Helicobacter pylori Alters the Expression of Circadian Clock Components PER2 and BMAL1 During Infection

Abstract

BackgroundIndividuals with persistent Helicobacter pylori (H. pylori) infection are known to have an increased risk of gastric adenocarcinoma development. The circadian clock has been shown to be intimately involved in various gastrointestinal functions and clock components BMAL1 and PER2 have been found to be disrupted in colorectal cancer tissues. Aged individuals have a dampened expression of such components which may further increase their susceptibility to gastric cancer development.HypothesisPersistent infection of H. pylori induces an unregulated proliferation of gastric epithelial cells via activation of BMAL1 leading to a predisposition to gastric cancer development.MethodsGastric organoids (hFGOs) were generated from either primary gastric tissue derived from aged (> 55 years of age) and young (14–20 years) individuals. Gastric organoids were then infected with H. pylori. BMAL1 and PER2 expression was then quantified over a period of 24 hours. Proliferation and expression of gastric cancer markers were quantified by qRT‐PCR.ResultsH. pylori infection correlated with a significant upregulation of cytoplasmic BMAL1 expression within the gastric fundus of infected individuals. Robust circadian rhythmicity of clock genes Bmal1 and Per2 were observed in human hFGOs. Phosphorylation (inactivation) of GSK‐3b showed circadian changes in hFGOs over 52 hours. H. pylori infection of hFGOs resulted in sustained GSK‐3b phosphorylation, increased BMAL1 expression and epithelial cell hyperproliferation when compared to uninfected controls. Organoids derived from elderly patients exhibited a dampened rhythmicity of of clock genes Bmal1 and Per2. Dampened rhythmicity correlated with increased gastric cancer biomarkers of intestinal metaplasia including Cdx1, Cdx2 and MUC2.ConclusionsChronic H. pylori infection induces a hyperproliferative response in gastric epithelial cells by inactivating GSK‐3β leading to the activation of BMAL1:CLOCK. This may be a plausible mechanism that predisposes individuals with persistent H. pylori infection to gastric cancer development and also heightens this risk in aged individuals.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.