Hypoxia-inducible factor-1α mediates reflux-induced epithelial-mesenchymal plasticity in Barrett's oesophagus patients.

INTRODUCTION: Epithelial-mesenchymal plasticity (EMP), the process through which epithelial cells acquire mesenchymal features, is needed for wound repair but also might contribute to cancer initiation. Earlier, in vitro studies showed that Barrett's cells exposed to acidic bile salt solutions (ABS) develop EMP. Now, we have (1) induced reflux oesophagitis in Barrett's oesophagus (BO) patients by stopping proton pump inhibitors (PPIs), (2) assessed their biopsies for EMP and (3) explored molecular pathways underlying reflux-induced EMP in BO cells and spheroids. METHODS: 15 BO patients had endoscopy with biopsies of Barrett's metaplasia while on PPIs, and 1 and 2 weeks after stopping PPIs; RNA-seq data were assessed for enrichments in hypoxia-inducible factors (HIFs), angiogenesis and EMP pathways. In BO biopsies, cell lines and spheroids, EMP features (motility) and markers (vascular endothelial growth factor (VEGF), ZEB1, miR-200a&b) were evaluated by morphology, migration assays, immunostaining and qPCR; HIF-1α was knocked down with siRNA or shRNA. RESULTS: At 1 and/or 2 weeks off PPIs, BO biopsies exhibited EMP features and markers, with significant enrichment for HIF-1α, angiogenesis and EMP pathways. In BO cells, ABS induced HIF-1α activation, which decreased miR-200a&b while increasing VEGF, ZEB1 and motility; HIF-1α knockdown blocked these effects. After ABS treatment, BO spheroids exhibited migratory protrusions showing nuclear HIF-1α, increased VEGF and decreased miR-200a&b. CONCLUSIONS: In BO patients, reflux oesophagitis induces EMP changes associated with increased HIF-1α signalling in Barrett's metaplasia. In Barrett's cells, ABS trigger EMP via HIF-1α signalling. Thus, HIF-1α appears to play a key role in mediating reflux-induced EMP that might contribute to cancer in BO. TRIAL REGISTRATION NUMBER: NCT02579460.

Visceral Adipose Tissue Reduction Measured by Deep Neural Network Architecture Improved Reflux Esophagitis Endoscopic Grade.

INTRODUCTION: Visceral obesity is a risk factor for reflux esophagitis (RE). We investigated the risk of RE according to visceral adipose tissue (VAT) measured by deep neural network architecture using computed tomography (CT) and evaluated the longitudinal association between abdominal adipose tissue changes and the disease course of RE. METHODS: Individuals receiving health checkups who underwent esophagogastroduodenoscopy (EGD) and abdominal CT at Seoul National University Healthcare System Gangnam Center between 2015 and 2016 were included. Visceral and subcutaneous adipose tissue areas and volumes were measured using a deep neural network architecture and CT. The association between the abdominal adipose tissue area and volume and the risk of RE was evaluated. Participants who underwent follow-up EGD and abdominal CT were selected; the effects of changes in abdominal adipose tissue area and volume on RE endoscopic grade were investigated using Cox proportional hazards regression. RESULTS: We enrolled 6,570 patients who underwent EGD and abdominal CT on the same day. RE was associated with male sex, hypertension, diabetes, excessive alcohol intake, current smoking status, and levels of physical activity. The VAT area and volume increased the risk of RE dose-dependently. A decreasing VAT volume was significantly associated with improvement in RE endoscopic grade (hazard ratio: 3.22, 95% confidence interval: 1.82-5.71). Changes in subcutaneous adipose tissue volume and the disease course of RE were not significantly correlated. DISCUSSION: Visceral obesity is strongly associated with RE. VAT volume reduction was prospectively associated with improvement in RE endoscopic grade dose-dependently. Visceral obesity is a potential target for RE treatment.

[Clinical and gastroscopic features of children with cyclic vomiting syndrome: an analysis of 63 cases]. / 儿童周期性呕吐综合征63例临床与胃镜分析.

