encountered. Reduction of heart rate was between 5.5 and 14% for cervical VNS and undetectable for abdominal VNS. CONCLUSION: In a porcine model, laparoscopic VNS is feasible and safe with cardiac pacing electrodes and may lead to a similar novel approach in humans in the near future.

Incidence of prolonged postoperative ileus after colorectal surgery: a systematic review and meta-analysis.

AIM: Prolonged postoperative ileus (PPOI) after colorectal surgery remains a leading cause of delayed postoperative recovery and prolonged hospital stay. Its exact incidence is unknown. The aim of this systematic review is to investigate the definitions and incidence of PPOI previously described. METHOD: MEDLINE, Embase and the Cochrane Database of Systematic Reviews (up to July 2014) were searched. Two authors independently reviewed citations using predefined inclusion and exclusion criteria. RESULTS: The search strategy yielded 3233 citations; 54 were eligible, comprising 18 983 patients. Twenty-six studies were prospective [17 of these being randomized controlled trials (RCTs)] and 28 were retrospective. Meta-analysis revealed an incidence of PPOI of 10.3% (95% CI 8.4-12.5) and 10.2% (95% CI 5.6-17.8) for non-RCTs and RCTs, respectively. Significant heterogeneity was observed for both non-RCTs and for RCTs. The used definition of PPOI, the type of surgery and access (laparoscopic, open) and the duration of surgery lead to significant variability of reported PPOI incidence between studies. The incidence of PPOI is lower after laparoscopic colonic resection. CONCLUSION: There is a large variation in the reported incidence of PPOI. A uniform definition of PPOI is needed to allow meaningful inter-study comparisons and to evaluate strategies to prevent PPOI.

Restoring airway epithelial barrier dysfunction: a new therapeutic challenge in allergic airway disease.

An intact functional mucosal barrier is considered to be crucial for the maintenance of airway homeostasis as it protects the host immune system from exposure to allergens and noxious environmental triggers. Recent data provided evidence for the contribution of barrier dysfunction to the development of inflammatory diseases in the airways, skin and gut. A defective barrier has been documented in chronic rhinosinusitis, allergic rhinitis, asthma, atopic dermatitis and inflammatory bowel diseases. However, it remains to be elucidated to what extent primary (genetic) versus secondary (inflammatory) mechanisms drive barrier dysfunction. The precise pathogenesis of barrier dysfunction in patients with chronic mucosal inflammation and its implications on tissue inflammation and systemic absorption of exogenous particles are only partly understood. Since epithelial barrier defects are linked with chronicity and severity of airway inflammation, restoring the barrier integrity may become a useful approach in the treatment of allergic diseases. We here provide a state-of-the-art review on epithelial barrier dysfunction in upper and lower airways as well as in the intestine and the skin and on how barrier dysfunction can be restored from a therapeutic perspective.

Esophageal stasis on a timed barium esophagogram predicts recurrent symptoms in patients with long-standing achalasia.

OBJECTIVES: In achalasia, early recognition of the need for retreatment is of crucial importance to reduce morbidity and long-term complications such as esophageal decompensation. In clinical practice, symptoms and parameters of esophageal function including lower esophageal sphincter (LES) pressure and esophageal emptying are used to decide whether additional treatment is required. However, which of these tests performs best remains unclear. METHODS: A cohort of 41 patients with long-standing achalasia (median 17 years), underwent esophageal manometry, timed barium esophagogram and symptom evaluation. Patients were followed up for 10 years, and were regarded as a therapeutic failure if Eckardt score was >3 or when retreatment was needed. Predictors of therapeutic failure were evaluated. RESULTS: Of the 41 included patients, 7 patients had an elevated LES pressure (>10 mm Hg) and 26 had esophageal stasis >5 cm on timed barium esophagogram. During follow-up, 25 patients had recurrence of symptoms and were considered therapeutic failures. Of the 25 patients, 5 had an elevated LES pressure, whereas 22 had esophageal stasis on barium esophagogram. Hence, the sensitivity to predict the need of retreatment is higher for esophageal stasis (88%) compared with LES pressure (20%). A total of 16 patients (39%) were in long-term remission, of which 12 patients (75%) did not have stasis at their initial visit. CONCLUSIONS: In contrast to LES pressure, esophageal stasis is a good predictor of treatment failure in patients with long-standing achalasia. Based on these findings, we propose to use timed barium esophagogram rather than esophageal manometry as test to decide on retreatment.

