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Review

Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer

by
Se-Young Park
1,†,
Byeong-Oh Hwang
1,†,
Mihwa Lim
2,
Seung-Ho Ok
1,
Sun-Kyoung Lee
2,
Kyung-Soo Chun
3,
Kwang-Kyun Park
2,
Yinling Hu
4,
Won-Yoon Chung
5 and
Na-Young Song
2,*
1
Department of Applied Life Science, The Graduate School, Yonsei University, and BK21 FOUR Project, Yonsei University College of Dentistry, Seoul 03722, Korea
2
Department of Oral Biology, Yonsei University College of Dentistry, Seoul 03722, Korea
3
College of Pharmacy, Keimyung University, Daegu 42601, Korea
4
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
5
Department of Oral Biology, Oral Cancer Research Institute, and BK21 FOUR Project, Yonsei University College of Dentistry, Seoul 03722, Korea
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2021, 13(9), 2124; https://doi.org/10.3390/cancers13092124
Submission received: 9 February 2021 / Revised: 5 March 2021 / Accepted: 9 March 2021 / Published: 28 April 2021
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Abstract

:

Simple Summary

Microbiota dysbiosis is correlated with numerous diseases in the human body. To date, the research on the microbiome-associated diseases been focused on an organ-specific microbiome. However, the interorgan microbial network is emerging as an important regulator in physiological functions and pathological processes. The oral cavity and gut are the two largest microbial ecosystems. Recent studies have demonstrated that the oral-to-gut and gut-to-oral microbial transmission can regulate pathogenesis, indicating the presence of the oral–gut microbiome axis. Here, we will review the role of the oral–gut microbiome axis in gastrointestinal disease and cancer, which may provide insight for precise diagnosis/prognosis and effective treatment.

Abstract

It is well-known that microbiota dysbiosis is closely associated with numerous diseases in the human body. The oral cavity and gut are the two largest microbial habitats, playing a major role in microbiome-associated diseases. Even though the oral cavity and gut are continuous regions connected through the gastrointestinal tract, the oral and gut microbiome profiles are well-segregated due to the oral–gut barrier. However, the oral microbiota can translocate to the intestinal mucosa in conditions of the oral–gut barrier dysfunction. Inversely, the gut-to-oral microbial transmission occurs as well in inter- and intrapersonal manners. Recently, it has been reported that oral and gut microbiomes interdependently regulate physiological functions and pathological processes. Oral-to-gut and gut-to-oral microbial transmissions can shape and/or reshape the microbial ecosystem in both habitats, eventually modulating pathogenesis of disease. However, the oral–gut microbial interaction in pathogenesis has been underappreciated to date. Here, we will highlight the oral–gut microbiome crosstalk and its implications in the pathogenesis of the gastrointestinal disease and cancer. Better understanding the role of the oral–gut microbiome axis in pathogenesis will be advantageous for precise diagnosis/prognosis and effective treatment.

Graphical Abstract

1. Introduction

The microorganisms in and on the human body outnumber the human cells by at least 10-fold [1]. The human microbiome is remarkably diverse even between healthy individuals [2]. In an individual, each microbial habitat shows a distinct pattern of microbial populations [3]. In an effort to characterize human microbial communities, the first phase human microbiome project (HMP) launched in 2007 and has analyzed microbial communities of 300 healthy adults, including 15 body sites in men and additional three vaginal sites in women [3,4]. Since the HMP has completed, a new era of “microbiome” has begun with breakthrough discoveries on the relationship between microbiomes and human health [5,6,7,8]. Currently, the human microbiome is emerging as an important regulator in the human physiology.
Gut and oral microbiomes are the two largest microbial ecosystems in the human body [9]. Based on the HMP, among the 15 different body habitats, oral and fecal microbiomes are ecologically rich and taxonomically diverse [3]. It is noteworthy that the oral cavity and gut are linked physically as well as chemically. However, most of the research on the oral and gut microbiomes has been conducted separately in an organ-specific manner, rather than in an integrative context. The latest studies have proven the involvement of microbiome in the interorgan networks, such as the gut–brain and gut–lung axes [10,11]. In this regard, the intestinal colonization of oral microbiota and fecal–oral transmission have been reported to frequently occur and modulate pathophysiological processes in the human body [12,13,14]. Here, we will highlight the oral–gut microbiome axis and its implications in the health and disease of the gastrointestinal (GI) system.

