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Patients who have esophageal eosinophilia without gastroesophageal reflux disease (GERD) nevertheless can respond to proton pump inhibitors (PPIs), which can have anti-inflammatory actions independent of effects on gastric acid secretion. In esophageal cell cultures, omeprazole has been reported to inhibit Th2 cytokine-stimulated expression of eotaxin-3, an eosinophil chemoattractant contributing to esophageal eosinophilia in eosinophilic esophagitis (EoE). The objective of this study was to elucidate molecular mechanisms underlying PPI inhibition of IL-4-stimulated eotaxin-3 production by esophageal cells. Telomerase-immortalized and primary cultures of esophageal squamous cells from EoE patients were treated with IL-4 in the presence or absence of acid-activated omeprazole or lansoprazole. We measured eotaxin-3 protein secretion by ELISA, mRNA expression by PCR, STAT6 phosphorylation and nuclear translocation by Western blotting, eotaxin-3 promoter activation by an exogenous reporter construct, and STAT6, RNA polymerase II, and trimethylated H3K4 binding to the endogenous eotaxin-3 promoter by ChIP assay. Omeprazole in concentrations ≥5 µM significantly decreased IL-4-stimulated eotaxin-3 protein secretion and mRNA expression. Lansoprazole also blocked eotaxin-3 protein secretion. Omeprazole had no effect on eotaxin-3 mRNA stability or on STAT6 phosphorylation and STAT6 nuclear translocation. Rather, omeprazole blocked binding of IL-4-stimulated STAT6, RNA polymerase II, and trimethylated H3K4 to the eotaxin-3 promoter. PPIs, in concentrations achieved in blood with conventional dosing, significantly inhibit IL-4-stimulated eotaxin-3 expression in EoE esophageal cells and block STAT6 binding to the promoter. These findings elucidate molecular mechanisms whereby patients with Th2 cytokine-driven esophageal eosinophilia can respond to PPIs, independent of effects on gastric acid secretion.

ObjectiveAlthough perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn’s disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD.DesignMale and female mice with inducible intestinal epithelial cell deletion of Phb1 (Phb1iΔIEC ) or Paneth cell-specific deletion of Phb1 (Phb1ΔPC ) and Phb1fl/fl control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1iΔIEC or Phb1ΔPC mice.Results Phb1iΔIEC mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1iΔIEC ileum. Deletion of Phb1 specifically in Paneth cells (Phb1ΔPC ) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1iΔIEC or Phb1ΔPC mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo.ConclusionOur results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn’s disease patients exhibiting Paneth cell defects.

Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, and are widely regarded as the agents of choice for the treatment of acid-peptic disorders. For patients with upper gastrointestinal symptoms of uncertain etiology, improvement with PPI therapy is considered prima facie evidence of a pathogenetic role for acid-peptic disease. In addition to anti-secretory effects, however, PPIs have been found to have anti-oxidant properties and direct effects on neutrophils, monocytes, endothelial, and epithelial cells that might prevent inflammation. Those anti-inflammatory effects of the PPIs might influence a variety of inflammatory disorders, both peptic and non-peptic, within and outside of the gastrointestinal tract. The purpose of this report is to review the mechanisms whereby PPIs might exert anti-inflammatory effects exclusive of gastric acid inhibition, to discuss the clinical implications of those effects, and to emphasize that a clinical response to PPIs should not be construed as proof for an underlying acid-peptic disorder.

