Helicobacter pylori regulates pro- and anti-inflammatory macrophage responses to promote bacterial survival

Abstract Background Helicobacter pylori (H. pylori) establishes lifelong colonization of the human gastric mucosa and promotes chronic inflammation associated with gastric cancer. Although macrophages play a central role in pathogen clearance, H. pylori persists despite sustained immune activation, suggesting perturbed macrophage responses. However, the mechanism behind this paradox remains unclear. Methodology Here, we performed a comprehensive multi-omics analysis to define how H. pylori modulates macrophage polarization and transcriptional signatures controlling immune responses. We combined quantitative RNA-seq, proteomics, and lipidomics of H. pylori infected THP-1 macrophages, complemented by confocal microscopy analysis, cytokine profiling and bacterial survival assays. Results H. pylori induced a rapid pro-inflammatory response characterized by increased cytokine and chemokine production and enhanced phagocytosis. Concurrently, macrophages underwent a metabolic shift, including increased glycolysis, lipid remodeling, and lipid droplet accumulation. Time-resolved transcriptomics revealed a dynamic transition from early NF-κB dominated inflammatory responses to later STAT3 and HIF-1α associated regulatory and metabolic programs. Early induction of TNF-α and IL-10 was followed by sustained chemotactic signaling and partial attenuation of pro-inflammatory responses. Despite persisting induction of inflammatory cytokines such as IL-1β and IL-6, macrophages failed to fully clear internalized bacteria, suggesting the establishment of a non-resolving inflammatory state. Using isogenic H. pylori mutants, we found that CagA selectively enhanced HIF-1α stabilization, IL-6 secretion and increased bacterial survival, indicating that this virulence factor promotes bacterial persistence by modulating immuno-metabolic signaling. Conclusion Our findings demonstrate that H. pylori drives temporally structured macrophage responses, transitioning from early inflammatory activation to a hybrid state that supports bacterial persistence.