Search

Large-caliber dilation is an important therapeutic approach in the management of achalasia, but there is significant variability in how this is performed and taught worldwide. This article reviews the personal approaches to large-caliber of 2 experienced esophagologists—focusing on how they were personally taught to do the procedure, how their technique has evolved over the decades since, and how they current perform dilation.

INTRODUCTION: The advent of peroral endoscopic myotomy (POEM) shed some light on the role of the current standards in the treatment of idiopathic achalasia, namely endoscopic pneumatic dilatation (PD) and laparoscopic Heller myotomy (LHM). We analyzed the quality of the current evidence comparing LHM and PD. METHODS: A systematic literature search was performed in Pubmed/Medline, Web of Science, Google Scholar and Cochrane for meta-analyses/systematic reviews comparing PD and LHM or open surgery, limited to English language full-text articles. After a detailed review of these meta-analyses, all studies included were analyzed further in depth with respect to treatment protocol, assessment of success, complications and sequelae such as gastroesophageal reflux (GER), as well as follow-up details. RESULTS: Six randomized controlled trials (RCT), 5 with LHM and 1 with open surgery, were found, published in 10 papers. In contrast to a rather homogeneous LHM technique, PD regimens as well as the clinical dysphagia scores were different in every RCT; most RCTs also showed methodological limitations. There were nine meta-analyses which included a variable number of these RCTs or other cohort studies. Meta-analyses between 2009 and 2013 favored surgery, while the 4 most recent ones reached divergent conclusions. The main difference might have been whether repeated dilatation was regarded as part of the PD protocol or as failure. CONCLUSIONS: The variability in PD techniques and in definition of clinical success utilized in the achalasia RCTs on PD versus LHM render the conclusions of meta-analyses unreliable. Further randomized studies should be based on uniform criteria; in the meantime, publication of even more meta-analyses should be avoided. ispartof: SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES vol:35 issue:2 pages:602-611 ispartof: location:Germany status: published

IntroductionAchalasia is a primary motor disorder of the oesophagus characterised by absence of peristalsis and insufficient lower oesophageal sphincter relaxation. With new advances and developmen...

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and an altered defecation pattern. Depending on the criteria used, it affects between 5 and 10% of the general population and has a serious impact on quality of life. Most patients with IBS show an induction or exacerbation of their symptoms, particularly abdominal pain, after eating certain foods. This raises the question of the role played by food in IBS pathophysiology. In this review, we describe the multiple risk factors of IBS, and we give an overview of the role of food as a trigger of IBS, distinguishing between immune and non-immune reactions to food. We finally highlight recent findings identifying an immune-mediated mechanism underlying food-induced abdominal pain in IBS.

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that is characterized by abdominal pain and an altered defecation pattern. It affects between 5 and 20% of the general population and can seriously impact quality of life. The pathophysiology of IBS is rather complex and multifactorial including, for example, altered signalling by the gut-brain axis, dysbiosis, abnormal visceral pain signalling and intestinal immune activation. The latter has gained particular interest in recent years, with growing insight into the bidirectional communication between the nervous system and the immune system. In this Review, we detail the current evidence suggesting that immune activation contributes to the pathology seen in patients with IBS and discuss the potential mechanisms involved. Moreover, we describe how immune mediators, particularly those released by mast cells, can directly activate or sensitize pain-transmitting nerves, leading to increased pain signalling and abdominal pain. Finally, we discuss the potential of interventions targeting immune activation as a new therapeutic strategy for patients suffering from IBS. ispartof: NATURE REVIEWS IMMUNOLOGY vol:22 issue:11 pages:674-686 ispartof: location:England status: published

In this issue of Immunity, Schiller et al. report that local sympathetic nerve activation decreases endothelial expression of the adhesion molecule MAdCAM-1, reducing immune cell infiltration and colitis-induced inflammation. These findings suggest that local sympathetic stimulation provides a key gateway for regulating organ homeostasis. ispartof: Immunity vol:54 issue:5 pages:850-852 ispartof: location:United States status: published

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. ispartof: ACTA CLINICA BELGICA vol:77 issue:5 pages:889-896 ispartof: location:England status: published

Gastro-oesophageal reflux disease (GERD) is a common disorder in adults and children. The global prevalence of GERD is high and increasing. Non-erosive reflux disease is the most common phenotype of GERD. Heartburn and regurgitation are considered classic symptoms but GERD may present with various atypical and extra-oesophageal manifestations. The pathophysiology of GERD is multifactorial and different mechanisms may result in GERD symptoms, including gastric composition and motility, anti-reflux barrier, refluxate characteristics, clearance mechanisms, mucosal integrity and symptom perception. In clinical practice, the diagnosis of GERD is commonly established on the basis of response to anti-reflux treatment; however, a more accurate diagnosis requires testing that includes upper gastrointestinal tract endoscopy and reflux monitoring. New techniques and new reflux testing parameters help to better phenotype the condition. In children, the diagnosis of GERD is primarily based on history and physical examination and treatment vary with age. Treatment in adults includes a combination of lifestyle modifications with pharmacological, endoscopic or surgical intervention. In refractory GERD, optimization of proton-pump inhibitor treatment should be attempted before a series of diagnostic tests to assess the patient's phenotype.

