In recent decades, significant advances in sequencing technologies have expanded our knowledge on the microbiome, sparking researchers’ interest in the role of the human microbiome in homeostasis and disease. Consensus establishes that many diseases, ranging from Alzheimer’s to endocrine disorders, and cancer, are associated with microbial imbalances or dysbiosis (1).

The oral cavity is the entry portal to the gastrointestinal tract. Changes in the oral cavity’s bacterial diversity can have local and systemic consequences on health and disease (2, 3). Within the oral cavity, bacteria can be found in the saliva or as a part of biofilm-structured communities. Interestingly, previous studies have linked poor oral health and chronic periodontitis with oral cancer (4). Severe cases of periodontitis can result in tissue degradation and tooth loss, potentially correlating with an elevated risk of developing gastric cancer (GC). However, the existing evidence from case-control studies and five cohort studies regarding tooth loss as a potential marker remains inconclusive. Significant heterogeneity among studies and mixed results between case-control and cohort studies contribute to this association’s uncertainty (5).

Perhaps the best example of an association between dysbiosis and cancer is Helicobacter pylori (H. pylori) and GC. This gram-negative bacterium colonizes the stomach and plays a central role in developing this pathology. H. pylori is widely recognized as an oncogenic factor and a driver of gastric carcinogenesis. In fact, the International Agency for Research on Cancer (IARC) classifies the H. pylori infection within the group I of human carcinogens (6). Within the gastric mucosa, H. pylori modulates acid secretion, affecting the gastric microbiome, leading to further dysbiosis, H. pylori overgrowth, and associated diseases. Current hypotheses suggest that recurrent and persistent H. pylori infections cause chronic inflammation, eventually leading to gastric carcinogenesis (7). In addition to H. pylori, new evidence suggests that other bacteria, including oral bacteria and their metabolites, may contribute to gastric carcinogenesis and GC progression (8, 9).

The oral microbiome is the most complex and dynamic arrangement of microbial communities within the human body. Changes in the oral microbiome can have profound consequences in an individual’s homeostasis. As pointed out earlier, periodontitis is a chronic inflammatory disease characterized by oral dysbiosis. Recent studies postulate that the transition from a healthy state into dysbiosis is driven by specific “keystone pathogens” that alter the host immune system, modifying the conditions of the microenvironment and disrupting the balance among bacterial communities.

Porphyromonas gingivalis (P. gingivalis or Pg) is a gram-negative, anaerobic, rod-shaped oral bacteria, and a keystone pathogen in chronic periodontitis (10). Despite its role in periodontitis, high levels of P. gingivalis have also been documented in healthy subjects without oral disease (11). Unlike other oral bacteria, P. gingivalis is an acid-resistant bacterium and studies demonstrate it is able to migrate from the oral cavity to the colon (12, 13). This suggests that P. gingivalis in the ingested saliva may easily reach the stomach. In addition to being swallowed, everyday activities such as brushing, flossing, chewing, and dental procedures cause transient P. gingivalis bacteremia (14, 15). Some of these activities can result in the translocation of the bacterium into other tissues, such as the liver, placenta, or even coronary arteries (16). Similar to other bacteria, P. gingivalis possess a variety of virulence factors, including gingipains (cysteine proteases), capsule, lipopolysaccharides (hereafter called Pg-LPS), and fimbriae. These factors modulate systemic inflammation, dysbiosis, tumorigenesis, and contribute to the evasion of the innate immune response. In one hand, gingipains are responsible for the development of periodontitis (16, 17), inducing cell migration and the release of other pro-inflammatory mediators (18). On the other hand, Pg-LPS is responsible for the maintenance of chronic inflammation by increasing the secretion of proinflammatory cytokines. Interestingly, a recent article reports that P. gingivalis and its gingipains may play a central role in other chronic, age-related pathologies, such as Alzheimer’s disease (19). Also, studies in rats demonstrate that topical applications of Pg-LPS lead to severe complications, including neuroinflammation and impaired learning and memory (20).

We hypothesize that oral P. gingivalis infection contributes to GC progression by increasing Pg-LPS, PAMPs, Pg-gingipains, inflammatory mediators, and immune checkpoint components, such as the PD1/PDL1 axis. Our hypothesis was based on the fact that most oral pathogens are unlikely to survive in an acidic stomach environment. Additionally, it has been observed that P. gingivalis, when present in oral plaque, is associated with a higher risk of precancerous gastric lesions (49). Furthermore, individuals with periodontal disease and high levels of colonization of periodontal pathogens are related to high levels of immunoglobulin G (IgG) anti-P. gingivalis in the serum of patients, indicating that this pathogen may also increase the mortality risk of cancer patients through other independent mechanisms associated with periodontitis (21).