2. Oral and Gut Microbiomes: Connection and Segregation

2.1. Oral Cavity and Gut: Connected through GI Tract

The human digestive system consists of the GI tract and the accessory digestive organs, including liver and pancreas. The GI tract is well-lined by the mucous membrane, beginning at the mouth and ending at the gut—more precisely, the anus. Thus, the oral cavity and gut are anatomically continuous regions connected through the GI tract. Moreover, both sites are also chemically connected, since saliva and digested food pass through the GI tract [13]. Generally, the GI tract is thought to be external to the body due to the hollow canal structure. The oral cavity, a gateway of the digestive tract, is directly exposed to the outside environment, such as microorganisms, nutrients and other xenobiotics. In this regard, both oral cavity and gut provide a proper environment for divergent microbes to thrive. The HMP has revealed that more than half of bacteria in the human body reside in the GI tract (29%) and the oral cavity (26%) [9]. In addition to this abundance, the oral and gut microbiomes are highly diverse and concomitantly show unique signatures distinguished from each habitat [3].

2.2. Oral Microbiome Composition

According to the human oral microbiome database (HOMD), the oral cavity presents approximately 700 species of microorganisms (from the HOMD website; www.homd.org; accessed on 20 January 2021). Commensals in the oral cavity contain Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Fusobacteria, Neisseria, and TM7 at the phylum level [15,16,17]. The oral cavity has several distinct microbial habitats, including buccal mucosa, subgingival plaque, supragingival plaque, keratinized gingiva, hard palate, saliva, tonsil, tongue, and throat. The buccal and palatal mucosae showed lower diversity than other oral habitats [18]. Regardless of the niche location, all the oral sites of the healthy subject carry Streptococcus, Gemella, Veillonella, Haemophilus, Neisseria, Porphyromonas, Fusobacterium, Actinomyces, and Prevotella at the genus level [19,20]. In addition to these common bacterial clades, each niche has a well-differentiated bacterial composition. Based on the microbial community structure, the oral niches can be divided into three distinct groups as follows: Group 1—buccal mucosa, keratinized gingiva, and hard palate; Group 2—saliva, tongue, tonsils, and throat; Group 3—sub- and supragingival plaque [20]. This segregation of the oral microbiome by niches is plausibly attributed to several factors, such as pH, salinity, redox potential, oxygen, and nutrition [15,21]. Moreover, dental hygiene is another important factor that shapes the oral microbiome, since the oral cavity is directly open to the outside environment [22,23].

2.3. Gut Microbiome Composition

The gut is the largest and the most well-characterized microbial ecosystem in the human body, which harbors about 500 to 1000 species in more than 50 different phyla [24]. The gut microbiota, mostly anaerobes, is composed of five major phyla—Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Verrucomicrobia—but dominated by two phyla—Bacteroidetes and Firmicutes, which account for more than 90% [25]. At the genus level, Bacteroides is the most abundant [26]. The human gut microbiota is known to be established early in life and can then be changed by age and environments, such as diet and nutrition, similar to the human oral microbiome [27,28]. Thus, both oral and gut microbiomes directly reflect the health status of the host.
Although the gut is continuously linked to the oral cavity, the gut microbiota composition can be distinguished from the one of oral cavity. At the phylum level, the oral cavity is dominated by Firmicutes, while the stool microbiota is mostly abundant with Bacteroidetes [20]. This segregation could be attributed to gastric acid in the stomach and bile acids in the duodenum [29,30]. It has been reported that long-term usage of proton pump inhibitors (PPIs) increases risk of enteric infection [31,32]. Of note, low gastric acidity by PPIs can reduce the diversity of gut microbial ecosystem and change the gut microbiome composition [33]. Moreover, bile acids can induce damage on the membrane and/or DNA integrity of enteric bacteria, acting as a potent antimicrobial barrier between oral cavity and gut [34,35]. Thus, gastric acidity and bile acid pool are responsible for distinctive patterns of the gut and oral microbiomes.

