Unraveling the pathogenetic overlap of Helicobacter pylori and metabolic syndrome-related Porphyromonas gingivalis: Gingipains at the crossroads and as common denominator

Chronic bacterial infections exert profound systemic effects beyond their primary infection sites, influencing a range of inflammatory, metabolic, and neurodegenerative diseases. Helicobacter pylori (Hp) and Porphyromonas gingivalis (Pg) are two highly prevalent pathogens that, despite occupying distinct niches, share remarkable pathogenic similarities. Both bacteria, connected with metabolic syndrome, employ immune evasion strategies, induce chronic inflammation, and contribute to systemic diseases such as metabolic-associated steatotic liver disease, cardiovascular disease, and neurodegeneration, such as Alzheimer’s disease. A key unifying factor in their pathogenicity is the role of gingipains—cysteine proteases produced by Pg—which facilitate bacterial invasion, immune modulation, and tissue destruction. Emerging evidence suggests that Hp possesses analogous proteolytic enzymes, further supporting their potential synergistic impact on host health. Moreover, both pathogens have been implicated in metabolic syndrome-related blood-brain barrier disruption, chronic (smoldering) systemic inflammation, and lipid metabolism dysregulation, contributing to progressive neurodegenerative and cardiovascular disorders. The role of galectins, particularly galectin-3, in modulating microglial activation and inflammatory pathways further highlights their involvement in neuroinflammatory diseases. Targeting gingipains presents a promising therapeutic avenue, with bismuth compounds and novel inhibitors showing potential in disrupting these proteases and mitigating their systemic effects. Understanding the interactions between Hp and metabolic syndrome-related Pg is crucial for developing comprehensive treatment strategies, integrating gastroenterology, periodontology, and neurology. Addressing these infections at both local and systemic levels may improve long-term health outcomes and reduce the burden of chronic inflammatory diseases linked to microbial persistence.