Normal humans produce 0.75-1.5L saliva per day, which contains a considerable number of microbes. In mice experiments that establish oral microbial infection through oral administration or gavage of the saliva from periodontitis patients, an abnormal enrichment of oral pathobionts that were confirmed as secondary components of the salivary microbiota was detected in mice’s intestines (Atarashi et al., 2017; Bao et al., 2022). For human beings, most oral species (including core Soral taxa, Streptococcus, Veillonella, Actinomyces, and Haemophilus) that result in endogenous infection emerged in the GI tract in health and disease status, with high levels of variation across individuals (Schmidt et al., 2019) ( Figure 1 ).

Particularly for periodontitis and periapical inflammation patients, transient physiological bacteremia triggered by tooth extraction and periodontal procedures permits oral pathogens to stretch themselves systemically via the circulatory system (Olsen and Yamazaki, 2019)( Figure 1 ). For severe periodontitis, the subgingival plaque has direct access to the damaged periodontal pocket, bacteria are more likely to infiltrate periodontal blood vessels and gingival epithelium in the context of the increased mucosa permeability, through which, P. gingivalis and F. nucleatum can be parasitic on dendritic cells or macrophages and disrupt extraoral tissues (Carrion et al., 2012; Xue et al., 2018). It is widely acknowledged the linkage (not causation) between periodontal disease and atherosclerotic vascular disease. Oral microbes, including P. gingivalis, Actinomyces, Streptococcus, and Treponema denticola, have been confirmed as sources of infected heart valves, atherosclerotic plaques, and rheumatic heart valves (Figuero et al., 2014; Zhang et al., 2021; Deppe et al., 2022). In this way, pathogens and their metabolites may be disseminated to the intestine similarly. Periodontal patients possess a less diverse gut microbiota, and higher possession of oral taxa in the intestine, which gives rise to more serious gut inflammation (Lourenvarsigmao et al., 2018). A retrospective analysis of individuals’ blood samples indicates that patients with F. nucleatum or Streptococcus pepticus bacteremia are more likely to suffer from subsequent colorectal cancer (Kwong et al., 2018). For clinical CRC diagnosis, plasma is more advantageous than stool in sensitivity and holds a more unique and heterogeneous microbial community, the vast majority of circulating bacterial DNA could retrospect to the gastrointestinal tract and the oral cavity (Xiao et al., 2021).

However, the accurate location of oral microbes and the probability of colonization in the distal intestine remain controversial. Precise amplicon sequence variants analysis accomplished by Armin Rashidi et al. excluded a significant distinction of microorganisms between oral and gut (66 healthy adults from two countries), indicating more clinical pathologic examinations are still required (Rashidi et al., 2021). Vasapolli et al.’ s sequencing regarding healthy subjects’ saliva, mucosa, and stool samples from each segment of the GI tract displayed an approximate absence of major species of the upper GI tract in the lower GI tract (Vasapolli et al., 2019). Similarly, the correlation between oral taxa and pancreatic cancer did not present among an African-American population as previously speculated (Petrick et al., 2022). Via symbiotic analysis, Carr et al. discovered contrasting ARG-species correlations between saliva and stool samples (Carr et al., 2020). Whereas most 16S rRNA gene sequencing analyses only reliably classify taxa to the genus level and do not report species and strains usually. Using shotgun metagenomic sequencing, oral and gut bacterial communities show greater similarity than earlier studies suggested (de Cena et al., 2021; Maki et al., 2021). Moreover, diurnal variations, processing methods, race, and diet are irrelevant interference with measurement results, which requires further consideration in future studies (Superdock and Poole, 2022).