2.4. Physiological Functions of Gut Microbiome: Lessons from Germ-Free Mice

The human gut microbiome profiles can be shifted depending on health status, environmental factors, genetics, and even life styles [2]. The metagenomic analysis has revealed that the human gut-resident bacterial community regulates metabolic pathways, such as carbon metabolism and amino acid synthesis [26]. Microorganisms display conserved molecular motifs known as microbial-associated molecular patterns and pathogen-associated molecular patterns (PAMPs), which can be recognized by the host through pattern recognition receptors (PRRs), such as toll-like receptors [6,36]. This microbial–host interaction can stimulate the immune system and inflammatory responses in the human [36]. This means that the gut microbiota can modulate central biological functions, metabolism and immunity in the human body, and thus gut dysbiosis is associated with numerous human diseases, from infectious disease to Alzheimer’s disease [5,10,37]. However, it is challenging to prove whether the gut microbiota is the cause or consequence of the human health status.
Alternatively, germ-free (GF) animals have provided insightful clues for the physiological functions of the gut microbiome [38,39]. Compared to specific pathogen-free (SPF) mice, GF mice have reduced intestinal mass, shorter villi, and decreased total surface area of the small intestine, indicating defects in GI tract development [38]. In line with this, GF mice show metabolic abnormalities, such as altered cholesterol metabolisms and reduced intestinal amounts of short-chain fatty acids, one of the important energy sources [40,41]. GF mice thus display lower body fat contents and resistance to high fat diet-induced body weight gain, compared to SPF mice [42,43]. However, the body fat contents were restored by conventionalization of GF mice via applying cecal contents of SPF mice [43]. In aspects of the immunity, GF mice have defects in the development of Peyer’s patches and mesenteric lymph nodes, reduced numbers of CD4, CD8, and Foxp3 T cells, and decreased production of secretory immunoglobulin A in B cells [6]. These disorders can be recovered by microbiota reconstitution through either cohousing with SPF mice or oral inoculation of fecal contents from SPF mice [44,45,46]. Taken together, it is evident that the gut microbiota plays a crucial role in maintaining physiological homeostasis, primarily metabolism and immunity.

