Several studies suggest that PD may reshape the oral microbial environment, particularly in the setting of periodontitis. Yay et al. showed that PD was associated with altered subgingival microbiome composition in patients with periodontitis, supporting the view that PD-related host factors may modify periodontal dysbiosis rather than simply increase plaque accumulation^[17]. This is biologically plausible: bradykinesia and rigidity impair brushing and interdental cleaning, dysphagia changes oral clearance, and xerostomia reduces salivary buffering^[4-8,17].

In a subsequent oral-gut profiling study, Yay et al. found that salivary microbial β-diversity differed across healthy controls, periodontitis, and PD with periodontitis, whereas gut microbiome differences were less pronounced after accounting for the periodontal background^[18]. These findings suggest that PD may exert a clearer and more reproducible influence on oral ecological structure than on the gut microbiome within mixed periodontal cohorts^[17,18]. More recent work also points to potentially informative oral microbiome signatures in early PD and reinforces the idea that oral dysbiosis may have biomarker potential, although these observations still require external validation and standardization of sampling methods^[18].

The oral-gut-brain axis provides a broader mechanistic framework for interpreting these findings. Chronic periodontal infection can repeatedly expose the host to lipopolysaccharide (LPS), proteases, inflammatory cytokines, and bacterial extracellular vesicles, thereby altering intestinal permeability, immune tone, and possibly vagal or systemic routes of signaling to the brain^[10,19]. In mice, Bai et al. showed that oral pathogens aggravated motor dysfunction, enhanced dopaminergic neurodegeneration, and promoted both oral/gut microbial changes and immune-cell infiltration in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD^[19]. Feng et al. further demonstrated that oral P. gingivalis impaired gut permeability and triggered immune responses associated with neurodegeneration in LRRK2 R1441G mice, lending additional support to an oral-gut-immune route relevant to PD-like pathology^[22].

Taken together, these data suggest that oral dysbiosis in PD is not merely a secondary epiphenomenon of poor hygiene. Rather, a reciprocal model is more appropriate: PD can modify the oral habitat, while chronic periodontal infection may feed back into systemic inflammatory and microbial pathways relevant to neurodegeneration.

Among periodontal pathogens, P. gingivalis has attracted particular attention because of its ability to drive persistent mucosal inflammation and systemic immune activation^[10,20-22]. Its virulence repertoire includes LPS, gingipains, fimbriae, and outer membrane vesicles, all of which can disrupt host tissues and potentially contribute to extra-oral disease pathways^[10].

Although much of the early interest in P. gingivalis centered on Alzheimer’s disease, increasing attention has been directed toward PD. Reviews have proposed that P. gingivalis may influence PD through hematogenous spread of virulence factors, peripheral immune priming, blood-brain barrier vulnerability, and promotion of neuroinflammation^[10,20,21]. Ermini et al. provided especially notable neuropathological evidence by demonstrating ultrastructural localization of gingipains in dopaminergic neurons of the substantia nigra in PD brains and showing occasional spatial association with phosphorylated Ser129 α-syn aggregates^[20]. They also showed that recombinant α-syn could be proteolytically cleaved by gingipains in vitro, supporting a plausible biochemical interface between chronic periodontal infection and α-syn processing^[20].

A separate review specifically focused on P. gingivalis in PD with cognitive impairment and summarized evidence that this pathogen may contribute to cognitive and motor decline through neuroinflammation, altered proteostasis, and gut-brain signaling^[21]. In parallel, the animal study by Feng et al. linked oral P. gingivalis exposure to gut permeability changes and neuroimmune activation in a PD-related genetic model^[22]. These findings do not prove that P. gingivalis causes PD, but they make it one of the most biologically plausible periodontal candidates linking oral infection to PD-related neurodegenerative stress. The principal molecular pathways implicated in periodontal pathogen-driven neurodegeneration are summarized in Figure 3.

Immune dysregulation is one of the most convincing conceptual bridges between periodontitis and PD. Periodontitis is characterized by sustained activation of innate and adaptive immune pathways in response to a dysbiotic biofilm, whereas PD increasingly appears to involve both peripheral and central immune activation, microglial priming, and chronic neuroinflammatory signaling^[19,23-30]. A coherent working model is that chronic periodontal inflammation increases systemic inflammatory burden and immune activation, which may in turn lower the threshold for neuroinflammatory amplification in vulnerable nigrostriatal circuits^{[10,23,26-30]}.

Clinical observations support this concept, albeit indirectly. In a cross-sectional analysis of two American PD cohorts, self-reported periodontitis was associated with higher circulating high-sensitivity C-reactive protein (hs-CRP), suggesting that periodontal disease may further increase systemic inflammatory load in PD^[23]. This is consistent with broader evidence linking periodontitis to low-grade systemic inflammation^[9-11].

