Question

Helicobacter pylori alters the expression of circadian clock components per2 and bmal1 during infection

Answer 1

The circadian clock plays a fundamental role in gastrointestinal (GI) physiology. Moreover, disruption of key components of the molecular oscillator that generates circadian rhythms, such as Per2 and Bmal1, promotes GI tumorigenesis. Glycogen synthase kinase-3β (GSK-3β), a known regulator of epithelial cell proliferation, also regulates PER2. Here we test the hypothesis that Helicobacter pylori (H. pylori)-induced epithelial cell proliferation is dependent on the inactivation of GSK-3β leading to the activation of BMAL1. In vivo, H. pylori induced a significant upregulation of BMAL1 expression within the gastric fundus of infected mice C57BL/6 that correlated with a significant increase in epithelial proliferation and the development of metaplasia. Bioluminescent gastric-derived organoids generated from PER2::LUCIFERASE (PER2::LUC) mice showed robust circadian rhythms. H. pylori infection of PER2::LUC mouse-derived gastric organoids resulted in decreased PER2::LUC activity. Robust circadian rhythmicity of clock genes BMAL1 and PER2 were observed in human fundic-derived gastric organoids (hFGOs). Phosphorylation (inactivation) of GSK-3β showed circadian changes in hFGOs over 52 hours. H. pylori infection of hFGOs resulted in sustained GSK-3β phosphorylation, increased BMAL1 protein expression and epithelial cell hyperproliferation when compared to uninfected controls. These results indicate that H. pylori alters the expression of circadian clock components during infection in association with epithelial cell hyperproliferation and metaplasia.

Answer 2

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