Authors: Sifan Liu, Shidong Wang, Nan Zhang, Peng Li
Categories: Review Article, Oral microbiome, cancer, digestive disease, microbiota, upper gastrointestinal disease
Source: Journal of Oral Microbiology
Microbiomes are essential components of the human body, and their populations are substantial. Under normal circumstances, microbiomes coexist harmoniously with the human body, but disturbances in this equilibrium can lead to various diseases. The oral microbiome is involved in the occurrence and development of many oral and gastrointestinal diseases. This review focuses on the relationship between oral microbiomes and oral and upper gastrointestinal diseases, and therapeutic strategies aiming to provide valuable insights for clinical prevention and treatment.
To identify relevant studies, we conducted searches in PubMed, Google Scholar, and Web of Science using keywords such as “oral microbiome,” “oral flora, ” “gastrointestinal disease, ” without any date restrictions. Subsequently, the retrieved publications were subject to a narrative review.
In this review, we found that oral microbiomes are closely related to oral and gastrointestinal diseases such as periodontitis, dental caries, reflux esophagitis, gastritis, and upper gastrointestinal tumors (mainly the malignant ones). Oral samples like saliva and buccal mucosa are not only easy to collect, but also display superior sample stability compared to gastrointestinal tissues. Consequently, analysis of the oral microbiome could potentially serve as an efficient preliminary screening method for high-risk groups before undergoing endoscopic examination. Besides, treatments based on the oral microbiomes could aid early diagnosis and treatment of these diseases.
Oral microbiomes are essential to oral and gastrointestinal diseases. Therapies centered on the oral microbiomes could facilitate the early detection and management of these conditions.
KEYWORDS: Oral microbiome, upper gastrointestinal disease, microbiota, digestive disease, cancer
The microbiome is a crucial component of the human body, and the ratio of its number to the number of human cells is about 1 [1]. Moreover, the total number of genes within the microbiome is 150 times greater than that of all the genes in the human genome. Typically, microbiomes and the human body coexist in a state of harmony. However, any disturbance in this delicate balance can lead to various diseases [2–5]. Over the past few years, the association between the microbiome and the human body has gained significant attention.
The human oral cavity harbors a complex microbiome, owing to its specific anatomical structures, connection to the external environment, and humid conditions [2]. It boasts the highest density and diversity of microbial species compared with other parts of the body [6]. The oral microbiome mainly consists of bacteria, fungi, viruses, archaea, and protozoa [2]. These microorganisms predominantly colonize the oral mucosal pellicle and dental pellicle and will be prevalent in whole saliva [7]. Research has confirmed that after the initial acquisition of the first colonizing microorganisms in early life, the diversity of the oral microbiome changes throughout an individual’s lifespan [2,8]. The association between oral microbiome dysbiosis and its consequential impact on human health has been the subject of extensive investigation. Such an imbalance within the oral microbiota has been implicated in the pathogenesis of a plethora of oral diseases, notably dental caries, and periodontitis. Furthermore, emerging evidence suggests that dysbiosis of the oral microbiota may contribute to an increased risk of various systemic malignancies, including head and neck squamous cell carcinoma and pancreatic cancer, as well as systemic inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus [9–12]. These insights highlight the critical importance of preserving microbial homeostasis in the oral cavity as a measure to bolster overall health and forestall the development of a diverse array of diseases.
The oral cavity is an integral part of the upper gastrointestinal tract. Saliva swallowing, regardless of food intake, occurs continuously, serving as a means of oral clearance. During this process, certain opportunistic pathogens in the oral cavity may enter the gastrointestinal tract, potentially causing certain gastrointestinal diseases. Subsequently, these pathogens may colonize and multiply in the gastrointestinal tract and participate in the occurrence and development of related upper gastrointestinal diseases [13,14], especially cancer. As most upper gastrointestinal cancers are diagnosed at an advanced stage, the overall prognosis and quality of life of patients are poor, which is a major healthcare challenge [15,16]. Therefore, it is necessary to explore the relationship between the oral microbiome and upper gastrointestinal diseases.
In this review, we mainly focus on the association between the oral microbiome, and oral and upper gastrointestinal diseases, and current therapies. By shedding light on these associations, we aim to offer valuable insights for clinical prevention and treatment. The major conclusions are summarized in Figures 1 and 2.
Figure 1. Summary of changes in microbiome composition in different oral and upper gastrointestinal diseases. The figure was created with Biorender.com.
Figure 2. Summary of pathogenesis of oral and upper gastrointestinal tract cancers mediated by the oral microbiome. The figure was created with Biorender.com.
The microbiome of the oral cavity is the second-largest microbiota in the human body, harboring various microorganisms [17], including bacteria, fungi, viruses, archaea, and protozoa [2]. Owing to the accessibility and convenience of sampling in the oral cavity, the oral microbiome is one of the most extensively studied microbial communities [18]. The composition of the oral microbiome is complex and influenced by many factors, including genetics, the environment, and changes throughout an individual’s life [19,20]. In the initial moments following birth, the human body acquires its initial microbiome through direct contact with the mother and environment [20]. As individuals age, the composition of the human microbiome changes dynamically and forms a symbiotic equilibrium with the human body [2,8].
There are many species of microbiomes in the oral cavity, including more than 1000 different bacteria [2], 100 different fungi [21], archaea, viruses, protozoa [22] and so on. The oral bacterial species mainly include the phyla Actinobacteria, Bacteroidetes, Chlamydia, Euryarchaeota, Fusobacteria, Firmicutes, Proteobacteria, Spirochaetes, and Tenericutes [20]. Advances in molecular biology techniques, particularly gene sequencing and microbial culture, have led to the emergence of areas of interest like oral fungi and viruses, and candidate phyla radiation (CPR) [23]. Regarding fungi, approximately 100 species exist in the oral cavity, including those belonging to the genera Aspergillus, Aureobasidium, Candida, Cladosporium, Cryptococcus, Fusarium, Gibberella, Penicillium, Rhodotorula, and Schizophyllum, as well as the order Saccharomycetales [21]. Among healthy individuals, oral fungal species exhibit high interindividual variability. CPR phyla such as GN02, SR1, and TM7 can affect oral ecology by modulating oral microbial structure and function [24]. Owing to the inherent difficulties associated with the in vitro cultivation of CPR bacteria, there is a paucity of research elucidating their physiological roles and interactions with hosts. Within the CPR clade, the TM7 lineage has been subjected to the most comprehensive investigation. A recent breakthrough was the isolation of a TM7 strain, designated TM7x (strain TM7× HOT_952), along with its host, Actinomyces odontolyticus actinosynbacter (strain XH001), from the human oral microbiome [25]. This achievement marks a unique instance of successful in vitro culture and sustained maintenance of a CPR species. Studies of this co-culture have demonstrated that macrophages infected with the TM7X-associated XH001 display a significantly diminished cytokine response compared to those infected with XH001 alone. This observation suggests that the symbiotic relationship between TM7x and XH001 might extend beyond mere metabolic interdependence to encompass more intricate pathogenic-host dynamics [25]. In addition, it is important to note that archaea, viruses, and protozoa are also present in the oral cavity, albeit in lower abundance compared to bacteria and fungi [22]. Although some studies have indicated that oral archaea are non-pathogenic, they have been found in inflamed pulp tissue, peri-implant inflammation, and subgingival biofilms in patients with periodontitis and dental caries [26,27]. Moreover, there is evidence linking their presence to various gastrointestinal disorders, such as inflammatory bowel disease and colorectal cancer [28]. As for oral viruses, they encompass both eukaryotic viruses and bacteriophages [29]. Recent investigations have shed light on the distinctiveness, persistence, and sex-specific characteristics of oral viral communities, emphasizing the need for further exploration of their potential functions [30,31].
Microorganisms within the oral cavity adeptly colonize diverse sites, such as the surfaces of teeth, tongue, buccal mucosa, palate, and gingiva, as well as the planktonic environment of saliva [32]. Saliva plays a crucial role in facilitating the colonization by oral microorganisms. It not only provides nutrients for microbial growth but also contains an array of components that possess antibacterial properties, such as antimicrobial peptides, secretory immunoglobulin A (sIgA), lysozyme and lactoferrin. While catalase is present in saliva and contributes to the degradation of hydrogen peroxide, further research is needed to clarify its role as an antimicrobial protein in comparison to other well-established antimicrobial constituents [33,34]. These components significantly contribute to the control of oral microbial communities and the maintenance of homeostasis [35]. While salivary pellicle formation on tooth surfaces can facilitate microbial attachment, the flowing nature of saliva generates shear forces that help to minimize microbial colonization [36]. It is critical to distinguish between the mucosal biofilms on oral mucosal surfaces and dental plaque on tooth enamel, both of which involve aerobic and anaerobic microorganisms but differ in their adherence and structure [37]. The oral microbiota can be influenced by various factors, including sex [38], age [39], ethnicity [40], geographical location [41], and smoking [42]. Additionally, diet plays a main role in this process, especially in supragingival plaque [43]. Griffen et al. conducted a study on the acquisition and succession of the human oral microbiome. The oral cavity is sterile before birth, and within a few minutes after birth, a microbiome resembling vaginal or skin microbes can be detected in the mouth of newborns, which is influenced by the mode of delivery. This early established microbiome is swiftly replaced by a shared microbiome that is common to all infants and adults, leading to an organized microbial succession and the formation of a complex microbiome. The shared microbiota dominates the microbiota at all ages, indicating that the dominant microbiota is established early on and persists throughout life [44]. In addition, Griffen et al. have developed a high-throughput approach to characterize bacterial community subspecies/strains by targeting the ribosomal intergenic spacer region (ISR) to further investigate the acquisition of oral microbiota. Their results reveal that oral microbiota acquisition is primarily driven by the environment rather than host genetics. A diverse combination of factors, such as exposure and shared environments, contributes to the development of a highly personalized microbiome in humans [44]. Therefore, the diversity of oral microbiota plays a crucial role in the occurrence and development of human health and related diseases, warranting further exploration.