A plausible explanation for this association could involve a “hit-and-run” mechanism in which transiently resident P. gingivalis is rapidly inactivated and destroyed by the acidic stomach environment, avoiding the installment of a local infection. However, bacteria can still release virulence factors such as Pg-LPS and gingipain-containing outer membrane vesicles (OMVs) locally and systemically (50) (Figure 1).

According to our hypothetical model, poor oral health generates a bacterial imbalance, or dysbiosis, that reduces the diversity of local bacteria (Figure 2). Thus, P. gingivalis becomes dominant in a process that can lead to severe chronic periodontitis and tissue destruction (51). Uncontrolled proliferation of P. gingivalis increases the production and delivery of virulence factors such as PAMPs, mainly Pg-LPS and gingipains via OMVs, impairing the host immune surveillance and further potentiating oral dysbiosis (52). At this stage, P. gingivalis could be translocated systemically to other organs. Previous studies have demonstrated the presence of P. gingivalis DNA in the cerebrospinal fluid of living subjects diagnosed with probable Alzheimer’s disease (19, 53). Subsequently, Pg-LPS and OMVs-containing gingipain reach the bloodstream and the lymphatic system via gingival vessels. Then, following our arguments to consolidate the hypothesis, Pg-LPS accesses the lymphatic ganglia and the gastric tumor microenvironment, where it binds to TLR4 receptors, increasing the expression of ligands and receptors of the immune checkpoint pathway (PD1/PDL1 axis). Activation of TLR4 receptors by Pg-LPS triggers the NF-κB pathway and production of pro-inflammatory cytokines in innate immune cells (54). Studies on peripheral T-cell lymphomas have shown that TLR4 overexpression is associated with higher PDL1 expression, translating into poorer prognosis (55).

Additionally, studies in mice suggest that TLR4 activation by systemic Pg-LPS can modulate the response to PD1 therapy during chronic viral infection (56). Therefore, following our line of argument, TLR4 activation by Pg-LPS increases PD1/PDL1 expression in T-cells and GC cells, leading to simultaneous T-cell exhaustion by PD1 and an increase in PDL1, which allows gastric tumor progression, culminating in a decrease in patient survival which evidences this fact (Figure 2).

Interestingly, studies combining colorectal cancer cell lines and mouse models have demonstrated that Pg-LPS promotes metastasis by increasing cell invasion and migration via NF-κB (57). Furthermore, regarding the association between PD1/PDL1 expression and cancer patients’ survival, a Japanese study showed that PDL1 expression was associated with worse overall survival in stage II/III GC patients (58). However, this association has been inconsistent among other malignancies, showing no association or improved patient survival in some cancers, and remain controversial (59–61).

A dysbiotic oral microbiome may contribute to the development of both local (oral) and systemic diseases. This includes a wide range of illnesses from dental caries and periodontal disease (62, 63) to cardiovascular disease and cancer (64, 65). A genomic study analyzed the composition of the digestive tract microbiome and reported a 45% of overlap between oral and stool bacteria (66), suggesting the transfer of oral bacteria into the stomach is not uncommon. In fact, ingested saliva contains a great amount of oral bacteria. Although these are usually unable to colonize a healthy gut they have been reported in the intestine of individuals that suffer from colon cancer and inflammatory bowel disease, among others (67). This supports the idea of the oral cavity as a reservoir for potential gastrointestinal pathogens, which in turn can exacerbate gastrointestinal diseases.

However, microbiota components also induce immune evasion mechanisms to restore homeostasis in the host organism. Previous studies have demonstrated a correlation between various cancers, the presence of P. gingivalis, and its diverse virulence mechanisms. Additionally, these studies highlighted the activation of immune checkpoint mechanisms in the host.

While the prognostic significance of PDL1 in gastric carcinomas remains uncertain, certain studies have highlighted its relevance in clinical outcomes across the entire cohort via multivariate analysis. Specifically, PDL1(+) tumors were identified as an adverse prognostic factor in Epstein Barr Virus (EBV)-positive carcinomas but not MSI-high carcinomas. Also, CD8+ tumors have shown low tumor-infiltrating lymphocytes, and more advanced-stage tumors were associated with unfavorable clinical outcomes. Furthermore, the knockdown of PDL1 in gastric carcinoma cells demonstrated significant suppression of proliferation, invasion, and cell migration while increasing apoptosis. Notably, these effects were prominent in two EBV(+) cell lines but not consistently observed across all three EBV (–) cell lines (68).