OBJECTIVES: To study the clinical and gastroscopic features of children with cyclic vomiting syndrome. METHODS: A retrospective analysis was performed on the medical data of 63 children with cyclic vomiting syndrome who were hospitalized and followed up in Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University from August 2019 to March 2022. RESULTS: Among the 63 children, there were 30 boys and 33 girls, with a mean age of 6.11 years, a mean course of disease of 2.57 years, and a mean vomiting period of 4.04 days. The most common accompanying symptom was listlessness or somnolence (55/63, 87%), followed by anorexia (45/63, 71%), abdominal pain or abdominal discomfort (40/63, 63%), constipation (19/63, 30%), salivation (12/63, 19%), nausea (11/63, 17%), headache (11/63, 17%), fever (6/63, 10%), and rash (1/63, 2%). All 63 children underwent gastroscopy, among whom 3 had no marked abnormalities, 22 (35%) had chronic superficial gastritis or chronic non-atrophic gastritis alone, and 38 (60%) had other abnormal changes aside from chronic gastritis (16 children with reflux esophagitis, 12 with bile reflux gastritis, 13 with duodenitis, 10 with erosive gastritis, and 5 with gastric or duodenal ulcer). Among the 63 children, 42 underwent pathological examinations of gastric mucosa, among whom 5 had no marked abnormalities, 34 had mild chronic gastritis, 2 had moderate chronic gastritis, and 1 had severe chronic gastritis. Among the 63 children, 15 received 24-hour dynamic esophageal pH monitoring during the interictal period, among whom 9 children were found to have pathological acid reflux. CONCLUSIONS: In addition to recurrent vomiting, most children with cyclic vomiting syndrome also have the symptoms such as somnolence or listlessness, anorexia, and abdominal pain. The main manifestation on gastroscopy is chronic gastritis, and most children may also have reflux esophagitis, bile reflux gastritis, and erosive gastritis. Mild chronic gastritis is the main pathological change of gastric mucosa.

Obesity and its effects on the esophageal mucosal barrier.

Obesity is associated with gastroesophageal reflux disease (GERD) and its complications including reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Traditionally, these associations have been attributed to the mechanical effect of abdominal fat in increasing intra-abdominal pressure, thereby promoting gastroesophageal reflux and causing disruption of antireflux mechanisms at the esophagogastric junction. However, recent studies suggest that visceral adipose tissue (VAT) produces numerous cytokines that can cause esophageal inflammation and impair esophageal mucosal barrier integrity through reflux-independent mechanisms that render the esophageal mucosa especially susceptible to GERD-induced injury. In this report, we review mechanisms of esophageal mucosal defense, the genesis and remodeling of visceral adipose tissue during obesity, and the potential role of substances produced by VAT, especially the VAT that encircles the esophagogastric junction, in the impairment of esophageal mucosal barrier integrity that leads to the development of GERD complications.

The Impact of Erosive Reflux Esophagitis on the Decline of Lung Function in the General Population.

BACKGROUND: The impact of reflux esophagitis on the decline of lung function has been rarely reported. This study was performed to evaluate the association between erosive reflux esophagitis and lung function changes. METHODS: We included patients with normal lung function who underwent esophagogastroduodenoscopy for health screening from a health screening center. Patients with persistent erosive reflux esophagitis on two discrete endoscopic examinations were designated as the erosive reflux esophagitis group. We also selected patients without erosive reflux esophagitis and matched them 1:4 with patients from the erosive reflux esophagitis group. We estimated annual forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) changes from baseline and compared these estimates by the linear mixed regression model. We also estimated the biannual incidence of chronic obstructive pulmonary disease (COPD). RESULTS: In total, 1,050 patients (210 patients with erosive reflux esophagitis, and 840 matched controls) were included. The median follow-up duration for spirometry was six years. In patients with erosive reflux esophagitis, mild reflux esophagitis (A grade) was most common (165 patients, 78.6%). The adjusted annual FEV1 change in patients with erosive reflux esophagitis was -51.8 mL/yr, while it decreased by 46.8 mL/yr in controls (P = 0.270). The adjusted annual FVC decline was similar between the two groups (-55.8 vs. -50.5 mL/yr, P = 0.215). The estimated COPD incidence during the follow-up period was not different between the erosive reflux esophagitis and control groups. CONCLUSION: In patients with normal lung function, the presence of erosive reflux esophagitis did not affect the annual declines in FEV1 or FVC.