In general knowledge, P. gingivalis is a major pathogen for periodontitis and extensively involves in systemic diseases. To disrupt host-microbial homeostasis of the oral cavity, P. gingivalis only needs a microscopic colonization level (<0.01% of the total microbiota presented) (Hajishengallis et al., 2011). Extracellular translocation of P. gingivalis-nucleotide-diphosphate-kinase enzyme (NDKs) promotes microbial molecules to disrupt cytoplasm and establishes continuous infection in mucosal epithelial tissues (Atanasova et al., 2016). In mice experiments, a series of symptoms appeared after P. gingivalis infection (oral administration, gavage, or intravenous injection), including endotoxemia, intestinal inflammation, and systemic hypo-inflammation (Ohtsu et al., 2019; Kashiwagi et al., 2021). Regarding the intestine, P. gingivalis infection gives rise to microbiome dysbiosis. It increases serum endotoxin levels, allowing opportunistic pathogens to colonize in the oral cavity and stimulating the overgrowth of commensal microbes in the intestine (generally upregulates Bacteroidetes and Deferribacteres, and downregulates Firmicutes) (Nakajima et al., 2015; Ohtsu et al., 2019). Pyricularia pennisetigena and Alternaria alternata positively correlated with P. gingivalis administration in the fungal community. Serum metabolites are modified correspondingly with microbial alteration, especially lipid and tryptophan metabolic pathways (Chen et al., 2022). In P. gingivalis-administered mice, the biosynthesis of phenylalanine, tyrosine, and tryptophan in the intestinal microbiota are upregulated, with alanine, glutamine, histidine, tyrosine, and phenylalanine in serum promoted considerably in the serum (Kato et al., 2018). In terms of mechanism, P. gingivalis and its metabolites (e.g., gingipains and extracellular vesicles) activate antigen-presenting cells, initiating intestinal inflammation and immune reactions. Via stimulating TLR2/4 and inducing Th17 cells, P. gingivalis and its metabolites heighten the mRNA expression of TNF-α and IL-1β in the colon (Feng et al., 2020; Tang et al., 2021). Regional inflammation impairs the permeability of the intestinal barrier, specifically, downregulates tjp-1 and occludin gene expression, and decreases colic zonula occludens-1 (Zo-1) level (Nakajima et al., 2015; Feng et al., 2020). Next, the altered proinflammatory cytokines mentioned above modify methionine (Met) and homocysteine (Hcy) metabolism (i.e., 1-carbon metabolism), which potentially stimulates hyperhomocysteinemia (HHcy), another mechanism participating in intestinal dysbiosis (Stanisic et al., 2021). In terms of Th17 cells, a recent study reported a noticeable synergy between periodontal tissue and gut microbes. The intestinal translocation of P. gingivalis enhances Th17 cell differentiation, and mature Th17 cells systemically spread to peripheral immune tissue and then exacerbate intestinal inflammation (Sato et al., 2017; Nagao et al., 2022). Consistent with this, the Th17/Treg imbalance induced by disordered intestinal microbial metabolism directly generates NAFLD in P. gingivalis administration mice (Yao et al., 2022). Compared to normal individuals, CRC patients’ intestines are pathologically colonized with abnormally abundant P. gingivalis, whose infection gives rise to a poor CRC prognosis (Gao et al., 2021). Via activating NLRP3 inflammatory vesicles (activated hematopoietic NOD-like receptor protein 3 inflammasomes) in vitro and in vivo, P. gingivalis triggers low-grade systemic inflammation and intestinal dysbiosis, promoting CRC neoplasia progression (Wang et al., 2021a). Moreover, the peptidoglycan from P. gingivalis molecules induces programmed cell death 1 ligand 1 (PD-L1) up-regulation in colon carcinoma cells and mediates deep inhibition of T cells (involving activation of RIP2 and MAPK signaling pathways, and NOD1 and NOD2) (Adel-Khattab et al., 2021).

F. nucleatum normally resides in the intestine but increases synchronously with common oral microorganisms during CRC. 40% of the CRC patients detected identical F. nucleatum strains in both tumor tissue and saliva (Komiya et al., 2019). Moreover, successful periodontitis treatment reduces stool F. nucleatum levels (Yoshihara et al., 2021). Therefore, intestinal pathological F. nucleatum may derive from the oral. The continuum of its species and abundance in the GI tract could be an explanation. Transferring from saliva to the lower GI tract, the species diversity and abundance of F. nucleatum gradually dropped, indicating they resisted the selective stomach pressure (Richardson et al., 2020). Several F. nucleatum subspecies (nucleatum, animalis, vincentii, polymorphum) and potential new subspecies are isolated from the intestine of colorectal cancer patients, and the major encoding virulence factors for F. uncleatum showed evidence of horizontal gene transfer (Tran et al., 2022). Furthermore, intraperitoneal injection successfully established colonization of F. nucleatum in CRC tissue, which suggested the translocation of F. nucleatum through hematogenous route (Abed et al., 2020). Ponath et al. report FoxI, a conserved F. nucleatum oxygen-inducible picornavirus, acting as a post-transcriptional blocker of the major outer membrane porin FomA, is favorable for explicating how F. nucleatum colonizing in diverse segments in the intestine (Ponath et al., 2021).

