The relationship between the imbalance of flora and the development of various diseases is hot research topics at the moment (Gao et al., 2018; Cao et al., 2024). Relevant studies have shown that poor oral hygiene can lead to flora imbalance and increase the risk of periodontal disease (Hajishengallis et al., 2012), oral cancer (Chen et al., 2021), esophageal carcinoma (Chen et al., 2015), colorectal carcinoma (Cheng et al., 2020), pancreatic cancer (Pourali et al., 2024), Alzheimer’s disease (Zhang Y. et al., 2024), rheumatoid arthritis (Li Y. et al., 2022) and other diseases. The imbalance of flora is often closely related to factors such as smoking (Apatzidou, 2022), sugar intake (Ge et al., 2021), and antimicrobial use (Rashid et al., 2012). A team of researchers from the Chinese University of Hong Kong recently wrote in Cell: in addition to Helicobacter pylori (H. pylori), Streptococcus anginosus (S. anginosus) is also a pathogenic bacterium that promotes gastric cancer (Fu et al., 2024). The virulent surface protein TMPC binds to annexin A2 (ANXA2) on gastric epithelial cells, triggering downstream activation of bacterial attachment, invasion, and carcinogenic mitogen-activated protein kinase (MAPK) signaling. This clearly demonstrates that dysbiosis influences the onset and progression of disease, and that microbes may also act synergistically to collectively promote the development of certain disorders.

There are more than 700 kinds of oral bacteria, of which Treponema denticola, porphyromonas gingivalis (P. gingivalis) and Tannerella forsythia are called “red complex” (Aas et al., 2005). P. gingivalis, which is low in abundance but has a strong influence on the oral microflora, is known as a “keystone species” (Darveau et al., 2012). Epidemiological studies indicate that P. gingivalis is detected in 50% to 80% of patients with severe periodontitis, significantly higher than in healthy controls (10%–30%). The highest infection rates are observed in Asian populations (particularly China and Japan), while lower detection rates are reported in European and American countries. Notably, P. gingivalis colonization is detectable in 37% of individuals aged 0–18 years, suggesting potential early microbial establishment. We have previously confirmed that P. gingivalis is a specific pathogen that promotes the progression of esophageal squamous cell carcinoma (Meng et al., 2019). It can activate the nuclear factor-κB (NF-κB, dysfunction of it can lead to inflammatory related diseases and cancer) pathway to promote the proliferation and migration of esophageal squamous cell carcinoma. P. gingivalis is a non-glycolytic, gram-negative anaerobic bacterium that produces outer membrane vesicles (OMVs) (Fan et al., 2023), lipopolysaccharide (LPS) (Stasiewicz and Karpiński, 2022; Li et al., 2021), gingipains (Travis et al., 1997) and other virulence factors. These virulence factors can help P. gingivalis better invade host cells and cause damage to body tissues. They can activate the immune system through multiple mechanisms and promote the production of inflammatory mediators, with implications for cancer and other diseases. This review primarily provides a detailed exploration of the molecular pathways linking the virulence factors of P. gingivalis to disease pathogenesis. It aims to offer insights for both basic researchers and clinical scientists, with the hope of proposing new research directions at the intersection of microbiology, immunology, and clinical medicine. Here, we introduce some pathogenic factors of P. gingivalis in detail:

The outer membrane vesicles are bilayer spherical membrane structures with a diameter of 50–250 nm, containing proteins, lipids, nucleic acids, and other biologically functional molecules (Zhang Z. et al., 2020). Their production is regulated by factors such as the expression of the fimA gene, autolysins, gingipains, and PPAD (a unique peptidyl deiminase) (Vermilyea et al., 2021). The process of formation may be as follows: The accumulation of misfolded or overexpressed envelope proteins increases the pressure of the outer membrane, and “budding” is formed at the site where the connection between the outer membrane and peptidoglycan is missing. The “budding” of vesicles leads to increased local curvature of the bacterial outer membrane (Bohuszewicz et al., 2016). The outer membrane vesicles are deployed by P. gingivalis to selectively coat and activate neutrophils,and they trigger degranulation without affecting neutrophil viability. Granular ingredients with antibacterial activity are degraded by powerful proteases bound by OMVs to ensure the survival of bacteria (du Teil Espina et al., 2022). Small RNA molecules in OMVs have potential gene regulatory functions as interspecific communication molecules. Some studies have suggested that sRNA45033 packaged by P. gingivalis OMVs can inhibit the expression of CBX5 (Chromobox 5, also known as heterochromatin protein 1 alpha, is a structural protein) in host cells and reduce the H3K9me3 (trimethylated of lysine 9 of histone H3) level of p53, resulting in increasing the expression of p53 and promoting host cell apoptosis (Fan et al., 2023).

