Porphyromonas gingivalis-Induced Cognitive Impairment Is Associated With Gut Dysbiosis, Neuroinflammation, and Glymphatic Dysfunction

Abstract

BackgroundPeriodontal pathogen and gut microbiota are closely associated with the pathogenesis of Alzheimer’s disease (AD). Porphyromonas gingivalis (Pg), the keystone periodontal pathogen, can induce cognitive impairment. The gut has a connection and communication with the brain, which is an important aspect of the gut–brain axis (GBA). In the present study, we investigate whether Pg induces cognitive impairment through disturbing the GBA.MethodsIn this study, Pg was orally administered to mice, three times a week for 1 month. The effects of Pg administration on the gut and brain were evaluated through behaviors, gut microbiota, immune cells, glymphatic pathway clearance, and neuroinflammation.ResultsPg induced cognitive impairment and dysbiosis of gut microbiota. The α-diversity parameters did not show significant change after Pg administration. The β-diversity demonstrated that the gut microbiota compositions were different between the Pg-administered and control groups. At the species level, the Pg group displayed a lower abundance of Parabacteroides gordonii and Ruminococcus callidus than the control group, but a higher abundance of Mucispirillum schaedleri. The proportions of lymphocytes in the periphery and myeloid cells infiltrating the brain were increased in Pg-treated animals. In addition, the solute clearance efficiency of the glymphatic system decreased. Neurons in the hippocampus and cortex regions were reduced in mice treated with Pg. Microglia, astrocytes, and apoptotic cells were increased. Furthermore, amyloid plaque appeared in the hippocampus and cortex regions in Pg-treated mice.ConclusionsThese findings indicate that Pg may play an important role in gut dysbiosis, neuroinflammation, and glymphatic system impairment, which may in turn lead to cognitive impairment.

Porphyromonas gingivalis: A key role in Parkinson's disease with cognitive impairment?

“…Although the authors did not detect α-Syn in the brain or small intestine, this finding supports the previous point that the accumulation of aberrant α-Syn is initiated in the gut ( 53 , 58 ). In addition, emerging evidence by Chi et al ( 85 ) shows that oral P. gingivalis induces gut microbiota dysbiosis, exacerbates neuroinflammation, and ultimately lead to a decline in cognitive function. Furthermore, the number of neurons in the hippocampal and cortical regions was significantly decreased, and amyloid plaques appeared in brain.…”

La enfermedad periodontal es un factor de riesgo para la enfermedad de Alzheimer

“…El último mecanismo, explica que las infecciones periféricas por bacterias orales e intestinales pueden inducir cascadas inflamatorias sistémicas y, posteriormente, causar neuroinflamación y daño neurológico. 17 Lo anterior se ha comprobado, por ejemplo, colocado P. gingivalis en la cavidad oral de ratones, y cinco semanas después de su aplicación, se observó que los linfocitos Th17 aumentaron en el intestino. 18 En este sentido, es posible que los pacientes con EP deglutan bacterias, como P. gingivalis, y una vez que llegan al intestino, éstas pueden inducir la disbiosis de la microbiota intestinal, lo cual provoca un aumento de los linfocitos T y B inflamatorios, una inflamación sistémica posterior y finalmente, la neuroinflamación.…”

“…P gingivalis induce el deterioro cognitivo, acompañado de disbiosis intestinal, neuroinflamación y deterioro del sistema glifático. 17 Además, la disbiosis intestinal disminuye la producción de ácidos grasos de cadena corta, lo que está relacionado con las respuestas inflamatorias. Es por ello que se considera que la microbiota es un potente regulador de las respuestas inmunitarias del huésped.…”

“…Es por ello que se considera que la microbiota es un potente regulador de las respuestas inmunitarias del huésped. 17 La disbiosis del microbioma intestinal induce una inflamación local y, posteriormente, sistémica. En pacientes con EA se han demostrado que hay alteraciones significativas del microbioma intestinal.…”

Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory dysfunction in mice

“…Porphyromonas gingivalis (Pg) is a Gram-negative bacterium known as a major pathogen of periodontal disease ( Darveau et al., 2012 ). Many experimental studies conclude that Pg or its virulence factors could induce memory impairment and AD-related pathologies ( Wu et al., 2017 ; Ding et al., 2018 ; Ilievski et al., 2018 ; Zhang et al., 2018 ; Dominy et al., 2019 ; Hayashi et al., 2019 ; Nie et al., 2019 ; Gu et al., 2020 ; Hu et al., 2020 ; Chi et al., 2021 ; Hao et al., 2022 Jiang et al., 2021 ; Qian et al., 2021 ; Su et al., 2021 ; Tang et al., 2021 ). Gingipains are toxic proteases secreted by Pg, it is reported that gingipains are neurotoxic in vivo and in vitro , causing detrimental effects on tau, a protein needed for normal neuronal function ( Dominy et al., 2019 ), and gingipains could degrade tight junction proteins of human cerebral microvascular endothelial cells in vitro ( Nonaka et al., 2022 ), suggesting that gingipains may be responsible for blood–brain barrier (BBB) damage.…”