In mucosal tissues, the adhered F. nucleatum promotes inflammation and stimulates immunoreaction. F. nucleatum and its outer membrane vesicles (OMVs) activate TLR/MyD88/NF-κB pathway, promoting the secretion of a series of proinflammatory cytokines, including IL-8, TNF, keratinocyte-derived chemokine (KC), IL-6, IFN-γ, and monocyte chemoattractant protein-1 (MCP-1) (Chen et al., 2020b; Engevik et al., 2021b). The colonic structure and mucus layers are damaged and infiltrated with immune cells. When regarding UC, this inflammatory process involves a molecular network including caspase activation, recruitment domain 3 (CARD3), and IL-17F (Cao et al., 2020). In addition, the TLR4-dependent mechanism (TLR4/NF-κB/S100A9 axis and NF-κB/miR-1322/CCL20 axis) promotes the M2 polarization of macrophages (M2-Mφ) and immunosuppressive effect, suggesting that oral F. nucleatum evolves more powerful virulence after colonization (Chen et al., 2018). Another virulence factor Fusobacterium produced that participates in immune regulation is the Fap2 protein, which directly interacts with TIGIT, mediates NK cell and T cell inhibition, while T-cell regulates inflammatory factors IL-10, IL-1β, and IL-6 (Gur et al., 2015; Li et al., 2019). Regarding CRC, F. nucleatum and its main pathogenic factors (FadA (binding E-cadherin), Fap2 (a galactose-sensitive hemagglutinin and adhesin binding TIGHT receptors), RadD (autotransporter) and FomA) recruit tumor-infiltrating immune cells, generating tumor microenvironment and participating in immunosuppression and tumorigenesis (Walencik, 2022). F. nucleatum modifies colonic Th17 cell frequency and IL-17 expression recombinant free fatty acid receptor 2 (FFAR2)-dependently (Brennan et al., 2021). Moreover, it positively correlated with the expression of Wnt-β-catenin (activated by FadA─E-cadherin) and REG Iα signaling, both of which effectively promotes the proliferation of sessile serrated adenoma/polyp (Rubinstein et al., 2013; Nishimura et al., 2021). ENO1 gene and ANGPTL4 protein enhance the high glycolysis of colorectal cancer cells, and these two regulatory mechanisms could be upregulated by F. nucleatum either, which further support F. nucleatum colonization and positively collated with poor prognosis (Hong et al., 2021; Zheng et al., 2021). Besides, it is a notable phenomenon in periodontal disease that a variety of bacteria, including F. nucleatum and P. gingivalis, mutually coordinate for coexistence. Presumably, this symbiosis continues to the intestine. In the intestine, F. nucleatum coexists with Clostridium through adhesin RadD, encouraging the intestinal mucus layer’s bacterial biofilm formation in IBD patients. This symbiotic relationship accelerates the extracellular polysaccharides-producing process and chemotaxis level of C. difficile (Engevik et al., 2021a).

Klebsiella is an opportunistic pathogen in the GI and respiratory tracts. Although a few Klebsiella physiologically colonizes in the intestine, in pathological states such as periodontitis, it demonstrates signs of ectopic colonization from the oral. Researchers found that saliva K. pneumonia of IBD patients rapidly establishes colonization in mice’s intestines, triggering a strong inflammatory response (upregulates IFN-γ, TH1 in the lamina propria, raises epithelial TNF-α mRNA expression in the proximal colon, and significantly induces IL-17, IFN-γ and CD4⁺ T cells level) (Atarashi et al., 2017). In mice models that were orally administrated with K. pneumoniae, the hypervirulent strain could even translocate from the intestine and lead to hepatic infections (Young et al., 2020). Th17 cell induction acts as a critical step in IBD pathogenesis and involves in regulating intestinal immunity and inflammation. Oral pathobiont-reactive Th17 cells (Klebsiella and Enterobacter species), rather than intestinal native microbes-reactive, translocate into the intestine and affect colitis progress (Kitamoto et al., 2020). Moreover, translocated Klebsiella promotes the secretion of IL-1β (mainly from inflammatory macrophages) via cysteine-11-mediated inflammatory vesicles, activating intestinal inflammasome (Kitamoto et al., 2020). For the intestine-native microbiome, in the K. pneumoniae infection mice model, gut microbial composition (down-regulates Lactobacillus reuteri and Bifidobacterium pseudolongum) and cecal metabolome (SCFAs) are altered (Wu et al., 2020). Whereas sufficient symbiotic microbe protection from Bacteroidetes could prevent the host-to-host transmission and intestinal colonization of K. pneumoniae via IL-36 signaling (Sequeira et al., 2020).

