Porphyromonas Gingivalis Harms Cognition Via Gut-Brain Immune Pathway

P. gingivalis gut colonization disrupts microbiota and activates gut-brain axis, potentially promoting Alzheimer's-related cognitive decline. Young (8-week) and middle-aged (10-month) C57BL/6 mice received oral Pg or vehicle 3×/week for 4 weeks. Cognitive/motor functions were assessed via Morris maze (spatial memory), novel object recognition, open field, and rotarod tests. Gut microbiota (16SrRNA, FISH), intestinal integrity (HE staining), and inflammation (IFN-γ/WB) were analyzed. Flow cytometry quantified systemic immune changes (CD4+/CD8+ T cells, MDSCs). Neuropathology evaluations included glymphatic clearance (two-photon imaging), Aβ deposition, neuroinflammation (microglia/astrocytes: Iba1/GFAP; NLRP3/IL-1β), and neurodegeneration (TUNEL, caspase-3). Age-dependent Cognitive Impairment: Pg infection selectively compromised middle-aged mice, causing spatial/non-spatial memory deficits, anxiety-like behaviors, and reduced motor performance, with no significant effects observed in young mice. Gut Microbiome Dysbiosis & Barrier Disruption: Middle-aged mice exhibited significant gut microbiota alterations (↑Desulfovibrio, ↓Lactobacillus murinus), accompanied by intestinal barrier damage, IFN-γ overexpression, and localized inflammatory infiltration. Systemic Neurodegenerative Cascade: Pg triggered a systemic IFNγ+ T-cell response that propagated along the gut-brain axis, resulting in impaired glymphatic function, Aβ accumulation, neuronal apoptosis, and activated neuroinflammation (microglial/astrocyte activation with NLRP3/IL-1β upregulation). Pg colonization in middle-aged mice alters gut microbiota composition, inducing chronic systemic inflammation through immune hyperactivation. This gut-brain axis disruption impairs Aβ clearance, leading to cerebral Aβ accumulation, neuroinflammatory responses, and neuronal degeneration, culminating in cognitive dysfunction.