P. gingivalis colonizes the oral epithelium and forms part of the plaque beneath the gums. It can alter the symbiotic composition of bacteria in the oral cavity, leading to ecological dysbiosis. The production of P. gingivalis biofilms is associated with the formation of bacterial plaques in gingival tissue, which further exacerbates gingival damage by other oral bacteria (11, 12).

P. gingivalis possesses several unique properties and virulence factors that affect the host (2). One notable characteristic is the shedding of outer membrane vesicles (OMVs). These vesicles contain virulence factors, particularly gingival proteases and lipopolysaccharide (LPS) (13, 14). Gingipain triggers an immune escape response by modulating inflammatory mediators and suppressing immune cell activity, including the activities of the lysine-gingipain (Kgp) and arginine-gingipain (Rgp). P. gingivalis also produces P. gingivalis lipopolysaccharide (P.g-LPS), which activates the natural host immune response (15, 16). Most strains of P. gingivalis are covered by a capsule that protects the bacteria from attack and host complement killing (17). Some studies have shown that encapsulated strains are more virulent in a mouse model of infection (18, 19). Therefore, these toxins make P. gingivalis highly pathogenic, enabling its components to enter the brain through various pathways. This entry triggers pathological reactions and contributes to the development of neurodegenerative diseases.

Based on current research, we conclude that oral infections caused by P. gingivalis can affect the brain in three ways ( Figure 1 ). First, P. gingivalis causes local chronic inflammation and disrupts central nervous system (CNS) homeostasis through the blood-brain barrier, indirectly promoting neuroinflammation. The association of high loads of P. gingivalis with increased serum TNF-α levels suggests that P. gingivalis not only triggers the development of local inflammatory periodontitis but also leads to elevated serum levels of pro-inflammatory cytokines (20). In addition, prolonged exposure to harmful substances disrupts and increases blood-brain barrier permeability, allowing peripheral pro-inflammatory cytokines to enter the vagus nerve (21).

Second, P. gingivalis enters the intestine through the mouth and can disrupt the intestinal flora, leading to an inflammatory response transmitted to the brain through the gut-brain axis (GBA). Dysregulation of the gut microbiota is strongly associated with the development of neurodegenerative diseases through the regulation of the GBA, and P. gingivalis can alter the ratio of T lymphocytes to inflammatory T cells in mesenteric lymph nodes and increase inflammatory cytokines, disrupting the gut microbiota (22–24). Gut microbiota can alter immune cells and stimulate the production of pro-inflammatory cytokines (25–27), with immune cells and inflammatory mediators subsequently entering the brain (28).

Finally, TLR4 signaling activated by P. gingivalis induces OS, leading to mitochondrial dysfunction and neuroinflammation. In both cases, it is involved in the progression of degenerative diseases due to neuroinflammation. A recent study showed that Pg-LPS acts via TLR4. Furthermore, administering Pg-LPS triggers TLR4 signals and elevates markers of dementia and neuroinflammation that have been linked to AD (29). Additional research has revealed that neuroinflammation caused by Pg-LPS is facilitated by the activation of the TLR4 signaling route (30, 31). Research indicates that neurons are capable of expressing both TLR2 and TLR4, implying that these receptors are crucial for neuroinflammatory responses (32, 33).

An imbalance in the inflammatory response is a common issue in neurodegenerative diseases that leads to neuroinflammation in various parts of the brain, worsening the overall condition (36). The released mediators impact microglia and astrocytes, potentially harming neurons and the central nervous system (36–38). For instance, pyroptotic cell of microglia can lead to neuroinflammation, triggering various neurodegenerative diseases (39). Similarly, damage to astrocytes can lead to specific neuroinflammatory markers, resulting in further complications (40). Another notable feature of neurodegenerative diseases is oxidative stress. In the brains of patients with neurodegenerative diseases, elevated levels of reactive oxygen species are often seen, suggesting that oxidative damage might make the disease worse (41, 42).

Inflammation is the response of cells and tissues to injury, trauma, or infection. Research shows that there is a significant link between the brain and the immune system. Inflammation occurring in the brain is called neuroinflammation (43). Neuroinflammation is an early feature of neurodegenerative diseases. It can activate the immune system, leading to the release of pro-inflammatory cytokines, increased oxidative stress (OS), and abnormal protein deposition, all of which may harm neurons directly or indirectly (44–46). For instance, while neuroinflammation can help remove deposited Aβ, it can also generate cytotoxic substances that worsen Aβ deposition and contribute to neurodegenerative damage (47). Recent studies suggest that neuroinflammation might be a result of periodontitis (8). The immune cells in the brain mainly consist of microglia and astrocytes. Chronic inflammation in the body triggers the activation of microglia and astrocytes in the brain. For instance, when the Toll-like receptors (TLRs) in these cells get activated, they produce various pro-inflammatory cytokines, leading to neuroinflammation that causes damage or death to neurons (48–50).

