The pathogenic oral–gut–liver axis: new understandings and clinical implications

Abstract

Introduction:

Oral health is closely related to extra-oral disease status, as may be represented by the manifestations of gastrointestinal and liver diseases.

Areas covered:

This review focuses on the roles that the oral–gut or the oral–gut–liver axis play in the pathogenesis of inflammatory bowel disease, colorectal cancer, metabolic fatty liver disease, and nonalcoholic steatohepatitis. The discussion will begin with clinical data, including data from preclinical animal models, to elucidate mechanisms. We will also discuss ways to target oral dysbiosis and oral inflammation to treat gastrointestinal and liver diseases.

Expert opinion:

Several studies have demonstrated that oral pathobionts can translocate to the gastrointestinal tract where they contribute to inflammation and tumorigenesis. Furthermore, oral bacteria that migrate to the gastrointestinal tract can disseminate to the liver and cause hepatic disease. Thus, oral bacteria that ectopically colonize the intestine may serve as biomarkers for gastrointestinal and liver diseases. Also, understanding the characteristics of the oral–gut and oral–gut–liver microbial and immune axes will provide new insights into the pathogenesis of these diseases.

1.0. Introduction

The NIH Human Microbiome Project, launched as a part of the NIH Roadmap for Medical Research, recognized the need to accelerate our understanding of how our bodies and microorganisms interact to influence health and disease [1–3]. The complex ecosystem of the human gastrointestinal tract consists of many microorganisms, including bacteria, viruses, and fungi [4]. Advances in next-generation sequencing have made it possible to obtain large amounts of DNA sequencing data from all types of samples [5]. In particular, 16S rRNA analysis has enabled a high level of quantification in estimating the composition and abundance of bacteria in the community. Several studies have elucidated the vital role that the gut microbiota plays in host physiology, such as energy acquisition and the development of the immune system [1]. On the other hand, abnormalities in the gut microbiome, characteristic of various disease conditions, namely dysbiosis, have been reported. It is believed that gut dysbiosis is not simply a consequence of the disease. Rather, the dysbiotic microbiota harbors abnormalities in the context of its metabolic and immunogenic functions, and thereby directly contributes to disease pathogenesis [6].

The oral microbiome is the second-largest microbial community in the human body. As in the gut, resident microbes in the oral cavity play a vital role in homeostasis and disease. Conditions such as decreased salivary gland function, decreased oral clearance, decreased salivary pH, and changes in immunoglobulin A in saliva can affect the composition of the oral microbiome and cause oral dysbiosis [7]. It has been reported that certain oral bacteria, such as Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Prevotella intermedia, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans, are enriched in patients with oral disease, including periodontitis, and contribute to the disease pathogenesis [8,9]. Notably, accumulating evidence indicates that these oral pathobionts affect systemic diseases, such as arteriosclerosis, diabetes, and rheumatoid arthritis [10,11]. Furthermore, research supports a possible pathogenic impact of the oral microbiome and oral disease on gastrointestinal and liver diseases [12–14]. Here, we review the recent findings in studies of the oral–gut and the oral–gut–liver axes in the context of the pathogenesis of gastrointestinal and liver diseases. We also discuss the potential therapeutic options that target the oral microbiome and oral diseases to treat gastrointestinal and liver diseases. A research collection was performed using the PubMed electronic database for relevant full-text original articles or review articles published until April 2021.