LPS consists of three elements: O antigen, core polysaccharide,and lipid A (Qin et al., 2024). The key structure of LPS is the phosphorylated glucosamine disaccharide and the fatty acid lipid A,which can be specifically and sensitively recognized by the innate immune system (Herath et al., 2021). P. gingivalis has multiple forms of lipid A, and the lipid A domain influences the biological activity of host cells. Changes in domain fatty acids, the level of phosphorylation, and the deletion of phosphate or monosaccharide groups will affect the biological activity of host cells. LPS can promote cell proliferation and produce interleukin-1β (IL-1β), IL-6, and IL-8 (Kato et al., 2014). LPS is recognized by TLR4 (Toll-like receptor 4, TLR (Ferwerda et al., 2008) is a transmembrane glycoprotein that is expressed on the plasma membrane or the inner membrane of the cell,and it can form homologous or heterodimers and undergo conformational changes when ligands bind). TLR4 stimulates the myeloid differentiation primary response factor 88 (MyD88) to release nuclear factor κB (Stasiewicz and Karpiński, 2022).

Cysteine proteases from P. gingivalis have trypsin-like activity, which are important virulence factors in periodontitis, and they are called gingipains (Travis et al., 1997). Gingipains are classified into two primary categories: arginine-specific gingival proteases (Rgps, which can be subdivided into RgpA and RgpB) and lysine-specific gingival proteases (Kgps) (Nonaka et al., 2022). Gingipains play a role in host colonization, defense inactivation, iron and nutrient acquisition, and tissue destruction (Dominy et al., 2019). Firstly, Rgps are capable of binding to a variety of extracellular matrix proteins, thereby enhancing their adhesion within the host. Secondly, gingipains can proteolytically inactivate cationic antimicrobial peptides. They can degrade cytokines, complement formation, and several receptors, which collectively undermine host defense mechanisms (Imamura et al., 2003). Furthermore, gingipains degrade hemoglobin to liberate heme, facilitating the acquisition of nutrient peptides through a protein hydrolysis system composed of gingival protease-containing endopeptidases, oligopeptidases, and dipeptidyl and tripeptidyl peptidases, operating in a cascading manner. Ultimately, gingipains disrupt the equilibrium of proteolysis between host proteases and endogenous protease inhibitors, contributing to tissue destruction.

The fimbriae of P. gingivalis are filamentous surface appendages that extend from the outer membrane, consisting of two forms: long fimbriae composed of the FimA subunit and short fimbriae containing the Mfa1 subunit protein (Hasegawa and Nagano, 2021). Fimbriae enhance biomembrane formation, bacterial motility, bacterial adhesion to host cells, and bacterial invasion of cells (Xu et al., 2020). Each type of fimbriae consists of five FimA (A-E) and five Mfa1 (1–5) proteins, which are regulated by the fim and mfa gene clusters, respectively (Hasegawa and Nagano, 2021). Long fimbriae can activate NF-κB by binding TLR2, which promotes the production of pro-inflammatory cytokines, including IL-6, IL-1β, IL-8, and tumor necrosis factor-α (TNF-α) (Wielento et al., 2022). Long fimbriae also disrupt immune clearance by hijacking the complement pathway (Hajishengallis et al., 2008).

Periodontal disease is a chronic oral disease, including periodontitis and gingivitis, which can lead to bleeding and swelling of the gums, tooth loss, and its prevalence has increased year by year (Janakiram and Dye, 2020). There are many causative factors for periodontal disease, including dental plaque, tartar, tooth surface staining, food impaction, trauma, smoking, age, heredity, diabetes, sex hormones, psychological factors, of which dental plaque is the main cause. P. gingivalis has a great influence on the development of periodontitis, which colonizes the subgingival area and triggers periodontitis, producing virulence factors that further damage periodontal tissues (Hajishengallis et al., 2012).

