Clinical Significance of TNFSF14/LIGHT and CD160 in Gastric Cancer and Peptic Ulcer Dyspepsia.

BACKGROUND: Previous studies have reported the role of the Herpes Virus Entry Mediator (HVEM) in various cancer including gastric cancer. However, the expression level and clinical significance of CD160 and Tumor Necrosis Factor Ligand Superfamily Member 14 (TNFSF14) pathways in gastric cancer and gastric dyspepsia patients have remained unexplored. METHODS: The study involved the collection of gastric tissue biopsies from 42 patients with non-ulcerative dyspepsia (NUD) as the control group, 43 gastric cancer (GC) patients, and 48 patients with peptic-ulcerative dyspepsia (PUD). All the patients were endoscopically examined at Imam Khomeini Hospital in Sari, Mazandaran, Iran. The expression levels of TNFSF14 and CD160 mRNA were assessed using quantitative real-time PCR (qPCR) with the SYBR Green method. Statistical analysis was performed to investigate the potential association between the clinical and experimental data. RESULTS: Among the 133 gastric endoscopic biopsies examined, LIGHT exhibited a significant overexpression in GC patients (p-value < 0.01). Moreover, the expression of TNFSF14 was higher in GC patients with stages I and II (p-value<0.05). Furthermore, GC patients with TNM stages III+IV were accompanied by high expression levels of LIGHT (p-value < 0.01) as well as CD160 (p-value<0.05). The expression of CD160 was also higher in younger adults with PUD (p-value<0.05). Whereas TNFSF14 exhibited higher expression in older adults with GC (p-value<0.05). Furthermore, this research provided insights into the potential biological pathways and significant gene enrichment of TNFSF14 and CD160, suggesting the potential role of CD160 and TNFSF14 in the regulation of immune system in GC and PUD. CONCLUSION: These findings suggest the possible role of LIGHT and CD160 expression in gastric cancer patients in immune dysregulation toward gastric cancer. Targeted immunotherapy that harnessing co-stimulatory molecules like LIGHT and CD160 could be a promising approach in the treatment of GC as well as potential GC tumor markers.

Comparative Assessment of the Anti-Helicobacter pylori Activity and Gastroprotective Effects of Three Herbal Formulas for Functional Dyspepsia In Vitro.

Helicobacter pylori has been implicated in various gastrointestinal disorders, including functional dyspepsia. This study aimed to compare the anti-H. pylori activity and gastroprotective effects of three typical herbal formulas used for gastrointestinal disorders in Korea: Shihosogan-tang (ST), Yijung-tang (YT), and Pyeongwi-san (PS). Firstly, we assessed the total phenolic and flavonoid contents, as well as the antioxidative capacity. Additionally, we evaluated the antibacterial effect on H. pylori using an ammonia assay, minimum inhibitory concentration (MIC) test, and the disk agar diffusion method. Furthermore, we examined alterations in the gene expression of tight junction proteins, pro-inflammatory cytokines, and cellular vacuolation using an AGS cell model infected with H. pylori. While ST exhibited a higher total phenolic content, superior free radical scavenging, and inhibition of H. pylori compared to YT and PS, YT more evidently inhibited gastric cellular morphological changes such as vacuolation. All formulations significantly ameliorated changes in inflammatory and gastric inflammation-related genes and cellular morphological alterations induced by H. pylori infection. Overall, the present in vitro study suggests that all three herbal formulas possess potential for ameliorating gastrointestinal disorders, with ST relatively excelling in inhibiting H. pylori infection and inflammation, while YT potentially shows greater efficacy in directly protecting the gastric mucosa.

Redefining Histological Cell Counts Using a Standardized Method: The Leuven Intestinal Counting Protocol.