2.0. The oral–gut and oral–gut–liver axes: Lessons from clinical and preclinical studies

2.1. Inflammatory bowel disease

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic inflammatory disease of the gastrointestinal tract. Accumulating evidence suggests that aberrant immune responses to the gut microbiota are closely associated with the pathogenesis of IBD. It has been repeatedly demonstrated that atypical, potentially pathogenic members of commensal bacteria (pathobionts) are markedly enriched in the stool and the intestinal mucosa of IBD patients compared to non-IBD individuals [15,16]. The perturbed microbial community in the gut, so-called gut dysbiosis, is a hallmark of IBD [17]. For example, Gevers and colleagues analyzed the microbiome of newly diagnosed treatment-naïve pediatric patients with CD [18]. This study revealed a significant correlation between microbial alterations in the intestinal mucosa and disease status, with an increased abundance of Veillonellaceae, Pasteurellaceae, Enterobacteriaceae, Nisseriaceae, Gemellaceae, and Fusobacteriaceae, and a decreased abundance of Bacteroidales, Erysipelotrichales, and Clostridiales [12,18]). Notably, the enriched bacterial taxa are considered typical oral resident bacteria. Similarly, the accumulation of oral-derived bacteria in the gut is also reported in patients with UC. A cohort of new-onset, treatment-naïve pediatric UC patients with severe inflammation exhibited a striking increase in the abundance of oral bacteria, such as Veillonella dispar, Aggregatibacter segnis, Campylobacter spp, Lachnospiraceae, Veillonella parvula, Haemophilus parainfluenzae, and Megasphaera spp. [19]. Thus, bacteria derived from the oral cavity ectopically colonize the gut in patients with IBD, both CD and UC (Figure 1).

Figure 1. Oral bacteria found in patients with gut or liver pathology.

Oral bacterial species found in the gut of patients with inflammatory bowel disease (IBD), colorectal cancer (CRC), metabolic fatty liver disease (MAFLD), and nonalcoholic steatohepatitis (NASH) are listed. The taxonomic rank is shown in parentheses in the case that species information is not defined in references.

The possible impact of gut colonization by oral bacteria has been studied in IBD preclinical animal models. The oral administration of P. gingivalis disrupts the intestinal barrier, thereby increasing the severity of dextran sulfate sodium (DSS)-induced colitis in mice [20]. Likewise, gut colonization by F. nucleatum results in the skewed polarization of macrophages toward the M1 phenotype, disrupting the epithelial barrier, and thereby rendering the host susceptible to DSS-induced colitis [21,22]. Moreover, Atarashi and colleagues reported that transplantation of salivary bacteria isolated from IBD patients leads to colitis in genetically susceptible germ-free (GF) mice through the induction of pathogenic Th1 cell differentiation [23]. In this study, members of the family Enterobacteriaceae, in particular Klebsiella spp. were identified as the key colitogenic pathobionts that reside in the saliva of IBD patients. Likewise, we demonstrated that Klebsiella and Enterobacter spp. isolated from the oral cavity can exacerbate colitis when they ectopically colonize the gut through activation of the inflammasome in intestinal mononuclear cells [24]. Notably, we showed that oral inflammation promotes ectopic gut colonization by oral bacteria. In this study, mice that developed periodontitis displayed oral dysbiosis with the accumulation of Klebsiella and Enterobacter spp. [24]. This expansion of Klebsiella and Enterobacter spp. in the oral cavity resulted in an increased gut colonization by the same bacterial species, thereby increasing the susceptibility to DSS-induced colitis [24]. Besides the translocation of oral bacteria to the gut mucosa, it has become evident that immune cells, educated in the oral mucosa, can transmigrate to the gut and contribute to the pathogenesis of gastrointestinal disease. In this regard, it has been demonstrated that periodontitis leads to the expansion of oral pathobiont-reactive, pathogenic Th17 cells in the murine oral mucosa [24]. The oral pathogenic Th17 cells that arise during periodontitis express gut-homing markers, such as α4β7 integrin and CCR9, which enable the migration of these cells to the gut mucosa [24]. Gut-migrated oral pathogenic Th17 cells are then activated by gut-colonized oral pathobionts, exacerbating colitis [24]. All of these observations suggest that the inflamed oral mucosa, a characteristic feature of periodontitis, essentially serves colitogenic pathobionts and pathogenic immune cells to the gastrointestinal tract.

