Causal effect of Helicobacter pylori infection on brain health and potential mediation by immune cells.

Objective: Increasing evidence suggests an association between Helicobacter pylori(HP) infection and brain health and its clinical manifestations. A growing body of evidence underscored the profound influence of immune cells on brain health. However, the existing evidence is equivocal, and the causal link remains uncertain. This study aims to determine if there is a causal connection between Hp infections and 42 brain-related diseases, as well as 1,325 distinct brain structures, and to explore the potential role of immune cells in mediating these associations.

Methods: Both univariable and multivariable mendelian randomization (UVMR and MVMR) was applied to evaluate the causal relationships between Hp protein antibodies and 1325 brain structure, as well as various brain-related diseases. Finally, we assessed the relationship between immune cells and HP protein antibodies and brain health, and then calculated the mediating effect of immune cells on the significant causal associations.

Results: Hp antibodies exhibited disease-specific effects: CagA conferred protection against anorexia nervosa(OR = 0.94, p = 0.015) and schizophrenia(OR = 0.91, p = 0.038).Conversely, catalase antibodies increased risks for frontotemporal dementia(OR = 1.47, p = 0.002) and juvenile absence epilepsy(OR = 1.01, p = 0.007). MVMR confirmed persistent associations with 61 brain structural alterations, such as IgG's impact on anterior cingulate morphology(OR = 1.06, p = 6.09E-05).Immune cells mediated 8.6-47.4% of Hp-brain effects: CD27⁺IgD⁺CD24⁺ B cells linked IgG to depression(18.2% mediation), while HLA-DR⁺ dendritic cells mediated UreA-associated white matter changes (10.9%).

Conclusion: Hp infection may exert dual neuroprotective and pathogenic effects via antibody-specific mechanisms, modulated by immune cell phenotypes.This study underscores the gut-brain-immune axis as a pivotal frontier in neuropsychiatric research, with implications for precision interventions targeting Hp-related immune dysregulation.