Abnormal Regeneration of the Gastric Epithelium May Result in Increased H. pylori‐Induced Gastric Disease in the Elderly

Abstract

BackgroundIncreased incidence of gastric ulcer disease is often related to frequent nonsteroidal anti‐inflammatory drug (NSAID) use and Helicobacter pylori (H. pylori) infection. Studies have shown H. pylori adheres to the gastric epithelium through binding of bacterial Sialic Acid‐binding Adhesin (SAbA) to glycosylated gastric epithelial mucin receptor sialyl‐Lewis X (S‐LewX). Our group has reported that CD44v9 emerges during repair of the gastric epithelium after injury where it is co‐expressed with markers of Spasmolytic Polypeptide/TFF2‐Expressing Metaplasia (SPEM), a reparative phenotype which has been shown to emerge in response to gastric injury. H. pylori localizes specifically to SPEM glands within the corpus of the stomach. We hypothesize that SAbA adhesin and S‐LewX facilitate H. pylori preferential localization and adhesion to SPEM glands in response to injury.HypothesisThe aged gastric epithelium exhibits sustained SPEM glands expressing S‐LewX in response to injury. H. pylori preferential localization and adhesion to SPEM glands may contribute to the severity of disease in the aged epithelium.MethodsGastric ulcers were induced in young (2–3 months old) and aged (>8 months old) C57/BL6 mice using an acetic acid‐induced injury model. Twenty‐one days after ulcer injury, mice were inoculated with H. pylori or with Brucella broth. Gastric organoids were generated from biopsies collected from young (14–30 years) or elderly (>55 years) human patients and transferred to monolayer cultures for in vivo H. pylori adherence assays. Infected monolayers were treated with sialic acid analogs 3′‐sialyllactose or 6′‐sialyllactose. Flow cytometry and immunofluorescence was used to analyze the co‐localization and adherence of H. pylori to S‐LewX‐expressing SPEM glands.ResultsSixty days post‐injury, MUC5AC re‐localized to the surface of the gastric epithelium with complete regeneration of the gastric epithelium, expression of parietal, chief and endocrine cells and no evidence of SPEM in the young mice. The aged gastric epithelium exhibited decreased and irregular MUC5AC localization and the persistence of SPEM glands that expressed both CD44v9 and S‐LewX. Twenty‐one days post‐injury, H. pylori adherence was limited to the surface epithelium in young mice. However, in the aged mice, metaplasia was present, chief cells were decreased, and H. pylori adherence was localized at the base of the epithelial glands and co‐localized with CD44v9/S‐LewX‐expressing glands. Adherence assays demonstrated that H. pylori adherence was preferential to □‐2,3‐sialyl‐glycans.ConclusionFollowing injury in aged gastric tissues, the mucous layer becomes altered such that SPEM persists and there is loss of normal mucin expression and gastric cell lineages. H. pylori adherence to CD44v9‐positive cells is enhanced by S‐LewX and abnormal regeneration appears to influence the severity of H. pylori‐associated disease.Support or Funding InformationNIH (NIDDK) 5R01DK083402‐08 grant (YZ); Albert C. Yates Fellowship, Univ. of Cincinnati (MD)