Throughout the progression of periodontitis, bacteria instigate an inflammatory response in the periodontal tissues, triggering activation of the immune system. Subsequently, the immune system releases inflammatory mediators, including cytokines and chemokines, which serve to attract immune cells such as neutrophils to the inflamed area. The engagement of these inflammatory cells leads to tissue destruction and perpetuates additional inflammatory reactions, ultimately culminating in the advancement of periodontitis. Periodontitis is an inflammatory condition characterized by significant clinical hallmarks, including gingival bleeding, loss of periodontal attachment, alveolar bone loss, and irreversible tissue destruction [45]. These symptoms distinguish periodontitis from gingivitis, which involves only the superficial layers of the gums and is generally reversible [46]. The diagnosis of periodontitis is predicated on the detection of these irreversible signs, which is crucial for clinical assessment and management. Traditional culture-based approaches have identified Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola as the pathogenic trio [47,48] associated with periodontitis. Molecular techniques have extended the list of pathogens to include Gram-positive bacteria such as Filifactor alocis and Peptoanaerobacter stomatis, Gram-negative members of the Bacillotaphylum (Dialister spp., Megasphaera spp., and Selenomonas spp.), and species in the genera Prevotella, Desulfobulbus, and Synergistes, among others [49,50]. This observation highlights the involvement of numerous oral microorganisms in the etiology and progression of periodontitis. Therefore, it is imperative to investigate the pathogenesis and therapeutic strategies of periodontitis from the standpoint of oral microbial-host interactions.
Gingivitis is a prevalent site-specific inflammatory condition initiated by dental plaque accumulation. It is characterized by gingival erythema and edema without loss of periodontal attachment. Usually painless, gingivitis may be associated with bleeding during toothbrushing and probing, though spontaneous bleeding is rare. While gingivitis is a reversible condition, if left untreated, it may progress to periodontitis. Periodontitis is a more advanced stage of periodontal disease characterized not only by gingival inflammation but also by connective tissue attachment loss and bone loss, which may lead to tooth mobility and ultimately tooth loss [51,52]. Periodontitis manifests as gum redness, swelling, bleeding, and halitosis, accompanied by tooth mobility and potential tooth loss. Aggressive periodontitis, an uncommon but severe form of periodontal disease, primarily affects young individuals, exhibiting an accelerated disease progression and severe tooth destruction [53,54]. Notably, patients with invasive periodontitis typically demonstrate less plaque and calculus accumulation but present with specific microbial infections, including Aggregatibacter actinomycetemcomitans (Aa). Aa is capable of producing high levels of leukocytotoxin (LtxA), which selectively binds to human leukocytes and induces immunosuppression [55]. Furthermore, Aa can express cytolethal distending toxin (CDT), causing DNA damage, cell cycle arrest, and apoptotic cell death [56]. Additionally, the lipopolysaccharide (LPS) on the surface of Aa serves as a potent pro-inflammatory factor [56]. Although mild periodontal inflammation does not inevitably lead to tissue destruction, it is not always inherently controlled and has the potential to progress. It is important to recognize that such inflammation is controllable and, with proper management, can be prevented from advancing to a state that causes tissue destruction. Recent studies have introduced the polymicrobial synergy and dysbiosis (PSD) hypothesis [57–59], which emphasizes the relationship between dysbiosis of the oral microbiome and inflammation, which reinforce each other and promote periodontitis [60]. This suggests that the keystone pathogen impairs host immunity and promotes inflammation. Inflammation can destroy periodontal tissue and increase the flow of gingival crevicular fluid (GCF) in the oral cavity, which is rich in collagen-degrading compounds and heme [50]. Bacteria possessing proteolytic and asaccharolytic traits, along with iron-acquisition capabilities, can selectively exploit these compounds, leading to a competitive advantage over bacteria that lack these attributes, which are consequently outcompeted and diminished in the microbiome. This phenomenon ultimately disrupts the balance of the microbiome [57]. This enhances inflammation in turn. The consequence of heightened inflammation is that, in a susceptible state, the infection by pathogenic bacteria culminates in an escalation of the inflammatory response and, ultimately, the progression of periodontitis. The interplay of oral microbiome-host interactions may significantly contribute to the pathogenesis of periodontitis [50].
Dental caries, a multifactorial disease influenced by polymicrobial synergy, is one of the most common oral diseases affecting human quality of life [61], especially for the elderly and children, people with poor dietary and oral hygiene habits, and people with a family history of dental caries. The development of dental caries is determined by four an acidic environment, acidophilic microorganisms, dietary carbohydrates, and the host [62]. When carbohydrate consumption is low, certain acids that have the potential to demineralize enamel are still produced; however, saliva rapidly neutralizes these acids, thereby restoring pH levels and maintaining enamel mineralization, and thus preventing cavities. The Stephan curve is a model that elucidates the progression of dental caries [63]. According to this curve, when dietary carbohydrates are metabolized by acid-producing bacteria, acidic byproducts are generated, thereby altering the acid-base equilibrium within the oral cavity. During the acid stage, characterized by an acidic environment, tooth enamel experiences mineral loss. As the oral environment transitions away from this stage, the decline in acidity can be attributed to both a reduction in the population of acidogenic bacteria and a decrease in their metabolic activity. This shift discourages further acid production, enabling alkali-producing microbiomes to flourish, which in turn facilitates the restoration of oral pH to a neutral state, known as the acid neutralization stage. Finally, in a neutral environment, enamel undergoes remineralization, wherein mineral absorption takes place. However, if the acidic environment persists, remineralization may be impeded, leading to the formation of dental caries [64]. Simultaneously, certain microorganisms possess the ability to produce hydrogen peroxide (H2O2), earning them the designation of H2O2-producing bacteria. Hydrogen peroxide exhibits bactericidal properties that impede the proliferation of other bad bacteria which produce acid. Consequently, the presence of hydrogen peroxide-producing bacteria can exert a bactericidal effect, hindering the growth of other bacteria, thereby exerting a detrimental impact on dental caries development. Research has demonstrated a negative correlation between the abundance of hydrogen peroxide-producing bacteria and dental caries [65]. Individuals with few caries lesions appear to harbor a higher abundance of hydrogen peroxide-producing bacteria that those with high number of caries lesions [66,67]. This observation suggests that the bactericidal effect of hydrogen peroxide reduces the population of caries-causing bacteria, consequently impeding caries development.
Contrarily, excessive exposure to dietary carbohydrates leads to the production of a greater quantity of acidic metabolites and extracellular polymeric substances (EPS) [57,68]. These acidic metabolites primarily consist of organic acids, such as lactic acid, acetic acid, and pyruvate, which are generated by bacterial metabolism of carbohydrates. Their accumulation may contribute to the formation of dental plaques. If left unaddressed, the biofilm perpetually favors acidophilic microbiomes, thus maintaining an environment with a low pH. Concurrently, repeated and prolonged exposure to sugars results in continual acidification, causing demineralization of tooth enamel and proteolytic degradation of dental hard tissues, ultimately leading to the development of dental caries [57,62,69,70]. Streptococcus mutans and sucrose play crucial roles in the progression of dental caries. On one hand, Streptococcus mutans possesses various enzymes capable of hydrolyzing sucrose, producing polymers, as well as free glucose or fructose. These metabolic activities contribute to the acidification of the oral environment and subsequent demineralization of tooth enamel. On the other hand, Streptococcus mutans produces glucosyltransferases (Gtfs) that break down sucrose and convert it into extracellular glucans. These glucans serve as essential components of the cariogenic biofilm matrix, aiding in bacterial adhesion to tooth surfaces. Thus, sucrose and components associated with Streptococcus mutans play pivotal roles in facilitating the progression of dental caries [68]. In response to an influx of carbohydrates in the diet, cariogenic pathogens can adapt by swiftly altering their metabolism [68]. Observation of plaque pH levels following carbohydrate stimulation has revealed a rapid drop to 4.0 or below within a few minutes [71]. Most indigenous microorganisms are unable to withstand such an acidic environment, ceasing growth or even succumbing to the conditions when the pH drops below approximately 5.5. Acidogenic microorganisms employ various adaptive strategies to cope with this sudden decrease in pH, generating acid metabolites such as lactic acid, thereby promoting enamel demineralization. Therefore, the critical pH value associated with enamel demineralization is approximately 5.5.
Traditionally, Streptococcus mutans and Lactobacillus spp. have been implicated as major pathogens in the etiology of dental caries in both children and adults [72,73]. Recent advances in high-throughput genomic analyses have allowed for a more comprehensive assessment of the entire oral microbiota, revealing a complex interplay of potential pathogens involved in caries development. The ‘extended caries ecological hypothesis’, introduced in recent studies [74], extends beyond the conventional understanding by suggesting that while Streptococcus mutans may not be the most abundant species in the oral microbiome, it exhibits the highest cariogenic potential due to its unique acid-producing capabilities, adhesion properties, and ability to thrive in an acidic environment. This hypothesis is further supported by the succession model of caries progression proposed by Van Ruyven et al. [75], which describes a dynamic shift in microbial composition during the onset and development of dental caries. In this model, the early colonizers, primarily aciduric and acidogenic microorganisms like non-mutans Streptococci and Actinomyces spp., establish an acidic milieu within dental plaques. This acidification of the environment sets the stage for more cariogenic species, including Streptococcus mutans, to dominate and exacerbate the demineralization process, further advancing the caries lesion [76]. However, while these findings are significant, the intricate interrelationship between these microorganisms and their collective impact on caries progression warrant further investigation to develop targeted preventive strategies and therapeutic approaches.
