More than half of the bacterial species in the gastrointestinal system undergo oral-gut translocation (Schmidt et al., 2019). First, the oral cavity and gut are inherently linked through saliva. Studies have demonstrated that periodontal bacteria migrating via enteral dissemination (salivary pathway) are able to colonize and survive in the gut for at least 24 hours (Bao et al., 2022). Second, the rich blood circulation in the oral cavity and the ulcerated surface of the lining of periodontal pockets in patients with periodontitis also allow the oral microbiota to colonize the gut through hematogenous dissemination. A study comparing colorectal cancer (CRC) colonization by gavage vs. intravenous inoculated Fusobacterium nucleatum in a mouse model and found that hematogenous fusobacteria were more successful in CRC colonization than gavaged ones. This may indicate that the circulatory system appears to be theefficient route for some periodontal bacteria to reach the gut. However, more evidence is still needed to support this.

Finally, after invasion of host cells, periodontal pathogenic bacteria (e.g. P. gingivalis and F. nucleatum) may survive within them and subsequently disseminate to the gut (Xue et al., 2018; Kitamoto and Kamada, 2022a). For example, periodontal bacteria with virulence factors that inhibit phagolysosome formation are able to survive within the host cell and migrate intracellularly via Trojan horse mode or vesicular trafficking (Yilmaz et al., 2004; Sansores-España et al., 2021). P. gingivalis has been shown to survive within macrophages, epithelial cells, endothelial cells and smooth muscle cells and to spread from one cell to another (Wang et al., 2007; Li et al., 2008; Carrion et al., 2012). Thus, theoretically, periodontal bacteria may hijack these cells as a vehicle for migration to the gut (Kitamoto et al., 2020; Hajishengallis and Chavakis, 2021). However, more evidence is still required to support that periodontal bacteria translocated via this pathway are of sufficient pathogenic significance in the oral-gut axis mediating systemic disease progression. In conclusion, enteral dissemination (the main pathway), hematogenous dissemination, and host cell hijacking are all possible ways in which the oral microbiota can translocate to the gut, resulting in a complex association of the oral-gut axis based on microbial crosstalk ( Figure 3 ).

The oral-gut barrier is one of the important strategies for the host to maintain microbial homeostasis in order to limit microbial translocation between the oral cavity and the gut. The oral-gut barrier includes physical distances and chemical barriers (e.g. gastric acid and bile), as well as colonization resistance of the resident gut microbiota to the intestinal migration of oral microbes with pathogenic potential ( Figure 3 ). Intestinal commensal bacteria can play an important role in regulating intestinal mucosal homeostasis and inhibiting colonization of potential oral pathogens via distinct mechanisms (Suárez et al., 2021). For example, intestinal commensal bacteria can compete for nutrients and produce antimicrobial peptides and metabolites that affect the colonization and virulence of oral pathogens. Intestinal commensal bacteria also promote the induction of effector T and B cells locally and systemically in response to pathogens (Suárez et al., 2021). However, this protective mechanism of colonization resistance may be disturbed by microbiota imbalance or local changes in host response, leading to disruption of host-microbiome homeostasis.

The intestinal barrier has several physical and chemical barriers separating the host from the adjacent microbiota ( Figure 3 ). However, when the intestinal barrier function is pathologically altered, increased intestinal permeability and inflammatory response may allow the gut to “leak”, i.e. allowing pathogenic substances to cross the intestinal wall and spread systemically with pathological consequences (Hollander and Kaunitz, 2020). Prolonged translocation of periodontal bacteria to the gut may further trigger and exacerbate the putative disease “leaky gut syndrome” by affecting gut microbiota homeostasis and barrier function, thus participating in the pathogenesis of various gastrointestinal and systemic diseases (Kinashi and Hase, 2021) ( Figure 4 ). This will be discussed in more detail below.