Intestinal resident macrophages are at the front line of host defence at the mucosal barrier within the gastrointestinal tract and have long been known to play a crucial role in the response to food antigens and bacteria that are able to penetrate the mucosal barrier. However, recent advances in single-cell RNA sequencing technology have revealed that resident macrophages throughout the gut are functionally specialised to carry out specific roles in the niche they occupy, leading to an unprecedented understanding of the heterogeneity and potential biological functions of these cells. This review aims to integrate these novel findings with long-standing knowledge, to provide an updated overview on our understanding of macrophage function in the gastrointestinal tract and to speculate on the role of specialised subsets in the context of homoeostasis and disease. ispartof: Gut vol:70 issue:7 pages:1-13 ispartof: location:England status: Published online

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.

Gastro-oesophageal reflux disease (GERD) is a common disorder in adults and children. The global prevalence of GERD is high and increasing. Non-erosive reflux disease is the most common phenotype of GERD. Heartburn and regurgitation are considered classic symptoms but GERD may present with various atypical and extra-oesophageal manifestations. The pathophysiology of GERD is multifactorial and different mechanisms may result in GERD symptoms, including gastric composition and motility, anti-reflux barrier, refluxate characteristics, clearance mechanisms, mucosal integrity and symptom perception. In clinical practice, the diagnosis of GERD is commonly established on the basis of response to anti-reflux treatment; however, a more accurate diagnosis requires testing that includes upper gastrointestinal tract endoscopy and reflux monitoring. New techniques and new reflux testing parameters help to better phenotype the condition. In children, the diagnosis of GERD is primarily based on history and physical examination and treatment vary with age. Treatment in adults includes a combination of lifestyle modifications with pharmacological, endoscopic or surgical intervention. In refractory GERD, optimization of proton-pump inhibitor treatment should be attempted before a series of diagnostic tests to assess the patient's phenotype.

ObjectiveMonocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which microenvironmental factors are responsible for monocyte recruitment and neurotrophic Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue protective Mφs.DesignSingle cell RNA sequencing was performed on immune cells from the muscularis of wild-type and CCR2-/- mice at different timepoints after muscularis inflammation. CX3CR1GFP/+ and CX3CR1CreERT2 R26YFP mice were analyzed by flow cytometry and immunofluorescence. The transcriptome of enteric glial cells (EGCs) was investigated using PLPCreERT2 Rpl22HA mice. In addition, we assessed the effect of supernatant from neurosphere-derived EGCs on monocyte differentiation based on the expression of pro- and anti-inflammatory factors.ResultsMuscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c+ monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mφ subpopulations during the resolution of muscularis inflammation, i.e. Cd206+ MhcIIhi and Timp2+ MhcIIlo Mφs, which were both derived from CCR2+ monocytes. Interestingly, we found that EGCs were able to sense damage to the muscularis to stimulate monocyte recruitment and differentiation towards pro-resolving Mφs via CCL2 and CSF1, respectively.ConclusionOur study provides a comprehensive insight into pro-resolving Mφ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mφs, thereby highlighting pro-resolving Mφ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.

An LC-MS/MS method was developed enabling the separation and quantification of histamine and its main metabolites (imidazole acetaldehyde, imidazole acetic acid, methyl imidazole acetic acid, methyl histamine, acetyl histamine) in urine samples. A fast separation was achieved in 10 min on two HILIC columns connected in series by adopting a linear gradient followed by an isocratic hold. The sample preparation consisted of a simple dilution step wherein 10 μL of urine was diluted with acetonitrile (ACN) to a final volume comprising 95% ACN. For methyl imidazole acetic acid, an additional dilution step was incorporated due to its high natural levels. Hereafter, the samples were stored at -20 °C and centrifuged prior to injection. Matrix matched calibrators were unavailable due to the endogenous occurrence of the compounds of interest. The occurrence of matrix effects and the lack of labeled internal standards prompted the use of the standard addition method as a viable alternative to solvent calibration. The validation of the method entailed matrix effects, accuracy and precision and was performed in compliance with the recent guidelines on endogenous compounds issued by the International Conference of Harmonization (ICH). The method was then adopted for the quantification of histamine and its metabolites in human urine samples collected from healthy volunteers and patients suffering from gastrointestinal discomfort. ispartof: TALANTA vol:220 ispartof: location:Netherlands status: published

Up to 20% of people worldwide develop gastrointestinal symptoms following a meal(1), leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H-1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders. In mice, oral tolerance to food antigens can break down after enteric infection, and this leads to food-induced pain resembling irritable bowel syndrome in humans.