Oral ulcers are characterized by the disruption of the oral mucosa epithelium, resulting in the formation of lesions. There are many causes of oral mucosal ulcers, such as infectious, immune/vasculitic, neoplastic, etc [77]. Here we focus on the role of oral microorganisms in immune-related oral ulcers. These lesions are typically accompanied by symptoms such as pain, redness, discomfort, and bleeding [78]. Recent investigations have highlighted the involvement of oral microbiota in the onset and progression of oral ulcers [79–81]. Adibi et al. demonstrated that the oral microbiome exhibits potential as a noninvasive biomarker for the development of oral ulcers [82]. Significantly divergent bacterial species abundances were observed between individuals with mouth ulcers and healthy controls. Notably, the identified bacterial species, including Campylobacter, Granulicatella, and Haemophilus, were found to be substantially influenced by factors such as smoking and salivary surfactant protein A [83].
Crohn’s disease (CD) is an inflammatory bowel disease characterized by persistent and chronic inflammation throughout various segments of the gastrointestinal tract. It is associated with extraintestinal manifestations such as mouth ulcers, skin lesions, and joint involvement [84]. Recent studies have demonstrated that alterations in the oral microbiota of CD patients are closely associated with the occurrence and development of oral ulcers, providing a potential avenue for CD diagnosis. Notably, research conducted by Hu et al. revealed significant differences in the composition of the oral microbiome between individuals with and without CD, as well as between those with and without CD-related ulcers [81]. Furthermore, this study identified 32 microbial species exhibiting significant differential abundance, which were found to be accurate in diagnosing CD with an accuracy of over 70%. Additionally, functional analysis indicated a positive correlation between an enhanced representation of microbial enzymes in the butyrate pathway and the presence of oral ulcers. Such findings suggest a potential diagnostic biomarker and raise questions about the underlying mechanisms of microbiota-driven inflammation. In this context, the hygiene hypothesis and the widespread use of antibiotics emerge as relevant factors to consider. These might contribute to the dysbiosis observed in CD patients by reducing the diversity and resilience of the gut and oral microbiomes. This hypothesis invites a reassessment of our environmental and medical practices as they could inadvertently exacerbate the microbial imbalance seen in CD, thereby influencing both disease progression and the therapeutic response [85–88].
Behcet’s disease (BD) is a chronic, recurrent, inflammatory disease characterized by oral and genital ulcers and skin lesions as well as ocular involvement and large vessel, gastrointestinal and neurological involvement. The etiology of BD remains incompletely understood, with both genetic and environmental factors implicated in its pathogenesis. Particularly, the potential role of viral infections in the initiation and exacerbation of lesions in BD warrants further investigation. Current research suggests that viruses may contribute to the etiology of BD; however, viral infections could also occur secondary to the onset of BD, potentially exacerbating existing inflammation either via direct pathogenic effects or by inducing an immune response. This area necessitates further exploration to elucidate the precise mechanisms involved [89,90]. Among these manifestations, oral ulcers are particularly prominent [91]. BD is believed to be the consequence of an immune disorder stemming from a combination of genetic factors and exposure to infections or other pathogens, a phenomenon often described as ‘molecular mimicry’ [92]. Notably, the presence of high levels of Streptococcus mutans in saliva has been identified as the primary pathogen responsible for the increased occurrence of active oral ulcers in BD patients [93]. Additionally, colonization of high levels of Streptococcus sanguis in the oral cavity of BD patients has also been observed [94]. These bacteria have the ability to induce inflammation by interacting with mucosal epithelial cells and increasing the levels of cytokines and chemokines such as IL-6, IL-8, and tumor necrosis factor α (TNF-α) [95,96]. Furthermore, several studies have identified various viruses that are associated with oral ulcers in BD patients, including herpes simplex virus (HSV), human herpes virus (HHV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [97,98]. For instance, using the polymerase chain reaction method, Tojo et al. detected the presence of HSV-1 and HSV-2, as well as HHV-6 and HHV-7, in BD patients, suggesting a potential association between HSV-1 and/or HSV-2 and the pathogenesis of BD, while HHV-6 and HHV-7 may not be directly involved [89]. Additionally, Sun et al. found the presence of CMV in oral ulcer lesions of BD patients, and CMV DNA was also detected in mucosal specimens from the ileum, indicating a possible role of CMV as a pathogen in BD [99]. Furthermore, Irschick et al. detected viral DNA of EBV, CMV, and HHV8 in the serum of BD patients, suggesting their potential involvement in the pathogenesis of BD [100]. Although a single pathogen has not been conclusively identified as the cause of BD, these findings collectively suggest a potential pathogenic role of viruses in BD-associated oral ulcers.
The concept of oral potentially malignant disorders (OPMD) was first proposed by the World Health Organization (WHO) in 2007 [101]. OPMD refers to the occurrence and transformation of potentially malignant lesions in sites other than the originally identified lesion site, even in cases where a clear diagnosis of the lesion has been made. OPMD can manifest in various areas of the oral cavity, including the oral mucosa, gums, and tongue [102]. These disorders include oral lichen planus (OLP), oral leukoplakia (OLK), oral erythroplakia, palatal lesions in reverse smokers, actinic cheilitis, oral discoid lupus erythematosus and oral submucous fibrosis [103]. Recent studies have shed light on the relationship between oral microorganisms and OPMD, offering potential therapeutic targets for the prevention and treatment of oral precancerous lesions.
OLP is a chronic inflammatory disease that mainly affects the oral mucosa. Compared to male patients and female patients of other age groups, women aged 40 years and above demonstrate a higher risk for malignant transformation of OLP. The timeline to malignancy is shorter for the erosive, atrophic, and bullous variants of OLP as opposed to the reticular, papular, and plaque types. Research indicates that the rates of malignant transformation stand at 1.7% for erosive OLP and 1.3% for atrophic OLP, compared to a notably lower rate of 0.1% for reticular OLP [82,104,105]. It can be categorized into six clinical reticular, plaque, atrophic, papular, erosive, and bullous [106]. The etiology of OLP remains unknown; however, recent studies have shown that dysbiosis of the oral microbiome plays an important role in OLP [107,108]. During this process of oral microbial-host interaction, pathways associated with the defense against bacterial infections and inflammatory responses are activated, thereby promoting the occurrence and development of OLP. Deng et al. discovered that the salivary microbiota of patients with OLP exhibited changes compared to the control group, and there was an increased expression of inflammatory factors such as IL-6 and TNF-α, which are related to the TLR4-NF-κB inflammatory signaling pathway, in OLP patients [109]. Liu et al. demonstrated that Candida albicans can activate the TLR2-MyD88-NF-κB signaling pathway in OLP keratinocytes, resulting in increased cytokine expression and reduced keratinocyte apoptosis [110]. Furthermore, the interaction of human β-defensin 2 (hBD-2) [111], and CASP1 with RAC2, CYBB, and ARHGDIB [112] may also activate relevant inflammatory pathways, thus promoting the progression of OLP.
Many studies have investigated differences in the oral microbiomes of OLP patients versus healthy controls using 16S rRNA sequencing of bacteria or ITS2 region sequencing of fungi, respectively; however, there is no consensus among these studies. Baek and Choi et al. conducted research and discovered that there was an increase in oral microbial diversity in patients with reticular and erosive OLP [113]. Similarly, He et al. found that compared to healthy individuals, patients with reticular and erosive OLP had a greater diversity and richness of oral microorganisms [114]. They observed an increased abundance of certain microorganisms, such as Fusobacterium and Leptotrichia, while the abundance of others, such as Streptococcus, decreased [114]. In the clinic, reticular and erosive OLP are the two most common types of OLP. Reticular OLP is characterized by white striations. It is mostly asymptomatic and relatively responsive to treatment [115]. On the other hand, erosive OLP is characterized by ulcers and erosions. Patients often experience pain, discomfort, burning sensation, and other symptoms. This may progress to dysphagia [116]. Eventually, severe physical or even neuropathic pain in OLP can manifest, which is often explained by the disruption of sensory nerves within the inflamed mucosal tissues [117]. This type of pain is usually localized to the areas most affected by lesions [118]. In addition, malignant transformations, though infrequent, have been documented with varying incidence rates, with some study reporting rates as 1.7% [119]. Such complications pose a greater challenge for treatment and necessitate close monitoring and patient management. Wang et al. [120] and Du et al. [121] reported that patients with erosive OLP have more diverse microbiomes in the buccal mucosa than patients with reticular OLP. While there is ongoing debate regarding the differences in the oral microbiota between patients with OLP and healthy individuals, most studies indicate that the oral microbiota of OLP patients can indeed be distinguished from that of healthy individuals. While sampling saliva or oral mucosa for the isolation of oral microbes is a commonly used method, research has demonstrated that the microbes that invade the oral mucosa exhibit a closer association with OLP compared to those found in saliva. Consequently, further investigation into the oral mucosal microbiota of OLP patients is warranted [122].
The association between oral bacterial dysbiosis and OLP has been documented, but the extent of oral fungal biodiversity and its role in fungus-bacterial interactions remain unclear. In a study by Li et al. [123], the fungal composition in OLP patients and controls was investigated, revealing the presence of 6 phyla, 11 families, and 280 genera. The results indicated that patients with erosive or reticular OLP displayed reduced fungal diversity compared to controls. Notably, the relative abundance of Candida was significantly higher in OLP patients (49.6% and 41.3%, respectively) than in healthy subjects (27.1%). Additionally, Aspergillus was more frequently detected in the saliva of OLP patients [123]. The study further explored alterations in patterns of microbial coexistence and co-rejection and found that Candida exhibited a negative association with 18 out of 29 bacterial genera in healthy individuals, while it showed a positive association with specific bacterial genera in OLP patients (8 bacterial genera in both reticular and erosive OLP) [123]. These findings suggest significant changes in fungus-bacterial interactions within the oral cavity of OLP patients. Due to the limited number of studies on the composition of oral fungi in OLP patients and their interactions with the host, as well as the unclear role of such fungi in the pathogenesis and potential treatment of OLP, further research investigating the relationship between fungi and OLP is necessary.