Although most studies on treatments for eosinophilic esophagitis (EoE) have focused on effects in the epithelium, EoE is a transmural disease. Eosinophils that infiltrate the subepithelial layers of the esophagus lead to fibrosis and the serious complications of EoE, and current therapies have shown minimal effects on this fibrosis. We aimed to elucidate T helper (Th)2 cytokine effects on esophageal fibroblasts and to explore potential fibroblast-targeted therapies for EoE. We established telomerase-immortalized fibroblasts from human esophageal biopsies. We stimulated these esophageal fibroblasts with Th2 cytokines, and examined effects of omeprazole and inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT6) pathway (AS1517499, leflunomide, and ruxolitinib) on STAT6 phosphorylation, STAT6 nuclear translocation, and eotaxin-3 expression. We also measured the effects of these inhibitors in esophageal epithelial cells stimulated with Th2 cytokines. As in esophageal epithelial cells, Th2 cytokines increased STAT6 phosphorylation, STAT6 nuclear translocation, eotaxin-3 transcription and protein secretion in esophageal fibroblasts. Unlike in epithelial cells, however, omeprazole did not inhibit cytokine-stimulated eotaxin-3 expression in fibroblasts. In contrast, JAK-STAT6 pathway inhibitors decreased cytokine-stimulated eotaxin-3 expression in both fibroblasts and epithelial cells. Omeprazole does not inhibit Th2 cytokine-stimulated eotaxin-3 expression by esophageal fibroblasts, suggesting that PPIs will have limited impact on subepithelial EoE processes such as fibrosis. JAK-STAT6 pathway inhibitors block Th2 cytokine-stimulated eotaxin-3 expression both in fibroblasts and in epithelial cells, suggesting a potential role for JAK-STAT inhibitors in treating both epithelial inflammation and subepithelial fibrosis in EoE.

Recent data suggest that the interaction between gastroesophageal reflux disease (GERD) and eosinophilic esophagitis can be complex, and that the notion of establishing a clear distinction between the two disorders may be too simplistic. There are at least four situations in which GERD might be associated with esophageal eosinophils: (a) GERD causes esophageal injury that results in a mild eosinophilic infiltration, (b) GERD and eosinophilic esophagitis coexist but are unrelated, (c) eosinophilic esophagitis contributes to or causes GERD, or (d) GERD contributes to or causes eosinophilic esophagitis. The high frequency of GERD described in adult patients with eosinophilic esophagitis suggests that there may be more than a chance association between the two disorders. This report discusses potential mechanisms for the complex interaction between GERD and eosinophilic esophagitis. We hope that this information will serve as a conceptual basis for future studies on the relationship between the two disorders. Whereas there are a number of plausible mechanisms whereby GERD might contribute to the accumulation of eosinophils in the esophageal epithelium, it seems prudent to recommend a clinical trial of proton pump inhibitor (PPI) therapy even when the diagnosis of eosinophilic esophagitis seems clear-cut. Furthermore, we suggest that a favorable response to PPI therapy does not preclude a diagnosis of eosinophilic esophagitis.

Autophagy of damaged mitochondria, called mitophagy, is an important organelle quality control process involved in the pathogenesis of inflammation, cancer, aging, and age-associated diseases. Many of these disorders are associated with altered expression of the inner mitochondrial membrane (IMM) protein Prohibitin 1. The mechanisms whereby dysfunction occurring internally at the IMM and matrix activate events at the outer mitochondrial membrane (OMM) to induce mitophagy are not fully elucidated. Using the gastrointestinal epithelium as a model system highly susceptible to autophagy inhibition, we reveal a specific role of Prohibitin-induced mitophagy in maintaining intestinal homeostasis. We demonstrate that Prohibitin 1 induces mitophagy in response to increased mitochondrial reactive oxygen species (ROS) through binding to mitophagy receptor Nix/Bnip3L and independently of Parkin. Prohibitin 1 is required for ROS-induced Nix localization to mitochondria and maintaining homeostasis of epithelial cells highly susceptible to mitochondrial dysfunction.

The authors provide a state-of-the-art review of the epidemiology, pathogenesis, and natural history of Barrett's esophagus and management options for the disorder. It has been estimated that 5.6% of adults in the United States have Barrett's esophagus, 1 the condition in which a metaplastic columnar mucosa that confers a predisposition to cancer replaces an esophageal squamous mucosa damaged by gastroesophageal reflux disease (GERD). 2 GERD and Barrett's esophagus are major risk factors for esophageal adenocarcinoma, a deadly tumor whose frequency in the United States has increased by a factor of more than 7 during the past four decades. 3 , 4 The metaplastic columnar mucosa of Barrett's esophagus causes no symptoms, and the condition has clinical importance only because it confers a predisposition to cancer. Pathogenesis . . .

