Dysfunctional Gastric Emptying With Down-regulation of Muscle-Specific MicroRNAs in Helicobacter pylori-Infected Mice

Background & Aims

Little is known about the pathogenic mechanisms of functional dyspepsia. We investigated the role of microRNAs (miRNAs) in gastric motility disorders associated with Helicobacter pylori infection.

Methods

Male C57BL/6 mice were infected with H pylori. After long-term infection, gastric emptying was examined and compared with that of uninfected mice (controls). The miRNA expression profile was analyzed by miRNA microarray and quantitative reverse-transcriptase polymerase chain reaction. The results obtained from the animal study were confirmed by in vitro experiments.

Results

Gastric emptying was significantly accelerated in mice after chronic infection with H pylori. Histologic examination showed that the muscular layers of the stomachs of H pylori-infected mice were significantly thickened. The miRNA expression profile revealed that the muscle-specific miRNAs miR-1 and miR-133 were significantly down-regulated in the stomachs after long-term infection with H pylori. However, expression of histone deacetylase 4 and serum response factor, which are reported target genes of miR-1 and miR-133, increased. Down-regulation of miR-1 and miR-133 and increased cell proliferation were observed in C2C12 mouse myoblast cells after coculture with H pylori.

Conclusions

Chronic infection with H pylori down-regulates expression of muscle-specific miRNAs and up-regulates expression of histone deacetylase 4 and serum response factor. These might cause hyperplasia in the muscular layer of the stomach and dysfunction in gastric emptying. These findings provide insight into the molecular pathogenesis of gastric motility disorders, including functional dyspepsia.

Keywords: Functional Gastrointestinal Disorder, Noncoding RNA, Muscle Cell, Liquid Gastric Emptying

Abbreviations used in this paper: α-SMA, α-smooth muscle actin, BrdU, bromodeoxyuridine, CFU, colony-forming unit, DAPI, 4′,6-diamidino-2-phenylindole, ELISA, enzyme-linked immunosorbent assay, FD, functional dyspepsia, GI, gastrointestinal, HDAC4, histone deacetylase 4, H pylori, Helicobacter pylori, IBS, irritable bowel syndrome, IL, interleukin, miRNA, microRNA, RT-PCR, reverse-transcription polymerase chain reaction, SRF, serum response factor, TNF, tumor necrosis factor