Oral leukoplakia (OLK) is a potential malignant lesion originating from the oral mucosa, which may occur in any part of the oral cavity, such as the gingiva, tongue, and buccal mucosa. It can be categorized into two types according to its idiopathic OLK associated with smoking. Homogeneous and non-homogeneous lesions are common in clinical practice [124]. OLK is characterized by histopathological changes, such as hyperkeratosis, hyperorthokeratosis and hyperparakeratosis as well as epithelial dysplasia, or parakeratosis, acanthosis of the epithelium, and chronic inflammatory infiltrations into the lamina propria [125].
Gopinath et al. [100] proposed a decrease in Firmicutes and an increase in Bacteroidetes in patients with OLK. Both OLK and oral cancer (OC) patients have decreased abundances of Actinobacteria [126] in the saliva samples. Additionally, Hu et al. reported that Haemophilus was significantly increased in patients with OLK, whereas Bacillus and Abiotrophia were significantly decreased in saliva samples [127]. Using swab samples taken from the OLK lesion site and the contralateral normal site (if present), Amer et al. proposed that Fusobacterium, Leptotrichia, and Campylobacter were significantly elevated in patients with OLK, while Streptococcus and Gemella haemolysans were significantly elevated in healthy controls [127]. These two studies used different samples, which hampered reliable comparisons. Hence, future studies using the same types of samples are required to detect the relationship between microbiomes and OLK.
Kazanowska et al. suggest that oral Helicobacter pylori (H. pylori) infection may be related to OLP [128]. Li et al. have shown that H. pylori infection is significantly associated with the onset of erosive OLP and can affect the composition of oral microbiota [129]. However, more studies are needed to further explore the relationship between OLP and oral H. pylori infection.
Oral cancer, a prevalent form of head and neck tumors, presents a 5-year overall survival rate of approximately 68% and a 5-year disease-specific survival rate of 78% [130]. The pathological spectrum of OC is diverse, with oral squamous cell carcinoma (OSCC) accounting for over 80% of cases, followed by variants such as glandular carcinoma, basal cell carcinoma, undifferentiated carcinoma, and lymphatic carcinoma [131]. The OC discussed in this paragraph mainly refers to OSCC. Recent research has indicated a complex interplay between the oral microbiome and OSCC, suggesting that microbial profiles may potentially influence the risk and progression of the disease [132]. Studies have observed that compared to healthy controls, OSCC patients display higher α diversity in oral microorganisms, including Peptostreptococcus, Fusobacterium, Alloprevotella, and Capnocytophaga, while the abundance of Rothia and Haemophilus is lower [133]. Schmidt et al. also discovered significantly lower abundance of Firmicutes (particularly Streptococcus) and Actinobacteria (particularly Rothia) in the oral cavities of OSCC patients compared to healthy contralateral samples [134]. While these studies offer insights into potential associations, they underscore the multifaceted etiology of OSCC, wherein the microbiome may contribute to pathogenesis alongside genetic, environmental, and lifestyle factors [135]. Therefore, oral microorganisms may be potential targets for OC treatment from the perspective of regulating oral microbial composition and metabolic activities and developing antibiotic targeted therapies, which also emphasizes the need to fully understand the mechanism and role of their involvement in OC pathogenesis.
Acetaldehyde, reactive oxygen species (ROS), organic acids, and N‑nitrotrimethylamine are carcinogens that induce OC [6]. Certain Gram-negative bacteria, such as Stomatococcus and Neisseria spp., exhibit high alcohol dehydrogenase activity, converting ethanol into acetaldehyde [136,137]. Drinking can promote Neisseria growth and increase acetaldehyde production [6]. Streptococcus mutans [138], Streptococcus sanguinis [139] and Streptococcus gordonii [140], have been found to produce reactive oxygen species (ROS) [141]. ROS are involved in cellular metabolism and play a crucial role in signal transduction within eukaryotic periodontal cells, leading to cell differentiation and apoptosis. Furthermore, ROS have the potential to cause damage to DNA [142], lipids and proteins [140] and are known to play a significant role in cancer promotion. Additionally, certain bacteria, such as Streptococcus mutans, can produce lactic acid through fermentation [143], and fungi such as Candida spp. can produce N‑nitrotrimethylamine [144]. The production of lactic acid may contribute to the formation of acidic and hypoxic microenvironment in tumors, thereby increasing the efficiency of tumor metastasis, and thus participating in and promoting the progression of oral cancer. Domingues et al. reported that Candida may possess a potent capacity for nitrosation and can internally generate nitrosamine compounds, including N-nitrotrimethylamine [144], although the precise mechanism remains unclear. Chronic Candida infection is recognized as a risk factor for esophageal cancer [144]. Implementation of professional oral cleaning and maintenance of oral microbiota homeostasis can aid in diminishing the abundance of cancer-associated pathogens and diminishing the risk of tumor development. Furthermore, oral microbiota can promote the production of cytokines, such as IL-1, IL-6, and IL-17, thereby inducing chronic inflammation in OC. Alterations in host cell metabolism are recognized as one of the distinctive features of cancer. In recent years, there has been a growing body of research focused on investigating changes in fatty acid metabolism in OC [145]. Studies have revealed significant disparities in fatty acid (FA) expression patterns between patients with OC and healthy individuals [146,147]. Research indicates that there is a negative correlation between red blood cell levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the risk of OC. Measuring the levels of EPA and DHA in red blood cells could assist in assessing the risk for the development of OC. Additionally, findings indicate that FA-binding protein 4 (FABP4) and FA-binding protein 5 (FABP5) can enhance the proliferation and invasion of OC cells through the MAPK pathway and upregulation of MMP-9 expression, respectively [148,149]. These observations suggest the involvement of specific metabolites and signaling pathways in FA metabolism in the progression of OC [150]. Wu et al. identified that Porphyromonas gingivalis may participate in the FA synthesis pathway by upregulating the expression of FASN and ACC1, thereby influencing FA metabolism in OC and augmenting the risk of its occurrence and development [151]. Therefore, interventions targeting specific compounds, metabolites, and signaling pathways mediated by oral microorganisms may potentially attenuate the progression of OC.
Studies have shown that oral microbes vary between patients with OC and healthy controls, although the consensus of specific microbiota changes is not consistent. Takahashi et al. [133] and Zhao et al. [152] reported higher oral microbiome diversity and richness in patients with OC compared to healthy controls, whereas Schmidt et al. [134] demonstrated lower overall abundance. Conversely, other studies have indicated that the diversity and richness of the oral microbiome in patients with OC are lower than those in healthy controls [153,154]. Additionally, studies have shown that the diversity of Peptostreptococcus, Fusobacterium, Alloprevotella, and Capnocytophaga increased, whereas that of Rothia and Haemophilus decreased. The periodontitis-associated bacteria P. gingivalis and Nucleobacter spp. can induce OSCC by stimulating an inflammatory cascade of IL-6-STAT3, which was confirmed in a mouse model [154]. Binder et al. developed an animal model of OC associated with chronic P. gingivalis/F. nucleatum infection. Following infection, P. gingivalis/F. nucleatum binds to toll-like receptors present expressed by oral epithelial cells, thereby triggering the TLR signaling pathway. This, in turn, promotes the expression of IL-6 and activates the STAT3 pathway. These molecular events play a crucial role in the induction and progression of OC, facilitated by important effector factors such as cyclin D1, MMP9, and heparanase, which drive the growth and invasion of oral cancer cells. The study underscores the involvement of bacteria in the intricate molecular mechanisms and signaling pathways underlying the progression of OC. Additionally, it offers novel insights and approaches for the prevention and treatment of OC [155].
The role of HPV in cervical cancer has been extensively investigated, but its involvement in the occurrence and progression of OC remains uncertain. A meta-analysis comprising 5,478 patients with OC revealed that 24.2% of these individuals exhibited a positive result for HPV DNA presence [156]. Among them, HPV16 was identified as the most prevalent high-risk genotype, with a positivity rate of 14.9%. Research has indicated that smoking enhances susceptibility to HPV, amplifies viral load, and facilitates viral genome integration. Moreover, HPV oncoprotein E6 hampers the function of p53, thereby impeding DNA repair mechanisms and apoptosis. Additionally, E7 disrupts the pRB-E2F complex within host cells, leading to increased chromosomal instability and impaired regulation of the cell cycle. The combination of HPV-induced cellular immortality and DNA damage caused by smoking further fosters the carcinogenesis of host cells [157].
A clinical case-control study conducted in Mexico revealed a significant association between high-risk HPV infection and OSCC. The proportion of high-risk HPV infections among the OSCC cases was found to be six times higher compared to the control groups [158]. These findings strongly suggest that high-risk HPV infection contributes to the progression of OSCC, emphasizing the need for further research in this area.
Esophageal diseases encompass a wide range of conditions affecting the esophagus, including both structural disorders (such as esophageal stenosis and hiatal hernia) and functional disorders (such as gastroesophageal reflux disease and esophagitis). Common clinical presentations of these diseases often include dysphagia, chest pain, acid reflux, and heartburn, among others. In recent years, the prevalence of esophageal diseases has increased with high morbidity and mortality [159]. Several studies have focused on the influence of the microbiome on esophageal diseases [160–164]. Research studies have demonstrated that there is a significant overlap in the composition of the esophageal and oral microbiota, particularly in terms of Firmicutes and the Streptococcus genus. However, there exist notable differences in β diversity when comparing the oral and esophageal microbiota [165–167]. Alterations in the oral microbiome have been reported to occur before the onset of esophageal adenocarcinoma [165]. Endoscopic esophageal histopathological biopsy is the gold standard for clinical diagnosis. However, owing to the invasive nature of esophageal sampling and the simplicity of oral sampling, an increasing number of studies have been conducted on the effects of oral microorganisms on esophageal diseases, including whether oral microorganisms serve as new risk factors for cancers or systemic diseases [13,168–170].
