Extracellular vesicles derived from Porphyromonas gingivalis induce trigeminal nerve-mediated cognitive impairment.

INTRODUCTION: Porphyromonas gingivalis (PG)-infected periodontitis is in close connection with the development of Alzheimer's disease (AD). PG-derived extracellular vesicles (pEVs) contain inflammation-inducing virulence factors, including gingipains (GPs) and lipopolysaccharide (LPS). OBJECTIVES: To understand how PG could cause cognitive decline, we investigated the effects of PG and pEVs on the etiology of periodontitis and cognitive impairment in mice. METHODS: Cognitive behaviors were measured in the Y-maze and novel object recognition tasks. Biomarkers were measured using ELISA, qPCR, immunofluorescence assay, and pyrosequencing. RESULTS: pEVs contained neurotoxic GPs and inflammation-inducible fimbria protein and LPS. Gingivally exposed, but not orally gavaged, PG or pEVs caused periodontitis and induced memory impairment-like behaviors. Gingival exposure to PG or pEVs increased TNF-α expression in the periodontal and hippocampus tissues. They also increased hippocampal GP+Iba1+, LPS+Iba1+, and NF-κB+Iba1+ cell numbers. Gingivally exposed PG or pEVs decreased BDNF, claudin-5, and N-methyl-D-aspartate receptor expression and BDNF+NeuN+ cell number. Gingivally exposed fluorescein-5-isothiocyanate-labeled pEVs (F-pEVs) were detected in the trigeminal ganglia and hippocampus. However, right trigeminal neurectomy inhibited the translocation of gingivally injected F-EVs into the right trigeminal ganglia. Gingivally exposed PG or pEVs increased blood LPS and TNF-α levels. Furthermore, they caused colitis and gut dysbiosis. CONCLUSION: Gingivally infected PG, particularly pEVs, may cause cognitive decline with periodontitis. PG products pEVs and LPS may be translocated into the brain through the trigeminal nerve and periodontal blood pathways, respectively, resulting in the cognitive decline, which may cause colitis and gut dysbiosis. Therefore, pEVs may be a remarkable risk factor for dementia.

Alleviation of Porphyromonas gingivalis or Its Extracellular Vesicles Provoked Periodontitis and Cognitive Impairment by Lactobacillus pentosus NK357 and Bifidobacterium bifidum NK391.

Porphyromonas gingivalis (PG) is closely involved in the outbreak of periodontitis and cognitive impairment (CI). Herein, we examined the effects of anti-inflammatory Lactobacillus pentosus NK357 and Bifidobacterium bifidum NK391 on PG- or its extracellular vesicles (pEVs)-induced periodontitis and CI in mice. Oral administration of NK357 or NK391 significantly decreased PG-induced tumor necrosis factor (TNF)-α, receptor activator of nuclear factors κB (RANK), and RANK ligand (RANKL) expression, gingipain (GP)+lipopolysaccharide (LPS)+ and NF-κB+CD11c+ populations, and PG 16S rDNA level in the periodontal tissue. Their treatments also suppressed PG-induced CI -like behaviors, TNF-α expression and NF-κB-positive immune cells in the hippocampus and colon, while PG-suppressed hippocampal BDNF and N-methyl-D-aspartate receptor (NMDAR) expression increased. The combination of NK357 and NK391 additively alleviated PG- or pEVs-induced periodontitis, neuroinflammation, CI-like behaviors, colitis, and gut microbiota dysbiosis and increased PG- or pEVs-suppressed BDNF and NMDAR expression in the hippocampus. In conclusion, NK357 and NK391 may alleviate periodontitis and dementia by regulating NF-κB, RANKL/RANK, and BDNF-NMDAR signaling and gut microbiota.