AD is characterized by the progressive cognitive decline resulting from synapse degeneration and neuronal death. It is an irreversible chronic degenerative neurological disease and the most common neurodegenerative disease leading to cognitive impairment (59, 60). AD is associated with cognitive dysfunction, Aβ plaques and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau are the two hallmark pathological features of AD (61, 62). Aβ plaques are recognized by the brain as foreign bodies, triggering inflammatory and immune responses through activation of microglia and cytokine release, ultimately leading to cell death and neurodegeneration (63). And phosphorylated tau proteins contribute to AD by causing microtubule rupture, synaptic loss, and, ultimately, cognitive dysfunction (64, 65). Moreover, both Aβ and tau aggregate impair synaptic plasticity and lead to neuronal cell death (66).

Firstly, P. gingivalis could induce neuroinflammation and neurodegeneration via OS. Le Sage et al. found that at the cellular level, P.g-LPS induces oxidative stress by increasing intracellular ROS production and altering the expression of genes encoding the oxidoreductases NOX2, NOX4, iNOS, and catalase (67). Accumulation of ROS, reduced MMP expression, and increased 4-HNE protein expression in neuroblastoma cells due to P.g-LPS underscore its significance in the pathogenesis of AD (29). Furthermore, LPS from P. gingivalis increases OS in periodontal ligament fibroblasts and brain endothelial cells (68, 69).

In addition to inducing neuroinflammation through OS, P. gingivalis can directly cause neuroinflammation. Animal studies have shown that P.g-LPS-induced neuroinflammation leads to cognitive impairment in C57BL/6 mice and that P.g-LPS significantly activates astrocytes and microglia and upregulates the TLR4/NF-κB signaling pathway (70). Hu et al. found that periodontitis caused by P.g-LPS exacerbates neuroinflammation by stimulating TLR4 and the NF-κB signaling pathway, which have been linked to learning and memory deficits in Sprague-Dawley rats (71). P. gingivalis OMV, which carries high levels of gingipain, may play a significant role in AD (72). Research have demonstrated that LPS derived from P. gingivalis OMV activates glial cells and induces brain inflammation. It is also linked to the expression of AD markers, such as Aβ and NFTs (73). In addition, the capsules of P. gingivalis play a central role in chronic inflammatory responses and cognitive deficits caused by short-term oral infections. More toxic capsules are likely to induce AD-like pathology and accelerate the pathogenic process (74).

At the same time, the pathogenic factors of P. gingivalis can also lead to the development of pathological features associated with AD, such as influencing Aβ accumulation and tau protein function. Animal studies corroborate that oral P. gingivalis infection in mice leads to brain colonization and enhances the generation of the amyloid plaque element Aβ1-42 (8). Similarly, Ryra et al. reported, using a rat model, that P.g-LPS induces an increase in serum levels of Aβ peptide (75). Tang et al. demonstrated that rats infected with P. gingivalis exhibit robust tau phosphorylation at the Thr181 and Thr231 loci linked to AD, and these loci are abundant in activated astrocytes (76).

At the cellular level, it has been established that prolonged contact with P.g-LPS led to the buildup of Aβ in the brains of mice of middle age. The exposure further led to the peripheral build-up of Aβ in inflammatory monocytes and macrophages (58). Gingipains, another toxic product of P. gingivalis, are associated with tau phosphorylation and tau cleavage (77, 78). Dominy et al. suggested that the origin of tau in the brains of patients with AD could stem from the transneuronal spread of P. gingivalis, Gingipain may also play a role in the adaptive elevation of tau protein synthesis in patients with AD (8).

In summary, P. gingivalis has been linked to the pathogenesis of AD through multiple mechanisms, including neuroinflammation, oxidative stress, Aβ accumulation, and interference with tau protein function, as summarized in Table 1 . These findings suggest that P. gingivalis may contribute to the development of AD through different pathways, whether at the cellular or animal, level, thus providing potential targets for future therapeutic strategies.

PD is the second most prevalent neurodegenerative disorder that results from the death of dopaminergic nerve cells in the substantia nigra pars compacta (SNPC) (84, 85). It leads to movement disorders such as tremors, bradykinesia, and cognitive impairment (86). Pathologically, PD involves alpha-synuclein (α-Syn) misfolding, neuroinflammation, and mitochondrial dysfunction (87, 88). In recent years, periodontitis, a common slow inflammatory disease, has been associated with the risk of PD (89, 90). Most previous associations between the two diseases have been based on PD-induced dyskinesias, which may lead to the progression of periodontal disease (90). And P. gingivalis is a major periodontal pathogen that induces intestinal dysbiosis (91, 92).