In this context, oral dysfunction accompanied by oral mucosal inflammation and oral dysbiosis are often manifest in patients with IBD. The prevalence of periodontitis is considerably increased in patients with IBD, particularly CD, compared to individuals who do not have IBD [25]. Moreover, oral salivary dysfunction and other oral health problems are often observed in CD and UC patients compared to healthy individuals [26,27]. For example, CD patients have a significantly higher concentration of mucin 5B (MUC5B) during active intestinal disease [26]. Given that MUC5B serves as a nutrient source for oral bacteria [28], an altered MUC5B level in the saliva may promote oral dysbiosis in patients with CD. Indeed, bacterial dysbiosis in saliva is more evident in IBD patients compared to healthy individuals [29]. Thus, in IBD patients, compromised oral health, such as periodontitis, leads to oral dysbiosis with the expansion of pathobionts in the oral cavity. Expanded oral pathobionts may naturally translocate to the lower digestive tract and may serve as colitogenic pathobionts. Unlike animal models, the immunological connection between the oral and gut mucosa in humans remains unexplored. Further studies are required to explore the potential role of oral immune cells, such as Th17 cells, in the pathogenesis of gastrointestinal inflammation in patients with IBD.

Some resident bacteria in the gut play a protective role of gut inflammation [30]. For example, some bacteria, in particular members of the phylum Firmicutes, generate beneficial metabolites, such as short-chain fatty acids (SCFAs), including butyrate, propionate, and acetate. SCFAs promotes the epithelial barrier integrity [31] and/or induce the differentiation of regulatory T cells [32–34], thereby regulating the homeostasis of the gastrointestinal tract. In addition to the accumulation of pathobionts, the reduction of these beneficial bacteria is also closely associated with the risk of IBD. However, there are no reports showing the relationship between SCFA-producing bacteria in the oral cavity and the potential risk of IBD.

2.2. Colorectal cancer (CRC)

Colorectal cancer (CRC) is one the most common types of cancer in both men and women [35]. Given that most of the known CRC risks such as age, obesity, and inflammation are closely associated with gut dysbiosis, it is conceivable that gut microbes contribute to the pathogenesis of CRC [12]. Indeed, gut microbiome and metabolome analyses have demonstrated the indispensable role of resident microbes and microbial by-products in the pathogenesis of CRC [36,37]. Several animal models of CRC facilitate the study of the causal role of the gut microbiota in carcinogenesis in the colon [38]. The pivotal role of the gut microbiota in the development of chemically induced colorectal tumors in rats was first reported in 1975 [39]. Investigators observed significantly fewer tumors in the colon of GF rats compared to conventional rats [39]. Several later reports confirmed the vital role of the gut microbiota in colonic tumorigenesis and proposed various carcinogenic mechanisms induced by bacteria [40–42]. For example, human colonic commensal bacteria promote colon tumorigenesis through the activation of Th17 responses [43]. Also, adherent–invasive Escherichia coli facilitate carcinogenesis by inducing genotoxic capabilities [44].

Nakatsu and colleagues reported that the enrichment of specific bacterial taxa in humans is an early sign of dysbiosis in adenoma, and coexclusive relationships are subsequently more common in cancer [45]. Another study of patients with adenomas identified multiple taxa that were significantly more abundant, including Bilophila and Desulfovibrio spp., proinflammatory bacteria in the genus Mogibacterium, and multiple species in the phylum Bacteroidetes [46]. Furthermore, increased numbers of Acinetobacter, Helicobacter, and Pseudomonas spp. have been reported in patients with rectal adenomas than in individuals without adenomas [47]. Although most CRC microbiome studies are conducted using fecal samples [48,49], some studies analyze the bacteria enriched in colorectal tissue specimens. Kostic and colleagues confirmed that Fusobacterium was enriched in carcinomas using quantitative PCR and 16S rDNA sequence analysis of 95 carcinoma/normal DNA pairs, whereas Bacteroidetes and Firmicutes were depleted [50]. These findings suggest that CRC may be initiated by modification of the balanced interaction between the host and the microbiome through the adoption of a proinflammatory profile by the intestinal microbiota [51].

