Hsp60-Bearing Exosomes in Helicobacter pylori-Induced Gastric Tumorigenesis: A Pathomorphological and Therapeutical Overview

Highlights What are the main findings? This review identifies Hsp60-bearing extracellular vesicles (EVs)-both bacterial (GroEL in OMVs) and host-derived (human exosomes)-as central mediators of the infection-inflammation-cancer axis in gastric mucosa. H. pyloriIt also introduces the novel concept of the as a fifth, functionally distinct layer of the gastric wall, serving as the key site for vesicle-mediated host-microbe interactions. What is the implication of the main finding? muco-microbiotic layerRecognizing Hsp60-bearing EVs as active pathogenic and immunomodulatory agents opens new diagnostic and therapeutic avenues, including EV-based biomarkers and Hsp60-targeted interventions. The proposed framework not only redefines gastric wall morphology but also provides a new conceptual and experimental basis for studying early events in H. pylori-associated gastric carcinogenesis.Highlights What are the main findings? This review identifies Hsp60-bearing extracellular vesicles (EVs)-both bacterial (GroEL in OMVs) and host-derived (human exosomes)-as central mediators of the infection-inflammation-cancer axis in gastric mucosa. H. pyloriIt also introduces the novel concept of the as a fifth, functionally distinct layer of the gastric wall, serving as the key site for vesicle-mediated host-microbe interactions. What is the implication of the main finding? muco-microbiotic layerRecognizing Hsp60-bearing EVs as active pathogenic and immunomodulatory agents opens new diagnostic and therapeutic avenues, including EV-based biomarkers and Hsp60-targeted interventions. The proposed framework not only redefines gastric wall morphology but also provides a new conceptual and experimental basis for studying early events in H. pylori-associated gastric carcinogenesis.Abstract Chronic infection with Helicobacter pylori is the leading environmental cause of gastric carcinogenesis, yet the molecular pathways remain incompletely defined. This review links H. pylori-derived outer membrane vesicles (OMVs) and host epithelial exosomes through their shared cargo of heat shock protein 60 (GroEL/Hsp60). We proposed the concept of the "muco-microbiotic layer" as a fifth, functionally distinct layer of the gastric wall, where bacterial and host extracellular vesicles (EVs) interact within the mucus-microbiota interface. In this compartment, OMVs carrying bacterial GroEL and exosomes containing human Hsp60 engage in bidirectional communication that may promote chronic inflammation and epithelial transformation, with putative participation of molecular mimicry. The high structural homology between microbial and human Hsp60 enables repeated immune exposure to trigger cross-reactive responses-potentially leading to autoimmune-driven tissue damage, immune tolerance, and immune evasion in pre-neoplastic lesions. This vesicular crosstalk aligns with the evolution from non-atrophic gastritis to atrophy, from intestinal metaplasia to dysplasia, and lastly adenocarcinoma. Therapeutically, targeting EV-mediated Hsp60/GroEL signaling might offer promising strategies: EV-based biomarkers for early detection, monoclonal antibodies against extracellular Hsp60/GroEL, modulation of vesicle release, and probiotic-derived nanovesicles to restore mucosal balance. Hence, recognizing the muco-microbiotic layer and its vesicle-mediated signaling provides a new framework for understanding the infection-inflammation-cancer axis and for developing diagnostic and therapeutic approaches in H. pylori-associated gastric cancer.