RA is a chronic inflammatory autoimmune disease characterized by bone destruction in multiple joints throughout the body. RA patients often have significant alterations in their oral and gut microbiota that correlate with the severity of joint destruction and the efficacy of antirheumatic treatment in RA patients (Phillips, 2015; Zhang X. et al., 2015; Drago et al., 2019; Möller et al., 2020). Several periodontal bacteria (e.g. P. gingivalis and Prevotella intermedia) are detected in the gut, serum and synovial fluid of RA patients (Martinez-Martinez et al., 2009; Pianta et al., 2017; Drago et al., 2019). RA may be a reactive arthritis aggravated by the repeated translocation of these periodontal bacteria to the joints. Whether oral pathobionts reach the joints through the oral-gut axis or through hematogenous dissemination, most studies suggest that both routes are possible, but more research is needed to determine which route is predominant or prior.

As the most important diagnostic biomarker for RA, serum levels of anti-citrullinated protein antibodies (ACPA) positively correlate with the severity of both RA and periodontitis (Lappin et al., 2013; Bellando-Randone et al., 2021). P. gingivalis can convert arginine residues in proteins to citrulline and increases serum levels of ACPA (Möller et al., 2020). A. actinomycetemcomitans can also indirectly increase protein citrullination through the pathway of leukotoxin (LtxA)-induced peptidyl-arginine deiminase (PAD) dysregulation, thereby increasing ACPA levels (Konig et al., 2016). Thus, one of the important mechanisms by which periodontal bacteria promote RA via the oral-gut axis is chronic exposure to citrullinated protein (CP) triggers the expression of ACPA in joint synovium throughout the body.

In an arthritis mouse model, oral administration of P. gingivalis induced dysbiosis of the gut microbiota, increased IL-6 and CP production in serum, joint and intestinal tissues, and exacerbated joint destruction (Hamamoto et al., 2020). Further, fecal microbiota transplantation (FMT) from P. gingivali-inoculated experimental arthritis mice reproduced donor gut microbiota and resulted in severe joint destruction with increased IL-6 and CP production in joint and intestinal tissues. This suggests that the gut dysbiosis induced by P. gingivalis oral infection may be sufficient to trigger or exacerbate arthritis.

F. nucleatum is also enriched in the gut of RA patients and positively correlate with RA severity (Hong et al., 2023). Mechanistically, F. nucleatum delivers FadA to the joints via outer membrane vesicles (OMVs) and triggers synovial inflammation by activating the Rab5a-YB-1 axis in synovial macrophages. In addition, some studies have treated with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity (modulating TJs), effectively reduces arthritis onset (Tajik et al., 2020).

The mechanism by which periodontal bacteria promote RA may also be related to the activation of Th17-related pathways. Furthermore, periodontal bacteria (e.g. P. gingivalis and Prevotella nigrescens) are involved in inflammatory bone destruction in RA by increasing the intestinal hyperimmune response triggered by Th17 cellular immune responses, which can induce higher levels of RANKL and TRAP⁺ osteoclasts (Vernal et al., 2014). P. nigrescens also can reduce the osteoprotective effects of Th2 (de Aquino et al., 2014). All of this evidence demonstrates that the oral-gut axis plays an important role in the influence of periodontal bacteria on RA.

Periodontal bacteria may be indirectly associated with brain diseases through the gut pathway. In addition to ischemic (e.g. stroke) and autoimmune (e.g. multiple sclerosis) brain diseases, evasion strategies of specific pathogens may also alter the function of the blood-brain barrier (BBB) (Daneman and Rescigno, 2009). Here we focus on the pathogenic mechanisms of the oral-gut-brain axis in brain disease, i.e., periodontal bacteria disrupt the gut barrier and BBB, further triggering neuroinflammatory and pathological changes in the brain ( Figure 5 ) (Sansores-España et al., 2021).

The gut microbiota may transport bacteria or metabolites directly to the liver via portal circulation (Hou et al., 2022). The impaired gastric acid and bile secretion prevalent in chronic liver disease (e.g. cirrhosis) may also make the gut more susceptible to translocation and colonization by oral bacteria (e.g. P. gingivalis and T. denticola) (Kakiyama et al., 2014; Qin et al., 2014; Wang et al., 2022). The anatomical dependence of the liver on the gut through metabolic exchange and pathogen translocation is therefore the basis for the pathophysiology of periodontal bacteria affecting liver disease via the gut pathway, the “oral-gut-liver axis” referred to in many current studies ( Figure 5 ).