INTRODUCTION: The diagnosis of eosinophilic gastrointestinal diseases is largely based on mucosal eosinophil counts, but thresholds and normal ranges beyond the esophagus are debated, calling for much-needed methodological standardization. We aimed to develop a standardized workflow for duodenal cell quantification and estimate duodenal eosinophil and mast cell numbers in healthy controls. METHODS: Software-based histological cell quantification using free-sized or fixed-sized regions was developed and applied to digitized hematoxylin and eosin (H&E)-stained slides from 58 individuals (healthy controls [HCs] and patients with functional dyspepsia). Intraclass correlation coefficients (ICCs) compared inter-rater reliability between software-based and microscopic quantification. Reproducibility of the software-based method was validated in an independent cohort of 37 control and functional dyspepsia subjects. Eosinophil identification on H&E staining was compared to immunohistochemistry (IHC). Normal eosinophil (H&E) and mast cell (cKit) ranges were determined in 70 adult HCs. RESULTS: Eosinophil quantification on digitized slides demonstrated excellent (ICC = 0.909) and significantly improved reproducibility over microscopic evaluation (ICC = 0.796, P = 0.0014), validated in an independent cohort (ICC = 0.910). Duodenal eosinophils were more abundant around crypts than in villi ( P < 0.0001), while counts were similar on matched H&E- and IHC-stained slides ( P = 0.55). Mean ± SD (95th percentile) duodenal eosinophils and mast cells in HC were 228.8/mm 2 ± 94.7 (402.8/mm 2 ) and 419.5/mm 2 ± 132.2 (707.6/mm 2 ), respectively. DISCUSSION: We developed and validated a standardized approach to duodenal histological cell quantification, generalizable to various mucosal cell types. Implementation of software-based quantification identified 400 eosinophils/mm 2 and 700 mast cells/mm 2 as thresholds for abnormal duodenal infiltration.

Mast cells disrupt the duodenal mucosal integrity: Implications for the mechanisms of barrier dysfunction in functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is a common functional gastrointestinal (GI) disorder, but its pathophysiology is poorly understood. Mast cells (MCs) may play a critical role in the development of FD. Therefore, the aim of this study was to investigate the effect of MCs on barrier function, tight junction (TJ) proteins and related signaling pathways. METHODS: The expression of the TJ proteins claudin-8, ZO-1 and occludin in biopsy tissues from seven FD patients and five controls was assessed. Based on the in vivo results, we further investigated the effect of (1) MC degranulation in a coculture model of Caco-2/RBL-2H3 cells and tryptase in Caco-2 monolayers, (2) MC degranulation in the presence or absence of a PAR-2 antagonist and (3) MC degranulation in the presence or absence of an ERK1/2 signaling pathway inhibitor. The epithelial integrity of Caco-2 cell monolayers was assessed by measuring the transepithelial electrical resistance (TEER). The expression of TJ proteins was evaluated by western blotting, QT-PCR and immunostaining. RESULTS: Epithelial claudin-8, ZO-1 and occludin protein expression were significantly reduced in tissues from FD patients compared with controls. MC degranulation and tryptase decreased the TEER and reduced the expression of TJ proteins in Caco-2 cell monolayers. A PAR-2 antagonist and an ERK1/2 signaling pathway inhibitor significantly reduced the effect of MC degranulation on the TEER and TJ protein expression in Caco-2 cell monolayers. CONCLUSIONS: MCs disrupt duodenal barrier function by modulating the levels of TJ proteins, and the PAR-2 and ERK1/2 signaling pathways may mediate the pathogenesis of FD.

Multi-omics analysis reveals the metabolic regulators of duodenal low-grade inflammation in a functional dyspepsia model.