Effect of azithromycin on acid reflux, hiatus hernia and proximal acid pocket in the postprandial period.

BACKGROUND: The risk for acidic reflux is mainly determined by the position of the gastric acid pocket. It was hypothesised that compounds affecting proximal stomach tone might reduce gastro-oesophageal reflux by changing the acid pocket position. OBJECTIVE: To study the effect of azithromycin (Azi) on acid pocket position and acid exposure in patients with gastro-oesophageal reflux disease (GORD). METHODS: Nineteen patients with GORD were included, of whom seven had a large hiatal hernia (≥3 cm) (L-HH) and 12 had a small or no hiatal hernia (S-HH). Patients were randomised to Azi 250 mg/day or placebo during 3 days in a crossover manner. On each study day, reflux episodes were detected using concurrent high-resolution manometry and pH-impedance monitoring after a standardised meal. The acid pocket was visualised using scintigraphy, and its position was determined relative to the diaphragm. RESULTS: Azi reduced the number of acid reflux events (placebo 8.0±2.2 vs Azi 5.6±1.8, p<0.01) and postprandial acid exposure (placebo 10.5±3.8% vs Azi 5.9±2.5%, p<0.05) in all patients without affecting the total number of reflux episodes. Acid reflux occurred mainly when the acid pocket was located above, or at the level of, the diaphragm, rather than below the diaphragm. Treatment with Azi reduced hiatal hernia size and resulted in a more distal position of the acid pocket compared with placebo (below the diaphragm 39% vs 29%, p=0.03). Azi reduced the rate of acid reflux episodes in patients with S-HH (38% to 17%) to a greater extent than in patients with L-HH (69% to 62%, p=0.04). CONCLUSION: Azi reduces acid reflux episodes and oesophageal acid exposure. This effect was associated with a smaller hiatal hernia size and a more distal position of the acid pocket, further indicating the importance of the acid pocket in the pathogenesis of GORD. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1970 NTR1970.

The Kagoshima consensus on esophageal achalasia.

Esophageal achalasia is a primary esophageal motility disorder characterized by lack of peristalsis and a lower esophageal sphincter that fails to relax appropriately in response to swallowing. This article summarizes the most salient issues in the diagnosis and management of achalasia as discussed in a symposium that took place in Kagoshima, Japan, in September 2010 under the auspices of the International Society for Diseases of the Esophagus.

Up-date on neuro-immune mechanisms involved in allergic and non-allergic rhinitis.

Non-allergic rhinitis (NAR) is a common disorder, which can be defined as chronic nasal inflammation, independent of systemic IgE-mediated mechanisms. Symptoms of NAR patients mimic those of allergic rhinitis (AR) patients. However, AR patients can easily be diagnosed with skin prick test or allergen-specific IgE measurements in the serum, whereas NAR patients form a heterogeneous group and are difficult to diagnose because of an extensive list of different phenotypes, all varying in severity, underlying etiology and type of inflammation. Characterization of those phenotypes, mechanisms and management of NAR represents one of the major unmet needs in the field of allergic and non-allergic diseases. This review aims at providing a comprehensive overview of the state of the art in classifying the NAR patients and focuses on the neuro-immune mechanisms involved in allergic and non-allergic rhinitis, including reflections on the pathophysiology and the currently available treatment options.

Local immune response as novel disease mechanism underlying abdominal pain in patients with irritable bowel syndrome.