2.5. Physiological Functions of Oral Microbiome: Local and Systemic Effects

Although the oral cavity is the second largest microbial habitat in the human body, the cumulative knowledge is not sufficient to fully understand the implications of oral microbiome in the human health. It is unquestionable that the oral microbiome is directly associated with dental health [23,47]. There are well-identified keystone pathogens in oral diseases, such as Streptococcus mutans for dental caries and Porphyromonas gingivalis for periodontitis [48,49]. Moreover, patients with oral squamous cell carcinoma showed alteration in oral microbiome compared to the healthy subjects [50,51]. Based on the oral microbiota analysis, Fusobacterium was enriched in oral squamous cell carcinoma (OSCC) patients at the genus level [52,53]. In GF mice, inoculation with oral microbiome promoted chemical-induced oral carcinogenesis, further supporting the direct involvement of oral microbiome in oral disease [54]. Thus, oral microbes modulate dental pathophysiology in a single key pathogen-dependent manner as well as a collective manner.
The oral microbiome can affect systemic health conditions, not limited to the dental health (see Figure 1) [55,56]. Epidemiological and experimental evidence supports that oral dysbiosis is closely associated with systemic diseases, including Alzheimer’s disease, diabetes, and cardiovascular disease [57,58,59]. In line with this, the oral microbiota profile was significantly altered in Alzheimer’s disease, such as prevalence of the genera Moraxella, Leptotrichia, and Sphaerochaeta [60]. The oral dysbiotic shifts were associated with the progression of Alzheimer’s disease [61]. Patients with type I diabetes showed higher abundance of the phyla Actinobacteria and Firmicutes compared to healthy controls [62]. Moreover, the enrichment of the genus Anaeroglobus has been reported in the oral micro-biome of patients with symptomatic atherosclerosis [63]. In case of periodontitis, an oral dysbiotic disease, its signature pathogen P. gingivalis infection can induce chronic inflammation locally as well as systemically [64,65]. Moreover, oral dysbiosis can induce production of PAMP signals, such as lipopolysaccharide (LPS), resulting in systemic stimulation of innate immune responses and inflammatory transcription factors, including nuclear factor κB [66,67]. These systemic inflammation and immune responses are thought to be one of the primary mechanisms, underlining that the oral microbiome regulates pathogenesis in distal organs.
Notably, oral microbiota can translocate to the other organs, which is considered as another mechanism of oral dysbiosis-induced systemic disease [68,69]. The oral pathogen P. gingivalis has been detected in the brain tissues of short-term postmortem Alzheimer’s disease patients [70]. The direct translocation of oral pathogen to brain can aggravate Alzheimer’s disease through inducing neuroinflammation and neurodegeneration [71,72]. Moreover, a number of oral commensal bacteria was detected in atherosclerotic plaques of coronary artery disease patients, further indicating the possible translocation of oral bacteria to the distal organs [73]. The migration of oral microbes can occur more frequently towards the GI system, due to the physical and chemical connections. In certain pathogenic conditions, some of the oral bacterial taxa are colonized and enriched in pancreas and gut, indicating the direct crosstalk between oral and gut microbiotas [74,75,76]. Thus, we will discuss the interaction between oral and gut microbiomes and its pathophysiological functions in the following sections.

3. Interconnection between Oral and Gut Microbiomes: Oral–Gut Microbiome Axis

3.1. Oral-to-Gut Microbial Translocation

The oral and gut microbiomes are well-segregated due to the presence of the oral–gut barrier, physical distance as well as chemical hurdles, such as gastric acid and bile [20,30,77]. However, the impairment of the oral–gut barrier can allow interorgan translocation and communication. In general, neonates and elderly people have immature or less functional barriers in the body [78,79]. Bifidobacterium is the most abundant bacterial genus in the neonatal gut [80]. Interestingly, the gut-resident Bifidobacterium has been detected in the oral fluid of neonates [81]. Likewise, elderly people showed prevalence of the oral bacteria in the gut compared to healthy adults, such as Porphyromonas, Fusobacterium, and Pseudoramibacter [82,83]. Moreover, low gastric acidity shifted the gut microbiota composition towards the oral microbiome, further indicating translocation of oral microbiota to gut under the oral–gut barrier dysfunction [33]. Li et al. have demonstrated in vitro that the oral microbiota can invade into the gut and reshape the gut microbial community by cohousing GF mouse groups introduced with human fecal and salivary microbiotas, respectively [84]. Taken together, these data suggest that the oral microbes can overcome the physical and/or chemical barriers between the oral cavity and gut under certain circumstances and potentially translocate into the gut.
Notably, typical oral-resident species have been detected under pathological conditions in the GI tract [74,75,85]. For instance, patients with inflammatory bowel disease (IBD) had significant enrichment of Haemophilus and Veillonella in the gut mucosa, which are known to be oral commensal microbes [86]. In patients with colon cancer, their gut microbiomes contained several oral taxa, including Fusobacterium [87]. This implies that the normal human oral microbiota can invade and colonize in the gut mucosa and become an opportunistic pathogen in conditions of disrupted mucosal homeostasis.
However, this oral–fecal transmission can occur under the physiological conditions as well, not only in pathological contexts or barrier disruption. When HMP consortium data were partitioned into community types for each body site, the oral and gut microbiome types show strong association, even though they were taxonomically different [3,88]. Among the salivary bacteria, Prevotella was abundantly found in the stool samples [88]. In line with this, several genera were concomitantly detected from both oral and stool samples of the same healthy subject [20]. By analyzing 310 species from oral and fecal microbiomes in 470 individuals, 125 species were prevalent in both saliva and stool samples, including strains of Streptococcus, Veillonella, Actinomyces, and Haemophilus [13]. Taken together, it is obvious that the oral microbiota can translocate into the gut more extensively than expected even in the healthy states, not only in the pathological circumstances.