Several gastrointestinal phenotypes and impairment of duodenal mucosal barrier have been reported in clinical studies in patients with functional dyspepsia (FD). Due to the preferential colonization of the mucosa, intestinal microbes and their metabolites are commonly involved in host metabolism and immune responses. However, there are no studies on the intertwined correlation among multi-level data. For more comprehensive illustrating, a multi-omics analysis focusing on the duodenum was performed in the FD rat model. We found that differential microbiomes in the duodenum were significantly correlated with the biosynthesis of lipopolysaccharide and peptidoglycan. The innate immune response-related genes, which were upregulated in the duodenum, were associated with the TLR2/TLR4-NFκB signaling pathway. More importantly, arachidonyl ethanolamide (anandamide, AEA) and endocannabinoid analogues showed linear relationships with the FD phenotypes. Taken together, multi-level data from microbiome, transcriptome and metabolome reveal that AEA may regulate duodenal low-grade inflammation in FD. These results suggest an important cue of gut microbiome-endocannabinoid system axis in the pathogenesis of FD.

Eosinophil and Mast Cell Counts in the Stomach and Duodenum of Patients with Functional Dyspepsia without a Helicobacter pylori infection.

Background/Aims: Symptom-based subtyping of functional dyspepsia (FD) is used to segregate patients into groups with homogenous pathophysiological mechanisms. This study examined whether subtyping could reflect the duodenal and gastric microinflammation in FD patients. Methods: Twenty-one FD patients without Helicobacter pylori infection were recruited. An endoscopic biopsy was performed in the duodenum 2nd portion, stomach antrum, and body. The eosinophil and mast cell counts per high-power field (×40) were investigated by H&E and c-kit staining, respectively. The degree of inflammatory cell infiltration, atrophy, and intestinal metaplasia was also determined by H&E staining in the stomach. The baseline characteristics and eosinophil and mast cell infiltrations were compared among the three groups (epigastric pain syndrome, postprandial distress syndrome, and overlap). Results: According to the symptom assessment, seven subjects were classified into the epigastric pain syndrome group, 10 into the postprandial syndrome group, and four into the overlap group. The baseline variables were similar in the three groups. Eosinophil infiltration was more prominent in the duodenum than in the stomach. In contrast, mast cell infiltration was similar in the duodenum and stomach. The eosinophil counts in the duodenum were similar in the three groups. The eosinophil counts in the stomach and mast cell counts in the duodenum and stomach were also similar in the three groups. Conclusions: Duodenal eosinophil infiltration was prominent in FD patients, but the eosinophil counts were similar regardless of the symptom-based subtypes of FD. Hence, the current symptom-based subtyping of FD does not reflect duodenal eosinophil and mast cell infiltration.

Duodenal eosinophilia is associated with symptomatic erosive gastro-oesophageal reflux disease, presence of co-morbidities, and ethnicity but not undifferentiated functional dyspepsia: A retrospective Malaysian study.

BACKGROUND: Duodenal eosinophilia is postulated to play a key role in the pathogenesis of functional dyspepsia, a common condition responsible for considerable impairment of quality of life. Our objective was to evaluate the relative strength of the associations between duodenal eosinophilia, functional dyspepsia, symptomatic erosive gastroesophageal reflux disease (GERD), the presence of co-morbidities, and a number of other variables. METHODS: Eosinophil counts of archived endoscopic duodenal biopsies of 289 subjects were determined by a pathologist blinded to the clinical data. Duodenal eosinophilia was defined by a count of more than 15 per 5 high power fields. Clinical charts were reviewed by a gastroenterologist blinded to the histology review. RESULTS: In the study sample, the primary diagnosis was functional dyspepsia (undifferentiated by subtypes) in 45, symptomatic erosive GERD in 29, gall stone disease in 17, irritable bowel syndrome in 23, and an alternative or undetermined diagnosis in 175 subjects, respectively. On logistic regression analyses, eosinophil counts were positively associated with symptomatic erosive GERD (Odds Ratio, OR 1.03, 95% Confidence Interval, 95%CI: 1.00, 1.05; p=0.035) but not functional dyspepsia. Pre-defined duodenal eosinophilia was associated with symptomatic erosive gastro-oesophageal reflux disease (OR 3.36, 95%CI 1.18,-9.60; p=0.023), the presence of co-morbidities (OR 2.00, 95%CI 1.10, 3.62; p=0.022), and Chinese (as compared to Malay and Indian) ethnicity but not with either functional dyspepsia, irritable bowel syndrome, gallstone disease, Helicobacter pylori infection, or gender. CONCLUSION: Duodenal eosinophilia was associated with symptomatic erosive GERD, the presence of co-morbidities, and Chinese ethnicity but not with undifferentiated functional dyspepsia.

