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Acidic bile salts induces mucosal barrier dysfunction through let-7a reduction during gastric carcinogenesis after Helicobacter pylori eradication.

ABSTRACT: Gastric cancer (GC) after eradication for Helicobacter pylori (H.pylori) increases, but its carcinogenesis is not elucidated. It is mainly found in acid non-secretion areas (ANA), as mucosal regeneration in acid secretory areas (AA) after eradication changes the acidity and bile toxicity of gastric juice. We aimed to clarify the role of barrier dysfunction of ANA by the stimulation of pH3 bile acid cocktail (ABC) during carcinogenesis. We collected 18 patients after curative endoscopic resection for GC, identified later than 24 months after eradication, and took biopsies by Congo-red chromoendoscopy to distinguish AA and ANA (UMIN00018967). The mucosal barrier function was investigated using a mini-Ussing chamber system and molecular biological methods. The reduction in mucosal impedance in ANA after stimulation was significantly larger than that in AA, 79.6% vs. 87.9%, respectively. The decrease of zonula occludens-1 (ZO-1) and let-7a and the increase of snail in ANA were significant compared to those in AA. In an in vitro study, the restoration of ZO-1 and let-7a as well as the induction of snail were observed after stimulation. High mobility group A2 (HMGA2)-snail activation, MTT proliferation, and cellular infiltration capacity were significantly increased in AGS transfected with let-7a inhibitor, and vice versa. Accordingly, using a mini-Ussing chamber system for human biopsy specimens followed by an in vitro study, we demonstrated for the first time that the exposure of acidic bile salts to ANA might cause serious barrier dysfunction through the let-7a reduction, promoting epithelial-mesenchymal transition during inflammation-associated carcinogenesis even after eradication.

SUBMITTER: Takahashi Y

PROVIDER: S-EPMC5915058 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Acidic bile salts induces mucosal barrier dysfunction through let-7a reduction during gastric carcinogenesis after Helicobacter pylori eradication.

Takahashi Yasushi Y Uno Kaname K Iijima Katsunori K Abe Yasuhiko Y Koike Tomoyuki T Asano Naoki N Asanuma Kiyotaka K Shimosegawa Tooru T

Oncotarget 20180406 26

Gastric cancer (GC) after eradication for Helicobacter pylori (H.pylori) increases, but its carcinogenesis is not elucidated. It is mainly found in acid non-secretion areas (ANA), as mucosal regeneration in acid secretory areas (AA) after eradication changes the acidity and bile toxicity of gastric juice. We aimed to clarify the role of barrier dysfunction of ANA by the stimulation of pH3 bile acid cocktail (ABC) during carcinogenesis. We collected 18 patients after curative endosc ...[more]

PMID: 29719591

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Project description:BackgroundHelicobacter pylori (Hp) eradication has been used for many years. Yet, the impact of this eradication on the normal gastric microflora is not well understood. In this study, we explored the effect of eradication on the stomach microbial community and its recovery after successful Hp eradication.MethodsAmong the 89 included patients, 23, 17, 40, and 9 were included in the Hp-negative, Hp-positive, successful eradication, and failed eradication groups, respectively. Four subgroups were further determined according to disease status (Hp-negative chronic gastritis [N-CG], Hp-negative atrophic gastritis [N-AG], successful-eradication chronic gastritis [SE-CG], and atrophic gastritis with successful eradication [SE-AG]). During the endoscopic examination, one piece of gastric mucosa tissue was obtained from the lesser curvature side of the gastric antrum and gastric corpus, respectively. In addition, 16S rDNA gene sequencing was used to analyze the gastric mucosal microbiome.ResultsIn the Hp-negative group, the gastric microbiota was dominated by five phyla: Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, and Fusobacteria. After successfully eradicating Hp, the bacterial flora in the stomach recovered to a considerable extent. In the failed eradication group, the flora was similar to the flora in Hp-positive subjects based on the alpha and beta diversities. Among the groups, Curvibacter and Acinetobacter were enriched in the presence of Hp (i.e., failed eradication and Hp-positive groups), suggesting that these two genera could be used as biomarkers in the symbiotic flora in the presence of Hp. SE-CG was characterized by an increase in Firmicutes taxa and a decrease in Proteobacteria taxa compared with N-CG. SE-AG was characterized by a decrease in Firmicutes relative to N-AG. Finally, no differences were found in the pairwise comparisons of nitrate and nitrite reductase functions of the microflora among the four subgroups.ConclusionsAfter Hp infection, the diversity and relative abundance of gastric microflora were significantly decreased. Yet, gastric microbiota could be partially restored to the Hp-negative status after eradication. Still, this effect was incomplete and might contribute to the long-term risks.

Dataset Information

Acidic bile salts induces mucosal barrier dysfunction through let-7a reduction during gastric carcinogenesis after Helicobacter pylori eradication.

Publications

Acidic bile salts induces mucosal barrier dysfunction through <i>let-7a</i> reduction during gastric carcinogenesis after <i>Helicobacter pylori</i> eradication.

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