Our previous study employed bioconfidence data mining to demonstrate that periodontitis is a high-risk causative factor of PD, and our results suggest that P. gingivalis, the main causative agent of periodontitis, can contribute to the development of PD (93). Previous studies have also detected P. gingivalis major virulence factors such as gingipain R1 and P.g-LPS in the blood of PD patients (94, 95). A recent study suggests that gingipains from P.gingivalis may accumulate in the SNPC of the human brain (96). An animal study confirmed that P. gingivalis reduces dopaminergic neurons in SNPC of mice with the leucine-rich repeat kinase 2 (LRRK2) R144G mutation, which is associated with late-onset PD (97, 98).

P. gingivalis may affect the onset and development of PD primarily through two mechanisms: OS and neuroinflammation. This mechanism was confirmed in various studies on animal models, including a report by La Vitola et al., which found that LPS from Escherichia coli (E. coli) induces neuroinflammation and enhances α-Syn toxicity along with cognitive impairment (99). Similarly, a previous study showed that P.g-LPS hindered spatial learning and memory in the Morris Water Maze (MWM) test, whereas the effects of the two LPS types were not significantly different (70). The findings imply that P.g-LPS, notwithstanding its structural variances, might possess a mechanism akin to Escherichia coli LPS that leads to the intensification of harmful impacts of α-Syn and cognitive deficits.

There is currently no direct evidence that P. gingivalis contributes to the development of PD via oxidative stress. However, studies indicate that P.g-LPS induces oxidative stress, leading to mitochondrial dysfunction and neuroinflammation in SH-SY5Y cells (29). In addition, a positron emission tomography (PET) study of patients with PD have shown that a widespread presence of activated microglia (100). Interestingly, this response does not correlate with clinical severity, suggesting it may occur early in the disease. The mechanism by which microglia are involved in PD may be similar to that seen in AD (51). Microglia internalize and degrade the proteinα-Syn. If this process fails, extracellular α-Syn accumulates, similar to Aβ (101). Microglia gather around α-Syn deposits and display pro-inflammatory properties base on receptors that also bind Aβ (102, 103). Therefore, we hypothesized that P. gingivalis may contribute to PD through oxidative stress and neuroinflammation.

MS is a progressive disorder of the central nervous system, characterized by invasion by immune cells, detachment of myelin sheaths, growth of reactive glial cells, and damage to neural axons. This sequence results in sensory, motor, and cognitive impairments (104). Although the exact cause of MS recurrence remains unclear, it is believed to stem from an autoimmune inflammatory condition in which environmental and genetic elements trigger CNS antigens, such as myelin basic protein, to be addressed by the immune system (105).

The correlation between MS and P. gingivalis is currently being investigated, although there are no published articles describing the role of P. gingivalis in the pathogenesis of MS. As one of the most prevalent neurodegenerative diseases, MS is also associated with neuroinflammation. Lucchinetti et al. showed that acute MS leads to astrocyte and microglial activation and occasionally to oligodendrocyte apoptosis (106).

Some relevant experiments have sought to demonstrate this link, including a report by Moreno et al. aimed to investigate whether systemic inflammatory stimuli exacerbate axonal damage. Through the use of rat models of autoimmune encephalomyelitis, the researchers showed that microglia activation leads to an increase in carbon monoxide synthase, IL-1β, and axonal damage (107). The findings confirmed a relationship between peripheral inflammation and neurodegeneration in a rodent model (91). In another study, Polak et al. engineered an MS mouse model by infecting it with P. gingivalis. Their experiment showed that tail weakness and paralysis in the extremities developed while exacerbating MS pathology and increasing lymphocyte proliferation (108). These findings suggest that P. gingivalis can contribute to the exacerbation of MS pathology by causing an inflammatory response.

ALS is the most common motor neuron (MN) disease, with an average age of onset of 50-65 years (109). Neuroinflammatory processes induced by microglia and astrocytes appear to play an important role in ALS pathology. Reactive astrogliosis occurs under pathological conditions such as ALS, shifting these cells from a ‘neuroprotective’ to a ‘neurodegenerative’ role (110).

In ALS, astrocyte activation is associated with motor neuron degeneration, which promotes inflammation and OS. In the early stages of disease, astrocytes provide neuroprotection. As the disease progresses, activated astrocytes promote a neurotoxic environment. This occurs either through microglial activation processes or through compounds released by motor neuron, ultimately resulting in motor neuron death (111). Microglia also play a key role in ALS, with M2 microglia being neuroprotective and M1 microglia being toxic. Studies in animal indicate that as the ALS progresses in fALS mice, the number of ‘neuroprotective’ M2 microglia increases. However, at later stage, these microglia transition to ‘neurotoxic’ M1 microglia (112–115). Inflammatory cytokines released by astrocytes and microglia may promote glutamatergic excitotoxicity, thereby linking neuroinflammation to excitotoxic cell death. When critical thresholds are reached, reactive astrocytes and microglia may trigger irreversible pathological processes that subsequently lead to non-cell-autonomous death of motor neurons in ALS patients (116).