Gastroesophageal reflux disease (GERD) is a disease in which gastric or duodenal contents regurgitate into the esophagus due to the impairment of the structure or function of the esophagogastric anti-reflux barrier, mainly manifests acid reflux and heartburn [171–174]. Patients with GERD had lower levels of Prevotella, Helicobacter [175], and Moraxella spp. [176] in the distal esophagus compared to healthy controls [177]. The saliva has a near-neutral pH of approximately 6.5. The reflux of gastric juice can lower the pH of the esophagus, oropharynx, and oral cavity to approximately 4.9 [178]. Lower salivary pH influences the composition of the oral microbiome [179,180]. The acidic environment created by an imbalance in oral pH can result in tooth demineralization, which not only facilitates the progression of existing dental caries but also contributes to the development of new carious lesions [181,182]. It also contributes to dental erosion. The latter is a chemical process not involving bacteria that causes the loss of enamel and dentin [183]. Moreover, this acidic milieu enhances the metabolic activity of acid-producing bacteria, leading to increased fermentation and subsequent lactic acid production, thus establishing a self-perpetuating cycle. The acidic environment provides a favorable habitat for acid-tolerant bacteria, such as lactic acid bacteria, while non-acid-tolerant bacteria may face limitations or even perish. Consequently, this disruption in the ecological equilibrium of oral microorganisms can occur [184,185].
Kawar et al. showed that P. gingivalis, Filifactor alocis, Fretibacterium fastidiosum, and Lachnospiraceae_^[G-8]^ were lower in saliva of GERD patients [186]. Ziganshina et al. assessed the differences between GERD and non-GERD patients using 16S rRNA sequencing in saliva samples. They showed that Actinomyces, Atopobium, Stomatobaculum, Ruminococcaceae_^[G-2]^, Veillonella, and Leptotrichia were higher at the genus level in patients with GERD, whereas Porphyromonas, Gemella, Peptostreptococcus, and Neisseria were lower [187]. Wang et al. [188] compared the composition of the oral microbiota in patients with reflux esophagitis (RE) and healthy controls in saliva samples using hypervariable tag sequencing and 16S rRNA analysis. The results showed no differences in microbiome composition (Shannon diversity index, p = 0.60; Simpson diversity index, p = 0.38). Prevotella, Veillonella, Megasphaera, Peptostreptococcus, Atopobium, Oribacterium, Eubacterium, and Lachnoanaerobaculum were higher in patients with RE at the genus level, whereas Neisseria, Streptococcus, Rothia, Granulicatella, Gemella, Aggregatibacter, Treponema, Campylobacter, Filifactor, Corynebacterium, and Lactivibrio were lower. Study revealed a notable association between certain oral microorganisms, particularly Streptococcus-OTU16, and biomarkers indicative of oxidative stress, with the composition of these microbiota exhibiting individual specificity [189]. Moreover, oxidative stress has been implicated in the pathogenesis of GERD [190]. It was further observed that oral microorganisms contribute to heightened expression levels of pro-inflammatory cytokines, including IL-1β and IL-6, while concurrently suppressing the expression of anti-inflammatory cytokines like IL-10 [191]. The upregulation of inflammatory cytokines may facilitate GERD progression by inflicting damage on the esophageal mucosal epithelium and provoking inflammation [192]. Furthermore, variations in oral microbiome composition can influence the metabolic profile of GERD patients, as different bacteria produce distinct metabolites. For instance, changes in the abundance of certain fermenting bacteria could lead to an altered production of volatile sulfur compounds (VSCs) [193], short-chain fatty acids (SCFAs) [194], and other metabolites that may have implications for GERD symptoms and disease progression [195,196]. Lastly, these microbial and metabolite disparities may manifest symptomatically. For example, an overrepresentation of acid-producing bacteria in the oral microbiome could exacerbate GERD symptoms by lowering the pH of the saliva, thereby aggravating acid reflux and its associated sensations such as heartburn [197,198]. Additionally, the alteration of taste or the presence of a persistent foul taste caused by certain microbial metabolites could also be a symptomatic manifestation associated with the oral microbiome in GERD patients [193,195]. These potential associations between the oral microbiome composition and GERD pathology suggest the need for a more detailed examination of oral microbial communities and their metabolic outputs in GERD patients, which could lead to a better understanding of the disease and the development of targeted therapeutic strategies. These differences could potentially trigger inflammatory responses and foster the production of acidic metabolites, such as acetic acid. Additionally, certain bacteria, such as Atopobium parvulum (representative of the Atopobium genus), have the capability to generate halitosis by metabolizing sulfides, fatty acids, and other compounds [199]. Hence, it is noteworthy that individuals with GERD not only experience compromised structure or function of the esophagogastric anti-reflux barrier and a diminished quality of life, but also encounter alterations in oral microbiome composition due to pH fluctuations induced by GERD. These changes have the potential to impact the progression of the disease.
Eosinophilic esophagitis (EoE) is a chronic esophageal disease characterized mainly by eosinophil infiltration and mediated by Th2 immunity [200,201]. It is characterized by esophageal dysfunction, such as vomiting, abdominal pain, and eosinophilic infiltration (≥15 eosinophils per high-power field) in at least one multiple mucosal biopsy of the esophagus [201]. Although it has been identified as a rare disease in the past its prevalence has significantly increased in recent years [202,203].
The mechanisms underlying EoE, including genetic and environmental factors, remain unclear. Environmental factors are believed to play important roles in the pathogenesis of EoE because they may disrupt host immune and metabolic responses [204,205]. Recent studies have focused on the influence of microorganisms on EoE.
Hiremath et al. [206] compared the microbial oral composition of children with and without EoE using 16S rRNA. The results showed that children with EoE had a reduced relative abundance of Leptotrichiaceae_unclassified, whereas Actinomyces, Lactobacillus, and Streptococcus were less abundant in children without EoE in saliva samples. Moreover, children with EoE had a higher abundance of Haemophilus than those without EoE. Benitez et al. conducted a study examining the discrepancies in microbiota composition within oral swabs (inner cheeks, hard palate, and distal third of the tongue) and esophageal biopsy samples between patients diagnosed with EoE and healthy controls. Their findings revealed that there was a conspicuous proliferation of the Proteobacteria phylum, with particular enrichment in bacterial genera such as Neisseria and Corynebacterium and the non-EoE control group exhibited a dominance of Firmicutes. The dissimilarity in microbiota composition between EoE patients and the control group was most pronounced during episodes of active allergic inflammation [207]. Grusell et al. [208] compared the microbiome compositions of patients with GERD and EoE. The results showed that the patients with EoE had a higher abundance of microbiota than those with GERD. All samples from patients with GERD, EoE, and healthy controls had predominant microbiomes (microbiomes described are predominant in GERD, EoE and healthy controls) including Streptococcus salivarius, Streptococcus mutans, Streptococcus mitis, Streptococcus sanguinis, and Streptococcus anginosus. These findings imply that alterations in the oral microbiome might contribute to the pathogenesis of EoE and could potentially serve as biomarkers for disease prediction. Therefore, further investigation is warranted to delve deeper into this topic.
Characterized as a special intestinal metaplasia that replaces healthy mucosa [171], Barrett’s esophagus (BE) is considered a precancerous state of esophageal cancer, and its incidence has gradually increased in recent years [209,210]. However, the specific pathogenic mechanisms remain unclear. Some researchers believe that changes in oral saliva and esophageal microbiome can affect the occurrence and development of BE [211]. However, related studies have reported inconsistent results. If oral microbiological changes in patients with BE are specific, early detection of salivary microbes can help detect BE and prevent it from progressing to esophageal cancer, rather than resorting to invasive and expensive endoscopic methods, especially for high-risk patients who are prone to developing BE.
The oral microbiomes of patients with BE differ significantly [212]. This may be caused by oral microorganisms migrating to the distal esophagus and shaping a stable microenvironment [213,214]. Snider et al. showed that patients with BE had an increased abundance of Streptococcus, Veillonella, and Enterobacteriaceae, whereas Neisseria, Lautropia, and Corynebacterium were decreased. Another study [215] obtained swabs from the uvula and endoscope itself, and biopsies were taken from the proximal, middle, distal, and BE of the esophagus to test for microbial composition. Some researchers have used microbiome metabolic models to predict significant changes in the metabolic capacities of the oral microbiome, including an increase in L-lactic acid and a decrease in butyric acid and L-tryptophan production. L-lactic acid has been identified as a primary energy source for advanced tumors, as it activates hypoxia-inducing factors, thereby facilitating tumor characteristics like proliferation and angiogenesis [216]. On the other hand, butyric acid potentially exerts its influence through diverse mechanisms, including modulating cancer cell growth and apoptosis, regulating immune responses, and functioning as an epigenetic regulatory molecule [217,218]. The aberrant metabolism of L-tryptophan may be implicated in tumor development, progression, and immune evasion [219], although a comprehensive understanding of the specific underlying mechanism necessitates further investigation. These findings suggest that changes in the oral microbial metabolome play a role in the development of precancerous lesions and tumors [220].
Esophageal cancer is one of the most common cancers in clinical practice, standing as the seventh most frequently diagnosed cancer globally [221]. In China, it is the fourth leading cause of cancer-related deaths [222]. Esophageal cancer is characterized by genetic variability, in which genes rearrange and drive somatic cell proliferation [223]. Lifestyle factors such as smoking, drinking [224], and excessive consumption of hot tea [225] are also known to exert influences on the occurrence and development of esophageal cancer. According to the different pathological types, esophageal carcinoma is mainly categorized into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) [226]. While Western countries predominantly report cases of EAC, most cases in other regions are ESCC. Recent studies have shown that the oral microbiome is associated with esophageal cancer. The changes of oral saliva microbes in patients with esophageal cancer have certain specificity, which may be helpful for early clinical recognition and diagnosis.