Epidemiological evidence suggests that having severe periodontitis increases the prevalence of non-alcoholic fatty liver disease (NAFLD), which recently renamed Metabolic dysfunction-associated fatty liver disease (MAFLD), mortality associated with cirrhosis, and progression of NAFLD towards fibrotic liver injuries (Akinkugbe et al., 2017; Ladegaard Grønkjær et al., 2018). In addition, patients with hepatocellular carcinoma in combination with periodontitis tend to have worse cancer stage, liver function and prognosis (Tamaki et al., 2011). Periodontitis may affect liver disease by modulating the oral and gut microbiota.

Dysregulated oral and gut microbiota may act as important mediators between periodontal bacteria and liver disease. Oral administration of periodontal bacteria (e.g. P. gingivalis and A. actinomycetemcomitans) may increase the risk of liver disease by altering the F/B ratio of the gut microbiota and increasing intestinal leakage (regulating TJs) and serum endotoxin levels (Arimatsu et al., 2014; Nakajima et al., 2015; Komazaki et al., 2017; Åberg and Helenius-Hietala, 2022). Dysregulated gut microbiota can also affect chronic liver disease by regulating bile acid metabolism and the production of short-chain fatty acids (SCFAs), ethanol and choline. Significant alterations in the composition of the gut microbiomes are present in patients with liver disease, including NAFLD, non-alcoholic steatohepatitis (NASH), cirrhosis and alcoholic liver disease (ALD). In contrast, FMT treatment can prevent NASH, ALD, hepatic encephalopathy (HE), and acute liver failure (ALF) in animal models by restoring intestinal homeostasis (Ferrere et al., 2017; Wang et al., 2017; Zhou et al., 2017; Liu et al., 2021a). Furthermore, genetic tracking revealed that the majority of species causing alterations in the gut microbiota of patients with liver disease are of buccal origin (Qin et al., 2014). Supporting this view, it has been shown that systemic periodontal therapy in cirrhotic patients modulates salivary and fecal microbiota dysbiosis, improves endotoxemia, as well as systemic and local inflammation (reduces inflammatory mediators), and improves quality of life and cognition in patients with HE (Bajaj et al., 2018). Periodontal treatment also improves biochemical markers (e.g. ALT and AST) in patients with NAFLD and cirrhosis (Yoneda et al., 2012; Komazaki et al., 2017; Nakahara et al., 2018). However, whether periodontal therapy improves organic liver changes remains to be investigated.

Periodontal bacteria and their virulence factors may reach the liver via the damaged gut and act directly on hepatocytes, Kupffer cells and hepatic stellate cells (HSCs) through activation of the PRR, hence triggering downstream pro-inflammatory cascades and ultimately affecting chronic liver disease (Schroeder and Bäckhed, 2016).

Periodontal treatment has been proposed as a potential approach to improve liver disease. It has also been suggested by some that the simultaneous treatment of periodontitis and intestinal disease may have a synergistic effect on patients with liver disease (Kuraji et al., 2023). That is, treatment of intestinal inflammation and intestinal ecological dysbiosis may prevent ectopic intestinal colonization caused by oral pathology, even in the presence of periodontitis. However, more studies are still needed to confirm these findings.

Obesity is a multifactorial chronic inflammatory disease characterized by the overgrowth of adipose tissue. The degree of obesity (e.g. body mass index) has been found to be positively correlated with the degree of periodontal inflammation (e.g. periodontal inflamed surface area index and the level of periodontal bacteria in the oral cavity) (Chaffee and Weston, 2010; Nascimento et al., 2015; Aoyama et al., 2021).