The outer membrane vesicles have strong inflammatory properties, and they can regulate neutrophils and macrophages, facilitating the invasion of oral epithelial cells (Ma and Cao, 2021). P. gingivalis can cause immune cells to release many pro-inflammatory factors and enhance its inflammatory damage and immune evasion by promoting the proliferation of immunosuppressive cells (Su et al., 2017). When proinflammatory cytokines (such as TNF-α, IL-1, IL-6, IL-11,and IL-17) reach critical concentrations, periodontal tissue damage occurs. P. gingivalis can induce mitochondrial dysfunction by altering mitochondrial metabolic status, quality control, production of reactive oxygen species (ROS) and the mediation of apoptosis, which promote the occurrence of periodontitis (Luo et al., 2024). After infection by P. gingivalis, the gingival fibroblasts were transformed to pro-inflammatory phenotype. And they secreted proteolytic enzymes and induced osteoclast formation (Wielento et al., 2023). The invasion of P. gingivalis into osteoblasts downregulates the expression of transcription factors core-binding factor alpha-1 (Cbfa-1) and Osterix, which inhibits osteoblast differentiation and osteogenesis (Zhang et al., 2010). Osterix is a zinc-finger osteoblast-specific transcription factor, which regulates various genes involved in the differentiation and maturation of bone cells (Liu et al., 2020). The LPS of P. gingivalis may activate NF-κB, p38/mitogen activated protein kinase (MAPK), and extracellular signaling kinase (ERK) 1/2 pathways through TLR2 or TLR4, thereby promoting the production of inflammatory mediators (as shown in Figure 1) (Ding et al., 2013). Binding of TLR2 to LPS requires the assistance of fimbriae, CD14, and peptidylarginine deiminase (PPAD), and the absence of any one of these may block its binding (Wielento et al., 2022).

Fimbriae-induced TLR2 also promotes the interaction between P. gingivalis and complement receptor 3 (CR3), which activates the ligand-binding capacity of CR3, thereby stimulating the production of TNF-α, IL-1α, IL-1β, and IL-6 in macrophages (as shown in Figure 1) (Wang et al., 2007). TLR4 must form a dimeric complex with myeloid differentiation factor 2 (MD-2) in order to capture its ligand LPS. LPS-binding protein (LBP) and CD14 improve the efficiency of LPS transport and the sensitivity of the assay (Ryu et al., 2017). Proinflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-8, are induced by the activated NF-ĸB pathway. p38/MAPK pathway upregulates IL-6 expression in monocytes (Pollreisz et al., 2010). ERK1/2 mainly activates c-Fos to increase production of the pro-inflammatory cytokines TNF, IL-1β, IL-6, and IL-12p40 (Lucas et al., 2021). Some researchers have produced red cell membrane nanovesicles that can accurately target and adhere to P. gingivalis, which can inhibit P. gingivalis and prevent its invasion of epithelial cells, thus alleviating the progression of periodontitis (Tang et al., 2024). Some researchers have also produced a targeting nanoagent antibody-conjugated liposomal drug carrier with ginsenoside Rh2 (ALR), which can reduce the proportion of P. gingivalis and maintain a relatively stable oral flora (Chen et al., 2023). Studies have shown that bacteroides glutaminyl cyclases can inhibit P. gingivalis, which is a promising target for drug development in the treatment of periodontitis (Taudte et al., 2021).

In summary, P. gingivalis primarily contributes to periodontitis pathogenesis through three key mechanisms: promoting oral inflammatory responses, destroying periodontal tissues, and disrupting the osteoblast-osteoclast homeostasis. This pathogenic process involves multiple virulence factors comprising OMV, LPS, and fimbriae, along with proinflammatory cytokines and key osteogenic transcription factors including Osterix (as shown in Figure 1).

Oral cancer is one of the most prevalent malignant cancers in the world, with more than 90% being oral squamous cell carcinoma (OSCC) (Bagan et al., 2010). Factors known to promote OSCC include tobacco, alcohol consumption, betel nut chewing, viral infections, diet, deficiencies in vitamins and minerals, occupational exposures, and hereditary diseases. However, a growing number of epidemiologic, clinicopathologic, and molecular studies have demonstrated that oral microorganisms, such as P. gingivalis, also have an effect on the carcinogenesis of OSCC (Chen et al., 2021). P. gingivalis may contribute to oral carcinogenesis mainly through the following mechanisms:

Esophageal carcinoma, primarily divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), is more common in developing countries (Abnet et al., 2018). ESCC patients have a significantly lower diversity of oral microbiota than healthy individuals and those with atypical hyperplasia (Chen et al., 2015). Using 16S rRNA sequencing, the enrichment of P. gingivalis in the oral microbiome is much higher than in healthy individuals. This article focuses on the following mechanisms through which P. gingivalis affects ESCC.

