Stuart Spechler M.D.

Nelson, M.R., Zhang, X., Pan, Z., Spechler, S.J. and Souza, R.F. (2020). “Mast Cell Effects on Esophageal Smooth Muscle and their Potential Role in Eosinophilic Esophagitis and Achalasia.” Am J Physiol Gastrointest Liver Physiol Dec 23. [Epub ahead of print].

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Mast cells and eosinophils are the key effector cells of allergic disorders. Although most studies on eosinophilic esophagitis (EoE), an allergic disorder of the esophagus, have focused on the role of eosinophils, recent studies suggest a major role for mast cells in causing the clinical manifestations of this disease. Cellular and animal studies have demonstrated that mast cells can cause esophageal muscle cells to proliferate and differentiate into a more contractile phenotype, and that mediators released by degranulating mast cells such as tryptase and histamine can activate smooth muscle contraction pathways. Thus, activated mast cells in the esophageal muscularis propria might cause esophageal motility abnormalities, including the failure of lower esophageal sphincter relaxation typical of achalasia. In addition, mast cells have been implicated in the pathogenesis of a number of neurodegenerative disorders of the central nervous system such as Alzheimer’s and Parkinson’s diseases, because degranulating mast cells release pro-inflammatory and cytotoxic mediators capable of damaging neurons. Such mast cell degranulation in the myenteric plexus of the esophagus could cause the loss of enteric neurons that characterizes achalasia. In this report, we review the molecular mechanisms of esophageal smooth muscle contraction, and how mast cells products might affect that muscle and cause neurodegeneration in the esophagus. Based on these data, we present our novel, conceptual model for an allergy-induced form of achalasia mediated by mast cell activation in the esophageal muscularis propria

Ustaoglu, A., Nguyen, A., Spechler, S., Sifrim, D., Souza, R. and Woodland, P. (2020). “Mucosal pathogenesis in gastro-esophageal reflux disease.” Neurogastroenterol Motil Oct 28;e14022. [Epub ahead of print].

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BACKGROUND: Despite gastro-esophageal reflux disease affecting up to 20% of Western populations, relatively little is known about the molecular mechanisms underlying its most troublesome symptom: heartburn. Recent findings have unveiled the role of components of the esophageal mucosa in the pathogenesis of GERD including sensory nociceptive nerves and inflammatory mediators. Erosive esophagitis was long believed to develop as a result of acid injury at the esophageal lumen, but novel concepts suggest the generation of reflux-induced esophageal injury as a result of cytokine-mediated inflammation. Moreover, the localization and characterization of mucosal afferent nerves vary between GERD phenotypes and could explain the heterogeneity of symptom perception between patients who experience similar levels of acid reflux. PURPOSE: The purpose of this review is to consider the crosstalk of different factors of the esophageal mucosa in the pathogenesis of GERD, with a particular focus on mucosal innervation and molecular basis of acid-induced cytokine response. We discuss the current understanding of the mucosal response to acid injury, the nociceptive role of acid-sensitive receptors expressed in the esophageal mucosa, and the role of esophageal epithelial cells in initiating the onset of erosive esophagitis.

Spechler, S.J. (2020). “Evaluation and Treatment of Patients with Persistent Reflux Symptoms Despite Proton Pump Inhibitor Treatment.” Gastroenterol Clin North Am 49(3): 437-450

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Despite the exceptional efficacy of proton pump inhibitors (PPIs) in healing reflux esophagitis complicating gastroesophageal reflux disease (GERD), up to 40% of patients who take PPIs for GERD complain of persistent GERD symptoms. There is no clear consensus on the type, dosing, and duration of PPI therapy required to establish a diagnosis of PPI-refractory GERD symptoms, but most authorities do not consider patients “PPI-refractory” unless they have been on double-dose PPIs. This article discusses the mechanisms that might underlie heartburn that does not respond PPIs and an approach to the management of patients with PPI-refractory GERD symptoms.

Spechler, S. J. (2020). “Refractory Gastroesophageal Reflux Disease and Functional Heartburn.” Gastrointest Endosc Clin N Am 30(2): 343-359.

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This report discusses the potential mechanisms that might underlie refractory GERD and functional heartburn, and how to distinguish among those mechanisms using a systematic evaluation that includes careful medical history, endoscopy with esophageal biopsy, esophageal manometry, and esophageal multichannel intraluminal impedance-pH monitoring. The report provides an approach to patient management that depends on the underlying mechanism identified by this systematic evaluation.

Huo, X., K. B. Dunbar, X. Zhang, Q. Zhang, S. J. Spechler and R. F. Souza (2020). “In Barrett’s epithelial cells, weakly acidic bile salt solutions cause oxidative DNA damage with response and repair mediated by p38.” Am J Physiol Gastrointest Liver Physiol 318(3): G464-g478.

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The frequency of esophageal adenocarcinoma is rising despite widespread use of proton pump inhibitors (PPIs), which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett’s esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett’s cells. Because p53 is inactivated frequently in Barrett’s esophagus and p38 can assume p53 functions, we explored p38’s role in DNA damage response and repair. We exposed Barrett’s cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38 dependent. We also measured phospho-p38 in biopsies of Barrett’s metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced bromodeoxyuridine incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease I (Ref-1/APE1). Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All of these effects were observed in p53-intact and p53-deficient Barrett’s cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett’s metaplasia. WABM exposure generates ROS, causing oxidative DNA damage in Barrett’s cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett’s esophagus.NEW & NOTEWORTHY We found that weakly acidic bile salt solutions, with compositions similar to the refluxed gastric juice of gastroesophageal reflux disease patients on proton pump inhibitors, cause oxidative DNA damage in Barrett’s metaplasia that could contribute to the development of esophageal adenocarcinoma. We also have elucidated a critical role for p38 in Barrett’s metaplasia in its response to and repair of oxidative DNA damage, suggesting a potential chemopreventive role for agents like ursodeoxycholic acid that increase p38 activity in Barrett’s esophagus.