Many essential gastrointestinal functions, including motility, secretion and blood flow are regulated by the autonomic nervous system (ANS), both through intrinsic enteric neurons and extrinsic (sympathetic and parasympathetic) innervation. Recently identified neuro-immune mechanisms, in particular the interplay between enteric neurons and muscularis macrophages, are now considered to be essential for fine-tuning peristalsis. These findings shed new light on how intestinal immune cells can support enteric nervous function. In addition, both intrinsic and extrinsic neural mechanisms control intestinal immune homeostasis in different layers of the intestine, mainly by affecting macrophage activation through neurotransmitter release. In this mini-review, we discuss recent insights on immunomodulation by intrinsic enteric neurons and extrinsic innervation, with a particular focus on intestinal macrophages. In addition, we discuss the relevance of these novel mechanisms for intestinal immune homeostasis in physiological and pathological conditions, mainly focusing on motility disorders (gastroparesis and post-operative ileus) and inflammatory disorders (colitis). ispartof: American Journal of Physiology. Gastrointestinal and Liver Physiology vol:314 issue:1 pages:G75-G80 ispartof: location:United States status: published

Visceral hypersensitivity is an important mechanism underlying increased abdominal pain perception in functional gastrointestinal disorders including functional dyspepsia, irritable bowel syndrome, and inflammatory bowel disease in remission. Although the exact pathophysiological mechanisms are poorly understood, recent studies described upregulation and altered functions of nociceptors and their signaling pathways in aberrant visceral nociception, in particular the transient receptor potential (TRP) channel family. A variety of TRP channels are present in the gastrointestinal tract (TRPV1, TRPV3, TRPV4, TRPA1, TRPM2, TRPM5, and TRPM8), and modulation of their function by increased activation or sensitization (decreased activation threshold) or altered expression in visceral afferents have been reported in visceral hypersensitivity. TRP channels directly detect or transduce osmotic, mechanical, thermal, and chemosensory stimuli. In addition, pro-inflammatory mediators released in tissue damage or inflammation can activate receptors of the G protein-coupled receptor superfamily leading to TRP channel sensitization and activation, which amplify pain and neurogenic inflammation. In this review, we highlight the present knowledge on the functional roles of neuronal TRP channels in visceral hypersensitivity and discuss the signaling pathways that underlie TRP channel modulation. We propose that a better understanding of TRP channels and their modulators may facilitate the development of more selective and effective therapies to treat visceral hypersensitivity. ispartof: American Journal of Physiology. Gastrointestinal and Liver Physiology vol:312 issue:6 pages:G635-G648 ispartof: location:United States status: published

This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron), non-absorbed antibiotic (rifaximin), secretagogues (lubiprostone, linaclotide), μ-opioid receptor (OR) and κ-OR agonist, δ-OR antagonist (eluxadoline), histamine H1 receptor antagonist (ebastine), neurokinin-2 receptor antagonist (ibodutant) and GABAergic agents (gabapentin and pregabalin). Efficacy and safety are discussed based on pivotal trials or published systematic reviews and meta-analysis, expressing ORs or relative risks and their 95% CIs. Potential new approaches may be based on recent insights on mucosal expression of genes, and microRNA and epigenetic markers in human biopsies and in animal models of visceral hypersensitivity.The objectives of this review are to appraise the physiology and anatomy of gut sensation and the efficacy in the relief of visceral pain (typically in IBS) of several classes of therapies. These include fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and different classes of medications (box 1). Box 1Classes of pharmacological agents for visceral painAntidepressants (tricyclic agents, selective serotonin reuptake inhibitors)Peppermint oil5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron)Non-absorbed antibiotic (rifaximin)Secretagogues (lubiprostone, linaclotide)μ-Opioid receptor (OR) and κ-OR agonist and δ-OR antagonist (eluxadoline)Histamine H1 receptor antagonist (ebastine)Neurokinin-2 receptor antagonist (ibodutant)GABAergic agents (gabapentin and pregabalin). ispartof: Gut vol:66 issue:5 pages:966-974 ispartof: location:England status: published

Highlights • Neuro-immune crosstalk occurs in distinct anatomical niches in the intestine. • Neuro-immune cell niches maintain gut homeostasis and modulate inflammation. • Neuron-macrophage crosstalk in the muscularis is crucial for neuronal survival and peristalsis. • Mast cell mediators activate and sensitize nerve terminals, leading to aberrant pain perception. • Neurons modulate ILC function during infection and inflammation., Intestinal homeostasis relies on the reciprocal crosstalk between enteric neurons and immune cells, which together form neuro-immune units that occupy distinct anatomical niches within the gut. Here we will review the recent advances in our understanding of neuro-immune crosstalk within the gut, with focus on macrophages, mast cells and innate lymphoid cells. In particular, we will discuss the role of neuron-immune cell crosstalk in homeostasis, and how aberrant communication may underlie disease in the gastro-intestinal tract.

BACKGROUND AND AIM Although an eight-residue insertion in HLA-DQβ1 has been recently identified as a genetic risk factor for idiopathic achalasia, other risk factors are still unknown. In the present study, we carried out an epidemiological survey and a genotype-phenotype (G×P) analysis to gain further insights into the etiology of achalasia. METHODS We obtained medical data from 696 achalasia patients and 410 controls, as well as their first-degree relatives (2543 of patients and 1497 of controls). For the G×P analysis, we stratified the patients into HLA-DQβ1 insertion carriers and noncarriers. RESULTS Our data show that patients are more often affected by viral infections before achalasia onset (P

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.