Colorectal carcinoma (CRC) is one of the three most common cancers worldwide, and its morbidity and mortality rates remain high (Mármol et al., 2017). With changes in healthier lifestyle choices, the increase in colonoscopy screening and the improvement of treatment, the incidence rate may show a downward trend. Risk factors for CRC generally include a history of precancerous adenomatous polyps, having CRC or precancerous adenomatous polyps in immediate family members, family history of hereditary CRC, inflammatory bowel disease, and poor dietary habits (such as long-term drinking, excessive intake of barbequed, salted, smoked, or high-fat foods). At present, many studies have shown that intestinal flora imbalance is associated with CRC (Cheng et al., 2020).

Pancreatic was once thought to be a sterile organ, but with increasing research, it has been found that the pancreas is not sterile and human pancreatic cancer (PC) tissues are rich in intra-tumoral microbiota (Wong-Rolle et al., 2021). The pathogenesis of PC may involve microbiota-induced local inflammation, which impair the host anti-tumor immune surveillance and change the tumor microenvironment (Pourali et al., 2024). Studies have found that the abundance of P. gingivalis in the control group without pancreatic cancer is significantly lower than that in PC patients (Ma et al., 2023). P. gingivalis can also be found in human pancreatic intraepithelial neoplasia (PanIN) lesions. And repeated administration of P. gingivalis to wild-type mice can cause pancreatic acinar duct metaplasia (ADM), thus P. gingivalis may accelerate the progression of PanIN to pancreatic ductal adenocarcinoma (PDAC) (Saba et al., 2024). We will further describe how P. gingivalis promotes the progression of PC next:

Rheumatoid arthritis (RA) is an autoimmune disease characterized by painful, swollen joints that cause damage to both the joints and the organs outside the joints, including the lungs, heart, digestive system, kidneys, eyes, skin, and nervous system (Gravallese and Firestein, 2023). Studies have demonstrated the effect of P. gingivalis on rheumatoid arthritis (Li Y. et al., 2022), and its DNA has been experimentally detected in synovial tissues. In RA patients, the concentration of anti-P. gingivalis antibodies is related to the expression of anti-citrulline protein antibodies (ACPA). Wegner tested 11 kinds of oral bacteria such as P. gingivalis, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Prevotella orali. Wegner found that P. gingivalis was the only microorganism capable of producing endogenously guanosinated fibrinogen and enolase (Wegner et al., 2010). Among them, Aggregatibacter actinomycetemcomitans can create favorable colonization conditions for other organisms; it can suppress the host immune system and damage periodontal tissue, and the cytolethal distending toxin plays an important role in this process (Kim et al., 2023). Prevotella intermedia is associated with periodontal disease as well as other systemic diseases, including cystic fibrosis, chronic bronchitis, and atherosclerosis (Choe et al., 2019). The main virulence factors of Prevotella intermedia include LPS and cysteine protease, which have proinflammatory effects and promote immune escape (Zhang S. et al., 2024). Autoantibodies to the citrullinated forms of these antigens are highly specific for RA, and they play a causative role in the progression of the disease (Mikuls et al., 2012). Studies have suggested that this association may be based on the ability of P. gingivalis to express peptidyl deiminase (PAD), an enzyme responsible for citrullination of arginine residues post-translation, which can expose individuals to citrullinated antigens and easily lead to ACPA in the appropriate immunogenetic background, possibly contributing to the pathogenesis of RA synovitis (Hitchon et al., 2010). Smoking stimulates citrullination of the peptides PAD2 and PAD4, which is also an environmental risk factor for RA. These two findings suggest that positive anti-citrulline protein antibodies play a role in RA development (Krutyhołowa et al., 2022). Some scholars have constructed an animal model of MHC-type C3H mice with ACPA-positive RA that combines P. gingivalis infection and collagen immunity. Compared with the control group, the expression of ACPA and citrulline protein in this model was elevated, and there are significant changes in the subpopulations of immune cells, which may be a key factor in increasing bone destruction, inflammation, and pain (Yang et al., 2024). P. gingivalis induces the activation of M1 macrophages, which produce a variety of inflammatory cytokines that promote the progression of RA, such as TNF-α, IL-1β, IL-12. Overnutrition of RA macrophages leads to excessive glucose uptake, which in turn produces high levels of ATP and mitochondrial ROS, and high levels of ROS are involved in the destruction of joints and cartilage in RA. LPS can reduce the levels of oxidative phosphorylation and increases the levels of glycolysis in macrophages, which leads to the accumulation of intermediate metabolites of the tricarboxylic acid cycle such as succinic acid (Yang X. et al., 2020). Intracellular succinic acid induces angiogenesis via HIF-1α, whereas extracellular succinic acid acts on the activation of G protein-coupled receptor 91 (GPR91), which together disrupt energy metabolism and exacerbate inflammation and angiogenesis in the synovial membrane of arthritic joints (Li et al., 2018). Metabolism in M1 macrophages promotes the production of lactic acid and succinic acid, which acidify the extracellular space, leading to the formation of a low-glucose and high lactic acid microenvironment, which is typical of the microenvironment in RA (Lin et al., 2022).