Factors affecting the treatment outcomes of laparoscopic fundoplication for erosive reflux esophagitis: findings of esophageal pathological function tests.

PURPOSE: To identify the factors that affect laparoscopic fundoplication (LF) treatment efficacy in patients with erosive gastroesophageal reflux disease (e-GERD) esophagitis, based on the findings of multichannel intraluminal impedance pH (MII-pH) and high-resolution manometry (HRM). METHODS: The subjects were 102 patients with e-GERD diagnosed by endoscopy, who underwent LF as the initial surgery. To analyze the findings of MII-pH and HRM, the patients were divided into two groups: a cured group (CR), comprised of patients whose esophagitis was cured postoperatively; and a recurrence group (RE), comprised of patients who suffered recurrent esophagitis. RESULTS: There were 96 patients in the CR group and 6 in the RE group. MII-pH indicated that the acid reflux time, the longest reflux time, and the number of refluxes longer than 5 min, were significantly higher in the RE group than in the CR group (p = 0.0028, p = 0.0008, p = 0.012, respectively). The HRM indicated that only the distal contractile integral (DCI) was significantly lower in the RE group (p = 0.0109). CONCLUSION: The results of this study indicate that esophageal clearance may affect the treatment outcome of LF. Based on the findings of MII-pH, the longest reflux time and the number of refluxes longer than 5 min were important factors influencing the therapeutic effect, whereas based on the HRM, the DCI value was most important.

Localization of Helicobacter pylori gastritis and the relation of existing histopathological features with reflux esophagitis.

Background/aims: Interactions between Helicobacter pylori (Hp) and gastroesophageal reflux disease (GERD), which are common diseases worldwide, are confusing. In this study, the aim was to compare and evaluate the relationship between reflux esophagitis (RE) and Hp infection in adult patients with both the gastric localization of Hp and its histopathologic features.Materials and methods: 248 patients with RE were compared with 249 age and sex matched control groups. Biopsy specimens obtained from the gastric antrum and corpus were histologically evaluated.Findings: The incidence of Hp infection was significantly lower in patients with RE than in the control group (Ratio 1.53, 95% CI 1.07-2.20; p = .02, p < .05). Corpus Hp colonization and corpus gastritis scores were notably lower in the study group (p = .01, p < .05), whereas there was no significant difference in Hp colonization and antrum gastritis scores in the antrum. Corpus Hp colonization and gastritis scores were found to be negatively correlated with esophagitis development (r = -0.11; p = .01; (r = -0.14; p = .00 respectively, p < .05). There was no difference between the groups in terms of atrophy development (p > .05).Conclusion: This study showed that the presence of Hp infection in the corpus and corpus gastritis score was significantly lower in patients with erosive reflux esophagitis than in the control group. It also showed that Hp colonization and corpus gastritis scores were negatively correlated with esophagitis development. This inverse relationship was independent of atrophy.

Efficacy of Vonoprazan for 48-Week Maintenance Therapy of Patients with Healed Reflux Esophagitis.

AIMS: We aimed to evaluate the efficacy of vonoprazan (VPZ) as maintenance therapy for healed reflux esophagitis (RE). METHODS: We enrolled 74 patients diagnosed with RE with frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) total score ≥8 after at least 8 weeks of treatment with standard proton pump inhibitors (PPIs). These patients were switched to VPZ 20 mg for 4 weeks. We also enrolled 71 patients with no endoscopic evidence of erosive esophagitis who received maintenance therapy with VPZ 10 mg for 48 weeks. The primary end point was the proportion of patients who maintained healed RE refractory to PPIs after 48 weeks of maintenance therapy with on demand 10 mg VPZ. Secondary assessment included the proportion of patients with symptomatic nonrelapse at 48 weeks. RESULTS: Fifty patients successfully completed 48-week maintenance therapy. Maintenance therapy with VPZ 10 mg prevented the relapse of esophageal mucosal breaks in 43 (86.0%) of 50 patients at 48 weeks. During the 48-week maintenance therapy, symptomatic nonrelapse rate for acid reflux-related symptom score of FSSG and acid reflux score of Gastrointestinal Symptom Rating Scale at 48 weeks were 70.0 and 72.0%, respectively. No serious adverse events were reported during the study. CONCLUSION: VPZ 10 mg is clinically effective for maintenance of healed RE for 48 weeks.