BACKGROUND: The role of persistent immune activation in postinfectious irritable bowel syndrome (PI-IBS) remains controversial. Here, we prospectively studied healthy subjects traveling to destinations with a high-risk to develop infectious gastroenteritis (IGE) in order to identify immune-mediated mechanisms and risk factors of PI-IBS. METHODS: One hundred and one travelers were asked to complete questionnaires on psychological profile and gastrointestinal (GI) symptoms before travel, 2 weeks, 6 months and 1 year after travel. At each visit, blood was collected for PBMC isolation and rectal biopsies were taken. PI-IBS was diagnosed using the Rome III criteria and subjects with persistent postinfectious abdominal complaints (PI-AC) were identified using 3 GSRS symptoms (ie, loose stools, urgency and abdominal pain). RESULTS: Forty-seven of the 101 subjects reported IGE during travel. After 1 year, two subjects were diagnosed with PI-IBS and eight subjects were presented with PI-AC versus two subjects with IBS and two with abdominal complaints in the non-infected group. PBMC analysis showed no differences in T and B cell populations in subjects with PI-AC vs healthy. Additionally, no differences in gene expression were observed in the early postinfectious phase or after 1 year. Regression analysis identified looser stools, higher anxiety and somatization before infection and several postinfectious GI symptoms as risk factors for PI-AC. CONCLUSIONS: The incidence of PI-IBS is low following travelers' diarrhea and there is need for larger studies investigating the role of immune activation in PI-IBS. Psychological factors before infection and the severity of symptoms shortly after infection are risk factors for the persistence of PI-AC. ispartof: Neurogastroenterology and Motility vol:31 issue:4 ispartof: location:England status: published

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.

BACKGROUND: Evaluation of the metabolomic profile of patients with irritable bowel syndrome offers an opportunity to identify novel pathophysiological targets and biomarkers that could discriminate this disorder from related conditions. AIM: To identify potential urinary biomarkers that discriminate irritable bowel syndrome patients from ulcerative colitis patients in remission and healthy controls and to explore the pathophysiology of irritable bowel syndrome using a metabolomic approach. METHODS: Urine samples were collected from 39 irritable bowel syndrome patients, 53 ulcerative colitis patients in clinical remission and 21 healthy controls. Urinary metabolites were identified and quantified using direct infusion/liquid chromatography tandem mass spectrometry and gas-chromatography mass spectrometry. RESULTS: Patients with irritable bowel syndrome had a unique urinary metabolome that could separate them from ulcerative colitis patients with an area under the curve = 0.99 (95% confidence interval 0.95-1.00). The most important metabolites for this separation were a group of amino acids and organic acids. In addition, subjects with irritable bowel syndrome could be discriminated from healthy controls using their metabolic fingerprints. Irritable bowel syndrome patients had lower urinary Phosphatidyl choline acyl-alkyl C38:6, dopamine and p-hydroxybenzoic acid than healthy controls. Levels of some urinary metabolites including histamine correlated significantly with irritable bowel syndrome symptom severity scores. CONCLUSIONS: Irritable bowel syndrome patients have a unique urinary metabolomic profile compared to ulcerative colitis patients in clinical remission or healthy subjects. These data suggest that metabolomic profiling may provide important insights into pathophysiology and testable biomarkers to discriminate irritable bowel syndrome from other disorders that can mimic this condition and can be used to assess its severity and identify potential novel pathophysiological pathways. ispartof: ALIMENTARY PHARMACOLOGY & THERAPEUTICS vol:49 issue:6 pages:723-732 ispartof: location:England status: published

While the roles of parenchymal microglia in brain homeostasis and disease are fairly clear, other brain-resident myeloid cells remain less well understood. By dissecting border regions and combining single-cell RNA-sequencing with high-dimensional cytometry, bulk RNA-sequencing, fate-mapping and microscopy, we reveal the diversity of non-parenchymal brain macrophages. Border-associated macrophages (BAMs) residing in the dura mater, subdural meninges and choroid plexus consisted of distinct subsets with tissue-specific transcriptional signatures, and their cellular composition changed during postnatal development. BAMs exhibited a mixed ontogeny, and subsets displayed distinct self-renewal capacity following depletion and repopulation. Single-cell and fate-mapping analysis both suggested that there is a unique microglial subset residing on the apical surface of the choroid plexus epithelium. Finally, gene network analysis and conditional deletion revealed IRF8 as a master regulator that drives the maturation and diversity of brain macrophages. Our results provide a framework for understanding host-macrophage interactions in both the healthy and diseased brain.