Alzheimer’s disease (AD) is a disease associated with progressive neurodegeneration that is characterized by intracellular amyloid beta protein (Aβ) plaques in the brain and neurofibrillary tangles (NFT). Diagnosis currently relies on positron emission tomography (PET) with tracer molecules and analysis of proteins in the cerebrospinal fluid (CSF) (Khan et al., 2020). Studies have proved that Alzheimer’s disease is strongly associated with dysbiosis (Zhang Y. et al., 2024). Various P. gingivalis biomolecules have been identified in the cortical gray matter, basal forebrain and hypothalamus regions of the human AD brain.

Aspiration of oral bacteria aggravates lung disease and gastrointestinal microbiota-gut-brain axis disorder. It induces chronic systemic inflammation, which manifests itself in the brain as an increased neuroinflammatory load (Xue et al., 2020). At the same time, the epithelial damage in the inflamed periodontal pocket makes it easier for periodontal bacteria to invade the adjacent primary afferent nerves and blood vessels. Periodontal bacteria that escape from the mouth go directly into the brain along these nerves and blood vessels, causing brain infections. This brain inflammation causes activated microglia and reactive astrocytes to produce inflammatory mediators that promote the production of Aβ. The accumulation of Aβ leads to hyperphosphorylation of Tau, which constitutes the histopathological signature of AD (Selkoe and Hardy, 2016). P. gingivalis OMVs can disrupt and penetrate the blood-brain barrier (BBB) by a number of mechanisms, and gingipains enriched on the surface of OMV can cleave a number of protein components of the barrier, including extracellular matrix proteins, connexins and integrins (Zhao et al., 2015). P. gingivalis OMVs can cleave endothelial adhesion protein blood plates/endothelial cell adhesion molecule-1 (PECAM-1) that is present at the BBB adhesion junction,and vascular permeability can be increased in vitro in a gingivalis-dependent manner (as shown in Figure 6) (Farrugia et al., 2020). Gingipains degrade β1-integrin. The deficiency of β1-integrin in endothelial cells resulted in an imperfect blood-brain barrier and significant cerebral hemorrhage in mice (Qiu et al., 2018). Gingipains have a strong affinity for several extracellular matrix proteins, such as astrocyte laminin, which can regulate pericyte differentiation to affect the integrity of the blood-brain barrier (as shown in Figure 6) (Yao et al., 2014). LPS of P. gingivalis can activate NF- κB and STAT3 pathways by binding to TLR2 and TLR4 on microglia, which can increase the expression and secretion of proinflammatory cytokines, including TNF- α, IL-1 β, IL-6, IL-17 and IL-23 (Qiu et al., 2021). Specifically, the activation of NF-κB pathway by LPS of P. gingivalis promotes the production of cathepsin B in microglial cells, which leads to the production of IL-1β in microglia. IL-1 β acts on neuronal IL-1 receptors and promotes the expression and processing of amyloid precursor protein (APP) and tau phosphorylation in neurons that can cause chronic activation of neuroinflammation (as shown in Figure 6) (Liu et al., 2024). LPS of P. gingivalis activates GSK-3β in microglia, leading to increased expression of TNF-α, which can trigger AKT-GSK-3β-mediated tau hyperphosphorylation in neurons (as shown in Figure 6) (Jiang et al., 2021). Gingipains may play a key role in this process, and inhibition with gingipains can reduce the bacterial load of P. gingivalis brain infection, which can reduce neuroinflammation and save neurons in the hippocampus (Dominy et al., 2019). Although all strains can invade the brain, only the most virulent P. gingivalis strains K1 and K2 effectively induce proinflammatory cytokine production, astrogliosis, Aβ secretion, Tau hyperphosphorylation, and cognitive decline under short exposure to infection (Díaz-Zúñiga et al., 2020). Regarding the role of gingipains in AD, gingipain inhibitors (COR388, Atuzaginstat) have been developed. This small-molecule inhibitor specifically targets gingipains, reducing P. gingivalis brain infection, decreasing Aβ deposition, and improving cognitive function in animal models. In clinical trials, COR388 treatment slowed cognitive decline by 57% in Pg-positive AD patients (measured by ADAS-Cog11 scores). The next-generation inhibitor, LHP588, exhibits superior blood-brain barrier permeability. Currently undergoing Phase 2 trials, LHP588 demonstrates significant therapeutic promise for AD treatment.