OBJECTIVES: Irritable bowel syndrome (IBS) is the most frequently diagnosed functional gastrointestinal disorder, with a prevalence of up to 25% of the global population. IBS patients suffer from abnormal abdominal pain, or visceral hypersensitivity (VHS), associated with altered bowel habits in the absence of an organic detectable cause. The pathophysiology of the disease is incompletely understood, but the dysregulation of the brain-gut axis is well established in IBS. METHODS: IBS onset is mainly triggered by infectious gastroenteritis, psychological factors, and dietary factors, but genetic predispositions and intestinal dysbiosis might also play a role. Additionally, immune activation, and particularly chronic mast cell activation, have been shown to underlie the development of abdominal pain in IBS. RESULTS: By releasing increased levels of mediators, including histamine, mast cells sensitize enteric nociceptors and lead to VHS development. The mechanisms underlying aberrant mast cell activation in IBS are still under investigation, but we recently showed that a local break in oral tolerance to food antigens led to IgE-mediated mast cell activation and food-induced abdominal pain in preclinical models and in IBS patients. CONCLUSION: The concept of food-mediated VHS highlights the potential of therapies targeting upstream mechanisms of mast cell sensitization to treat IBS.

Neuroimmune mechanisms in postoperative ileus.

Postoperative ileus (POI) is a common clinical condition arising after almost every abdominal surgical procedure, leading to increased patient morbidity and prolonged hospitalisation. Recent advances in insight into the underlying pathophysiology have identified intestinal inflammation triggered by handling of the intestine as the main mechanism. Not only does the local inflammatory process compromise the contractile activity of the handled intestine, but it also activates inhibitory neural pathways and possibly triggers inflammation at distant untouched areas, leading to a generalised impairment of gastrointestinal motility. Macrophages residing in the muscularis externa and mast cells are the key players in this inflammatory cascade. Pharmacological interventions preventing the activation of these immune cells reduce the influx of leucocytes into the intestine, an effect associated with a reduction of the duration of POI. New potential therapeutic strategies to shorten POI based on these new insights will undoubtedly enter the clinical arena soon.

European guidelines on achalasia: United European Gastroenterology and European Society of Neurogastroenterology and Motility recommendations.

INTRODUCTION: Achalasia is a primary motor disorder of the oesophagus characterised by absence of peristalsis and insufficient lower oesophageal sphincter relaxation. With new advances and developments in achalasia management, there is an increasing demand for comprehensive evidence-based guidelines to assist clinicians in achalasia patient care. METHODS: Guidelines were established by a working group of representatives from United European Gastroenterology, European Society of Neurogastroenterology and Motility, European Society of Gastrointestinal and Abdominal Radiology and the European Association of Endoscopic Surgery in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. A systematic review of the literature was performed, and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Recommendations were voted upon using a nominal group technique. RESULTS: These guidelines focus on the definition of achalasia, treatment aims, diagnostic tests, medical, endoscopic and surgical therapy, management of treatment failure, follow-up and oesophageal cancer risk. CONCLUSION: These multidisciplinary guidelines provide a comprehensive evidence-based framework with recommendations on the diagnosis, treatment and follow-up of adult achalasia patients.

Stepwise radiofrequency ablation of Barrett's esophagus preserves esophageal inner diameter, compliance, and motility.

BACKGROUND AND AIM: Stepwise endoscopic circumferential and focal radiofrequency ablation is safe and effective for the eradication of Barrett's esophagus. In contrast to other techniques, radiofrequency ablation appears to avoid significant esophageal scarring or stenosis. Our aim was to evaluate whether radiofrequency ablation has an adverse effect on esophageal function in patients treated for Barrett's esophagus containing intramucosal cancer and/or high-grade dysplasia. METHODS: Twelve patients with Barrett's esophagus containing intramucosal cancer or high-grade dysplasia were included in the study. After endoscopic resection of visible abnormalities, stepwise circumferential and focal ablation were performed every 2 months up to a maximum of five sessions. Measurement of the inner diameter was performed at 1-cm intervals in the distal esophagus. Manometry was performed using a water-perfused sleeve catheter. Compliance was evaluated using the functional lumen imaging probe (FLIP), measuring eight cross-sectional areas within a saline-filled bag with two pressure side holes, one proximal to and one inside the bag. Esophageal sizing, manometry, and compliance were recorded in patients at baseline and at least 2 months after the final ablation session. In addition, FLIP and manometry measurements were performed in 10 healthy volunteers. RESULTS: All patients achieved complete eradication of dysplasia and Barrett's esophagus, without severe complications or ablation-related stenoses. The esophageal diameter was unchanged by the ablation. Lower esophageal sphincter pressure and length and esophageal contraction amplitude before and after ablation were not significantly different. Baseline compliance was significantly different between healthy volunteers and Barrett's esophagus patients. Compliance was not, however, significantly changed by ablation. CONCLUSIONS: Stepwise circumferential and focal ablation of Barrett's esophagus is an effective and safe treatment modality for early Barrett's neoplasia that appears to preserve the functional characteristics of the esophagus.