Obesity patients have been shown to have alterations in both oral and gut microbiota (Wu et al., 2018; Benahmed et al., 2021). Microorganisms play an essential role in digestion, absorption, metabolism, energy use and immune regulation in the body (Turnbaugh et al., 2008). Just as germ-free (GF) mice were protected against high fat diet (HFD) induced obesity, whereas receiving FMT from obese mice increases fat deposition and metabolic disturbances in GF mice (Rabot et al., 2010). Oral administration of periodontal bacteria (e.g. P. gingivalis and A. actinomycetemcomitans) significantly alters the F/B ratio in the gut microbiota, which in turn may induce insulin resistance, hepatic steatosis and macrophage infiltration in adipose tissue, and promote further increases in body weight and adipose tissue in diet-induced obese mice (Arimatsu et al., 2014; Nakajima et al., 2015; Komazaki et al., 2017; Rojas et al., 2021).

The triggering of endotoxemia via the leaky gut is one of the risk factors for periodontal bacteria affecting obesity. In a mouse model, P. gingivalis significantly elevated serum endotoxin levels after only 1 hour of single oral administration, which in turn activated pro-inflammatory genes in the adipose tissue, blood vessels and liver of mice, ultimately increasing the risk of insulin resistance, atherosclerosis (AS) and NAFLD, respectively (Arimatsu et al., 2014). Recent studies suggest that P. gingivalis-induced endotoxemia may affect obesity by altering endocrine functions in brown adipose tissue (BAT) in mice, including glucose homeostasis, insulin sensitivity, and thermogenesis (Stanford et al., 2012; Hatasa et al., 2021). In addition, P. gingivalis administration may increase inflammation-related mRNA expression in BAT, such as TNF-α and IL6, and downregulate the expression of genes related to lipolysis and metabolism in BAT, such as Lipe and Pnpla2 (Hatasa et al., 2021).

The chronic low inflammatory state caused by periodontal bacteria via the oral-gut axis promotes increased expression of pro-inflammatory adipokines (e.g. resistin) and decreased expression of anti-inflammatory adipokines (e.g. adiponectin) (Zimmermann et al., 2013). In contrast, periodontal treatment significantly reduced resistin levels and increased adiponectin levels in obesity patients (Bharti et al., 2013; Akram et al., 2017). However, there is no further evidence that periodontal therapy improves obesity by affecting adipokine secretion via the intestinal pathway.

DM is a group of metabolic diseases characterized by hyperglycemia caused by abnormal insulin secretion and/or action (Cho et al., 2018). A systematic review confirmed that severe periodontitis increased the prevalence of type 2 Diabetes mellitus (T2DM) by 53% (Wu et al., 2020). Periodontal patients with established DM tend to have poorer glycemic control and higher prevalence of DM-related complications and all-cause mortality (Sharma et al., 2016; Graziani et al., 2018; Ziukaite et al., 2018; Genco et al., 2020; Nguyen et al., 2020; Wu et al., 2020; Song et al., 2021). Periodontal treatment also facilitates effective glycemic management in DM patients (Chang et al., 2020).

The increased susceptibility of DM patients to certain infections due to altered innate immune response is thought to facilitate the systemic (including intestinal) dissemination of periodontal bacteria in the case of periodontitis (Toniolo et al., 2019; Barutta et al., 2022). The presence of P. gingivalis has been detected in fecal samples from DM mice following oral administration of P. gingivalis (Kashiwagi et al., 2021). DM Patients with periodontitis have significant alterations in both oral and gut microbiota, systemic pro-inflammatory cytokines and metabolic parameters (Li et al., 2020; Barutta et al., 2022; Silva et al., 2022). Studies have demonstrated that oral administration of periodontal bacteria (P. gingivalis and P. intermedia) induces altered gut microbiota and leaky gut prior to the development of systemic inflammation (Yamazaki et al., 2021).