Studies have shown that oral flora dysbiosis and the enrichment of certain specific pathogenic bacteria are strongly associated with heart-related diseases (Ghanem et al., 2024). The pathogenesis of atherosclerosis by P. gingivalis may start from the stage of promoting the pathological changes of lipid metabolism, which induces the oxidation of high-density lipoproteins and compromises the atherosclerotic protective function of these lipoproteins (Kim et al., 2018). P. gingivalis and its gingipains promote the production of ROS and consume antioxidants, such as Rgp and Kgp, which can cause lipid peroxidation (Lönn et al., 2018). Entry of P. gingivalis into vascular endothelial cells was positively correlated with bacterial load as well as with some virulence proteins such as gingipains, fimbria, and hemagglutinin A. The Kgp significantly causes endothelial homeostasis imbalance by reducing plasminogen activator inhibitor-1 levels in endothelial cells, ultimately leading to permeability and dysfunction of the vascular endothelial barrier (Song et al., 2022). P. gingivalis can cause cells to lose the ability of self-repair by inhibiting endothelial cells proliferation, promoting endothelial mesenchymal transition and endothelial cell apoptosis. P. gingivalis promotes the expression of macrophage migration inhibitory factor (MIF) in endothelial cells, which stimulates the secretion of proinflammatory cytokines by macrophages, prolonging macrophage survival and exacerbating inflammatory responses (Xu et al., 2018). Macrophage migration inhibitors enhance the formation of foam cells (Chen et al., 2017). Gingipains have effects on the proliferation and phenotypic transformation of smooth muscle cells (SMC) in rats (Cao et al., 2015). The fragmentation of vascular IV collagen can be caused by matrix metallopeptidase 9 produced by macrophages that are induced by P. gingivalis. P. gingivalis infection not only leads to platelet activation and aggregation, but also increases the expression of P-selectin and the binding of fibrinogen to platelets, which may promote thrombosis, increasing the risk of thrombus formation (Czerniuk et al., 2022).

At present, studies have suggested that the abundance of P. gingivalis in patients with chronic obstructive pulmonary disease (COPD) was significantly higher than that in the non-COPD group (Wu et al., 2017). P. gingivalis in the tracheal aspirates of patients with AECOPD was highly homologous to the strains present in dental plaque, and the number of P. gingivalis was higher than that in the mouth (Tan et al., 2014). The above studies have shown that COPD was related to P. gingivalis. Compared with the normal control group, the relative content of P. gingivalis in patients with COPD was significantly negatively correlated with FEV1% (Tan et al., 2019). Compared with neighboring lung tissues, the positivity rate of P. gingivalis staining slices in cancer tissues of small-cell lung cancer, pulmonary adenocarcinoma, and pulmonary squamous cell carcinoma was higher, and the survival rate and median survival time of lung cancer patients were also significantly reduced due to bacterial infection with P. gingivalis (Liu Y. et al., 2021). Some studies have found a positive correlation between the risk of lung cancer and the level of IgG antibodies to P. gingivalis (Ampomah et al., 2023). Clinical data further demonstrate that patients testing positive for P. gingivalis infection demonstrate significantly reduced overall survival, with the most statistically significant difference observed in lung squamous cell carcinoma (LSCC) patients. P. gingivalis is a potent inflammatory stimulant in human bronchial and pharyngeal epithelial cells, stimulating the production of TLR2-mediated cytokines IL-6 and IL-8, which may lead to episodes of aspiration pneumonia (Watanabe et al., 2020). Intratracheal inoculation of P. gingivalis W83 in female BALB/c mice significantly increases TNF-α, IL-6, monocyte chemotactic protein-1 (MCP-1), and CRP levels within 24 h compared to gingipain-deficient mutants (Benedyk et al., 2016). TNF-α is an effective activator of NF-κB that promotes neutrophil inflammation and activates macrophages, which may be implicated in the development of lung cancer and COPD (Benoot et al., 2021). MCP-1 recruits and activates inflammatory cells in the airways, including T lymphocytes and B lymphocytes and monocytes. Gingipains may play a role in the production of these proinflammatory cytokines. Mice inoculated with a strain of P. gingivalis that knocked out gingivalis-related genes showed only brief and mild pneumonia with no significant change in pro-inflammatory cytokines, whereas mice inoculated with wild-type P. gingivalis showed symptoms of respiratory failure (Shi et al., 2023).