Besides gut resident bacteria, mounting evidence suggests the possible involvement of oral bacteria in colonic tumorigenesis [49] (Figure 1). To reiterate, Fusobacterium species, including F. nucleatum, are significantly enriched in patients with CRC [50,52,53]. Colorectal carcinoma harboring F. nucleatum are more abundant in the proximal colon (cecum) than distal colon (rectum) [54]. The abundance of F. nucleatum positively correlate with microsatellite instability (MSI)-high status and shorter survival, indicating the association of the abundance of F. nucleatum and worse clinical outcomes [55,56]. Moreover, the abundance of F. nucleatum is associated with the risk of relapse after neoadjuvant chemoradiotherapy [57]. The monoassociation of F. nucleatum promotes colonic tumors in GF Apc^Min/+ mice, suggesting that F. nucleatum is the direct cause of tumorigenesis in the gut [53]. Also, F. nucleatum is capable of activating β-catenin signaling and oncogenic responses through its unique adhesin called FadA, which binds to E-cadherin expressed on colorectal cancer cells [58] Fap2 protein in F. nucleatum directly interacts with TIGIT expressed on natural killer cells, thereby inhibiting their antitumor immunity [59]. Moreover, F. nucleatum enhances the proliferation and invasion of tumor cells through the activation of TLR4 signaling and the upregulation of miR21 expression [60]. The overgrowth of F. nucleatum in CRC tissue samples is associated with KRAS mutation and tumor size and correlated with reduced overall survival [61]. Further, the amount of tissue F. nucleatum in CRC tissue is inversely correlated with the density of CD3⁺ but not FOXP3⁺ T cells [62]. These findings suggest that the oral pathobiont F. nucleatum can trigger or promote tumor development in the gut. F. nucleatum usually coexists with other members of the oral microbiota, such as Porphyromonas spp., mainly P. gingivalis, which are some of the most typically increased taxa in individuals with CRC [45,63,64]. One study showed higher amounts of P. gingivalis, as well as F. nucleatum, in the saliva of CRC patients [65]. P. gingivalis, which is a primary causative bacterium of periodontitis, may be a risk factor for various systemic diseases, including Alzheimer disease, cardiovascular disease, diabetes, and rheumatoid arthritis [66–68]. P. gingivalis remodels the oral microbiota into a dysbiotic state by exploiting complement [69]. This pathobiont may also significantly affect the pathogenesis of CRC.

Chronic inflammation in the gut is considered as a potent risk factor for CRC. Richard and colleagues reported that patients with colitis-associated cancer (CAC) display different microbial profiles compared to the sporadic CRC. In patients with CAC, Enterobacteriacae and Sphingomonas are increased, while Fusobacterium and Ruminococcus are decreased compared to sporadic CRC [70].

2.3. MAFLD / NASH

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a phenotype of liver diseases associated with metabolic syndrome [71–73]. It was previously referred to as nonalcoholic fatty liver disease (NAFLD); in 2020, the new name MAFLD was proposed to more accurately reflect the pathogenesis of fatty liver disease and to help stratify patients for better management [71]. It has been reported that nonalcoholic steatohepatitis (NASH) is closely related to the lifestyle diseases obesity and diabetes [74] and leads to the development of hepatocirrhosis and hepatic carcinoma [75]. The global prevalence of NAFLD is 25.24% (95% CI: 22.10–28.65), with the highest prevalence in the Middle East and South America and the lowest in Africa [76]. Although a fatty liver is induced by hepatic fat accumulation arising from lifestyle diseases, Younossi and colleagues revealed the weak predictivity of the prevalence of obesity and daily caloric excess for the prevalence of NAFLD and NASH [76,77]. In this context, the two-hit theory is widely supported as a possible mechanism of the onset and progression of NASH [78,79]. Obesity causes fatty liver development – the first hit. Then, NASH develops due to oxidative stress, dysregulated cytokines, and mitochondrial dysfunction – the second hit [79]. Various factors, such as genetic susceptibility, induce hepatic inflammation and fibrosis in the fatty liver [80,81].

