Exosomal CagA from Helicobacter pylori aggravates intestinal epithelium barrier dysfunction in chronic colitis by facilitating Claudin-2 expression.

BACKGROUND

The chronic infection with Helicobacter pylori (H. pylori), especially cytotoxin-associated gene A-positive (CagA) strains, has been associated with various extragastric disorders. Evaluating the potential impacts of virulence factor CagA on intestine may provide a better understanding of H. pylori pathogenesis such as colitis. The intestinal mucosal barrier is essential for maintaining its integrity and functions. However, how persistent CagA H. pylori colonization influences barrier disruption and thereby affects chronic colitis is not fully understood.

RESULTS

Chronic colitis models of CagA H. pylori-colonized mice treated with 2% Dextran sulphate sodium (DSS) were established to assess the disease activity and pertinent expression of tight junction proteins closely related to mucosal integrity. The aggravating effect of CagA H. pylori infection on DSS-induced chronic colitis was confirmed in mouse models. In addition, augmented Claudin-2 expression was detected in CagA H. pylori infection conditions and selected for mechanistic analysis. Next, GES-1 human gastric epithelial cells were cultured with CagA H. pylori or a recombinant CagA protein, and exosomes isolated from conditioned media were then identified. We assessed the Claudin-2 levels after exposure to CagA exosomes, CagA exosomes, and IFN-γ incubation, revealing that CagA H. pylori compromised the colonic mucosal barrier and facilitated IFN-γ-induced intestinal epithelial destruction through CagA-containing exosome-mediated mechanisms. Specifically, CagA upregulated Claudin-2 expression at the transcriptional level via a CDX2-dependent mechanism to slow the restoration of wounded mucosa in colitis in vitro.

CONCLUSIONS

These data suggest that exosomes containing CagA facilitate CDX2-dependent Claudin-2 maintenance. The exosome-dependent mechanisms of CagA H. pylori infection are indispensable for damaging the mucosal barrier integrity in chronic colitis, which may provide a new idea for inflammatory bowel disease (IBD) treatment.