Two-group pheromone-based subsystem BlpRH is the core node coordinating bacteriocin production and integrating signals of competence activation cascade, typically for S. pneumoniae and S. mutans. Whereas human co-salivary Streptococcus lacks functional BlpRH pairs, the couples bacteriocin production and competence commitment is directly guided by the competence signaling system ComRS, which is the undetermined basis for its optimal adaptation, potentially explaining the high prevalence of S. salivarius in the human GI tract (Mignolet et al., 2018). Aside from benefiting oral health, in terms of its effect on intestinal function, the S. salivarius in the lower gastrointestinal tract is crucial for inhabiting intestinal inflammation response. It positively adjusts microbiome composition and intestinal immunity, even in healthy individuals, the predominant intestinal Streptococcus species is S. salivarius (Kaci et al., 2014; Li et al., 2022). It is confirmed that S. salivarius downregulates NF-κB pathway that triggered by LPS and inhibits peroxisome proliferator-activated receptor γ (PPARγ) activation in small intestinal epithelial cells in vitro (Couvigny et al., 2015). Likewise, both mice experiment and metabolic gene sequencing (I-FABP and Angptl4, these gene products regulate intracellular lipid accumulation) revealed S. salivarius’s protective ability to diminish intestinal epithelial inflammation (Kaci et al., 2014; Couvigny et al., 2015). For non-small cell lung cancer patients, S. salivarius and S. agalactiae react upon gastrointestinal-derived CD4⁺ T cells and effectively activate monocytes to secrete higher levels of IL-6, IL-12 and TNF, or so-called, the Th1- and Th17-skewed cytokines (Ma et al., 2017). However, S. salivarius is also reported to disturb intestinal microbiota composition. Oral S. salivarius was found to be enriched and of concordant strains in both intestinal and oral microbiota in Crohn’s disease patients, and the species diversity of the infected intestine was considerably depleted (Hu et al., 2021).

Although most Prevotella species physiologically colonize in oral and gut mucosa, a small number of Prevotella show pathobiontic properties and have been confirmed to participate in opportunistic infections. Distinct from intestinal native microbes, Prevotella owns a unique nitrogen assimilation metabolic network that rarely limits their growth. Jong Nam Kim et al. observed different patterns of transcript abundances in genes involving ammonium assimilation between the classical “enteric paradigm” and Pretovella (Kim et al., 2017). Pretovella act as a vital keystone bacterium of the gut. Binding or attaching to other bacteria and epithelium, Pretovella creates a larger infection than in previously infected areas. A higher abundance of P. intermedia and P. nigrescens (Pretovella species that are commonly resident in the oral cavity) was observed in the intestine of CRC patients (Wirbel et al., 2019). In mice experiments, oral administration of P. intermedia induces NAFLD (Yamazaki et al., 2021). In terms of IBD, Prevotella is a potential alternative biomarker for UC, tightly matched with feces and other oral areas (Xun et al., 2018). Moreover, Prevotella predominates in the intestinal microbiome in the preclinical phase of rheumatoid arthritis, promoting pathological progression in a TH17 cell-dependent manner (Alpizar-Rodriguez et al., 2019; Maeda and Takeda, 2019). In a metagenome-wide association study (MWAS) of the gut microbiome from rheumatoid arthritis patients, Toshihiro Kishikawa et al. identified five species that belong to the Prevotella (i.e., P. denticola, P. marshii, P. disiens, P. corporis, and P. amnii) (Kishikawa et al., 2020). Additionally, the major task for intestinal Prevotella is metabolizing various proteins and carbohydrates. Consequently, high animal protein and saturated fat diet western people own higher diversity of inflammation-associated Prevotella in the oral cavity, with intestinal microbes demonstrating upregulated virulence factor and antibiotic resistance gene levels. (Prasoodanan et al., 2021).