Despite the absence of P. g-LPS, research has shown that microglia in ALS models can be stimulated by various LPS sources. This triggers a transition from protective to pro-inflammatory conditions, resulting in the production of IL-12, TNFα, NO, superoxide anion, and peroxynitrite. This process causes motor neuron deterioration and exacerbates the disease in mice models of ALS. Additionally, these molecules enhance the interaction between extracellular glutamate and its receptor on motor neurons, causing increased calcium influx into the cells and triggering cellular death (117–119). In ALS, the motor regions of the CNS may be affected by neuroinflammation and OS, evidenced by the activation of reactive astrocytes and microglia, moderate invasion of peripheral immune cells, and increased levels of inflammatory mediators (120). Animal models primarily show unusual growth of astrocytes and the presence of inflammatory indicators such as cyclooxygenase-2, inducible NOS, and neuronal NOS (121). Clinical studies have found that astrocytes in the spinal cords of patients with ALS are cytotoxic to MN in culture (122). Cytokines, such as G-CSF, IL2, IL15, IL17, MCP-1 MIP1α, TNFα, and VEGF found in the cerebrospinal fluid of individuals with ALS were found to be unusually elevated (123). Furthermore, patients with ALS exhibit increased IL-6 levels in exosomes derived from astrocytes, indicating a potential role of CNS-derived exosomes in uncovering neuroinflammation in patients with ALS and a direct relationship with the rate of disease progression (124).

Moreover, in ALS, OS may play a role in the deterioration of neuromuscular junctions. Mouse models show enhanced sensitivity of nerve endings to ROS, which may lead to the degeneration of presynapses at neuromuscular junctions. Concurrently, excessive activation of excitatory amino acids leads to the irregular release of acetylcholinesterase, diminishing acetylcholine levels in the synaptic gap and potentially resulting in diminished muscle strength in patients with ALS. These initial malfunctions, coupled with diminished inflammation and nutritional aid, potentially culminate in neurodegenerative disorders (125).

Although no direct evidence exists that P. gingivalis is involved in the pathogenesis of ALS, we can conclude that neuroinflammation and OS are intertwined mechanisms involved in the pathophysiology of ALS. Although further research is needed to determine whether P. gingivalis influences ALS through mechanisms of neuroinflammation and OS, P. gingivalis can trigger neuroinflammation and OS, and we, therefore, hypothesize that it is involved in the development of ALS through neuroinflammation and OS.

Apart from the associations between P. gingivalis and AD, PD, and MS, which has been summarized above, no studies on the effects of P. gingivalis on other neurodegenerative diseases, such as ALS, have been reported. However, the unifying clinical feature or disease phenotype of these disorders is neuroinflammation. P. gingivalis not only induces neuroinflammation directly but also mediates neuroinflammation through the oral-intestinal-brain axis.

The oral cavity is the starting site of the digestive tract, and humans ingest approximately 1.5 × 10¹² oral bacteria daily from swallowed saliva (126), and P. gingivalis of oral origin can induce dysbiosis of the intestinal flora (127, 128). For example, a clinical study found altered gut microbiota in patients with periodontitis (129). Furthermore, in a previous study, we found that periodontitis-associated periodontal pathogens disrupt the gut microbiota, exacerbate the systemic immune response, and worsen colitis (130). According to Wang et al., oral microbes can have an impact on the gut, and P. gingivalis was detected in the feces of patients with colorectal cancer (131).

All these studies suggest that oral pathogenic bacteria can affect the central nervous system via the Gut-brain axis, suggesting the existence of an oral-intestinal-brain axis. A previous study also defined the presence of the Oral-gut-brain axis (132). It has been shown that P. gingivalis affects neuroinflammation by influencing intestinal ecology by increasing the number of inflammatory T and B lymphocytes, thereby inducing neuroinflammation (133, 134). Dysbiosis of the gut microbiota reduces the production of short-chain fatty acids, which are linked to inflammatory responses (135, 136). Another study indicated that the gut microbiota affects both microglial maturation and normal function and that dysregulation of the microbiota can lead to neuroinflammation (137). Feng et al. found that oral administration of P. gingivalis reduces intestinal permeability and elevates IL-17a levels in the peripheral blood of R1441G mice, potentially linked to neuronal demise and neuroinflammation (97). Thus, the aforementioned studies suggest that P. gingivalis influences neuroinflammation via the oral-intestina-brain axis, which may be closely related to the pathogenesis of several neurodegenerative diseases.

Currently, there is convincing evidence that oral P. gingivalis may influence neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Here, we summarize the relationship between the two diseases ( Figure 2 ).