The gut-brain axis in neurodegeneration: impact of helicobacter pylori secretome and exosomal signaling

Abstract

Chronic Helicobacter pylori (H. pylori) infection is increasingly linked to neurodegenerative disorders, though the exact mechanisms still remain unclear. This study investigates how H. pylori modify exosome cargo of infected gastric cells to drive neuroinflammation and oxidative stress in a neural triculture model. Conditioned media from H. pylori-infected gastric cells induced significant upregulation of proinflammatory cytokines (IL-6, TNF-α, IL-1β, IL-10), chemokines (CXCL1, CXCL11), and the inflammasome component NLRP3 in neural cells, alongside oxidative stress marked by elevated ROS production. Neurodegenerative markers, including amyloid precursor protein (APP), apolipoprotein E4 (APOE4), presenilin 1 (PSEN1), and glial fibrillary acidic protein (GFAP), were profoundly elevated, suggesting direct involvement in pathogenic pathways. Exosomes isolated from infected gastric cells exhibited biophysical alterations, including increased surface roughness (observed via AFM) and aggregation propensity (SEM), likely due to oxidative stress or aberrant protein/lipid composition. These exosomes carried post-translationally modified CD63, a tetraspanin linked to immune evasion, and activated inflammatory signaling pathways in neural cells, notably enhancing phosphorylation of p38 MAPK and NF-κB while suppressing p44/42 ERK (1/2). These findings highlight H. pylori’s capacity to hijack host exosomal machinery, facilitating gut-brain axis disruption through oxidative and inflammatory pathways. The study underscores exosomes as critical mediators in H. pylori-associated neurodegeneration, linking bacterial persistence to chronic neuroinflammation and protein aggregation seen in conditions like Alzheimer’s disease.