An investigation on PDL1 levels in a prostate cancer cell line revealed that infection with P. gingivalis and its PAMPs positively influenced PDL1 expression. This positive regulation was facilitated through the nucleotide-binding oligomerization domain (NOD)1/NOD2 signaling pathway. Interestingly, no upregulation was observed following the treatment of cells with Pg-LPS. These findings suggest that chronic inflammatory conditions within the organ might play a role in tumor immune evasion by altering the tumor microenvironment (69).

In several studies conducted on different cancer types, such as PC, it has been observed that microbiota communities within tumors partially overlap with those found in the oral cavity. For instance, P. gingivalis has been found to aggregate significantly more in PC tissues than in adjacent normal tissues, thereby altering the tumor microenvironment and promoting pancreatic tumorigenesis in murine models. This altered microenvironment is characterized by a notable increase in neutrophil enrichment and a significant decrease in CD8+ cytotoxic T cells. In contrast, no significant changes were observed in CD4+ T cells and monocytes. These findings suggest that P. gingivalis may induce a neutrophil-dominated proinflammatory response in mice with PC, contributing to the suppression of the tumor immune environment (70).

Elevated levels of anti-P. gingivalis antibodies have been identified in patients with pancreatic cancer (PC) compared to healthy controls. Moreover, P. gingivalis and other microbiota members possess peptidyl arginine deaminase (PAD) enzymes. Together with mutations in the arginine of tumor protein p53 (TP53), these factors establish a close relationship between a microbiota component, virulence factors, and the progression of PC (71).

Current evidence supports the significant role of PDL1 in carcinogenesis, particularly in hepatocellular carcinoma (HCC), where the bidirectional regulation of PDL1 mediated by TP53/mechanistic Target of Rapamycin Complex 1 (mTORC1) has been elucidated. In HCC with non-mutated TP53, mTORC1 suppression leads to increased E2F1 transcription factor expression. This increase interrupts the cytoplasmic interaction between E2F transcription factor 1 (E2F1) and PDL1, facilitating the translocation of E2F1 into the nucleus, where it positively activates PDL1 transcription. Conversely, in HCC with mutated TP53, mTORC1 suppression promotes PDL1 protein degradation through autophagy. Additionally, it has been observed that tumor infiltration by CD8+ T cells is significantly reduced in this type of HCC. These findings highlight the pivotal role of TP53 in regulating PDL1 expression and modulating immune evasion in HCC (72).

Investigating the microbiota in low biomass environments like the stomach and lungs poses significant challenges for molecular studies, primarily due to the difficulty in detecting pathogenic agents. Nonetheless, these environments also display reduced microbial complexity, potentially limiting the number of causal agents and mitigating the risk of establishing spurious causal relationships (73, 74). Randomized control trials and prospective cohorts can confirm or refute the model that links GC, PD1/PDL1 axis, and periodontitis-related pathogens (75).

In the realm of human pathologies, the investigation into potential standard causal links between periodontitis and rheumatoid arthritis (RA) has revealed a connection between the ability of P. gingivalis to citrullinate peptides and the presence of autoantibodies against citrullinated peptides, which are particular and sensitive markers in the diagnosis of RA. Consequently, peptide citrullination has been implicated in triggering an autoimmune response, whereby the immune system perceives modified self-proteins and peptides as foreign. While citrullinated peptides may play a role in the pathogenesis of RA, the precise nature of their emergence and function remains unclear, and the potential contributions of the microbiota in the citrullination process are yet to be fully elucidated (76, 77).

Ultimately, prospective studies should evaluate oral health status at diagnosis and utilize next-generation sequencing (NGS) tools to fully examine the presence of specific oral bacteria and virulence factors. Enhanced methodologies for elucidating causal relationships and experimental disease models will contribute to a more comprehensive assessment of the role played by particular microbiome organisms and their virulence factors in GC onset, progression, and response to anticancer treatment (78), taking into account that the experimental design of such studies are the main cause of overstating or understating the importance of certain pathogens or microbiome profiles on cancer, as was detailed by a critical review (79).

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

MM-M: Conceptualization, Writing – original draft, Writing – review & editing. MP: Conceptualization, Writing – original draft, Writing – review & editing, Visualization. LG: Writing – original draft, Writing – review & editing. MC: Writing – original draft, Writing – review & editing. FV-E: Writing – original draft, Writing – review & editing. PM: Writing – original draft, Writing – review & editing. AP: Writing – original draft, Writing – review & editing. BG-B: Writing – original draft, Writing – review & editing. TM: Writing – original draft, Writing – review & editing. JG: Writing – original draft, Writing – review & editing. MG: Writing – original draft, Writing – review & editing. IR: Writing – original draft, Writing – review & editing, Conceptualization, Funding acquisition, Supervision, Visualization.