Given the direct connection between the intestine and the liver by way of the portal vein, the gut microbiota is believed to influence the pathophysiology of NAFLD and NASH [81,82]. Bacterial phylum Proteobacteria, family Enterobacteriaceae, and genus Escherichia are enriched in patients with NASH compared to healthy individuals [83]. Children with NAFLD show the increased abundance of Gammaproteobacteria and Prevotella [84] and increased Prevotella copri is associated with the severity of fibrosis in children with NASH [85]. Enterobacteriaceae, Streptococcus, and Gallibacterium are enriched and Akkermansia is decreased in NAFLD-cirrhosis patients [86–89]. Studies in animal models and humans have shown that colonic inflammation increases intestinal permeability in NASH cirrhosis, resulting in the translocation of bacteria and bacterial products to the liver [13,90,91] (Figure 1). In this context, it is possible that bacteria or their by-products in the oral cavity disseminate to the liver – the secondary event, after the oral–gut bacterial translocation – and thus contribute to the pathogenesis of liver diseases [13]. Indeed, it is a routine clinical practice to treat periodontitis prior to liver transplantation to eliminate all potential infectious foci and reduce the risk of postoperative complications [13,92]. Consistent with this notion, P. gingivalis, a well-known causative agent of periodontitis, is associated with liver inflammation. Several reports describe the relationship between NASH and P. gingivalis in clinical settings. Yoneda and colleagues reported that the detection frequency of P. gingivalis in saliva from NASH patients is significantly higher than in saliva from healthy individuals [93]. Nakahata and colleagues reported a significant correlation between serum IgG antibody titers against P. gingivalis fimA and the progression of liver fibrosis in 200 patients with biopsy-proven NASH [94]. Moreover, a cross-sectional analysis of adult outpatients conducted by Takamisawa and colleagues suggested the association between P. gingivalis infection and alanine aminotransferase (ALT) levels in women [95]. The application of the serum IgG antibody titer against P. gingivalis as a screening test for periodontitis has been evaluated [96].

Hepatocellular carcinoma (HCC) is an end-stage manifestation of a variety of chronic liver diseases. MAFLD and NASH have a low relative individual risk of developing HCC but, due to their high incidence, have a high overall population contribution to the development of HCC [86,97]. Enterobacter cloacae, Methylorubrum populi BJ001, and Rothia dentocariosa are enriched in HCC tissues compared to adjacent normal tissues in a subset of patients (HBV negative drinkers) [98]. Ponziani and colleagues reported that the gut microbiota of NAFLD-related cirrhosis with HCC is enriched with Bacteroides, Ruminococcaceae, Enterococcus, Phascolarctobacterium, and Oscillospira compared to patients with cirrhosis but without HCC [89]. Given E. cloacae, R. dentocariosa, and Enterococcus spp. are considered to be components of the oral microbiome [99–101], it is possible that the oral-gut-liver axis may be associated with HCC. Similar to studies of IBD and CRC, several animal experiments have proven that oral bacteria may contribute to the pathogenesis of NASH and MAFLD. Of note, experimental periodontitis caused by P. gingivalis in animals fed a high-fat diet induces the development of NASH [93,102,103]. Moreover, P. gingivalis infection exacerbates the hepatic fibrosis of NASH through the activation of hepatic stellate cells [104]. Likewise, P. gingivalis–derived lipopolysaccharide contributes to the accumulation of intracellular lipids and the elicitation of inflammatory reactions in hepatocytes through the activation of NF-κB and JNK signaling pathways [105]. These findings increase the understanding of the oral–gut–liver axis in the pathogenesis of NASH and advance the design of new treatment strategies for this disease.

3.0. Targeting oral inflammation and dysbiosis to treat gut and liver diseases

3.1. Oral maintenance therapy

Given that oral conditions may closely associate with the pathogenesis of gastrointestinal and liver diseases, it is plausible that the maintenance of oral health may affect disease activity in these distant organs (Figure 2). In this context, Kamata and colleagues devised a prospective, multicenter, randomized comparison trial to evaluate the impact of periodontal treatment on patients with NAFLD [106]. This ongoing clinical trial is expected to show that patients with liver disease who receive periodontal treatment will have improved outcomes. IBD is associated with several extraintestinal manifestations [107,108]. Among them, oral lesions are relatively common, with a prevalence ranging from 5% to 50% [109]. Likewise, IBD patients show a significantly higher risk of periodontitis compared to non-IBD patients [110]. Although the impact of oral inflammation on IBD outcomes remains largely unknown, knowledge from animal studies supports the possible benefits of treating oral conditions for intestinal inflammation in IBD. As well as gastrointestinal and liver diseases, oral maintenance may also affect the outcomes of other diseases. It was reported that periodontal treatment affects serum antibody levels to P. gingivalis and decreases the C-reactive protein (CRP) level and the disease activity score in patients with rheumatoid arthritis [111].