The disruption of intestinal homeostasis mediated by oral administration of periodontal bacteria (e.g. P. gingivalis and A. actinomycetemcomitans) was confirmed by animal studies to induce systemic inflammation, metabolic changes and hepatic fat deposition in non-diabetic mice, while exacerbating fasting and postprandial hyperglycemia in DM mice (Arimatsu et al., 2014; Blasco-Baque et al., 2017; Komazaki et al., 2017; Kato et al., 2018; Sasaki et al., 2018; Kashiwagi et al., 2021). That is, in the pathogenic mechanism of periodontitis for DM, intestinal transmission of periodontal bacteria may induce/exacerbate insulin resistance and glucose intolerance by mediating entero-hepatic metabolic derangements. In addition, in a ligature-induced periodontitis mouse model, fasting blood glucose (FBG), serum glycated hemoglobin (HbA1c) and glucose intolerance levels were higher in the periodontitis group than in the control group (Li et al., 2021). In contrast, FBG, HbA1c, glucose tolerance levels and systemic inflammatory load were reversed in mice after elimination of periodontitis or depletion of the gut microbiota with antibiotics (Li et al., 2021). This further suggests that the gut microbiota may mediate the influence of periodontal bacteria on DM.

Firstly, intestinal transmission of periodontal bacteria leads to reduced diversity and altered F/B ratio in the intestinal microbiota. Individuals with low diversity of gut microbiota tend to exhibit more pronounced insulin resistance, hyperinsulinemia and increased susceptibility to DM (Cotillard et al., 2013; Le Chatelier et al., 2013). There are also mechanistic drivers for the correlation between taxa representation (Bacteroidetes and Firmicutes) of the gut microbiota and glycemic control (Larsen et al., 2010; Napolitano et al., 2014). For example, metformin is known to be a first-line treatment in patients with T2DM. Influencing bile acid metabolism and entero-endocrine hormone secretion by altering the gut microbiota is one of the important pharmacological mechanisms of metformin in the treatment of T2DM (Napolitano et al., 2014). Further studies found that serum concentrations of cholic acid and conjugates in T2DM patients were positively correlated with the microbiota abundance of Firmicutes and negatively correlated with Bacteroidetes (Napolitano et al., 2014). In addition, the F/B ratio of the gut microbiota was significantly correlated with circulating concentrations of peptide tyrosine-tyrosine (PYY) in serum (Napolitano et al., 2014). PYY, an intestinal hormone, has been shown to restore normal glucose regulation of insulin and glucagon secretion in DM rats (Ramracheya et al., 2016).

Secondly, alterations in gut metabolites mediated by periodontal bacteria may also contribute to the development of DM. In animal models, the presence of periodontitis or oral administration of P. gingivalis can disrupt the gut microbiota and serum metabolite profiles, and increase fasting hyperglycemia and entero-hepatic metabolic derangements associated with altered gut metabolism in DM mice (Kato et al., 2018; Kashiwagi et al., 2021). SCFAs are known to play an important role in mediating glucose metabolism and insulin sensitivity through multiple signaling pathways (Psichas et al., 2015). It was found that increased serum HbA1c levels in mice with periodontitis were associated with a decrease in SCFAs (e.g. butyrate) producing bacteria in the gut (Li et al., 2021). Also, butyrate supplementation reduced fasting glucose and insulin levels in mice and improved insulin sensitivity, the effects of which were mediated through inhibition of HDACs (McNabney and Henagan, 2017). Thus, reduced production of intestinal SCFAs may mediate the effect of periodontitis on diabetes. Furthermore, branched-chain amino acids (BCAA) are one of the links between periodontal bacteria and insulin resistance via the gut microbiota (Khor et al., 2021). Elevated levels of BCAA are characteristic of insulin resistance and have been suggested as a predictor of DM development (Pedersen et al., 2016; Nawaz and Siddiqui, 2020). Periodontal pathogenic bacteria (e.g. P. gingivalis) have been reported to alters the gut microbiota composition and serum metabolite profiles in mice, increasing BCAA levels and inducing insulin resistance (Tian et al., 2020). Mechanistically, BCAA activates the mTOR-S6K1 pathway, which induces insulin resistance by phosphorylating IRS-1 (Yoon, 2016).

Finally, gut dysregulation following swallowing of periodontal bacteria implies elevated levels of circulating LPS and induced/amplified systemic hypo-inflammation, which may be one of the potential mechanisms explaining the association between periodontitis and DM. Consistent with this, continuous infusion of P. gingivalis-LPS induced endotoxemia, glucose intolerance and insulin resistance in HFD-fed mice (Arimatsu et al., 2014; Blasco-Baque et al., 2017). Lowering circulating LPS concentration could be a potent strategy for the control of metabolic diseases. Gut microbiota dysbiosis may induce the expression of pro-inflammatory cytokines through the TLR4/MyD88/NF-κB signaling pathway, thereby promoting DM progression (Hou et al., 2022).