GATA4 promotes columnar epithelial cell fate during gastric development. When ectopically expressed in the developing mouse forestomach, the tissue emerges as columnar-like rather than stratified squamous with gene expression changes that parallel those observed in the pre-malignant squamous to columnar metaplasia known as Barrett’s esophagus (BE). GATA4 mRNA up-regulation and gene amplification occur in BE and its associated cancer, esophageal adenocarcinoma (EAC), and GATA4 gene amplification correlates with poor patient outcomes. Here, we explored the effect of ectopic expression of GATA4 in mature human esophageal squamous epithelial cells. We found that GATA4 expression in esophageal squamous epithelial cells compromised squamous cell marker gene expression and up-regulated expression of the canonical columnar cell cytokeratin KRT8 . We observed GATA4 occupancy in the p63 , KRT5 , and KRT15 promoters, suggesting that GATA4 directly represses expression of squamous epithelial cell marker genes. Finally, we verified GATA4 protein expression in BE and EAC and found that exposure of esophageal squamous epithelial cells to acid and bile, known BE risk factors, induced GATA4 mRNA expression. We conclude that GATA4 suppresses expression of genes marking the stratified squamous epithelial cell lineage and that this repressive action by GATA4 may have implications in BE and EAC.

Autophagy is an adaptive response to extracellular and intracellular stress by which cytoplasmic components and organelles, including damaged mitochondria, are degraded to promote cell survival and restore cell homeostasis. Certain genes involved in autophagy confer susceptibility to Crohn's disease. Reactive oxygen species and pro-inflammatory cytokines such as tumor necrosis factor α (TNFα), both of which are increased during active inflammatory bowel disease, promote cellular injury and autophagy via mitochondrial damage. Prohibitin (PHB), which plays a role in maintaining normal mitochondrial respiratory function, is decreased during active inflammatory bowel disease. Restoration of colonic epithelial PHB expression protects mice from experimental colitis and combats oxidative stress. In this study, we investigated the potential role of PHB in modulating mitochondrial stress-related autophagy in intestinal epithelial cells. We measured autophagy activation in response to knockdown of PHB expression by RNA interference in Caco2-BBE and HCT116 WT and p53 null cells. The effect of exogenous PHB expression on TNFα- and IFNγ-induced autophagy was assessed. Autophagy was inhibited using Bafilomycin A(1) or siATG16L1 during PHB knockdown and the affect on intracellular oxidative stress, mitochondrial membrane potential, and cell viability were determined. The requirement of intracellular ROS in siPHB-induced autophagy was assessed using the ROS scavenger N-acetyl-L-cysteine. TNFα and IFNγ-induced autophagy inversely correlated with PHB protein expression. Exogenous PHB expression reduced basal autophagy and TNFα-induced autophagy. Gene silencing of PHB in epithelial cells induces mitochondrial autophagy via increased intracellular ROS. Inhibition of autophagy during PHB knockdown exacerbates mitochondrial depolarization and reduces cell viability. Decreased PHB levels coupled with dysfunctional autophagy renders intestinal epithelial cells susceptible to mitochondrial damage and cytotoxicity. Repletion of PHB may represent a therapeutic approach to combat oxidant and cytokine-induced mitochondrial damage in diseases such as inflammatory bowel disease.

Barrett's esophagus (BE) is a common condition associated with chronic gastroesophageal reflux disease. BE is the only known precursor to esophageal adenocarcinoma, a highly lethal cancer with an increasing incidence over the last 5 decades. These revised guidelines implement Grading of Recommendations, Assessment, Development, and Evaluation methodology to propose recommendations for the definition and diagnosis of BE, screening for BE and esophageal adenocarcinoma, surveillance of patients with known BE, and the medical and endoscopic treatment of BE and its associated early neoplasia. Important changes since the previous iteration of this guideline include a broadening of acceptable screening modalities for BE to include nonendoscopic methods, liberalized intervals for surveillance of short-segment BE, and volume criteria for endoscopic therapy centers for BE. We recommend endoscopic eradication therapy for patients with BE and high-grade dysplasia and those with BE and low-grade dysplasia. We propose structured surveillance intervals for patients with dysplastic BE after successful ablation based on the baseline degree of dysplasia. We could not make recommendations regarding chemoprevention or use of biomarkers in routine practice due to insufficient data.