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

Abstract

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.

Plant Polyphenols Attenuate DSS-induced Ulcerative Colitis in Mice via Antioxidation, Anti-inflammation and Microbiota Regulation

“…TJs include the transmembrane proteins, occludin and claudin family members, and proteins such as claudin-2 and ZO-1 [ 23 , 41 , 42 ]. ZO-1, a major TJ protein, is associated with epithelial integrity and can be used as a marker of the intestinal barrier.…”

Both extracellular vesicles from helicobacter pylori-infected cells and helicobacter pylori outer membrane vesicles are involved in gastric/extragastric diseases

“…Exosomes transport CagA proteins to remote locations from the primary disease, potentially causing extra-gastric diseases. However, the mechanism by which H. pylori and its products traverse the epithelial barrier and enter the bloodstream is still under investigation [ 67 ].…”

“…Additionally, Guo et al [ 67 ] discovered that CagA-positive H. pylori strains disrupted the integrity of the intestinal mucosal barrier and heightened the damage inflicted on the intestinal epithelium by IFN-gamma. These effects were facilitated by exosomes that functioned as mediators and involved CagA.…”

The Proteomics Analysis of Exosomes Revealed the Possible Function of HSPD1 Protein in Helicobacter pylori Infection

“…Previous studies on the functions of exosomes in the host immune response have focused on bacterial infection (particularly intracellular bacteria such as H. pylori) [7, 8]. Exosomes are membrane-enclosed vesicles with a diameter of 30-150 nm, which are produced by nearly all cell types [9].…”

“…Other 0.1% of patients will suffer mucosa-related lymphoid tissue lymphoma [6]. The fact that H. pylori infection causes gastritis and GC has been recognized worldwide, but the speci c molecular mechanism remains unclear.Previous studies on the functions of exosomes in the host immune response have focused on bacterial infection (particularly intracellular bacteria such as H. pylori) [7, 8]. Exosomes are membrane-enclosed vesicles with a diameter of 30-150 nm, which are produced by nearly all cell types [9].…”