Gut dysbiosis and subsequent increased circulating levels of pro-inflammatory cytokines induced by swallowing periodontal bacteria may impair glycemic control in DM patients (Arimatsu et al., 2014; Hajishengallis and Chavakis, 2021). For example, chronic low-grade inflammation caused by periodontal bacteria can aggravate pancreatic β-cell dysfunction in DM mice through IL-12 regulation on Klotho, thereby worsening glucose control as well as glucose-stimulated insulin secretion (Liu et al., 2016). Studies have demonstrated that improved metabolic control (lower HbA1c and plasma glucose concentrations) after periodontal treatment is accompanied by a reduction in systemic inflammatory markers (D’Aiuto et al., 2018).

Rebuilding the gut microbiota may be an important way to inhibit the pathogenic effects of periodontitis on DM. Intervention studies using FMT in human and animal models have demonstrated the role of the gut microbiota in improving diabetes (Vrieze et al., 2012; Aron-Wisnewsky et al., 2019; Wang et al., 2020). Lean donor FMT in patients with metabolic syndrome showed altered gut microbiota and improved insulin sensitivity (Vrieze et al., 2012; Kootte et al., 2017). Gut microbiota from DM-resistant mice can also transfer DM protection to otherwise highly susceptible to DM hosts. A study reported that gut microbiota transfer from DM-protected MyD88-deficient non-obese diabetic (MyD88-/-NOD) mice could lead to delayed onset of DM and reduced insulitis in NOD mice (Peng et al., 2014). The study further found that the microbiota and mucosal immune system (elevated levels of IgA, TGF-β, etc.) were significantly altered in the gut of NOD mice after receiving the gut microbiota from DM-resistant mice (Peng et al., 2014). This suggests that inhibiting or reversing the alteration of the gut microbiota by periodontal bacteria might improve DM.

AS is the pathological basis for the development of cardiovascular disease. Epidemiological studies have shown that periodontitis can significantly increase the risk and prevalence of atherosclerotic cardiovascular disease (ASCVD), including cardiovascular death, myocardial infarction, heart failure, atrial fibrillation and stroke (Linden et al., 2012; Dietrich et al., 2013; Chen et al., 2016; Liljestrand et al., 2017; Nordendahl et al., 2018; Park et al., 2019; Zhou et al., 2021). Periodontitis can also significantly increase the intima-media thickness (IMT) and atherosclerotic plaque area in the common carotid artery (Montenegro et al., 2019; Meurman and Söder, 2022). Many hypotheses have been proposed regarding the cause of AS, and it is now generally accepted that infection is an initiating factor and an important mechanism in promoting atherosclerotic changes in blood vessels (Slocum et al., 2016).

There are significant pro-inflammatory alterations in the gut microbiota of ASCVD patients, including reduced microbial diversity, altered F/B ratios and increased relative abundance of oral bacteria (Koren et al., 2011; Gregory et al., 2015; Emoto et al., 2016; Emoto et al., 2017; Jie et al., 2017; Yoshida et al., 2018). Relatively low abundance of SCFAs-producing bacteria and high abundance of LPS-producing bacteria have also been reported in the gut of ASCVD patients infected with periodontal bacteria (Arimatsu et al., 2014; Kramer et al., 2017). These intestinal alterations have not only been shown to predict and accelerate ASCVD, but have also been associated with dyslipidemia, elevated marker levels and a state of low systemic inflammation in ASCVD (Le Chatelier et al., 2013; Nie et al., 2019; Yeh et al., 2020). Conversely, FMT can reduce or transmit susceptibility to AS (Vrieze et al., 2012; Gregory et al., 2015). Quercetin has also been shown to modulate immune and metabolic function by restoring intestinal homeostasis, reducing the production of pro-inflammatory cytokines and atherosclerotic lipid metabolites, thereby significantly reducing areas of atherosclerotic lesions and sizes of plaques (Nie et al., 2019).