[DIAGNOSTIC EFFICIENCY OF THE USE OF A MAGNIFYING CHROMOENDOSCOPY WHEN EXAMINING THE ORAL CAVITY IN PATIENTS WITH A GASTROENTEROLOGICAL PROFILE WITH EXTRAESOPHAGEAL MANIFESTATIONS OF REFLUX DISEASE].

The article is devoted to the study of the diagnostic effectiveness of using magnifying chromoendoscopy when examining the oral cavity in patients with a gastroenterological profile with extra-esophageal manifestations of reflux disease. Pathologies of the oral cavity are often one of the additional symptoms, according to the Montreal Consensus and classification of gastroesophageal reflux disease (GERD). Barrett's esophagus is a serious complication of GERD, in which a cylindrical epithelium with intestinal metaplasia is found in the epithelial lining of the mucous membrane of the esophagus, which is a marker of this disease often in combination with dysplasia instead of squamous stratified non-keratinized epithelium. The relevance is due to the fact that this disease is considered as a precancerous condition and is associated with an increased risk of developing adenocarcinoma of the lower third of the esophagus. In this regard, timely diagnosis of Barrett's esophagus and monitoring of these patients will improve the prognosis of the disease and reduce the frequency of deaths.

Esophagitis in Pediatric Esophageal Atresia: Acid May Not Always Be the Issue.

OBJECTIVE: Esophagitis is highly prevalent in patients with esophageal atresia (EA). Peptic esophagitis has long been assumed to be the primary cause of esophagitis in this population, and prolonged acid suppressive medication usage is common; such treatment is of unknown benefit and carries potential risk. METHODS: To better understand the role of commonly used antireflux treatments in EA, we analyzed all patients with repaired EA who underwent endoscopy with biopsies at our institution between January 2016 and August 2018. Macroscopic erosive and histologic esophagitis on biopsy was graded per predefined criteria. Clinical characteristics including acid suppressive medication usage, type of EA and repair, presence of hiatal hernia, and history of fundoplication were reviewed. RESULTS: There were 310 unique patients (33.5% long gap EA) who underwent 576 endoscopies with biopsies during the study period. Median age at endoscopy was 3.7 years (interquartile range 21-78 months). Erosive esophagitis was found in 8.7% of patients (6.1% of endoscopies); any degree of histologic eosinophilia (≥1 eosinophil/high power field [HPF]) was seen in 56.8% of patients (48.8% of endoscopies), with >15 eosinophils/HPF seen in 15.2% of patients (12.3% of endoscopies). Acid suppression was common; 86.9% of endoscopies were preceded by acid suppressive medication use. Fundoplication had been performed in 78 patients (25.2%). Proton pump inhibitor (PPI) and/or H2 receptor antagonist (H2RA) use were the only significant predictors of reduced odds for abnormal esophageal biopsy (P = 0.011 for PPI, P = 0.048 for H2RA, and P = 0.001 for PPI combined with H2RA therapy). However, change in intensity of acid suppressive therapy by either dosage or frequency was not significantly associated with change in macroscopic erosive or histologic esophagitis (P > 0.437 and P > 0.13, respectively). Presence or integrity of a fundoplication was not significantly associated with esophagitis (P = 0.236). CONCLUSIONS: In EA patients, acid suppressive medication therapy is associated with reduced odds of abnormal esophageal biopsy, though histologic esophagitis is highly prevalent even with high rates of acid suppressive medication use. Esophagitis is likely multifactorial in EA patients, with peptic esophagitis as only one of multiple possible etiologies for esophageal inflammation. The clinical significance of histologic eosinophilia in this population warrants further investigation.

Bacterial species and total bacterial load in the distal oesophagus in patients with and without clinical gastric reflux.