CLINICAL, ENDOSCOPIC, AND HISTOLOGICAL CHARACTERISTICS OF HELICOBACTER PYLORI POSITIVE AND NEGATIVE ARMENIAN CHILDREN WITH RECURRENT ABDOMINAL PAIN AND/OR DYSPEPSIA.

Recurrent abdominal pain (RAP) and dyspepsia are common complaints in children. These symptoms are often associated with Helicobacter pylori (Hp) infection. The aim of the present study was to prospectively analyze clinical, endoscopic, and histological characteristics of Hp+ and Hp- children with RAP and/or dyspepsia. Patients aged 2-18 years with RAP and/or dyspepsia, referred for an upper endoscopy to Arabkir Medical Center - Institute of Child and Adolescent Health (Arabkir MC-ICAH) from November 2015 to December 2017, were involved in the study. Histology was assessed according to the updated Sydney system. Gastric and duodenal specimens were stained by modified Giemsa staining for Hp infection. One antral biopsy was cultured in Hp selective media. 150 patients were included into the study: 70.7% Hp+, 29.3% Hp-. Nausea and vomiting were significantly more common in Hp+ patients (p<0.05). Gastric nodularity (p=0.02), erosions in the stomach (p=0.056), and duodenal erosions (p=0.019) were more common in Hp+. Chronic active (p=0.027) and non-active gastritis (p=0.002), cumulative findings of metaplasia/dysplasia/atrophy in the stomach (p=0.014) and chronic non-active duodenitis (p=0.016), were significantly more common in Hp+ patients. Hp infection prevalence is high in Armenian children with dyspepsia and/or RAP. Clinical symptoms, endoscopic findings, and histopathological findings were significantly different in Hp+ patients as compared to Hp- patients.

Duodenal Mucosal Barrier in Functional Dyspepsia.

BACKGROUND & AIMS: In addition to gastric sensorimotor dysfunctions, functional dyspepsia (FD) is also variably associated with duodenal micro-inflammation and epithelial barrier dysfunction, the pathogenesis and clinical significance of which are unknown. Our hypothesis was that miRNAs and/or inflammation degrade epithelial barrier proteins, resulting in increased duodenal mucosal permeability in FD. METHODS: We compared the duodenal mucosal gene expression and miRNAs, in vivo permeability (lactulose-mannitol excretion between 0 and 60 and 60 and 120 minutes after saccharide ingestion), ex vivo assessments (transmucosal resistance, fluorescein isothiocyanate [FITC]-dextran flux, and basal ion transport), and duodenal histology (light and electron microscopy) in 40 patients with FD and 24 controls. RESULTS: Compared with controls, the mRNA expression of several barrier proteins (zonula occludens-1, occludin, claudin-12, and E-cadherin) was modestly reduced (ie, a fold change of 0.8-0.85) in FD with increased expression of several miRNAs (eg, miR-142-3p and miR-144-3-p), which suppress these genes. The urinary lactulose excretion and the lactulose:mannitol ratio between 60 and 120 minutes were greater in FD than in controls (P < .05). The FITC-dextran flux, which reflects paracellular permeability, was inversely correlated (r = -0.32, P = .03) with transmucosal resistance and directly correlated (r = 0.4, P = .02) with lactulose:mannitol ratio. Other parameters (mucosal eosinophils, intraepithelial lymphocytes, and mast cells, transmucosal resistance, FITC-dextran flux, average intercellular distance, and proportion of dilated junctions) were not significantly different between groups. CONCLUSIONS: In FD, there is a modest reduction in the expression of several duodenal epithelial barrier proteins, which may be secondary to up-regulation of regulatory miRNAs, and increased small intestinal permeability measured in vivo.

Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia.

Background: Functional dyspepsia is characterised by chronic symptoms of post-prandial distress or epigastric pain not associated with defined structural pathology. Increased peripheral gut-homing T cells have been previously identified in patients. To date, it is unknown if these T cells were antigen-experienced, or if a specific phenotype was associated with FD. Objective: This study aimed to characterise T cell populations in the blood and duodenal mucosa of FD patients that may be implicated in disease pathophysiology. Methods: We identified duodenal T cell populations from 23 controls and 49 Rome III FD patients by flow cytometry using a surface marker antibody panel. We also analysed T cell populations in peripheral blood from 37 controls and 61 patients. Where available, we examined the number of duodenal eosinophils in patients and controls. Results: There was a shift in the duodenal T helper cell balance in FD patients compared to controls. For example, patients had increased duodenal mucosal Th2 populations in the effector (13.03 ± 16.11, 19.84 ± 15.51, p=0.038), central memory (23.75 ± 18.97, 37.52 ± 17.51, p=0.007) and effector memory (9.80±10.50 vs 20.53±14.15, p=0.001) populations. Th17 populations were also increased in the effector (31.74±24.73 vs 45.57±23.75, p=0.03) and effector memory (11.95±8.42 vs 18.44±15.63, p=0.027) subsets. Peripheral T cell populations were unchanged between FD and control. Conclusion: Our findings identify an association between lymphocyte populations and FD, specifically a Th2 and Th17 signature in the duodenal mucosa. The presence of effector and memory cells suggest that the microinflammation in FD is antigen driven.

Subcortical-cortical functional connectivity as a potential biomarker for identifying patients with functional dyspepsia.

The diagnosis of functional dyspepsia (FD) presently relies on the self-reported symptoms. This study aimed to determine the potential of functional brain network features as biomarkers for the identification of FD patients. Firstly, the functional brain Magnetic Resonance Imaging data were collected from 100 FD patients and 100 healthy subjects, and the functional brain network features were extracted by the independent component analysis. Then, a support vector machine classifier was established based on these functional brain network features to discriminate FD patients from healthy subjects. Features that contributed substantially to the classification were finally identified as the classifying features. The results demonstrated that the classifier performed pretty well in discriminating FD patients. Namely, the accuracy of classification was 0.84 ± 0.03 in cross-validation set and 0.80 ± 0.07 in independent test set, respectively. A total of 15 connections between the subcortical nucleus (the thalamus and caudate) and sensorimotor cortex, parahippocampus, orbitofrontal cortex were finally determined as the classifying features. Furthermore, the results of cross-brain atlas validation showed that these classifying features were quite robust in the identification of FD patients. In summary, the current findings suggested the potential of using machine learning method and functional brain network biomarkers to identify FD patients.

Dyspepsia in Montenegrin chronic kidney disease patients undergoing hemodialysis: endoscopic and histopathological features.