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS. ispartof: GASTROENTEROLOGY vol:155 issue:1 pages:168-179 ispartof: location:United States status: published

Background Oxazolone-induced colitis has been frequently used in literature as a model of IBD, but insights into the underlying immune response and pathological features are surprisingly still very limited. Vagus nerve stimulation (VNS) has proven to be effective in innate and Th1/Th17 predominant inflammatory models, including pre-clinical models of colitis, however to what extent VNS is also effective in ameliorating Th2-driven colitis remains to be studied. In the present study, we therefore further characterized the immune response in oxazolone-induced colitis and investigated the potential therapeutic effect of VNS. Methods Colitis was induced in Balb/c mice by cutaneous sensitization with 3% oxazolone followed by intracolonic administration of 1% oxazolone 7 days later. To evaluate the effect of VNS on the development of Th2-driven colitis, VNS and sham-treated mice were challenged with 1% oxazolone. Results Intracolonic oxazolone administration resulted in a severe destruction of the colonic mucosa and a rapid drop in body temperature leading to a 65% mortality rate at day 5. Severe infiltration of neutrophils and monocytes was detected 6h after oxazolone administration which was associated with a Th2-type inflammatory response. VNS significantly improved survival rate which correlated with decreased levels of HMGB1 and reduced colonic (il6 and cxcl1 mRNA) and serum cytokine levels (IL-6, TNFα and CXCL1) compared to sham treated mice. Conclusions Oxazolone-induced colitis rather represents a model of sepsis and, at best, may resemble a severe type of ulcerative colitis, associated with early and severe mucosal damage and a high mortality rate. VNS reduces colonic inflammation and improves survival in this model, supporting the anti-inflammatory properties of VNS, even in an aggressive model as oxazolone-induced colitis.

Summary The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases. Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%–20% of variance. Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation. Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation. Early and memory B cell differentiation stages are associated with variation in LARP1B and SP4. Finally, the latrophilin family member ADGRL2 correlates with baseline pro-inflammatory interleukin-6 levels. Suggestive associations reveal mechanisms of autoimmune disease associations, in particular related to pro-inflammatory cytokine production. Pinpointing these key human immune regulators offers attractive therapeutic perspectives., Graphical Abstract, Highlights • GWAS provides understanding of genetic factors shaping adaptive immune system • Common and less common variants explain 10% of variance in cellular variables • Associations pinpoint key regulators of B and T cell differentiation • Associations offer therapeutic targets for controlling pro-inflammatory traits, Lagou et al. identify genetic factors explaining interindividual variation in composition of the adaptive immune system. Factors pinpoint key human immune regulators controlling B and T cell differentiation and levels of disease-relevant T helper and regulatory cells. These findings shed light on mechanisms of autoimmune disease and offer therapeutic perspectives.

Background The orexigenic peptide ghrelin has anti-inflammatory properties in colitis, however, the mechanism of action and the immune cells targeted remain still to be elucidated. Here, we assessed the possible effect of ghrelin on T helper (Th) cells in a T cell transfer model of chronic colitis. Methods Disease was induced in the recombination activating gene 1 knockout mice (Rag1(-/-) ) by adoptive transfer of naive Th cells from ghrelin receptor knockout mice (GRLN-R(-/-) ) or littermate wild-type (WT) mice. The course and severity of colitis was assessed by monitoring body weight, diarrhea score, histological analysis, gene expression, and flow cytometry analysis. The possible effects of ghrelin on Th cell proliferation, polarization, and apoptosis was examined in vitro. Key results Our data showed that Rag1(-/-) mice injected with GRLN-R(-/-) Th cells displayed increased severity of colitis compared to mice injected with WT Th cells. In addition, Rag1(-/-) mice injected with GRLN-R(-/-) Th cells had significantly higher intestinal inflammation and increased accumulation of Th1 and Th17 cells in the colon. In vitro, ghrelin directly affected proliferation of Th cells and induced apoptosis whereas it did not influence Th cell polarization. Conclusion & inferences Our observations suggest that ghrelin modulates Th effector cells in the gut controlling proliferation and inducing apoptosis. Our findings further support the use of ghrelin as a novel therapeutic option to treat intestinal inflammatory diseases.

Background: Although never evaluated for efficacy, n-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs) are commercially offered as treatment for irritable bowel syndrome (IBS). Objective: This study was designed to investigate, in a mast cell-dependent model for visceral hypersensitivity, whether this pathophysiologic mechanism can be reversed by dietary LCPUFA treatment via peroxisome proliferator-activated receptor γ (PPARG) activation. Methods: Maternally separated rats were subjected to hypersensitivity-inducing acute stress at adult age. Reversal was attempted by protocols with tuna oil-supplemented diets [4% soy oil (SO) and 3%tuna oil (SO-T3) or 3% SO and 7% tuna oil (SO-T7)] and compared with control SO diets (7% or 10% SO) 4 wk after stress. The PPARG agonist rosiglitazone was evaluated in a 1 wk preventive protocol (30 mg · kg-1 · d-1). Erythrocytes were assessed to confirm LCPUFA uptake and tissue expression of lipoprotein lipase and glycerol kinase as indicators of PPARG activation. Colonic mast cell degranulation was evaluated by toluidine blue staining. In vitro, human mast cell line 1 (HMC-1) cells were pretreated with rosiglitazone, eicosapentaenoic acid, or docosahexaenoic acid, stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore or compound 48/80 and evaluated for tumor necrosis factor α (TNF-α) and β-hexosaminidase release. Results: Stress led to visceral hypersensitivity in all groups. Hypersensitivity was not reversed by SO-T3 or control treatment [prestress vs. 24 h poststress vs. posttreatment area under the curve; 76 ± 4 vs. 128 ± 12 (P