Studies have shown that the bacteria on the back of the tongue, in saliva, in other parts of the mouth, and in the esophagus can produce carcinogens such as nitrite and acetaldehyde, contributing to the development of esophageal cancer. Bacteria on the back of the tongue can convert approximately 30% of nitrates into nitrites [227,228], which can be converted into cancer-causing N-nitroso compounds that lead to GERD and esophageal cancer. Additionally, some microbes in the mouth can metabolize to produce acetaldehyde [229], a carcinogen. In the distal esophagus, certain Gram-negative bacteria, can produce specific lipopolysaccharide antigens [165], which can cause inflammation and subsequent cancer.
Human cells lack nitrate reductase activity, and the conversion of nitrate to nitrite in the human body relies mainly on the activity of bacterial nitrate reductase, particularly bacteria present in the oral cavity and digestive tract. The bacterial community found on the posterior region of the tongue, which is frequently exposed to saliva, can convert approximately 30% of nitrate into nitrite [226,228]. This conversion process involves various bacterial genera, including Veillonella, Actinomyces, Staphylococcus, Rothia, Neisseria, and Haemophilus. Veillonella and Neisseria, in particular, are widely distributed in the oral cavity and have demonstrated efficient nitrate-to-nitrite conversion abilities [230–232]. Additionally, certain oral microbes have the capacity to metabolize and produce acetaldehyde, a known carcinogen [233]. Neisseria and Streptococcus display elevated alcohol dehydrogenase (ADH) activity, contributing to significant aldehyde production from ethanol [127]. Other core oral microbiome species, such as Rothia and Prevotella, are also capable of converting substantial amounts of ethanol into acetaldehyde [234]. Furthermore, fungi, particularly Candida species (including Candida albicans, Candida luminaria, and Candida tropicalis), possess ADH activity and can contribute to increased acetaldehyde production [235,236], thereby promoting carcinogenesis. Certain bacterial antigens, such as LPS from Gram-negative bacteria, including Campylobacter jejuni and Escherichia coli, play a role in inflammation promotion and cancer development [132,237]. LPS induces the expression of NF-κβ, a key factor in inflammation, and its expression is elevated during the progression from BE to EAC [238]. The oral microbiome, with its diverse array of microorganisms including Gram-negative bacteria, plays an integral role in the pathogenesis of gastrointestinal diseases. Lipopolysaccharides (LPS), a structural component of Gram-negative bacteria, enters the gastrointestinal tract via ingested saliva, impacting the function and structural integrity of the gastrointestinal system. Certain oral bacteria can reduce nitrate to nitrite, such as Rothia and Neisseria [239]. When the nitrite produced is regurgitated in the acidic environment of the distal esophagus and the cardia, it can form carcinogenic N-nitroso compounds, thus further promoting the progression of esophageal cancer [240]. Particularly in GERD, LPS derived from oral bacteria may contribute to the pathophysiology by weakening the lower esophageal sphincter, impeding gastric emptying, and amplifying reflux events, which could accelerate the progression of BE [241,242]. Additionally, the conversion of nitrate to nitrite by oral bacteria, followed by the formation of carcinogenic N-nitroso compounds in the acidic milieu of the refluxed esophagus, suggests a potential mechanistic link between oral microbial activities and esophageal carcinogenesis [228]. Thus, the oral microbiome is implicated not only in maintaining oral health but also in systemic effects that may influence the development and exacerbation of gastrointestinal conditions, including BE and esophageal cancer.
Studies have shown that an abundance of P. gingivalis is associated with a higher risk of ESCC [161]. Patients with ESCC have higher levels of P. gingivalis antibodies than healthy controls [243]. Furthermore, Treponema denticola, Streptococcus mitis, and Streptococcus anginosus play important roles in carcinogenesis by stimulating inflammation [244]. Chen et al. [245] showed that patients with ESCC exhibit decreased microbial diversity compared to healthy control group. The presence of Lautropia, Bulleidia, Catonella, Corynebacterium, Moryella, Peptococcus, and Cardiobacterium was significantly decreased in patients with ESCC. For EAC, the periodontitis-associated pathogenic bacterium, Tannerella forsythia, has been linked to an increased disease risk [161]. Decreases in Neisseria and Streptococcus pneumoniae were associated with an increased risk of EAC. Moreover, nitrites in the body can undergo metabolic processes to form carcinogenic nitrosamine compounds, which are subsequently metabolized by liver enzymes into active intermediates. These active intermediates then transfer alkyl groups to DNA bases, resulting in a process known as alkylation [246,247]. Alkylation can lead to changes in the original DNA structure, and if not properly repaired by cellular mechanisms, DNA mutations may occur. If these DNA mutations affect genes responsible for regulating cell growth and division, such as tumor suppressor genes or oncogenes, it can result in uncontrolled cell proliferation. If the immune system fails to recognize and eliminate these abnormal cells in a timely manner, and if the accumulation of mutations persists, it can ultimately progress into cancer [248].
Some researchers have shown that oral microorganisms produce several specific virulence factors that lead to esophageal cancer. These virulence factors have the ability to induce cell apoptosis, stimulate uncontrolled cell proliferation, disrupt intercellular adhesion, and enhance cell invasion potential, consequently facilitating the advancement of esophageal cancer. Kawasaki et al. showed that Aggregatibacter actinomycetemcomitans produces the virulence factors leukotoxins and cytotoxic distension toxin [249]. cagE is derived from actinomycetes associated with the risk of periodontitis. It shares homology with virB1 and virB4, which encode proteins involved in the T4SS system (known for its functions in DNA transport and virulence factor secretion) [250,251]. Research studies have demonstrated that cagE can induce apoptosis in various human primary epithelial cells, endothelial cells, osteoblasts, and T cells in vitro. Additionally, it has been found to have the capacity to induce cell apoptosis, impair the immune system, and potentially contribute to the pathogenesis of diseases caused by actinomycetes, such as periodontitis [252,253]. Fusobacterium nucleatum can produce specific virulence factors, such as adhesin, which can strongly adhere to host cells and may cause rapid disease development [254,255]. Patients infected with P. gingivalis are more likely to develop esophageal cancer. Liang et al. conducted a study where they demonstrated that Porphyromonas gingivalis infection promoted the proliferation and migration of ESCC through the miR-194/GRHL3/PTEN/Akt pathway [256]. Their findings indicated an increase in miR-194 expression following Porphyromonas gingivalis infection, and miR-194 was found to directly target the 3’ UTR region of GRHL3, leading to the inhibition of GRHL3 expression. This inhibition subsequently resulted in the downregulation of PTEN expression, which is regulated by GRHL3. Consequently, the activated PI3K/Akt pathway facilitated ESCC proliferation and migration [256]. Chen et al. demonstrated that infection with P. gingivalis induces the production of IL-6 by host cells, a cytokine known to be associated with epithelial-mesenchymal transition and the recruitment of myeloid-derived suppressor cells [257].
The oral microbiome can also reach the stomach through swallowing, eating, and drinking, potentially impacting the development of gastric diseases, including functional dyspepsia, chronic gastritis, intestinal metaplasia, and gastric cancer.
Functional dyspepsia (FD) is characterized by abdominal pain, abdominal distension, and other clinical manifestations, excluding organic, systemic, or metabolic lesions in the gastrointestinal tract [258]. The pathogenesis of FD remains unclear, but may be related to delayed gastric emptying, brain-gut axis dysfunction, and autonomic nervous system dysfunction [259–262]. Psychological disorders and stress also have certain effects [263–265]. Studies on the relationship between oral microbiome and FD are limited.
Humans introduce saliva into the gastrointestinal tract through various activities such as swallowing and drinking on a daily basis [266]. Swallowing of saliva takes places regularly and every time approx 1 ml of saliva is present in the oral cavity. Oral microbiome dysbiosis may play an important role in FD; however, only a few related studies have been conducted. Liu et al. [267] reported that the oral microbiome in patients with FD was significantly different from that in healthy controls in saliva samples. They identified Kingella and Abiotrophia at the genus level and Prevotella intermedia at the species level as potential biomarkers for FD. Additionally, they found that salivary pH was lower in patients with FD than in healthy controls (6.78 vs. 7.38). Lower pH is associated with oral microbiome dysbiosis and may subsequently lead to oral diseases. Furthermore, changes in the composition of the oral microbiota can promote the occurrence of OLP disease, periodontitis, and other inflammatory diseases [122,268,269]. Oral inflammation can aggravate gastrointestinal disorders because both the mouth and gastrointestinal tract are suitable sites for microbial colonization [267]. Hence, although it is not certain whether changes in the oral microbiome play a decisive role in the pathogenesis of FD, they should be considered important pathogenic factors.
Atrophic gastritis (AG) and intestinal metaplasia (IM) are common types of precancerous gastric lesions. Characterized by inflammatory infiltration of the gastric mucosa, gastritis is associated with an increased risk of gastric cancer [270,271]. IM is defined as the replacement of normal, differentiated, and mature mucosal tissue with intestinal epithelium, a phenomenon commonly observed in the stomach and esophagus [272,273]. Traditionally, H. pylori has been considered a key indicator of gastritis. However, studies have shown that approximately 25% of cases are not associated with H. pylori infection, implying that other microorganisms play important roles in the development of gastritis [274]. Several studies have shown that the oral microbiome is closely associated with precancerous gastric lesions [275–277].