3.2. Fecal-to-Oral Microbial Translocation

Enteric microorganisms can be transmitted by fecal–oral routes through direct contact or indirect exposure via contaminated fluids and foods [89]. The human hand microbiota profile was highly overlapped with oral and gut microbiome patterns, suggesting that the human hand is a carrier for fecal-to-oral microbial transmission [14]. Thereby, the fecal–oral route of microorganisms has been frequently reported in developing countries, due to poor hygienic status, such as lack of clean water supply and public health system [90,91]. Furthermore, immunocompromised individuals are susceptible to fecal–oral transmission as well. In case of head and neck cancer patients, radiation therapy was highly associated with oral colonization of gram-negative enteric rods, which can be further exacerbated by poor oral hygiene conditions [92,93]. Thus, poor hygienic and/or immunocompromised conditions can facilitate the fecal–oral route in the same individuals.
In addition to intrapersonal transmission, the fecal–oral route is considered as an important mechanism for human-to-human transmission of pathogens as well. Enteric viruses, such as hepatitis A virus (HAV) and hepatitis E virus (HEV), are well-known to transmit through the fecal–oral route and thus easily spread by person-to-person contact, particularly in insanitary conditions [94,95,96]. The enteric viruses can interact with the gut microbiota in both direct and indirect manners, resulting in devastating effects on the gut microbial ecosystem [97,98]. HEV infection has been reported to increase the abundance of Lactobacillaceae and Gammaproteobacteria in the fecal samples of patients with acute liver failure [99]. In contrast, supplementation with the probiotic bacterium Enterococcus faecium NCIMB 10415 can effectively promote HEV removal in infected pigs [100]. In addition to enteric viruses, Helicobacter pylori, major causal bacteria of severe gastroduodenal diseases, can transmit via the fecal–oral route as well, showing a correlation with HAV infection [101,102]. Although further investigation is required to understand the role of the fecal–oral transmission in oral and gut microbiomes, it is convincing that the oral and gut microbiomes are closely connected through both oral-to-gut and fecal-to-oral routes (see Figure 2). This bidirectional interaction can mutually shape and/or reshape the microbial ecosystem of both habitats, finally modulating physiological and pathological processes in the GI system. Thus, both oral–gut and fecal–oral directions will collectively be referred to as the “oral-gut microbiome axis” in the following sections.