AIMS: The purpose of this study is to compare distal oesophagus of persons with and without gastric reflux in terms of bacterial load and presence of certain bacterial species. METHODS AND RESULTS: Two biopsy specimens were obtained from the distal oesophagus at 5 cm above the gastroesophageal junction of each of the 50 patients (20 with normal oesophagus and 30 with reflux oesophagitis) under endoscopic examination and used for histological examination and DNA isolation. We used a real-time PCR-based assay to quantify the bacterial load and the presence of certain bacterial species from one of the biopsy samples. The biopsy specimens taken from the patients with reflux oesophagitis were consistent with gastroesophageal reflux disease (GERD). The bacterial load did not significantly differ between the groups (P < 0·005). CONCLUSION: While there was no difference between the bacterial load in the two groups, variation was observed in bacterial species. Most of the bacteria identified in distal oesophagus of the patients with gastroesophageal reflux were Gram negative. SIGNIFICANCE AND IMPACT OF THE STUDY: The human oesophagus was considered sterile until quite recently. Molecular techniques displayed the presence of a diverse bacterial species in the oesophagus. Although it is known that dysbiosis in the oesophagus causes GERD, and that Barrett's oesophagus can trigger the development of oesophageal adenocarcinoma, its etiopathogenesis is not clear. A limited number of published studies support the importance of the present study.

Comparison of Clinical Characteristics of Patients with Acute Esophageal Mucosal Lesion and those with Severe Reflux Esophagitis.

BACKGROUND: The term "acute esophageal mucosal lesion (AEML)" includes black esophagitis, and non-black esophagitis characterized by diffuse circumferential erosions without black-appearing mucosa. Black esophagitis is easily diagnosed, whereas non-black esophagitis is often misdiagnosed as severe reflux esophagitis (sRE). The aim of this study was to determine differences in clinical characteristics of patients with AEML and those with sRE. METHODS: Thirty-nine patients with sRE and 32 patients with AEML were diagnosed on the basis of endoscopic findings from 2009 to 2016. Characteristics assessed included age, sex, medication use, coexisting endoscopic finding, comorbidities, laboratory tests results, and chief complaints. RESULTS: In contrast with sRE, male sex, need for emergency endoscopy, presence of duodenal lesions, hypertension, and renal dysfunction were positively associated with AEML. Analysis of associations between laboratory data and AEML showed that high white blood cell count, blood urea nitrogen, and blood glucose were significantly associated with an increase OR for AEML. CONCLUSIONS: We showed that AEML differed from sRE regarding both endoscopic findings and clinicopathological features. AEML has not been widely recognized, but it should be defined as a distinct inflammatory disease of the esophagus consisting of both black and non-black esophagitis.

Pattern of oesophageal diseases in Madinah region, Saudi Arabia: An 11 years experience.

The oesophagus can be a site for a variety of lesions including inflammatory disorders, infections, mechanical conditions, toxic and physical injuries, vascular disorders and neoplastic conditions. hence the oesophageal diseases have a wide spectrum of pathological features. An understanding of histopathological details of oesophageal diseases is essential for their accurate diagnosis and management. The main objective of our study was to provide a comprehensive audit of oesophageal diseases in the province of Madinah in Saudi Arabia. From January 2006 to December 2017, were viewed the histopathological patterns of oesophageal lesions in patients at a tertiary care referral hospital who were diagnosed with oesophageal disease after upper gastroendoscopy. Of the 201 patients, 144 (71.6%) cases were found to be non-neoplastic and 57 (28.4%) cases were neoplastic. Our findings were comparable with earlier studies that helped establish a baseline of an oesophageal disease pattern, on the basis of histopathological examinations.

Effect of Low-Dose Aspirin on Chronic Acid Reflux Esophagitis in Rats.