PURPOSE: The main purpose of this study was to analyze the characteristics of dyspepsia and contributing factors in Montenegrin maintenance hemodialysis patients. METHODS: The study included 43 patients undergoing hemodialysis with symptoms of dyspepsia and 40 control dyspeptic subjects with preserved kidney function. All subjects underwent an interview about dyspeptic symptoms, physical and biochemical examination, and upper gastrointestinal endoscopy with pathohistological analysis of biopsy specimens. RESULTS: Early satiety, bloating and heartburn were the most common symptoms in hemodialysis patients but without significant difference in frequency in relation to controls. Chronic kidney disease patients had statistically lower concentration of total proteins and albumin (p < 0.001), as well lower BMI values (p = 0.002). Despite this, no significant correlation of laboratory parameters with dyspeptic symptoms was found. Pathohistological examination indicated that the most common finding in hemodialysis patients was chronic active gastritis (58%), while chronic atrophic gastritis was significantly more common in dialytic patients (p = 0.032). Patients on hemodialysis had more frequently atrophy of corpus mucosa, which was positively related to dialysis duration (p = 0.001) and negatively related to pH values (p = 0.004) and bicarbonate concentration (p = 0.049). Helicobacter pylori was considerably more common in patients who underwent shorter time on hemodialysis (p < 0.001) and had higher values of bicarbonate (p = 0.037). CONCLUSION: Maintenance hemodialysis patients are at risk for chronic gastric diseases that correlated with both dialysis vintage and duration.

Heartburn in children and adolescents in the presence of functional dyspepsia and/or irritable bowel syndrome correlates with the presence of sleep disturbances, anxiety, and depression.

ABSTRACT: The aim of this study was to assess the relationship of heartburn in pediatric patients with functional dyspepsia (FD) and irritable bowel syndrome (IBS) with gastrointestinal symptoms, sleep disturbances, and psychologic distress.The overlap in symptoms of FD, IBS, and gastroesophageal reflux disease (GERD) predicts greater symptom severity and decreased quality of life and presents opportunities for improved diagnostic classification and personalized therapeutics.A cross-sectional observational study of 260 pediatric patients with abdominal pain was conducted. Patients completed standardized questionnaires assessing clinical symptoms, sleep quality, and psychologic symptoms during routine clinical care. Questionnaire data were compared for patients reporting heartburn and not reporting heartburn using χ2 and t tests where appropriate.Gastrointestinal symptoms were significantly more prevalent among patients with a positive report of heartburn (vs a negative report of heartburn): pain with eating (83% vs 67%, P = .007), bloating (63% vs 44%, P = .005), acid regurgitation (47% vs 24%, P ≤ .001), and chest pain (45% vs 20%, P ≤ .001). Likewise, initiating and maintaining sleep (P = .007), arousal/nightmares (P = .046), sleep-wake transition (P = .001), hyperhidrosis during sleep (P = .016), and anxiety (P = .001) and depression (P = .0018) were also significantly increased in patients who reported heartburn versus patients who did not report heartburn.Patients with a positive report of heartburn, whether classified as having FD and/or IBS, had increased gastrointestinal symptoms, sleep disturbances, anxiety, and depression than patients with a negative report of heartburn. A better understanding of these associations may allow for personalized treatment for youth with abdominal pain and heartburn as a primary symptom.

Helicobacter pylori infection rates in dyspeptic Serbian HIV-infected patients compared to HIV-negative controls.

Helicobacter pylori infection does not belong to the spectrum of opportunistic infections in people living with HIV (PLHIV). To evaluate the Helicobacter pylori infection prevalence rate trends in HIV co-infected individuals in comparison to the HIV-negative population, we compared histopathological findings of H. pylori positive gastritis (gastritis topography and histopathology) between 303 PLHIV and 2642 HIV-negative patients who underwent esophagogastroduodenoscopy (EGD) between 1993 and 2014 due to dyspeptic symptoms. The prevalence of H. pylori infection was significantly higher in HIV-negative controls than in PLHIV (50.2% vs. 28.1%). A significantly positive linear trend of H. pylori co-infection in PLHIV was revealed in the observed period (b = 0.030, SE = 0.011, p = 0.013), while this trend was significantly negative in HIV-negative patients (b = - 0.027, SE = 0.003, p < 0.001). Patients with HIV/H. pylori co-infection had significantly higher CD4+ T cell counts and more often had undetectable HIV viremia, due to successful anti-retroviral therapy (ART). Stomach histopathological findings differed between HIV co-infected and H. pylori mono-infected patients. Our findings confirm that the ART has changed the progression of HIV infection, leading to a significant increase in the prevalence of H. pylori infection in dyspeptic PLHIV over time. Our data also suggests that a functional immune system may be needed for H. pylori-induced human gastric mucosa inflammation.