Cui et al. [278] observed lower oral microbiome diversity in patients with gastritis than that in healthy controls in terms of α diversity (p = 0.01), Shannon indices indicating a more even distribution of oral microbiota species in gastritis (p < 0.01). The samples were taken from tongue-coating swabs from the surface of the tongue dissolved in PBS. The microbial diversity was not significantly different between the H. pylori-positive and H. pylori-negative gastritis groups. Using 16S rRNA analysis, they identified 21 species that significantly differed among gastritis and control tongue coating Veillonella parvula, Corynebacterium matruchotii, Kingella oralis, Atopobium rimae, Aggregatibacter aphrophilus, Streptococcus sanguinis, Acinetobacter lwoffii, Prevotella amnii, Prevotella bivia, Cardiobacterium hominis, and Oribacterium sinus were decreased in the gastritis samples; Streptococcus infantis, Treponema vincentii, Leptotrichia unclassified, Campylobacter rectus, Campylobacter showae, Capnocytophaga gingivalis, Leptotrichia buccalis, Campylobacter concisus, Selenomonas flueggei, and Leptotrichia hofstadii were increased in the gastritis samples. The varying abundances of these microorganisms indicate significant differences in the composition of tongue coating microorganisms between gastritis patients and healthy individuals. These differences can potentially serve as distinguishing factors for the diagnosis of gastritis, highlighting the potential of these microorganisms as biomarkers for gastritis diagnosis. Additionally, Chen et al. [279] found increased Lactobacillaceae, Porphyromonas, and Faecalibaculum were increased in the saliva samples of patients with gastritis. The observed alterations in the oral microbiome among gastritis patients indicate the involvement of oral microbiota in the pathogenesis of gastritis. These changes further suggest the potential utility of the oral microbiome as a non-invasive biomarker for the diagnosis of gastritis.
IM is an important node in gastric carcinogenesis. H. pylori is a key marker of IM. However, in the later stages of carcinogenesis, other pathogenic microorganisms enriched and replace H. pylori [280,281]. Salazar et al. [276] assessed the relationship between selected oral pathogens and precancerous gastric lesions using salivary samples. In this study, patients underwent an oral examination, during which periodontal probing depth was measured, including clinical attachment loss, bleeding on probing, and periodontal probing depth. Subsequently, a stratified analysis was conducted based on periodontal indexes to investigate the association between specific pathogens and gastric cancer precursor lesions. They identified significant differences in A. actinomycetemcomitans among those with ≥ median of percent tooth sites with a pocket depth (PD) ≥3 mm in gastric precancerous lesions. Periodontal disease-related pathogens such as P. gingivalis, Tannerella forsythensis, and Treponema denticola were associated with an increased risk of gastric precancerous lesions. Wu et al. [277] used shotgun metagenomics to evaluate the changes in the oral microbiota associated with IM using saliva samples. The results showed that Peptostreptococcus stomatis, Johnsonella ignava, Neisseria elongata, and Neisseria flavescens were abundant in patients with IM, whereas the prevalence of Lactobacillus gasseri, Streptococcus mutans, Streptococcus parasanguinis, and Streptococcus sanguinis decreased. Changes in the oral microbiome may be related to the regulation of inflammatory pathways in IM. In future research, it is imperative to investigate the characteristics of oral microbiome alterations in patients with gastric precancerous lesions and their contribution to the pathogenesis of such lesions. The development of novel diagnostic and predictive methods, as well as treatment strategies, centered around the oral microbiome of gastric precancerous lesions will significantly facilitate advancements in this field.
H. pylori is a key factor in the development of multiple gastrointestinal diseases. In 1994, the World Health Organization defined H. pylori as a class I oncogenic factor for gastric cancer (GC) [282]. H. pylori mainly colonizes the stomach, and multiple studies have shown that it can be detected in the oral cavity and is associated with dysbiosis of the oral microbiome [283–285].
Periodontitis, especially in its severe form, is associated with H. pylori infection, which may increase the risk of various gastrointestinal cancers [285], such as GC [286], and can also raise mortality associated with these cancers. Sung et al. showed that H. pylori infection has a significant role in regulating the association of periodontitis with gastrointestinal cancer. They speculated that the inflammatory state of periodontitis may lead to changes in the composition of the oral microbial community, resulting in more common H. pylori in the oral cavity, and subsequently indirectly causing systemic transmission and infection of H. pylori, thereby increasing the risk of gastrointestinal cancer. This suggests a link between oral microbes and gastrointestinal cancers such as GC. Moreover, studies have shown that dental caries and their severity are associated with H. pylori infection; the oral cavity is the extra-gastric reservoir for H. pylori, and the main reservoir is possibly the dental pulp [287–289]. The findings of this study indicate a significantly higher incidence of severe dental caries in individuals with H. pylori in the pulp compared to other diseases such as periodontitis, tooth fractures, and pericoronitis [288]. Several reasons can be attributed to the colonization of H. pylori in the dental pulp based on the anatomical structure of the Firstly, the presence of gastric H. pylori in the pulp cavity offers a relatively isolated environment, protecting it from clearance. Secondly, within the dental pulp, H. pylori may contribute to biofilm formation, offering additional bacterial protection against antibiotics and immune clearance. Thirdly, the microenvironment within the dental pulp may provide optimal temperature and pH conditions for H. pylori similar to those found in the gastric mucosa [288,290]. Nevertheless, the specific causes and underlying mechanisms of these interactions remain unclear [291–295]. Other studies have shown that oral lichen planus [128,129], oral leukoplakia [124], and oral cancer [294,295] are associated with oral H. pylori infection. Therefore, early control of oral H. pylori infection is important for the prevention and early intervention of GC.
Although H. pylori plays a significant role in the initiation of GC, other microorganisms appear to play major roles in the development of later stages of GC [296]. When H. pylori is dominant, the gastric microenvironment is characterized by decreased pH and microbial diversity [297,298]. The physiological pH in the stomach is known to be highly acidic, ranging between approximately 1.5 and 3.5, posing a lethal environment for most bacteria. However, H. pylori possesses the enzyme urease, which facilitates the hydrolysis of urea in the stomach into carbon dioxide (CO2) and ammonia (NH3). Ammonia, being an alkaline substance, can react with hydrogen ions (H^+^) present in the stomach acid, leading to the formation of ammonium ions (NH4^+^). Consequently, this neutralizes the surrounding environment, counteracting the acidity [299]. The urease activity of H. pylori plays a crucial role in elevating the pH of the immediate vicinity, thereby enabling the bacteria to survive within the acidic conditions of the stomach. This mechanism allows H. pylori to establish colonization in the gastric mucosa and proliferate by creating a relatively higher pH microenvironment, effectively shielding itself from the detrimental effects of stomach acid. In the later stages, as H. pylori decreases, a new microenvironment characterized by increased pH is established, allowing for greater diversity of gastric microorganisms and the proliferation of opportunistic pathogens [281,298,300,301]. These new dominant bacteria may be the pathogenic factors in GC. Therefore, in addition to H. pylori, other pathogenic bacteria such as Prevotella, Streptococcus and Halomonas [296] in the stomach are also related to the occurrence and development of GC.
Yamamura et al. [302] demonstrated a significant association between the presence of Fusobacterium nucleatum in the oral cavity and the development of GC, as observed in paraffin-embedded pathological samples. Similarly, Sun et al. [303] reported alterations in the microbial composition of saliva and plaque samples in GC patients. They identified an increase in the abundance of Veillonella, Prevotella, Aggregatibacter, and Megasphaera, while noting a decrease in Leptotrichia, Rothia, Capnocytophaga, Campylobacter, Tannerella, and Granulicatella. In this study, subgingival plaque samples were collected from the first molar or the last tooth of each quadrant, in addition to two additional teeth with the deepest periodontal pockets. Wu et al. [247] compared the oral microbiota composition of patients with GC with that of healthy controls. The results showed that Firmicutes, Bacteroidetes, and Streptococcus were abundant in the tongue coating of patients with GC, whereas Neisseria, Prevotella, and Porphyromonas were less abundant.
Moreover, studies have shown that some viruses such as the Epstein‑Barr virus is related to GC [304–306]. EBV infection-associated GC represents a distinct subgroup within the spectrum of GC, accounting for approximately 10% of all GC cases. This particular subtype predominantly affects male individuals, with a relatively young age of onset, and primarily manifests in the proximal region of the stomach [307]. Following infection of GC cells with EBV, the virus exists in a free form without integration into the host genome or undergoing viral replication, indicating a latent infection. Notably, EBV-associated GC exhibits a latency I pattern, whereas latency II tumors encompass nasopharyngeal carcinoma and Hodgkin lymphoma, and latency III tumors include AIDS and organ transplant-related lymphomas [307]. Upon EBV infection of GC cells, several latent proteins are expressed by the virus within these cells. For instance, latent membrane protein 2A (LMP2A) plays a role in upregulating the survivin gene through the NF-kB pathway, consequently attenuating apoptosis in GC cells [308]. Additionally, EBV is involved in the induction of tumor suppressor gene methylation in GC, thereby promoting disease progression. Exploring the virus-host interaction provides a promising avenue for potential therapeutic approaches targeting EBV-associated GC. Examples include bortezomib induction and radiotherapy targeting viral enzymes [306,306,309].