V. parvula is an anaerobic commensal and opportunistic pathogen that plays a crucial role in bacteria adhesion and biofilm formation for oral and gut microbiomes. Type V secreted autotransporters that typically exist in diderm bacteria determine this character. Whereas inactivation of the gene coding for a poorly characterized metal-dependent phosphohydrolase HD domain protein in Firmicutes could inhibit autotransporter-mediated biofilm formation (Bechon et al., 2020). Intestinal Veillonella attaches to the mucosa of the distal gut and positively coexists with Clostridioides in C. difficile colonization (CDC) patients (Crobach et al., 2020). Besides, it was detected the existence of Veillonella and Streptococcus in atherosclerotic plaques, whose bacterial abundances positively correlated with their abundance in the oral cavity, indicating that oral Veillonella probably spread to extraoral organs via the circulatory system (Koren et al., 2011). Veillonella extensively participates in a range of diseases associated with gastrointestinal microbial dysbiosis, for instance, hepatic and gall diseases (autoimmune hepatitis, alcoholic hepatitis, biliary atresia, and PSC) (Kummen et al., 2017; Song et al., 2021). Actually, Veillonella is acid-sensitive, the abundance of Veillonella heightens when aldafermin-mediated suppressions of bile acid synthesis, particularly toxic bile acids, are inhibited (Loomba et al., 2021). When regarding IBD, the enrichment of adhesive bacteria (involving Veillonella) increases Th17 cell activation and luminal secretory IgA (Chen et al., 2020a; Gonzalez-Soltero et al., 2020). In periodontitis-associated type 2 diabetes (T2D), Streptococcus and Veillonella are dominant in the symbiosis network, and microbial shifts may contribute to systemic inflammation and metabolic dysfunction (Li et al., 2020; Letchumanan et al., 2022).

It is almost impossible for fungi to survive in healthy people’s intestines, and C. Albicans dominate among the cultivable mycobiota that longitudinally persists. Intestinal C. Albicans probably as commensals constantly supplemented from the oral cavity, frequent teeth cleaning dramatically reduces fecal C. Albicans abundance (Auchtung et al., 2018; Raimondi et al., 2019). Whereas for immunocompromised individuals, intestinal fungi and fungal molecules could result in serious infections and produce severe bacterial sepsis via cytokine storm induction or macrophage-killing activity. C. Albicans gavage worsens the colitis in mice experiments, gut-leakage induces pro-inflammatory cytokines in the intestine and blood, which was hypothesized as a more severe translocation of LPS, serum (1→3)-β-D-glucan (BG) and bacteria from the gut into the systemic circulation (Panpetch et al., 2020). Regarding colonization and dissemination, in the gut, dead fungi are nutrients for bacterial fermentation. In the presence of C. Albicans, the opportunistic bacterium C. difficile can tolerate aerobic conditions, and the p-cresol produced by C. difficile inhibit C. Albian’s hypha formation, biofilm formation, and virulence (van Leeuwen et al., 2016). This symbiotic relationship leads to more severe infection of C. difficile in mice models and increases IL-8 production in experimental intestinal epithelial cell-lines (Panpetch et al., 2019). Regarding the susceptibility to C. Albicans, C. Albicans infection could be promoted by intestinal taurocholic acid (TCA) that weakens mucosal innate and adaptive immune responses (Datta et al., 2022). Besides, the host’s high iron level enhances C. Albicans infection severity and its dissemination from the oral to the gut (Tripathi et al., 2022). However, endogenous invasion by C. Albicans could be prevented by intestinal TLR2, and intravenous immunoglobulin (IVIg) has been proven useful for treating C. Albicans infection and maintaining intestinal homeostasis, which negatively regulates PPARγ and TLR-4 (Prieto et al., 2016; Charlet et al., 2019).

The intestinal microecological disorder is a process affecting multi-bacterial composition. In addition to common oral pathogens mentioned above, for instance, Peptostreptococcus stomatis engages in gastrointestinal cancers and is of significant centralities in the gastric carcinoma (GC) ecological network, which mediates the pathogenesis of precancerous gastric atrophy (GA) and intestinal metaplasia (IM) (Coker et al., 2018; Wu et al., 2022). Regarding IBD and CRC, P. stomatis is among the oral-derived biomarker panel of CRC either (Yu et al., 2017; Osman et al., 2021). Gemella enriches in the intestinal mucosa of IBD and CRC, while Mogibacterium is significantly more abundant in patients with adenomatous polyps (Hale et al., 2017; Rengarajan et al., 2020; Avuthu and Guda, 2022). Intestinal bacteriophages could communicate with gut-oral bacterial commensals, which promotes individuals’ virome profile differentiation at the early and late stages of CRC (Nakatsu et al., 2018). In terms of gastrointestinal motility disorders, a polybacterial infection (P. gingivalis, T. denticola, and Tannerella forsythia) is discovered to alter vascular and colonic BH4/nNOS/NRF2 pathways and to damage vascular relaxation and colonic motility (Gangula et al., 2015). In addition, oral lantibiotics (it has a considerable antimicrobial effect on intestinal gram-positive bacteria) produced by S. mutans decrease the diversity of intestinal microbes and reduce the abundance of Firmicutes (Yonezawa et al., 2021).