Pro-inflammatory alterations in the gut microbiota induced by periodontal bacteria may contribute to AS by modulating the production of its bioactive metabolites (Yeh et al., 2020). Plasma levels of trimethylamine N-oxide (TMAO) are an important predictor of adverse cardiovascular events, and a disordered gut microbiota can increase the conversion of TMAO (Tang et al., 2013; Wang et al., 2015). TMAO can inhibit reverse cholesterol transport to exacerbate foam cell accumulation, as well as induce platelet hyperactivity to increase thrombus formation, ultimately affecting atherosclerotic plaque formation and progression (Zhu et al., 2016; Yeh et al., 2020; Qian et al., 2022). In animal studies, transplantation of TMAO-rich gut microbiota feces into GF mice promotes platelet function and arterial thrombus formation (Huynh, 2020). In addition, TMAO also promotes the release of the inflammatory cytokines IL-18 and IL-1β by activating the NF-κB pathway (Liu M. et al., 2019).

The impact of infection on AS is now thought to be related to the total pathogen burden, i.e. the bacterial load determines the inflammatory status and stability of the atherosclerotic plaque (Emoto et al., 2016). Studies investigating the oral, gut and plaque microbiota in AS patients have confirmed that the atherosclerotic plaque microbiota is at least partly oral and gut in origin (Koren et al., 2011). The number and abundance of periodontal bacteria species detected in AS patients tends to be more significant and positively correlated with the size of atherosclerotic plaques (Ford et al., 2006; Otomo-Corgel et al., 2012; Rivera et al., 2013; Calandrini et al., 2014). Endotoxemia associated with the oral and gut dysbiosis may induce the recruitment of macrophages and their infiltration of adipose tissue, culminating in the formation of foam cells that accumulate in the artery walls (Diet, 2001; Michelsen et al., 2004; Mullick et al., 2005).

The pathogenic effect of periodontal bacteria on AS has been demonstrated in multiple types of animal model studies (Brodala et al., 2005; Velsko et al., 2014; Lin et al., 2015; Widziolek et al., 2016). A possible theoretical mechanism by which periodontal bacteria could reach the atherosclerotic plaque via the gut is currently mentioned, namely the phagocytosis by macrophages at epithelial linings of the gut (Schenkein and Loos, 2013; Emoto et al., 2016). Macrophage abundance and function can be regulated and driven by the gut microbiota and convey immune responses at distal organs (Yeh et al., 2020). periodontal bacteria are phagocytosed by macrophages in the dysregulated gut and carried into circulation. When they reach the activated endothelium of atherosclerotic plaques, they leave the bloodstream to enter the plaque and transform into cholesterol-laden foam cells (Wang et al., 2007; Emoto et al., 2016). P. gingivalis has been detected in circulating phagocytes from patients with severe cardiovascular disease suffering from periodontitis, supporting the possibility that phagocytes may play a role in harboring and transporting periodontal bacteria to atherosclerotic plaques (Carrion et al., 2012). However, the current study only demonstrates the theoretical validity of this periodontal bacteria transport mechanism and does not indicate the extent of its contribution in AS pathogenesis.

Both the skin and the gut are important barrier structures for the immune and neuroendocrine functions of the body (O’Neill et al., 2016). It is now widely accepted that there is a close bidirectional relationship between the gut and the skin, and a “gut-skin axis” has been proposed to further explore the link between gut and skin homeostasis (Salem et al., 2018).

A number of studies have referred to preliminary evidence that the oral and gut microbiota may play a role in the pathogenesis of skin diseases as regulators of the “gut-skin axis”. Sjögren’s syndrome, psoriasis, systemic lupus erythematosus (SLE) and leukoaraiosis may all be linked to dysbiosis of the oral and gut microbiota (Szymula et al., 2014; Consolandi et al., 2015; Coit et al., 2016; Ungprasert et al., 2017; Ma and Morel, 2022). Some oral microbiota species are enriched in the gut of SLE patients. In both SLE and psoriasis, the severity of skin lesions, including the SLE Disease Activity Index and the Psoriasis Area and Severity Index, were positively correlated with the severity of periodontitis and altered gut microbiota profiles (Masallat and Moemen, 2016; Azzouz et al., 2019; Qiao et al., 2019; Hussain et al., 2022).

