Helicobacter pylori-Epstein Barr virus Coinfection Reprograms Microglial Immune-Metabolic State via the Gut-Brain Axis

The gut-brain axis provides an essential route to influence central nervous system through peripheral infections, yet the impact of gastric infections on the microglia function remains poorly understood. Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), frequently coexisting in the gastric epithelium, generate inflammatory and metabolic signals capable of disseminating systemically. Here, we investigated whether the secretomes from gastric epithelial cells coinfected with H. pylori and EBV carry the ability to modulate human microglia. Exposure to coinfected secretome showed coordinated downregulation of microglial motility and surveillance markers, including TMEM119, Iba1, and CD68, indicative of loss of microglial motile phenotype. Additionally, metabolomic analysis revealed suppressed mitochondrial and redox pathways, characterized by depletion of L-carnitine, acyl-carnitine, NAPDH, and glutathione with altered bile and energy-related signaling. Such immune and metabolic changes produced pronounced modulations in coinfection-derived secretome compared to single-pathogen exposures, indicating the bacterial-viral coinfection generated a distinctive signaling capable of reprogramming microglia. Together, our findings indicate H. pylori-EBV coinfection as a driver of microglial metabolic remodeling via the gut-brain axis signaling, providing mechanistic insights into chronic gastric infections and altered CNS homeostasis.