4. Oral–Gut Microbiome Axis in Human GI Diseases and Cancers

4.1. Inflammatory Bowel Disease

IBD represents chronic inflammatory disorders of the colon and small intestine, including Crohn’s disease (CD) and ulcerative colitis (UC). IBD is thus strongly associated with the gut microbiome dysbiosis. The gut microbiomes of IBD patients show reduced diversity and shifts in bacterial composition, including loss of the bacterial phylum Firmicutes and increased abundance of the phyla Proteobacteria and Bacteroidetes [103,104,105,106]. These dysbiotic events have been observed more profoundly in intestinal mucosal tissue biopsies, rather than in the stool [86]. On the intestinal mucosal surface, bacterial invasion and biofilm formation were frequently detected in IBD patients compared to the healthy subjects, indicating that gut barrier dysfunction is involved in IBD pathogenesis [13,107,108].
In healthy states, the gut microbiome is barely invaded and colonized by microbes derived from other habitats, due to the intact mucosal barrier [109]. However, IBD patients manifest increased gut epithelial permeability due to impaired mucosal barrier [110,111]. It is noteworthy that the oral-resident bacterial strains are isolated from the gut microbiome of IBD patients, possibly due to the gut leakiness. Fusobacterium nucleatum resides commonly in the oral cavity but rarely in the guts of healthy individuals [112]. Interestingly, IBD patients showed colonization of F. nucleatum in the gut, which was more invasive than other F. nucleatum strains, indicating the presence of the oral–gut microbiome axis in IBD patients [74,75]. This has been confirmed in vitro by transplantation of the oral microbiota into animal models. In rats, F. nucleatum-gavage led to shifts in the gut microbiome and aggravated visceral hypersensitivity [113]. Moreover, salivary microbiota of CD patients successfully colonized in the gut of GF mice [114]. Klebsiella was the most prevalent colonizer, which can promote Th1 cell induction and inflammation in the intestine, the key events in IBD pathogenesis [114]. These results further support that oral microbiota, either commensal or pathobiont, can be transmitted into the intestine, promoting IBD pathogenesis via gut dysbiosis.
Hence, oral dysbiosis can directly modulate pathogenesis of IBD by recruiting the oral–gut axis. Periodontitis, a chronic inflammatory oral disease, is strongly associated with alteration of oral microbiota—in particular, with the overgrowth of its keystone pathogen P. gingivalis [48,115]. In C56BL/6 mice, oral administration of P. gingivalis attenuated the intestinal barrier function via downregulating tight junction proteins, leading to significant alteration of gut microbiome, including enrichment of the family Clostridiaceae [116,117,118,119]. Moreover, P. gingivalis-inoculated mice showed intestinal as well as systemic inflammation, which can be mediated by P. gingivalis-derived endotoxins, such as LPS [117,118,120,121]. Consistent with animal experiments, the meta-analyses have demonstrated that periodontitis is strongly associated with two major forms of IBD, CD, and UC, respectively [122,123]. Taken together, the oral pathogen(s) can interfere with intestinal barrier function and invade the gut mucosa, which induces the intestinal dysbiosis and chronic inflammation, consequently leading to IBD pathogenesis. Notably, IBD patients as well as colitis-induced mice displayed alterations in their salivary microbiota compositions, which were associated with inflammatory responses, indicating that the oral–gut microbial interactions could be bidirectional [124,125].

4.2. Colorectal Cancer

Colorectal cancer (CRC) is one of the most common cancer types and the second leading cause of cancer mortality worldwide [126]. IBD is the most well-established risk factor for development and progression of CRC [127]. Thus, IBD and CRC share etiological factors in pathogenesis, including distinct changes in the gut microbiome [128,129]. Similar to IBD, CRC is strongly associated with gut dysbiosis. CRC patients show the distinct patterns of microbial compositions in both fecal and intestinal mucosal samples compared to healthy individuals [87,130,131,132]. Consistently, profound alterations of gut microbiota have been found in both colitis-associated and chemical-induced CRC mouse models, supporting the relationship between gut dysbiosis and CRC [133,134]. Research using GF mice has further demonstrated that alteration of gut microbiota can directly facilitate inflammation-associated CRC development [135,136].
Interestingly, several oral taxa have been detected in the gut of CRC patients, which include Parvimonas, Peptostreptococcus, and Fusobacterium, indicating the presence of the oral–gut microbiome axis in CRC [87]. Among these oral resident bacteria, F. nucleatum was prevalent in tumor tissues and feces of CRC patients compared to the healthy subjects, which is consistent with IBD [87,137,138,139]. In mouse colitis models, oral administration of F. nucleatum induced inflammation as well as tumorigenesis in the small and large intestines [139]. F. nucleatum seems to readily attach to the host CRC cells that express endothelial cadherin, and then stimulate proinflammatory responses and cell proliferation [138,139]. Similar to IBD, colorectal tumors showed impaired intestinal barrier functions, which might explain the intestinal colonization of oral microbiota [140,141].
Moreover, it has been reported that F. nucleatum can coaggregate and coinfect with the oral pathogen P. gingivalis [142,143]. Despite the limitations of in vitro approaches, P. gingivalis invaded CRC cells and promoted cancer cell proliferation, indicating the involvement of periodontal pathogen in colorectal tumorigenesis [144]. In line with this, P. gingivalis serum antibody levels were positively correlated with mortality in CRC patients [145]. Furthermore, a meta-analysis demonstrated that periodontitis is associated with increased CRC risk [146,147]. Taken together, these investigations serve as evidence of the association between oral dysbiosis, oral–gut microbiome axis, and CRC pathogenesis.

