Helicobacter pylori infection in the stomach induces neuroinflammation: the potential roles of bacterial outer membrane vesicles in an animal model of Alzheimer’s disease

Abstract

Helicobacter pylori (HP) is a Gram-negative bacterium that colonizes the human stomach chronically. Colonization of HP in the gastric mucosa not only causes gastrointestinal diseases, but also is associated with extra-gastric diseases, such as idiopathic thrombocytopenic purpura and neurological diseases. Among neurological diseases, epidemiological studies have shown that HP infection increases the prevalence of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Since HP does not invade the central nervous system (CNS), it has been considered that systemic immunological changes induced by HP infection may play pathogenic roles in AD and PD. Here, we investigated the effects of HP infection on the CNS in vivo and in vitro. In the CNS, chronically HP-infected mice had microglial activation without HP colonization, although systemic immunological changes were not observed. This led us to explore the possibility that HP-derived outer membrane vesicles (HP-OMVs) could cause neuroinflammation. OMVs are small, spherical bilayer vesicles (20–500 nm) released into the extracellular space from the outer membrane of Gram-negative bacteria; OMVs contain lipopolysaccharide, proteins, peptidoglycan, DNA, and RNA. OMVs have also been shown to activate both innate and acquired immune cells in vitro, and to disrupt the tight junctions of the gastric epithelium (“leaky gut”) as well as cross the blood-brain barrier in vivo. Thus, in theory, OMVs can activate immune responses in the remote organs, including the lymphoid organs and CNS, if only OMVs enter the systemic circulation. From the exosome fraction of sera from HP-infected mice, we detected HP-specific DNA, suggesting the presence of HP-OMVs. We also found that microglia incubated with HP-OMVs in vitro increased the cell proliferation, inflammatory cytokine production, and migration. On the other hand, HP-OMVs suppressed the cell proliferation of neuroblastoma in vitro. Lastly, we found that AD model mice infected with HP had amyloid plaques adjacent to activated microglia and astrocytes in vivo. Based on the literature review and our experimental data, we propose our working hypothesis that OMVs produced in chronic HP infection in the gut induce neuroinflammation in the CNS, explaining the higher prevalence of AD in HP-infected people.

Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles

“…These bacterial EVs have emerged as novel communicators within the GBA, traversing to the host brain via circulatory or neural pathways [117,118]. For instance, Helicobacter pylori (HP) EVs can breach the BBB and provoke neuroinflammation through mechanisms involving glial cell activation and complement pathway signaling, potentially exacerbating amyloidogenic pathology [119,120]. Moreover, neurotoxic EVs from pathogens, like Pseudomonas aeruginosa, Paenalcaligenes hominis, and Aggregatibacter actinomycetemcomitans, contain components such as lipopolysaccharides (LPS) that can invoke a robust immune response in the CNS [115,121,122].…”

Chlamydia pneumoniae in Alzheimer's disease pathology

“…Different oral Treponema species have been observed in the trigeminal ganglia, pons, and hippocampus (Riviere et al, 2002 ). Helicobacter pylori (Hp) IgG titer was higher in AD patients compared with control patients (Malaguarnera et al, 2004 ), and epidemiological studies suggested that it is involved in the activation of innate immunity pathways that can exacerbate the CNS system leading to AD-like complications (Park and Tsunoda, 2022 ). Other studies also show a positive relation between Hp infection and AD (Park et al, 2017 ; Liu et al, 2021 ).…”

Effects of Helicobacter pylori and Moluodan on the Wnt/β-catenin signaling pathway in mice with precancerous gastric cancer lesions

“…Helicobacter pylori ( H. pylori ) is a type of bacteria that thrives in the stomach and damages the gastric mucosa primarily through the production of urease and induction of immune responses[ 5 ]. Numerous reports, including the Kyoto Global Consensus, have identified H. pylori as a leading risk factor for GC[ 6 ].…”