Figure 2. Targeting oral dysbiosis to diagnose and treat gut and liver diseases.

Monitoring of oral health and the oral dysbiosis (e.g., the abundance of oral pathobionts) could be used as a biomarker for inflammatory bowel disease (IBD), colorectal cancer (CRC), metabolic fatty liver disease (MAFLD), and nonalcoholic steatohepatitis (NASH). Also, optimal oral care has the potential to reduce the risk for these diseases.

3.2. Probiotics

Probiotic bacteria have a positive impact on the resident microorganisms and host immunity when administrated in an appropriate proportion [112]. Probiotics exert their immunomodulatory effects on many processes [113], and several studies have demonstrated their efficacy in the treatment of gastrointestinal and liver diseases, including IBD, CRC, and NASH [114–122]. Although the precise mechanisms of action are unclear, probiotics may prevent ectopic gut colonization by oral pathobionts, which in turn, reduces the intestinal or liver inflammation caused by these bacteria (Figure 2).

Also, it is possible that probiotics affect the inflammation in the oral cavity, as they are generally delivered through oral gavage. In this regard, Shimauchi and colleagues indicated that periodontal clinical parameters were improved in volunteers after an 8-week intervention using freeze-dried Lactobacillus salivarius, and especially in the current smokers who had a high risk of periodontal disease [123]. The review of a meta-analysis confirmed that probiotic treatment improves several clinical parameters, such as bleeding on probing, probing depth, and gingival index, but has no significant effect on colony-forming unit (CFU) counts of periodontal pathogens [124]. Randomized controlled trials with homogeneous methodologies and long-term follow-up periods are needed to confirm the contribution of probiotics in the management of periodontal diseases.

3.3. Prognostic marker

As oral dysbiosis is observed in various gut and liver diseases and may correlate with risk or severity, it may serve as a prognostic marker for these diseases (Figure 2). A meta-analysis has indicated that periodontal bacterial infection increases the incidence of cancer and is associated with poor overall survival, disease-free survival, and cancer-specific survival [125]. Further subgroup analysis indicated that the risk of cancer, including CRC, was associated with P. gingivalis and P. intermedia infections [125]. As the abundance of F. nucleatum in CRC tissue correlates with tumor size and KRAS mutation and is significantly associated with shorter overall survival, the measurement of F. nucleatum levels may help predict clinical outcomes in CRC [61]. Wong and colleagues used the abundance of F. nucleatum in feces as a biomarker alongside fecal immunochemical test (FIT) results to demonstrate a complementary role for the bacterial marker to detect lesions missed by FIT alone [126]. Consistently, the frequency of detection of F. nucleatum in colorectal specimens significantly correlates with CRC [127–129]. Moreover, the combination of F. nucleatum, Enterococcus feacalis, Streptococcus bovis, Enterotoxigenic Bacteroides fragilis, and Porphyromonas spp. showed improved diagnostic performance, compared to each bacterium alone [130]. Thus, the measurement of oral pathobionts in the gut is a potential CRC screening tool.

Reports have indicated that NASH severity is associated with gut dysbiosis and a shift in the metabolic function of the gut microbiota. Thus, gut microbiota analysis may provide valuable information to predict the severity of NASH [131]. There is preliminary evidence that nonsurgical periodontal treatment of 10 patients with NAFLD for 3 months ameliorates liver function parameters, such as the serum levels of AST and ALT [106]. These findings suggest that oral dysbiosis could be a prognostic marker for liver diseases.