Emerging drugs for gastroesophageal reflux disease.

Proton pump inhibitors (PPIs) are very effective and safe drugs for the treatment of erosive and non-erosive gastroesophageal reflux disease (GERD). Nevertheless, a significant proportion of GERD patients (30 - 40%) continue to suffer from symptoms during PPI treatment, which has stimulated the search for better drugs. Improvement of PPI pharmacokinetics and pharmacodynamics has been the main focus of drug development in the past decade with the ultimate goal of optimizing acid inhibition. New inhibitors of the proton pump with a longer half-life, acting faster and longer, have been developed, including potassium-competitive acid blockers. Recent data, however, suggest that the therapeutic efficacy of acid suppression may have reached its maximum and other mechanisms may have to be targeted to further improve symptom control. Potential drugs interacting with different targets are reflux inhibitors such as GABA(B) receptor agonists and mGluR5 antagonists. These agents reduce the number of transient lower esophageal sphincter relaxation thereby reducing both acid and non-acid reflux. Theoretically, visceral analgesics to modulate visceral perception or even growth factors to enhance mucosal healing may be other emerging drugs to treat GERD.

Morphological changes of the enteric nervous system, interstitial cells of cajal, and smooth muscle in children with colonic motility disorders.

OBJECTIVES: To evaluate the relation between colonic manometry findings and the colonic enteric nervous system, interstitial cells of Cajal, and smooth muscle morphology. PATIENTS AND METHODS: Colonic specimens from surgical resections or full-thickness biopsy specimens were assessed from a cohort of children who underwent colonic manometry before surgery. Colonic manometric patterns were subdivided into high-amplitude propagating contractions, low-amplitude propagating contractions, absence of contractions, and low-amplitude simultaneous contractions. Immunohistochemistry was performed to identify abnormalities in the enteric nervous system, interstitial cells of Cajal, and smooth muscle layers. RESULTS: Study participants included patients with Hirschsprung disease (n = 4), chronic intestinal pseudo-obstruction (n = 1), and idiopathic intractable constipation (n = 8). Thirty-seven ganglionic segments were studied. Abnormalities in myenteric plexus were recognized in segments of all manometry groups, and no differences could be identified when they were compared with segments with high-amplitude propagating contractions. All of the segments showed an abnormal interstitial cells of Cajal plexus, and no statistical difference could be identified between the 4 groups (n = 0.08). Homogeneous expression of smooth muscle actin was observed in all of the segments. CONCLUSIONS: In this cohort we were unable to classify specific manometric findings as reflective of myopathic or neuropathic abnormalities in patients with motility disorders. Caution should be used when predicting the type of neuromuscular disorder based on colonic manometry.

Pathophysiology and management of gastroesophageal reflux disease.

Gastroesophageal reflux is a physiological phenomenon but becomes pathological if troublesome symptoms and/or complications occur. Gastroesophageal reflux disease (GERD) has different phenotypes ranging from non-erosive reflux disease (NERD), through reflux esophagitis and Barrett's esophagus, and can present with either typical symptoms such as regurgitation and heartburn, or extra-esophageal symptoms such as cough and laryngitis. In the diagnosis of GERD endoscopy, empirical PPI test, and pH impedance testing all have their own position. Although proton pump inhibitors (PPIs) are very effective in the treatment of esophagitis, a significant proportion of patients have persistent symptoms even during high dosing of PPIs. Therefore, insight into the multifactorial pathophysiology of GERD is needed to develop new anti-reflux therapies. The predominant mechanism underlying reflux is the transient lower esophageal sphincter relaxation (TLESR). Hiatal hernia, impaired esophageal clearance and reduced lower esophageal sphincter pressure play a significant role in patients with moderate to severe reflux disease. Refluxate containing acid, pepsin and bile can cause epithelial injury when epithelial barrier of the esophagus fails to defend. In the majority of patients there is histopathological evidence of epithelial injury, even with NERD where there are more dilated intercellular spaces. The perception of heartburn can be enhanced due to visceral hypersensitivity, leading to more and more severe symptoms. Anti-reflux surgery is as effective as PPI therapy, but has higher morbidity and results decline in the long term. Therefore, new pharmacological, endoscopic and surgical interventions are being developed for these patients.