In addition, elevated levels of markers of intestinal barrier function impairment are often observed in a variety of skin diseases. elevated levels of fecal calprotectin have been found in patients with SLE and atopic dermatitis (Seo et al., 2018; Azzouz et al., 2019; Smirnova et al., 2020). Elevated levels of claudin-3 and intestinal fatty acid-binding protein have also been found in the blood of patients with psoriasis (Sikora et al., 2019a; Sikora et al., 2019b). A compromised gut barrier allows periodontal or other bacteria to move from the gut lumen into the internal environment where they can accumulate in the skin and disrupt skin homeostasis. Studies have detected periodontal bacteria and gut-derived bacterial DNA in the blood of patients with psoriasis, while finding that those with bacterial DNA-positive psoriasis patients showed higher serum inflammatory cytokine levels, longer duration of disease and younger onset of disease (Ramírez-Boscá et al., 2015; Dalmády et al., 2020). In Sjögren’s syndrome, Sjögren’s syndrome Antigen A (SSA)/Ro60-reactive T cells can be activated by peptides originating from oral and gut bacteria, and thus may be involved in disease progression (Szymula et al., 2014).

Periodontal bacteria-induced gut dysbiosis may be involved in the pathogenesis of autoimmune (e.g. psoriasis) and allergic (e.g. atopic dermatitis) skin diseases through immune, metabolic and neuroendocrine pathways. First, disruption of Th17/Treg balance can be involved in the pathogenesis of several chronic inflammatory skin diseases (Salem et al., 2018). In particular, psoriasis is mainly considered to be a Th17 disease (Grine et al., 2015). Activation of Th17 cells and increased expression of IL17 are major factors mediating the pathogenesis of psoriasis, which could be induced by periodontal bacteria and their products (Blauvelt and Chiricozzi, 2018; Bunte and Beikler, 2019; Zhao X. et al., 2021). After antibiotic treatment, reduced skin inflammation caused by reduced Th17 activation in the gut was observed in a mouse model of imiquimod-induced psoriasis (Zákostelská et al., 2016). It was further shown that IL-17 disrupts the integrity of the skin barrier through downregulation of filaggrin and adhesion molecule expression from keratinocytes, and further induces keratinocyte hyperproliferation (Gutowska-Owsiak et al., 2012). Thus, systemic Th17 hyperactivation or overproduction of IL-17 may be the link between periodontal bacteria-induced disturbances in the gut microbiota and the development of psoriasis. In addition to this, skin diseases such as Sjögren’s syndrome, SLE, leukoplakia and scleroderma have also been linked to the pathogenic mechanisms by which periodontitis regulates Th17 cell differentiation and its key cytokines (IL-17 and IL-23) (Bunte and Beikler, 2019; Tong et al., 2019).

Secondly, periodontal bacteria may mediate skin inflammation by affecting the normal metabolic activity of the intestinal commensals. For example, elevated serum levels of free phenol and p-cresol may affect epidermal differentiation and epidermal barrier function by decreasing keratin 10 expression (Miyazaki et al., 2014). Both oral and gut microbiota dysbiosis in SLE patients may be related to amino acid metabolism. In SLE progression, amino acid (e.g. tryptophan) metabolism can modulate immune tolerance in lupus. We can therefore speculate that alterations in the oral and gut microbiota of SLE patients with periodontitis may initiate autoimmunity by manipulating amino acid metabolism. However, this needs to be verified by further studies.

Finally, some studies support the idea that alterations in the gut microbiota can be involved in the development of skin diseases by affecting the levels of circulating neuroendocrine molecules such as tryptamine, trimethylamine and serotonin, inducing skin barrier dysfunction and immune system dysregulation (Jin et al., 2014; O’Neill et al., 2016).