P. gingivalis not only promotes the occurrence and development of the above diseases, but also is strongly associated with diabetes, depression, metabolic dysfunction-associated fatty liver disease (MAFLD), adverse pregnancy outcomes and other diseases.

Diabetes is a metabolic disease characterized by high blood sugar (Harreiter and Roden, 2023). Studies have found that treatment of periodontal disease leads to improved metabolic control in diabetic patients (Vergnes, 2010). Lipopolysaccharide of gram-negative bacteria can lead to insulin resistance (Cani et al., 2007). Periodontal dysbiosis may first trigger regional metabolic inflammation and then systemic metabolic inflammation, promoting insulin resistance and type 2 diabetes mellitus (T2DM) (Blasco-Baque et al., 2017). P. gingivalis OMVs attenuate insulin-induced Akt/GSK-3β signaling in a gingipain-dependent manner, inducing changes in glucose metabolism in the liver and contributing to the progression of diabetes (Seyama et al., 2020). Clinical evidence suggests that T2DM and periodontitis show higher susceptibility to the highly virulent FimA genotype II strain of P. gingivalis compared to periodontitis patients without systemic diseases. The use of antimicrobial mouthwash in T2DM patients has been shown to significantly reduce oral colonization of P. gingivalis and other periodontal pathogens, with associated reductions in glycated hemoglobin (HbA1c) levels observed in some patients.

Metabolic dysfunction-associated fatty liver disease is classified by histologic features into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) (Guo et al., 2022). Epidemiologic investigations suggest that a history of periodontitis may be an independent risk factor for MAFLD (Akinkugbe et al., 2017). P. gingivalis infection leads to disruption of the oral mucosal barrier, causing bacteremia and endotoxemia that may accelerate the progression of MAFLD (Wang T. et al., 2022). P. gingivalis may contribute to the progression of NASH by activating the LPS-TLR2 pathway and inflammatory vesicles (Furusho et al., 2013). P. gingivalis LPS may promote intracellular lipid accumulation and inflammatory responses in HepG2 cells (a type of liver tumor cell line) by activation of the NF-κB and JNK signaling pathways (Ding et al., 2019).

Severe depression is one of the most common personal and public health conditions in the world that can debilitate people (Monroe and Harkness, 2022). Studies have found that periodontitis is an independent risk factor for depression (Hsu et al., 2015). The hypothesis of deficiency of neurotrophic factors in the pathogenic mechanism of depression refers to the reduction of neurotrophic factors that prevents the brain from adapting to environmental stimuli, leading to the onset of depression (Duman et al., 1997). LPS from P. gingivalis activates astrocytes and downregulates p75NTR via TLR4, which inhibits the maturation of brain-derived neurotrophic factor (BDNF) and ultimately promotes depression (Wang et al., 2019).

Adverse pregnancy outcomes generally include ectopic pregnancy, spontaneous abortion, stillbirth, premature delivery,low birth weight fetuses, gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (Farland et al., 2019). Studies have found that periodontal disease is associated with adverse pregnancy outcomes (Figuero et al., 2020). LPS of P. gingivalis has an effect on the growth of placenta and fetus (Kunnen et al., 2014). P. gingivalis may induce the production of antibodies that cross-react with beta2-glycoprotein I (beta2GPI), the target antigen of autoimmune anticardiolipin antibodies (aCL), which cause abortion in mice (Schenkein et al., 2013). Dentists should provide safe periodontal disease treatment for pregnant women to reduce some adverse effects (Bobetsis et al., 2020).