Background To date, genetic-association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune-related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk. Methods We conducted two independent case–control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta-analysis which included 12 additional, earlier studies. The meta-analysis comprised a total of 2894 patients (839 IBS-C, 1073 IBS-D, 502 IBS-M), and 3138 healthy volunteers with self-reported Caucasian ancestry. Key Results The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta-analysis: IBS (OR 1.19, 95% CI 1.08–1.31), and IBS-C (OR 1.24, 95% CI 1.08–1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes. Conclusions & Inferences Our meta-analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS-C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.

Post-infectious irritable bowel syndrome (PI-IBS) is a common gastrointestinal disorder characterized by persistent abdominal pain despite recovery from acute gastroenteritis. The underlying mechanisms are unclear, although long-term changes in neuronal function, and low grade inflammation of the bowel have been hypothesized. We investigated the presence and mechanism of neuronal sensitization in a unique cohort of individuals who developed PI-IBS following exposure to contaminated drinking water 7 years ago. We provide direct evidence of ongoing sensitization of neuronal signaling in the bowel of patients with PI-IBS. These changes occur in the absence of any detectable tissue inflammation, and instead appear to be driven by pro-nociceptive changes in the gut micro-environment. This is evidenced by the activation of murine colonic afferents, and sensitization responses to capsaicin in dorsal root ganglia (DRGs) following application of supernatants generated from tissue biopsy of patients with PI-IBS. We demonstrate that neuronal signaling within the bowel of PI-IBS patients is sensitized 2 years after the initial infection has resolved. This sensitization appears to be mediated by a persistent pro-nociceptive change in the gut micro-environment, that has the capacity to stimulate visceral afferents and facilitate neuronal TRPV1 signaling. ispartof: Scientific Reports vol:7 issue:1 pages:13606- ispartof: location:England status: published

Highlights • Muscularis macrophages densily colonize the outermost layer of the gastrointestinal tract. • Muscularis macrophages communicate with enteric neurons in a bidirectional matter. • Muscularis macrophages are tissue-protective but can contribute to disease. • Current challenges are to decipher therapeutic potentials of muscularis macrophages., Macrophages residing in the muscularis externa of the gastrointestinal tract are highly specialized cells that are essential for tissue homeostasis during steady-state conditions as well as during disease. They are characterized by their unique protective functional phenotype that is undoubtedly a consequence of the reciprocal interaction with their environment, including the enteric nervous system. This muscularis macrophage-neuron interaction dictates intestinal motility and promotes tissue-protection during injury and infection, but can also contribute to tissue damage in gastrointestinal disorders such as post-operative ileus and gastroparesis. Although the importance of muscularis macrophages is clearly recognized, different aspects of these cells remain largely unexplored such their origin, longevity and instructive signals that determine their function and phenotype. In this review, we will discuss the phenotype, functions and origin of muscularis macrophages during steady-state and disease conditions. We will highlight the bidirectional crosstalk with neurons and potential therapeutic strategies that target and manipulate muscularis macrophages to restore their protective signature as a treatment for disease.

The mechanical properties of the esophagogastric junction (EGJ) are of major importance for the competence of the EGJ. Although manometry reliably measures sphincter pressure, no information is provided on distensibility, a crucial determinant of flow across the EGJ. Recently, a new technique, impedance planimetry, was introduced allowing accurate measurement of compliance or distensibility. This review discusses the recent advances in this area and highlights the clinical relevance of this new technique evaluating the mechanical properties of the esophageal wall and EGJ.

New Findings What is the central question of this study? Supernatants from colonic mucosal biopsies from patients with irritable bowel syndrome (IBS) activate enteric and dorsal root ganglion (DRG) neurons. Based on the discomfort/pain threshold during rectal distension, IBS patients may be subtyped as normo- or hypersensitive. However, the link between neuronal activation and visceral sensitivity remains unknown. What is the main finding and its importance? We found that supernatants from hypersensitive IBS patients caused stronger activation of enteric and DRG neurons than supernatants from normosensitive IBS patients. The level of activation correlated with the individual discomfort/pain threshold pressure values. We therefore conclude that mucosal biopsy supernatants have biomarker potential and may, in the future, help to personalize treatment of IBS patients with different visceral sensitivities. Based on the discomfort/pain threshold during rectal distension, irritable bowel syndrome (IBS) patients may be subtyped as normo- or hypersensitive. We previously showed that mucosal biopsy supernatants from IBS patients activated enteric and visceral afferent neurons. We tested the hypothesis that visceral sensitivity is linked to the degree of neuronal activation. Normo- and hypersensitive IBS patients were distinguished by their discomfort/pain threshold to rectal balloon distension with a barostat. Using potentiometric and Ca2+ dye imaging, we recorded the response of guinea-pig enteric submucous and mouse dorsal root ganglion (DRG) neurons, respectively, to mucosal biopsy supernatants from normosensitive (n = 12 tested in enteric neurons, n = 9 tested in DRG) and hypersensitive IBS patients (n = 9, tested in both types of neurons). In addition, we analysed the association between neuronal activation and individual discomfort/pain pressure thresholds. The IBS supernatants evoked Ca2+ transients in DRG neurons and spike discharge in submucous neurons. Submucous and DRG neurons showed significantly stronger responses to supernatants from hypersensitive IBS patients as reflected by higher spike frequency or stronger [Ca2+]i transients in a larger proportion of neurons. The neuroindex as a product of spike frequency or [Ca2+]i transients and proportion of responding neurons correlated significantly with the individual discomfort/pain thresholds of the IBS patients. Supernatants from hypersensitive IBS patients caused stronger activation of enteric and DRG neurons. The level of activation correlated with the individual discomfort/pain threshold pressure values. These findings support our hypothesis that visceral sensitivity is linked to activation of peripheral neurons by biopsy supernatants.

Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus(1,2). This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQ beta 1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P = 1.73 x 10(-19)). In addition, two amino acid substitutions in the. extracellular domain of HLA-DQ alpha 1 at position 41 (lysine encoded by HLA-DQA1*01:03; P = 5.60 x 10(-10)) and of HLA-DQ beta 1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P = 1.20 x 10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.

Achalasia is the best characterized primary esophageal motility disorder of the esophagus and typically presents with absent peristalsis of the esophageal body and a failure of the lower esophageal sphincter to relax upon swallowing on manometry, associated with progressively severe dysphagia, regurgitation, aspiration, chest pain, and weight loss. The diagnosis is suggested by barium swallow and endoscopy, and confirmed by manometry. As there is no curative treatment for achalasia, treatment is confined to disruption of the lower esophageal sphincter to improve bolus passage. Treatment modalities available for this purpose include pneumatic dilation, laparoscopic Heller myotomy and since recently peroral endoscopic myotomy or POEM. In this review, we will discuss the current diagnosis, management, and treatment options of achalasia.

Background Postoperative ileus (POI) is characterized by impaired gastrointestinal motility resulting from intestinal handling-associated inflammation. The introduction of laparoscopic surgery has dramatically reduced the duration of POI. However, it remains unclear to what extent this results in a reduction of intestinal inflammation. The aim of the present study is to compare the degree of intestinal inflammation and gastrointestinal transit following laparoscopic surgery and open abdominal surgery. Methods Mice were subjected to laparoscopic surgery or laparotomy alone or, in combination with standardized intestinal manipulation of the small bowel (IM). Gastrointestinal transit and intestinal inflammation were assessed 24 h after surgery by the number of myeloperoxidase (MPO) positive cells and the level of cytokine expression. The recovery time and the degree of inflammation were also analyzed in patients subjected to colectomy under open conditions (laparotomy) or laparoscopic conditions. Key Results Mice undergoing IM by laparotomy (open IM), but not by laparoscopy (Lap IM) developed a significant delay in gastrointestinal transit compared to laparotomy or laparoscopy alone. In addition, there was significant intestinal inflammation only after open IM. Similarly, cytokine levels in peritoneal lavage fluid were lower while recovery time was faster in patients subjected to colectomy under laparoscopic conditions compared to open colectomy. Conclusions & Inferences Our data confirms that intestinal inflammation is underlying the delayed gastrointestinal transit observed after open surgery. Most importantly, we demonstrate that intestinal inflammation under laparoscopic conditions is significantly lower compared to open surgery, most likely explaining the faster recovery following laparoscopic surgery.

Gastroesophageal reflux disease (GERD) is one of the most common digestive diseases in the Western world, with typical symptoms, such as heartburn, regurgitation, or retrosternal pain, reported by 15% to 20% of the general population. The pathophysiology of GERD is multifactorial. Our understanding of these factors has significantly improved in recent years, with increased understanding of the acid pocket and hiatal hernia and how these factors interact. Although our insight has significantly increased over the past years, more studies are required to better understand symptom generation in GERD, especially in patients with therapy-resistant symptoms.

Irritable bowel syndrome is a prevalent and chronic disorder, characterized by recurrent abdominal pain/discomfort, bloating and altered bowel habits. This condition affects an estimated 10-15% of the population worldwide and impacts heavily on a patient's daily life and ability to work, as well as healthcare resource utilization. Drug therapy aimed at correcting the primary symptoms of diarrhea/constipation/bloating may have little effect on abdominal pain, which results from visceral hypersensitivity. Smooth muscle relaxants or antispasmodics decrease the tone and contractility of intestinal smooth muscle, effectively managing abdominal pain. Otilonium bromide has been widely used worldwide and has been found to be safe and well tolerated, and superior to placebo for the reduction of symptoms and the prevention of symptom relapse in patients with irritable bowel syndrome.