Rectal compliance and rectal sensation in constipated adolescents, recovered adolescents and healthy volunteers.

OBJECTIVES: A subgroup of children with functional constipation (FC) are unresponsive to conventional treatment. Abnormal rectal function due to increased distensibility (compliance) might be an underlying mechanism of therapy-resistant FC. It is hypothesised that rectal compliance is normal in patients who are successfully recovered from FC (RC). METHODS: Using a barostat, a pressure-controlled intermittent distension protocol was performed in FC patients, RC subjects free of symptoms for at least 4 years and healthy volunteers (HVs). Rectal compliance was calculated using a non-linear mixed-effect model for volume-pressure curves. RESULTS: Forty-seven FC patients, median (range) age of 12 (11-17) years, and 20 RC subjects, 15 (11-18) years, were studied and compared with 22 HVs, 14 (8-16) years. The median (5th-95th percentile) rectal compliance in HVs was 16 (12-20) ml/mm Hg. FC patients had a median rectal compliance of 25 (13-47) ml/mm Hg and RC subjects 20 (12-35) ml/mm Hg, which was significantly higher compared with HVs (p<0.001 and p = 0.003). RC subjects had lower rectal compliance when compared with FC patients (p = 0.02). Forty-five percent of RC subjects had a rectal compliance above the upper limit of normal (>95th percentile of HVs), which was significantly less compared with 75% of FC patients (p = 0.02). CONCLUSION: While rectal compliance in RC subjects is lower when compared with adolescents with FC, almost half of the RC subjects showed an increased rectal compliance. The role of rectal compliance in therapy-resistant FC seems limited, because recovery is possible despite an increased rectal compliance.

Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus.

BACKGROUND: Murine postoperative ileus results from intestinal inflammation triggered by manipulation-induced mast cell activation. As its extent depends on the degree of handling and subsequent inflammation, it is hypothesised that the faster recovery after minimal invasive surgery results from decreased mast cell activation and impaired intestinal inflammation. OBJECTIVE: To quantify mast cell activation and inflammation in patients undergoing conventional and minimal invasive surgery. METHODS: (1) Mast cell activation (ie, tryptase release) and pro-inflammatory mediator release were determined in peritoneal lavage fluid obtained at consecutive time points during open, laparoscopic and transvaginal gynaecological surgery. (2) Lymphocyte function-associated antigen-1 (LFA-1), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) mRNA as well as leucocyte influx were quantified in non-handled and handled jejunal muscle specimens collected during biliary reconstructive surgery. (3) Intestinal leucocyte influx was assessed by 99mTc-labelled leucocyte single photon emission computed tomography (SPECT) - computed tomography (CT) scanning before and after abdominal or vaginal hysterectomy. RESULTS: (1) Intestinal handling during abdominal hysterectomy resulted in an immediate release of tryptase followed by enhanced interleukin 6 (IL6) and IL8 levels. None of the mediators increased during minimal invasive surgery except for a slight increase in IL8 during laparoscopic surgery. (2) Jejunal ICAM-1 and iNOS mRNA transcription as well as leucocyte recruitment were increased after intestinal handling. (3) Leucocyte scanning 24 h after surgery revealed increased intestinal activity after abdominal but not after vaginal hysterectomy. CONCLUSIONS: This study demonstrates that intestinal handling triggers mast cell activation and inflammation associated with prolonged postoperative ileus. These results may partly explain the faster recovery after minimal invasive surgery and encourage future clinical trials targeting mast cells to shorten postoperative ileus.