In addition to the potential pathogenic changes in the oral microbiota in the development and progression of GC, oral microbiota can also contribute to tumorigenesis through a variety of mechanisms, including excessive inflammatory responses, host immunosuppression, promotion of malignant transformation, anti-apoptotic activity, and the secretion of carcinogens [310,311]. Certain researchers have postulated that specific glycans and glycoproteins can modulate the oral microbiota composition, particularly fucosylated glycans known as salivary protein glycopatterns in GC patients. This observation holds potential for the development of novel carbohydrate-based therapies that target the oral microbiome [312]. The glycoprotein component of saliva plays a pivotal role in regulating the oral microbiota. Salivary mucins and salivary lectins, among other specific saliva components, are involved in the clearance of oral bacteria. Patients with different diseases may exhibit distinct alterations in protein glycotypes within their saliva when compared to healthy individuals [313,314]. The occurrence and progression of GC can influence changes in salivary protein glycosylation patterns, particularly alterations in sugar patterns [315]. Shu et al. discovered that compared to healthy subjects and patients with AG, GC patients exhibited significantly lower proportions of fucosylated N-linked glycans and fucosylated O-linked glycans in their saliva. Subsequent investigations by Shu et al. revealed that fucose-neoglycoproteins impact the biological behavior of Aggregatibacter segnis (A. segnis) in the oral cavity [312]. These effects include reducing the adhesion and toxicity of A. segnis to oral epithelial cells and oral cancer cells, modifying the polysaccharide structure on the surface of A. segnis, and enhancing its ability to trigger innate immune responses. These alterations may potentially lead to an imbalance in the oral microbiota’s ecology. Furthermore, these findings offer a foundation for future development of novel carbohydrate-based treatments aimed at maintaining oral microbiota balance.
In summary, the oral microbiome is closely associated with multiple oral and upper gastrointestinal diseases. Currently, the pathogenesis of upper gastrointestinal diseases caused by oral microorganisms remains unclear, and precise and effective clinical treatments are lacking. Therefore, it is of great significance to prevent and treat upper gastrointestinal diseases from the perspective of the oral microbiome. This may include the elimination of harmful microorganisms, the use of antibiotics, the changes in lifestyle habits, the use of prebiotics, genetic engineering, and targeted delivery systems [7].
Studies have shown that microbiome plays an important role in tumor resistance to chemotherapy and novel targeted immunotherapies. Alexander et al. summarized the ‘TIMER’ mechanistic framework, which reflects how the microbiome modulates drug resistance in cancer patients [316] through mechanisms such as translocation, immunomodulation, metabolism, enzymatic degradation, reduced diversity, and ecological variation. Sevcikova et al. have summarized how microbiomes regulate resistance in various chemotherapeutic agents and immunotherapy [317]. For instance, Fusobacterium nucleatum can induce autophagy by down-regulating miR-4802 and miR-18a and activate the innate immune system to promote oxaliplatin chemotherapy resistance in patients with colorectal cancer (CRC) [318]. MiR-4802, belonging to the class of microRNAs, exerts its regulatory role in gene expression and tumor biology by binding to target mRNA molecules, thereby inducing sequence-specific cleavage or inhibiting translation [318]. This study examined the impact of Fusobacterium nucleatum infection on colon cancer cell lines HCT116 and HT29. The findings revealed a significant downregulation of miR-4802 in HCT116 cells and miR-18a* in HT29 cells following Fusobacterium nucleatum infection. Moreover, Fusobacterium nucleatum was observed to activate autophagy in cancer cells and enhance chemotherapy resistance in colon cancer cells by selectively reducing the levels of miR-18a* and miR-4802. Targeting Fusobacterium nucleatum represents a potential strategy to ameliorate chemotherapy resistance and improve clinical prognosis in patients with CRC. Additionally, patients with melanoma who respond well to PD-1 blockade (the use of anti-PD-1 therapy) exhibit a higher bacterial diversity and enrichment of Faecalibacterium spp., while those who response poorly exhibit enrichment of Anaerotruncus colihominis, Bacteroides thetaiotaomicron, and Escherichia coli. Faecalibacterium is associated with longer progression-free survival; however, patients with higher levels of Bacteroidales have lower survival rates [319].
Regular tooth brushing can effectively remove harmful microorganisms related to oral diseases, such as dental plaque [320]. Studies have shown that periodontal pathogens, such as P. gingivalis, Tannerella forsythensis, T. denticola, and Treponema socranskii, can be significantly decreased after mechanical debridement [321]. However, these mechanical clearances are nonspecific, and some beneficial bacteria may be removed, thereby reducing the microbial diversity of the mouth. Therefore, accurate targeted antibacterial therapy is necessary. In the context of periodontal therapy, topical application of antibiotics is preferred because it can increase the local concentration of the drug, improve its effectiveness, and reduce systemic side effects [322]. Winkel et al. reported that P. gingivalis, P. intermedia, and T. forsythensis decreased after amoxicillin/metronidazole combination therapy in tablet form, and periodontal parameters were also significantly improved [323]. Nevertheless, the treatment objective must be it is designed to combat specific pathogenic bacteria implicated in periodontal disease while striving to preserve the beneficial oral microbiota. Moreover, the potential for antibiotic resistance underscores the need for judicious use of such treatments. While these results underscore the potential effectiveness of antibiotics in managing periodontal pathogens, the emerging challenge of antibiotic resistance cannot be overlooked. Ready et al. reported that the oral microbiota of children using amoxicillin was more resistant than that of children not using amoxicillin [324]. This underscores the complex nature of antibiotic use, where the benefits must be carefully weighed against the risks of promoting resistance. Hence, there is an ongoing controversy surrounding the long-term sustainability of antibiotic therapy in periodontal treatment, necessitating a balanced discussion on its merits and potential drawbacks.
Lifestyle choices, particularly dietary habits, can modulate the oral microbiome, which in turn may influence health outcomes. Study indicates that tea consumption is associated with an enhanced abundance and diversity of the oral microbiome, including specific changes in microbial taxa such as Fusobacterium, which could have positive health implications. In contrast, coffee consumption did not exhibit a significant impact on the oral microbiome’s composition [325]. Furthermore, we’ve delineated the shifts in microbiome diversity observed in smokers, such as decreases in Proteobacteria and increases in Streptococcus, to underscore the potential deleterious effects of certain lifestyle habits on oral health, and by extension, on overall wellbeing [42]. This suggests that a healthy diet, including tea consumption, may contribute to the maintenance of oral microbiome balance and potentially reduce the risk of associated diseases.
Recently, probiotics have played an increasingly important role in treating various diseases owing to their ability to stimulate the growth of beneficial bacteria and inhibit the growth of pathogens. Probiotics are defined by the International Scientific Association as ‘live microorganisms that, when administered in adequate amounts, confer a health benefit on the host’ [326]. Studies have shown that proper use of probiotics can decrease the prevalence of dental caries [327] and periodontitis [7]. Guglielmetti et al. [328] have shown that a combination of probiotics can increase the abundance of Faecalibacterium and Akkermansia, thus reducing microbiome disorders and preventing the development of GC. Fecal microbiota transplantation (FMT) therapy has been shown to regulate the microbiome with effects extending beyond the gut, potentially influencing systemic immune responses. Transplanting feces from anti-PD-1 blocker responders into mice led to slower tumor growth, enhanced T-cell responses, and improved efficacy of anti-PD-L1 therapy. Conversely, transplantation from non-responders correlated with faster tumor growth [329]. The findings highlight the interconnectedness of the microbiome across different body sites. The oral and upper gastrointestinal tract microbiomes serve as gateways to the gut and are integral to the initiation and maintenance of immune responses. Disruptions in the oral microbiomes can influence the gut microbiomes and vice versa, due to the continuous interaction along the gastrointestinal tract. Therefore, a balanced oral and upper gastrointestinal microbiome could potentially enhance the effectiveness of FMT in cancer therapy by further modulating the systemic immune response. This connection underscores the importance of considering the health of the entire gastrointestinal tract, including the oral and upper regions, in the context of FMT treatment strategies.
A wealth of evidence from basic and clinical studies highlights the crucial roles of the oral microbiome in oral and upper digestive diseases. Oral specimens, such as saliva and buccal mucosa, are easy to collect, and exhibit better sample stability than gastrointestinal tissues. Oral microbiome analysis is expected to be an effective triage method for high-risk populations prior to endoscopic screening.
In this paper, we discussed the relationship between the oral microbiome and oral and upper gastrointestinal diseases, particularly malignant tumors with poor prognosis, such as oral, esophageal, and gastric cancers. Initial findings suggest that the oral microbiome may hold potential as an indicator for oral and upper gastrointestinal diseases. However, while there are specific microbial signatures associated with health and disease states, the use of the oral microbiome as a clinically validated biomarker is not yet established. Further research is required to explore these associations in depth and to develop robust biomarkers for the clinical prediction of such conditions. Additionally, we discussed potential treatments for oral and upper gastrointestinal diseases based on the oral microbiome, which may provide support for early diagnosis and treatment. However, studies on the mechanisms underlying oral microbiomes and esophageal and stomach diseases are still lacking. Therefore, more prospective, multicenter, large-sample studies are necessary.
This work was supported by National Natural Science Foundation of China grant number 82070575, Beijing Hospitals Authority ‘Dengfeng’ talent training plan grant number DFL20220101, Capital’s Funds for Health Improvement and Research grant number 2020-2-2026, Beijing Hospitals Authority Clinical Technology Innovation Project grant number XMLX202131.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
CPR, candidate phyla radiation. HMP, Human Microbiome Project. PSD, polymicrobial synergy and dysbiosis. GCF, gingival crevicular fluid. EPS, extracellular polymetric substances. BD, Behcet’s disease. TNF-α, tumor-necrosis factor-alpha. OPMD, oral potential malignant disorders. OLP, oral lichen planus. OLK, oral leukoplakia. GERD, gastroesophageal reflux disease. RE, reflux esophagitis. EoE, eosinophilic esophagitis. BE, Barrett’s esophagus. ESCC, esophageal squamous cell carcinoma. EAC, esophageal adenocarcinoma. FD, functional dyspepsia. IM, intestinal metaplasia. Hp, helicobacter pylori. GC, gastric cancer. CRC, colorectal cancer.
Sifan Liu: study design, written and revision of manuscript. Shidong Wang, Nan Zhang, Peng Li: revision of the manuscript. Peng Li: Funding support. All authors have approved the final version of the manuscript.
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Data sharing is applicable to this article.