BACKGROUND: Clinical role of low-dose aspirin (LDA) in pathogenesis of gastroesophageal reflux disease is by far controversial. This can be attributed to the paucity of basic research detailing the mechanism of LDA-induced esophageal mucosal injury (EI) on underlying chronic acid reflux esophagitis (RE). AIM: The aim of this study was to clarify the effect of LDA on chronic RE in rats. METHODS: Esophagitis was induced in 8-week-old male Wistar rats by ligating the border between forestomach and glandular portion with a 2-0 silk tie and covering the duodenum with a small piece of 18-Fr Nélaton catheter. Seventy-eight chronic RE rat models were divided into five treatment groups, consisting of orally administered vehicle (controls), and aspirin doses of 2, 5, 50 or 100 mg/kg once daily for 28 days. EI was assessed by gross area of macroscopic mucosal injury, severity grade of esophagitis and microscopic depth of infiltration by inflammatory cells. RESULTS: Area of esophagitis in animals with aspirin dose of 100 mg/kg/day showed a 36.5% increase compared with controls, although it failed to achieve statistical significance (p = 0.812). Additionally, the rate of severe EI was increased in animals with aspirin dose of 100 mg/kg/day as compared with controls (p < 0.05). The grade of severity correlated with the depth of inflammation (r s = 0.492, p < 0.001). CONCLUSIONS: Maximal dose aspirin (100 mg/kg/day) contributed in exacerbating preexisting EI. LDA (2 and 5 mg/kg/day), on the other hand, did not affect chronic RE in this model. LDA seems to be safe for use in patients with chronic RE.

Estrogen-Dependent Nrf2 Expression Protects Against Reflux-Induced Esophagitis.

BACKGROUND: Gastroesophageal reflux disease is more common in males than in females. The enhanced antioxidative capacity of estrogen in females might account for the gender difference. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the host defense mechanism against oxidative stress. AIMS: This study aimed to clarify the role of Nrf2 in reflux-induced esophageal inflammation, focusing on the gender difference and nitric oxide. METHODS: Gastroesophageal reflux was surgically induced in male and female rats. Nitrite and ascorbic acid were administered for 1 week to provoke nitric oxide in the esophageal lumen. Male rats with gastroesophageal reflux were supplemented with 17ß-estradiol or tert-butylhydroquinone, an Nrf2-inducing reagent. Esophageal squamous cell carcinoma KYSE30 cells were treated with 17ß-estradiol. Nrf2 expression was examined by Western blotting and quantitative real-time PCR. Antioxidant gene expression profiles were examined by a PCR array. RESULTS: In the presence of nitric oxide, reflux-induced esophageal damage was less evident, whereas esophageal expression of Nrf2 and its target genes such as Nqo1 was more evident in female or male rats supplemented with 17ß-estradiol than in male rats. 17ß-Estradiol increased nuclear Nrf2 expression in KYSE30 cells. tert-Butylhydroquinone increased tissue Nqo1 mRNA expression, leading to a reduction in reflux-induced esophageal damage. CONCLUSIONS: Estrogen-dependent Nrf2 expression might contribute to protection against the development of gastroesophageal reflux disease in females.

Dichloromethane Extracts of Geranium Koreanum Kom. Alleviates Esophagus Damage in Acute Reflux Esophagitis-Induced Rats by Anti-Inflammatory Activities.

Reflux esophagitis (RE) is a gastrointestinal disease caused by the reflux of gastric acid and stomach contents, and it leads to esophageal damage. Therefore, it is necessary to study the improvement of esophageal damage on a RE-induced model. The present study was accomplished to demonstrate the protective effects of a dichloromethane fraction of Geranium koreanum (DGK) plant on esophageal damage in an acute RE rat model. First, we examined the potential of anti-inflammatory effects of various fractions measured by cell cytotoxicity, morphological changes and nitric oxide (NO) production on lipopolysaccharide (LPS)-induced Raw 264.7 macrophage cells. Then, to evaluate the protective effects on RE, rats were partitioned into the following groups: normal control, RE-induced control and RE rats pre-treated with DGK 100 and 200 mg/kg body weight. The esophageal mucosal ulcer ratio was measured by the Image J program and histological changes were examined using a hematoxylin and eosin staining of the esophageal mucosa. The expression of pro-inflammatory proteins, cytokines and tight junction proteins involved in the esophageal mucosal damage were investigated using Western blotting and an enzyme-linked immunosorbent assay (ELISA) kit with esophagus tissue. DGK chemical profile and phenolic contents were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). The results showed that DGK exhibited anti-inflammatory effects against LPS-stimulated cells by significantly inhibiting NO production. Additionally, the results in vivo showed that improvement effects of DGK on esophageal mucosal damage. The expression of inflammatory proteins involved in nuclear factor κB (NF-κB) signaling pathways and tight junction protein (claudin-4 and -5) were significantly decreased in esophageal mucosa. We found the potential of DGK as source of replacement therapy products for inflammatory and RE disease.