More direct support comes from experimental studies. Bai et al. reported that oral pathogens exacerbated motor dysfunction and dopaminergic injury in MPTP-treated mice while increasing Th1-cell infiltration in the brain, cervical lymph nodes, ileum, and colon; importantly, neutralization of interferon-γ (IFN-γ) attenuated neuronal loss, implicating a Th1-IFN-γ-microglia axis^[19]. This finding is mechanistically important because it connects oral infection not only to systemic inflammation, but also to adaptive immune polarization and central glial activation.

Bioinformatics studies further suggest shared inflammatory architectures between PD and periodontitis. Hu et al. identified FMNL1, MANSC1, PLAUR, RNASE6, and TCIRG1 as potential crosstalk genes linking the two disorders^[24]. A separate study by Wen et al. also identified common molecular biomarkers and immune-related pathways shared by PD and chronic periodontitis^[25]. These findings are hypothesis-generating rather than definitive, but they support the notion that shared immune and inflammatory networks may underlie the overlap between periodontal inflammation and neurodegeneration.

Aging is the strongest risk factor for PD and also strongly influences oral health, immune regulation, and barrier integrity^[1,9,28]. Blood-brain barrier (BBB) dysfunction has become an increasingly important topic in PD because barrier breakdown may allow greater trafficking of inflammatory mediators, microbial products, and immune cells into the central nervous system^[27-29]. Reviews have highlighted that BBB alterations in PD can interact with α-syn pathology, oxidative stress, and inflammation, thereby facilitating neurodegenerative progression^[27-29].

This concept is particularly relevant to periodontitis. Chronic periodontal inflammation can sustain peripheral cytokine production and repeated exposure to microbial products, which in an aging host may be more likely to influence the central nervous system because of impaired immune homeostasis and altered BBB resilience^[10,26-29]. Bendig et al. emphasized that aging-related changes in vulnerable neurons, the immune system, and the BBB may collectively shape PD susceptibility, making peripheral inflammatory sources more relevant in older adults^[28].

Oxidative stress is a convergent process in both PD and periodontitis. In PD, dopaminergic neurons are particularly vulnerable to reactive oxygen species because of high metabolic demand, dopamine auto-oxidation, mitochondrial dysfunction, and impaired antioxidant defenses^[1-3,30,31]. In periodontitis, persistent activation of neutrophils and macrophages within inflamed periodontal tissues generates sustained reactive oxygen species production and local oxidative damage, with potential systemic spillover^[9,10,23,30].

Ferroptosis - an iron-dependent form of regulated cell death driven by lipid peroxidation - has emerged as an important framework for understanding dopaminergic degeneration in PD^[30,31]. Reviews have highlighted the importance of iron dyshomeostasis, glutathione depletion, glutathione peroxidase 4 dysfunction, mitochondrial damage, and lipid reactive oxygen species accumulation in PD-related ferroptotic injury^[30,31] . This concept can be linked back to periodontitis in several ways. Chronic periodontal inflammation may increase systemic oxidative burden, alter redox signaling, and sustain inflammatory cytokine exposure that sensitizes neurons to lipid peroxidation. In addition, pathogen-associated inflammation may disturb iron handling and mitochondrial function, thereby lowering the threshold for ferroptotic neuronal death^{[10,21,22,30,31]}. At present, direct experimental evidence that periodontal inflammation triggers ferroptosis in nigral neurons is still limited, but the model is biologically coherent and worthy of dedicated testing. As illustrated in Figure 3, redox imbalance, inflammasome activation, and iron-dependent lipid peroxidation may converge to enhance dopaminergic neuronal vulnerability.

Reviewer concerns about vitamin D and diet are well founded and should be explicitly addressed. Systematic reviews and meta-analyses have shown that serum vitamin D levels are lower in people with periodontitis, and vitamin D has recognized roles in bone metabolism, immune modulation, and host defense relevant to periodontal stability^[32-34]. Separate reviews and meta-analyses have also reported lower vitamin D levels in PD and suggested associations between low vitamin D status, symptom severity, and PD risk, although causal inference and intervention efficacy remain uncertain^[35-37].

Diet should also be considered explicitly. Reviews of PD indicate that dietary patterns may influence disease risk and symptom burden through metabolic, inflammatory, and microbiome-related pathways^[38]. Likewise, systematic reviews in periodontology increasingly suggest that dietary patterns and micronutrient intake may influence periodontal inflammation and disease susceptibility^[41,42]. Therefore, future studies on PD and periodontitis should not treat diet and vitamin D merely as nuisance variables; they may represent shared biological modifiers and potential intervention targets.