Functional Dyspepsia and Gastroparesis in Tertiary Care are Interchangeable Syndromes With Common Clinical and Pathologic Features.

BACKGROUND: The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better-understood syndrome of gastroparesis. METHODS: Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models. RESULTS: Of 944 patients enrolled during a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206+ macrophages in both groups compared with obese controls. CONCLUSIONS: A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders. CLINICALTRIALS. GOV IDENTIFIER: NCT00398801, NCT01696747.

Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia.

BACKGROUND & AIMS: Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been investigated systematically. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has not been assessed. METHODS: Duodenal biopsy specimens from FD and control subjects, and peroxisome proliferator-activated receptor-α (PPARα) null mice were cultured at a pH of 3.0 and 7.4. Mast cell (MC) number, the release of their mediators, and the expression of transient receptor potential vanilloid receptor (TRPV)1 and TRPV4, were evaluated. All measurements also were performed in the presence of a selective blocker of neuronal action potential (tetradotoxin). FD and control biopsy specimens in acidified medium also were incubated in the presence of different PEA concentrations, alone or combined with a selective PPARα or PPAR-γ antagonist. RESULTS: An acid-induced increase in MC density and the release of their mediators were observed in both dyspeptic patients and controls; however, this response was amplified significantly in FD. This effect was mediated by submucosal nerve fibers and up-regulation of TRPV1 and TRPV4 receptors because pretreatment with tetradotoxin significantly reduced MC infiltration. The acid-induced endogenous release of PEA was impaired in FD and its exogenous administration counteracts MC activation and TRPV up-regulation. CONCLUSIONS: Duodenal acid exposure initiates a cascade of neuronal-mediated events culminating in MC activation and TRPV overexpression. These phenomena are consequences of an impaired release of endogenous PEA. PEA might be regarded as an attractive therapeutic strategy for the treatment of FD.

Functional Dyspepsia and Duodenal Eosinophil Count and Degranulation: A Multiethnic US Veteran Cohort Study.

BACKGROUND: Duodenal eosinophilia may play a role in functional dyspepsia (FD), but existing study results are conflicted. We investigated the association between duodenal eosinophils (count and degranulation) and FD symptoms, accounting for atopic conditions, medications, and seasonal variations. METHODS: In a cross-sectional study conducted in the Michael E. DeBakey VA Medical Center in Houston, Texas, we analyzed duodenal histopathology of 436 patient samples from a prospective cohort with a validated symptom survey data and chart reviews. FD was defined using Rome II symptom criteria. Eosinophil count was number per 5 high-power fields (HPF), and eosinophil degranulation was eosinophilic granules in the stroma both determined by two independent investigators. RESULTS: The study cohort was predominantly male (87.4%) with a mean age of 59.3 (standard deviation (SD) ± 9.8). Mean and median eosinophil counts were 75.5 (± 47.8) and 63 (IQR: 43, 101) per five HPF, respectively. Duodenal eosinophilia (defined as ≥ 63 per 5 HPF) and eosinophil degranulation were present in 50.5% and 23.1% of patient samples, respectively. FD was observed in 178 patients (41.7%), but neither the mean eosinophil count nor duodenal eosinophilia was associated with FD. Eosinophil degranulation was independently associated with FD overall (OR 1.74; 95% CI 1.08, 2.78; p = 0.02) and early satiety (OR 2.04; 95% CI 1.26, 3.30; p = 0.004). CONCLUSIONS: In this large, ethnically diverse cohort of adult patients, we found no significant association between duodenal eosinophilia and FD. However, the presence of duodenal eosinophilic degranulation, an activated eosinophil marker, was significantly associated with FD, especially early satiety.