Hypoxia-inducible factor-2α plays a role in mediating oesophagitis in GORD.

OBJECTIVE: In an earlier study wherein we induced acute reflux by interrupting proton pump inhibitor (PPI) therapy in patients with reflux oesophagitis (RO) healed by PPIs, we refuted the traditional concept that RO develops as an acid burn. The present study explored our alternative hypothesis that RO results from reflux-stimulated production of pro-inflammatory molecules mediated by hypoxia-inducible factors (HIFs). DESIGN: Using oesophageal biopsies taken from patients in our earlier study at baseline and at 1 and 2 weeks off PPIs, we immunostained for HIF-1α, HIF-2α and phospho-p65, and measured pro-inflammatory molecule mRNAs. We exposed human oesophageal squamous cell lines to acidic bile salts, and evaluated effects on HIF activation, p65 function, pro-inflammatory molecule production and immune cell migration. RESULTS: In patient biopsies, increased immunostaining for HIF-2α and phospho-p65, and increased pro-inflammatory molecule mRNA levels were seen when RO redeveloped 1 or 2 weeks after stopping PPIs. In oesophageal cells, exposure to acidic bile salts increased intracellular reactive oxygen species, which decreased prolyl hydroxylase function and stabilised HIF-2α, causing a p65-dependent increase in pro-inflammatory molecules; conditioned media from these cells increased T cell migration rates. HIF-2α inhibition by small hairpin RNA or selective small molecule antagonist blocked the increases in pro-inflammatory molecule expression and T cell migration induced by acidic bile salts. CONCLUSIONS: In patients developing RO, increases in oesophageal HIF-2α correlate with increased pro-inflammatory molecule expression. In oesophageal epithelial cells, acidic bile salts stabilise HIF-2α, which mediates expression of pro-inflammatory molecules. HIF-2α appears to have a role in RO pathogenesis. TRIAL REGISTRATION NUMBER: NCT01733810; Results.

A novel murine model of esophageal nonerosive reflux disease: from inflammation to impairment in mucosal integrity.

Nonerosive reflux disease (NERD) is a highly prevalent phenotype of the gastroesophageal reflux disease. In this study, we developed a novel murine model of NERD in mice with microscopic inflammation and impairment in the epithelial esophageal barrier. Female Swiss mice were subjected to the following surgical procedure: the transitional region between the forestomach and the glandular portion of the stomach was ligated, and a nontoxic ring was placed around the duodenum near the pylorus. The control group underwent sham surgery. The animals were euthanized at 1, 3, 7, and 14 days after surgery. Survival and body weight were monitored daily. Esophageal wet weight, macroscopic lesion, histopathological alterations, myeloperoxidase (MPO) activity, cytokine levels, transepithelial electrical resistance (TEER), and mucosal permeability were evaluated. The survival rate was 78% at 14 days, with mild loss in body weight. Surgery did not induce erosive esophagitis but instead induced microscopic inflammation and increased esophageal wet weight, IL-6, keratinocyte-derived cytokine (KC) levels, and MPO activity with maximal peak between 3 and 7 days and resolution at 14 days postsurgery. Epithelial esophageal barrier was evaluated in operated mice at 7 and 14 days postsurgery; a decrease in TEER and increase in the esophageal epithelial permeability were observed compared with the sham-operated group. In addition, the inhibition of acid secretion with omeprazole significantly prevented the esophageal inflammation and impairment of barrier function at 7 days postsurgery. Thus we established a novel experimental model of NERD in mice, which can contribute to understanding the pathophysiological events associated with NERD.NEW & NOTEWORTHY In this study, we standardized an experimental model of nonerosive reflux disease (NERD) in mice. This model involves an acute inflammatory response followed by impaired esophageal mucosal integrity, even in the absence of inflammation. Thus this model can serve for evaluation of pathophysiological aspects of NERD and open new perspectives for therapeutic strategies for patients with this disorder.