4.3. Chronic Liver Disease

Cirrhosis is a late-stage liver disease caused by chronic liver disorders, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [148]. Interestingly, a broad spectrum of chronic liver diseases has been related to intestinal dysbiosis [149,150,151,152,153]. Patients with NAFLD, NASH, or cirrhosis showed significant increase in the phylum Proteobacteria in their stool samples compared to the healthy controls, indicating the association of the gut microbiome in hepatopathogenesis [150,151,152]. In this regard, GF mice were protected from high fat diet-induced lipid accumulation in the liver, compared to SPF mice [41]. Moreover, GF mice colonized with NAFLD-prone gut microbes developed severe hepatic steatosis, further supporting that the gut dysbiosis can be a direct causal of chronic liver diseases [154].
Since the gut and liver are physically connected by the biliary tract and portal vein, gut microbes can translocate to the liver if the mucosal barrier is impaired [155]. Bile acids possess antimicrobial activities and circulate between gut and liver for recycling, dual-functioning as a barrier as well as a bridge [34]. Chronic liver diseases are often related to defective formation and/or secretion of bile acids, which can increase the intestinal permeability [156,157]. Thereby, biliary obstruction facilitates bacterial translocation from gut to liver [158,159]. In gallstone patients, the microbial composition was shifted in both biliary tract and gut compared to the normal controls, such as enrichment of Proteobacteria, supporting the presence of the gut–liver microbiome axis in chronic liver diseases [160].
By converging with the gut–liver microbial crosstalk, the oral–gut microbiome axis is emerging as an important modulator in chronic liver diseases. It is noteworthy that the metagenomic analysis has proven invasion and colonization of oral commensals in the gut of patients with cirrhosis [152]. Another study also showed the enrichment of oral microbes in the gut of cirrhotic patients with alcohol dependence [161]. These data support that intestinal transition of oral microbes is associated with cirrhosis; however, the underlying mechanism is not clear yet. As mentioned earlier, PPI promoted oral-to-gut microbial transition due to low gastric acidity [33]. Likewise, PPI treatment altered the gut microbiota composition in cirrhotic patients, particularly displaying overgrowth of oral-resident bacteria in the gut [162]. The same research group has demonstrated the concomitant changes of salivary and stool microbiomes in cirrhosis, further suggesting that the oral–gut microbiome axis regulates hepatic pathogenesis [163].
Oral dysbiosis thus potentially aggravates chronic liver diseases via shifts in the gut microbiome. Indeed, periodontitis is significantly associated with NASH, NAFLD, and cirrhosis [164,165,166,167]. P. gingivalis, a periodontal keystone pathogen, has been detected in oral samples from NAFLD and viral infection-related cirrhosis patients [168,169]. In high fat diet-fed mice, odontogenic infection by P. gingivalis facilitated progression of NAFLD and NASH through lipid accumulation, fibrosis, and inflammation in the liver [170,171]. Overall, oral dysbiosis can exacerbate chronic liver diseases, possibly through modulation of the gut ecosystem. Concomitantly, oral dysbiosis might reflect the intestinal dysbiotic ecosystem driven by hepatic diseases.