4.0. Conclusion

Clinical and preclinical studies have shown that inflammation or microbial dysbiosis in the oral cavity affect the pathophysiology of gastrointestinal and liver diseases, including IBD, CRC, NASH, and NAFLD. Optimal oral care has the potential to reduce the risk for these diseases. Moreover, the monitoring of oral health and the oral microbiome could be used as a biomarker for these diseases.

5.0. Expert opinion

It has been suggested that the typical members of the oral bacterial community accumulate in extra-oral organs in certain disease conditions, such as IBD and CRC [18,19,49]. Furthermore, oral bacteria that relocate to the gut can further disseminate from the gut lumen to the liver by way of the portal vein and cause liver disease, such as NAFLD, NASH, and hepatocellular carcinoma [81,82]. Notably, the results of animal studies suggest that the commensal symbionts in a healthy oral cavity are harmless and have no adverse effect on gastrointestinal diseases even if they reach the gastrointestinal tract [24]. On the other hand, oral pathobionts that accumulate during the course of an oral disease, such as periodontitis, have pathogenetic characteristics and can induce intestinal inflammation if they ectopically colonize the gastrointestinal tract [23,24]. As discussed, oral inflammation and dysbiosis are often observed in patients with IBD, indicating that oral pathobionts may be enriched in the disease state compared to the healthy state. Therefore, optimal oral health may reduce the risk of extra-oral diseases, such as IBD, through decreasing the colonization of the gut by opportunistic oral pathobionts.

The expansion of oral pathobionts due to oral inflammation, such as periodontitis, may be the decisive trigger for the ectopic colonization of extra-oral organs such as the gut and the liver by these bacteria. Other factors affecting the integrity of the gut microbiota or the luminal metabolic microenvironment may also determine the susceptibility to opportunistic colonization by oral pathobionts. Patients with gastrointestinal and liver diseases have been reported to have a perturbed composition of the gut microbiota (i.e., gut dysbiosis) [17,83]. Gut dysbiosis may lead to a decrease in metabolic competitors and promote the growth and colonization of exogenous bacteria of oral origin. In addition, intestinal inflammation creates a microenvironment conducive to the colonization and expansion of pathogenic bacteria, including oral pathobionts, by supplying them with inflammation-related nutrients (e.g., iron, by-products of reactive oxygen species) and altering the epithelial metabolism [132]. Thus, the treatment of gut inflammation and gut dysbiosis may prevent the ectopic gut colonization by oral pathobionts, even in the presence of oral disease. Nevertheless, the simultaneous treatment of oral and intestinal diseases may have synergistic effects for patients with IBD, CRC, and liver diseases.

In addition to treating oral inflammation and oral dysbiosis as complementary therapy for intestinal inflammation, the condition of the oral cavity, especially the oral microbiome, can be a valuable biomarker for gastrointestinal and liver diseases. Once the causative oral pathobionts that correlate with the risk of extra-oral diseases are identified, detecting the presence or increased presence of these bacteria in the oral cavity can predict the risk of disease, such as the flare of IBD or the development of CRC. For example, oral dysbiosis with the expansion of Enterobacteriaceae, such as Klebsiella and Enterobacter spp., could be used as an indicator to predict the patients at risk for disease flares [23,24]. The composition of the oral microbiota may also identify subpopulations of patients who will respond to specific therapies, such as biologics or fecal microbiota transplantation. We expect that more studies will correlate specific changes in the oral microbiota with disease outcome and response to treatment. This will increase the potential for the use of the oral microbiome as a biomarker for extra-oral diseases. It is noteworthy that oral pathobionts can be detected in saliva. As the collection of a saliva sample is noninvasive and self-administered, it would be a cost-effective and convenient way to monitor the risk for gastrointestinal and liver diseases and to predict the response to treatment.

Article highlights.

• Oral bacteria can translocate to the gastrointestinal tract where they contribute to inflammation and tumorigenesis.

• Gut colonized oral bacteria can further disseminate to the liver and cause liver pathologies.

• Oral treatment has the potential to improve the gastrointestinal and liver diseases.