P. gingivalis produces many virulence factors such as OMVs, LPS, gingipains, and fimbria, which allow P. gingivalis to better invade the organism and lead to the development of a series of diseases in the host (as shown in Table 1). Among the diseases mentioned in this paper, the diseases caused by LPS activating NF-κB are periodontal disease (Ding et al., 2013), esophageal cancer (Meng et al., 2019), colorectal cancer (Wang et al., 2021), Alzheimer’s disease (Qiu et al., 2021), cardiovascular disease (Lei et al., 2011) and MAFLD (Ding et al., 2019). The diseases of GSK-3β activated by LPS are oral cancer (Lee et al., 2017), esophageal cancer (Liu et al., 2023) and Alzheimer’s disease (Jiang et al., 2021). STAT3 activation by LPS is associated with esophageal cancer (Gao et al., 2017) and Alzheimer’s disease (Qiu et al., 2021). P. gingivalis LPS activates astrocytes, which inhibits brain-derived neurotrophic factor (BDNF) maturation and promotes depression (Wang et al., 2019). LPS can also affect the adverse pregnancy outcomes (Kunnen et al., 2014). The pathway activated by P. gingivalis LPS mainly promotes the production of inflammatory cells, and fimbriae can help LPS bind to TLR2. P. gingivalis Mfa1 may bind to TLR2, which can induce human bronchial epithelial cells to produce IL-6 and IL-8 (Takahashi et al., 2022). The diseases caused by gingipains virulence factors are periodontal disease (Imamura, 2003; Cichońska et al., 2024), esophageal cancer (Malinowski et al., 2019), colorectal cancer (Mu et al., 2020), Alzheimer’s disease (Zhao et al., 2015), aspiration pneumonia (Benedyk et al., 2016) and RA (Ahmadi et al., 2023). Gingipains can cleave IgG in the Fc region and convert it into rheumatoid factor (RF) antigen. OMVs can promote the occurrence and development of AD (Zhao et al., 2015) and diabetes (Seyama et al., 2020). Other studies have suggested that it is related to RA, because 78 citrullinated proteins have been found in OMVs (Larsen et al., 2020). OMVs can also increase vascular permeability and promote cardiovascular disease, which may be related to the mechanism of proteolysis of endothelial cell adhesin molecules (such as PECAM-1) (Farrugia et al., 2020). P. gingivalis can promote the occurrence of oral cancer (Abdulkareem et al., 2018), colorectal cancer (Wawruszak et al., 2019) and pancreatic cancer (Li R. et al., 2022) by inducing EMT formation. From the above, we can find that the diseases promoted by P. gingivalis have a common pathway, but some of them are different. Reasons for this effect may be that many virulence factors of P. gingivalis play a strong or weak role and the occurrence of the diseases in various parts of the body.

This review synthesizes extensive literature on P. gingivalis through critical evaluation and systematic summarization, deliberately excluding studies with unclear or unsubstantiated mechanisms to ensure the objectivity and scientific validity of the presented pathogenic mechanisms. Nevertheless, certain limitations must be acknowledged. Some disease-related research remains confined to in vitro experiments, resulting in a translational gap for clinical applications, while other mechanistic observations lack sufficient experimental data for comprehensive interpretation. Emerging therapeutic strategies against P. gingivalis-associated diseases warrant discussion. A novel detection method utilizing recombinase polymerase amplification combined with lateral flow (RPA-LF) technology has been successfully developed, demonstrating clinical potential for point-of-care diagnosis. The FimA genotype of P. gingivalis, particularly prevalent in diabetic populations, correlates with heightened virulence and may serve as a molecular biomarker for high-risk individuals. Probiotic interventions involving the gut commensal Akkermansia muciniphila have shown promise—this bacterium enhances oral mucosal immunity via the TLR-MYD88-NF-κB pathway, upregulates antimicrobial peptide expression, and inhibits P. gingivalis adhesion and invasion (Hu et al., 2025). Exploiting P. gingivalis’ heme-dependent growth, erythrocyte-mimicking nanovesicles loaded with gallium protoporphyrin can be selectively internalized by the bacterium. Subsequent blue light irradiation generates ROS to achieve targeted bactericidal effects while preserving commensal microbiota. The aforementioned gingipain inhibitor COR388 (Atuzaginstat) has exhibited potential in slowing cognitive decline in AD patients. Integrated multi-omics approaches, incorporating genomic, proteomic, and metabolomic data, could refine personalized therapeutic strategies. Furthermore, interdisciplinary convergence of microbiology, immunology, and materials science is poised to advance precision-targeted interventions against P. gingivalis.

Through investigating the relationship between P. gingivalis and these diseases, we can gain deeper insights into its pathogenic mechanisms in disease development. This article primarily examines the pathological mechanisms underlying P. gingivalis-associated diseases. However, specific mechanisms of P. gingivalis virulence factors for some diseases are not clear at present, which require further research and discussion. Our research has demonstrated that reducing P. gingivalis colonization significantly benefits oral health maintenance, particularly in preventing and controlling periodontal disease progression. How to eradicate P. gingivalis and the relationships between P. gingivalis and other oral pathogens and intestinal microbiota are topics that we need to study next. The multi omics approach combining metagenomics, transcriptomics, and metabolomics may become an important breakthrough for future research.