BACKGROUND & AIMS: Approximately 30% of patients with gastroesophageal reflux disease have symptoms resistant to treatment with proton pump inhibitors (PPIs). Several mechanisms such as esophageal hypersensitivity, increased mucosal permeability, and possibly the position of the gastric acid pocket might underlie a partial response to PPIs. To what extent these mechanisms interact and contribute to PPI-resistant symptoms, however, has not been investigated previously. METHODS: In 18 gastroesophageal reflux disease patients (9 PPI responders and 9 PPI partial responders), esophageal sensitivity, mucosal permeability, and postprandial reflux parameters were determined during PPI use. Esophageal sensitivity for distension was measured by gradual balloon inflation at 5 and 15 cm above the lower esophageal sphincter. The mucosal permeability of 4 esophageal biopsy specimens per patient was determined in Ussing chambers by measuring the transepithelial electrical resistance and transmucosal flux of fluorescein. Postprandial reflux parameters were determined using concurrent high-resolution manometry/pH impedance after a standardized meal. In addition, the acid pocket was visualized using scintigraphy. RESULTS: No difference in the rate of postprandial acid reflux, in the pH of the acid pocket (PPI responders 3.7 +/- 0.7 vs PPI partial responders 4.2 +/- 0.4; P = .54), or in the position of the acid pocket was observed in PPI partial responders compared with PPI responders. In addition, the permeability of the esophageal mucosa was similar in both groups, as shown by a similar transepithelial electrical resistance and flux of fluorescein. PPI partial responders had more reflux episodes with a higher mean proximal extent, compared with PPI responders, and were more sensitive to balloon distension, both in the upper and lower esophagus. CONCLUSIONS: PPI-resistant symptoms most likely are explained by increased proximal reflux in a hypersensitive esophagus and less likely by increased mucosal permeability or the position of the acid pocket.

BACKGROUND: Infectious gastroenteritis is a risk factor for development of Irritable Bowel Syndrome (IBS). Exposure to the dietary antigen ovalbumin (OVA) during infection with Citrobacter rodentium resulted in an increased visceromotor response to colonic distension and increased mucosal permeability following re-challenge with OVA. It is unknown whether colonic immune mediators released following re-challenge of OVA could subsequently increase the excitability of nociceptive neurons. AIMS: Determine whether colonic mediators released in response to dietary antigen re-challenge increase excitability of nociceptive neurons and whether the histamine receptor H1 is involved in a model of post infectious IBS. METHODS: Mice were infected with C. rodentium in the presence (infected OVA/OVA) or absence of OVA (infected saline/OVA) and were subsequently re-challenged with OVA 5 weeks post-infection. A third group of mice were not infected but exposed to OVA and re-challenged with OVA at 5 weeks (non-infected OVA/OVA). Following OVA re-challenge, mice were euthanized and the colons were incubated in media, supernatants were collected after 4 hrs. Supernatants were incubated overnight with nociceptive DRG neurons from control mice. Perforated patch clamp recordings were employed to assess neuronal excitability by measuring rheobase (minimum current to evoke an action potential) and action potential discharge (AP) at twice rheobase. Some DRG neurons were also pre-incubated with the H1 receptor antagonist pyrilamine (1µM) 1 hour prior to incubation with supernatants. Two-way ANOVA with Bonferroni post hoc test were used to analyze the data. RESULTS: Infected OVA/OVA supernatants decreased the rheobase compared to the other two groups (Infected OVA/OVA= 68 ± 4.2 pA* vs Non-infected OVA/OVA= 81.2 ± 4 pA vs Infected saline/OVA = 85.6 ± 4.5 pA; *p

Background: Mucosal immune activation has been postulated to play an important role in the pathogenesis of irritable bowel syndrome (IBS). However, data are conflicting and often based on small patient cohorts. Here, we aimed to evaluate the gene expression of a large set of immune‐related genes in mucosal biopsies from IBS patients and healthy volunteers (HV). Methods: A total of 171 IBS patients and 127 HV were included in the study. Rectum biopsies were collected from a cohort of 70 HV and 77 IBS patients (Rome III) and colon descendens biopsies from another cohort of 57 HV and 94 IBS patients (Rome II). Gene expression was assessed using OpenArray technology, and validated questionnaires were used to evaluate clinical characteristics (GI symptoms, somatization, anxiety, and depression). Key Results: A subset of IBS patients (33%) with increased immune activation in the colon descendens was identified using multivariate analysis and displayed increased gene expression of IL1B (3‐fold change), prostaglandin synthase PTGS2 (2.1‐fold change), and the G‐protein‐coupled receptor MRGPRX2 (10.7‐fold change). Clinical characteristics in this subgroup were however similar to the rest of the patient cohort. Analysis of rectal biopsies failed to identify such subgroup of “immuno‐active” IBS patients in the other patient cohort. Conclusion: A subset of IBS patients reveals evidence of immune activation in the colon descendens, but not in the rectum; however, gene expression is unrelated to clinical symptoms. To what extent this subgroup might however respond to anti‐inflammatory therapy remains to be investigated. ispartof: Neurogastroenterology and Motility vol:31 issue:6 pages:1-10 ispartof: location:England status: published