Gastroesophageal flap valve reflected EGJ morphology and correlated to acid reflux.

OBJECTIVE: The anatomy of esophagogastric junction (EGJ) serves as the anti-reflux barrier. The gastroesophageal flap valve (GEFV) is a component of EGJ. The aim of the current study was to assess its correlation with the esophageal acid exposure and the impact on anti-reflux barrier function by using the metrics of EGJ contraction. METHODS: Eighty three patients with typical GERD symptoms were included in the study. Upper endoscopy, high-resolution manometry (HRM) and 24 h multichannel intraluminal impedance-pH (MII-pH) monitoring were performed in all patients. GEFV was determined as four grades during endoscopic examination based on the Hill classification. The esophageal pressure topography (EPT) metrics defined in the updated Chicago Classification were measured by HRM, including integrated relaxation pressure (IRP), EGJ contractile index (EGJ-CI),expiratory EGJ pressure(EGJP-exp) and inspiratory EGJ pressure (EGJP-insp). RESULTS: The GEFV grade III and IV was more commonly found in patients with esophagitits (p < 0.05). The acid exposure time (AET%) and supine AET% were lower in patients with GEFV grade I (p < 0.01). There was weak correlation between AET% and GEFV grades (r = 0.27, p = 0.013). There were more EGJ morphology type III in patients with GEFV grade IV (p < 0.05).There were no significant differences on the values of four HRM metrics among the patients with different GEFV grades (p > 0.05). CONCLUSION: The GEFV grades were associated with acid reflux positively and could be a good reflection of EGJ morphology in HRM. But it had no impact on the four HRM metrics. Our research revealed that GEFV may play an assistant role in the anti-reflux barrier.

Transoral fundoplication offers durable symptom control for chronic GERD: 3-year report from the TEMPO randomized trial with a crossover arm.

BACKGROUND: Four randomized controlled trials have demonstrated the short-term efficacy and safety of transoral esophagogastric fundoplication (TF) performed with the EsophyX® device in eliminating troublesome gastroesophageal reflux disease (GERD) symptoms in well-selected patient populations. The aim of this study was to assess the durability of these outcomes at 3 years post-procedure. METHODS: The TF EsophyX versus Medical PPI Open Label trial was conducted in seven US sites. Between June and August 2012, we enrolled patients with small (<2 cm) or absent hiatal hernias who suffered from troublesome GERD symptoms while on PPI therapy for at least 6 months and had abnormal esophageal acid exposure (EAE). Randomization was to TF group (n = 40) or to PPI group (n = 23). Following evaluation at 6 months, all remaining PPI patients (n = 21) elected to undergo crossover to TF. Fifty-two patients were assessed at 3 years for (1) GERD symptom resolution using three GERD-specific quality of life questionnaires, (2) healing of esophagitis using endoscopy, (3) EAE using 48-h Bravo testing, and (4) discontinuation of PPI use. Two patients who underwent revisional procedures by year 3 were included in the final analysis. RESULTS: At 3-year follow-up, elimination of troublesome regurgitation and all atypical symptoms was reported by 90 % (37/41) and 88 % (42/48) of patients, respectively. The mean Reflux Symptom Index score improved from 22.2 (9.2) on PPIs at screening to 4 (7.1) off PPIs 3 years post-TF, p < 0.0001. The mean total % time pH <4 improved from 10.5 (3.5) to 7.8 (5.7), p = 0.0283. Esophagitis was healed in 86 % (19/22) of patients. At the end of study, 71 % (37/52) of patients had discontinued PPI therapy. All outcome measures remained stable between 1-, 2-, and 3-year follow-ups. CONCLUSION: This study demonstrates that TF can be used to achieve long-term control of chronic GERD symptoms, healing of esophagitis, and improvement in EAE.