4.4. Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is developed through a stepwise progression, from NAFLD/NASH to cirrhosis and finally to HCC [172]. In a mouse hepatocarcinogenesis model, SPF mice were more susceptible for HCC development than GF mice, similar to the chronic liver diseases [173]. In a gnotobiotic mouse model, certain types of intestinal bacteria, such as Escherichia coli and Streptococcus faecalis, can significantly increase liver tumorigenesis, indicating the direct involvement of the gut microbiota in HCC pathogenesis [174]. In line with this notion, HCC patients showed decrease in butyrate-producing genera, such as Ruminococcus, Oscillibacter, Faecalibacterium, Clostridium IV, and Coprococcus, while an increase in LPS-producing genera, including Klebsiella and Haemophilus in the stool samples, compared to the healthy controls [175]. Moreover, the level of gut dysbiosis tends to increase with the progression of HCC [176]. In HCC patients with cirrhosis, the fecal microbiota composition was distinguished from that of cirrhosis patient without HCC, such as significant enrichment of E. coli and Fusobacteriia [177,178]. In a chemically induced HCC mouse model, an enteric bacteria Helicobacter hepaticus has been found within tumors, which directly caused HCC development and progression, further supporting that gut dysbiosis can induce HCC pathogenesis [179,180]. However, H. hepaticus was not detected in human HCC samples, while the presence of other Helicobacter species, such as H. pylori, was confirmed [181,182]. Thus, HCC development is strongly associated with gut dysbiosis.
Interestingly, changes of oral microbiota profiles have been reported in HCC patients compared to healthy subjects [183,184,185]. HCC patients showed high abundance of the genera Haemophilus, Porphyromonas, and Filifactor in the salivary microbiota [184]. In HCC patients with cirrhosis, the genera Oribacterium and Fusobacterium were prevalent based on the microbiome profiles of tongue coat [185]. Moreover, chronic periodontitis was associated with advanced HCC stages, suggesting the correlation between oral dysbiosis and HCC [186]. Of note, Fusobacterium has been enriched in both oral and gut microbiomes in HCC patients with cirrhosis, which confers a possibility that the oral microbes can regulate HCC pathogenesis through the oral–gut microbiome axis, but needs further investigation [176,178,185].

4.5. Pancreatic Ductal Adenocarcinoma

The pancreas is a part of the digestive system that secretes enzymes to break down lipids, proteins, and carbohydrates. The main pancreatic duct combines with the common bile duct, which both connect to the duodenum. Under normal healthy conditions, the pancreas is thought to be a sterile organ [187]. However, patients with pancreatic ductal adenocarcinoma (PDAC) showed increased abundance of bacteria, such as Gammaproteobacteria within tumors and Enterococcus faecalis in the pancreatic juice and pancreatic tissues [188,189]. Moreover, intratumoral microbiome diversity was correlated with prognosis of PDAC [190]. With a more integrative view, PDAC patients display the distinct microbiome patterns in the pancreatic tissues, tumors, as well as fecal samples, indicating the involvement of gut–pancreatic microbial crosstalk in PDAC pathogenesis [190,191]. In particular, Proteobacteria was concomitantly enriched in both gut and pancreas of PDAC patients [188,191]. In experimental mice, increased intestinal permeability was associated with gut-to-pancreatic microbial translocation, which could accelerate PDAC progression [190,191,192]. In the gut microbiome-ablated mice, repopulation with the fecal microbiome from PDAC-bearing mice can significantly promote pancreatic tumorigenesis, indicating the direct contribution of gut microbiome to PDAC progression [191]. Thus, the intestinal microbiome seems to be closely coordinated with the pancreatic microbial ecosystem, which plays a crucial role in PDAC pathogenesis.
Surprisingly, the oral microbiome is also associated with PDAC pathogenesis. Based on meta-epidemiological studies, periodontitis, a major oral dysbiotic disease, can significantly increase the risk and mortality of PDAC [193,194]. In consistent, carriage of its key pathogen, P. gingivalis, positively correlates to higher risk and mortality in PDAC patients [145,195,196]. In a mouse PDAC model, oral administration of P. gingivalis accelerated cell proliferation and epithelial–mesenchymal transition, finally promoting PDAC progression [197]. Interestingly, intracellular P. gingivalis directly promoted tumor cell growth in human pancreatic cancer cell lines [198]. These suggest that oral dysbiosis can be a direct etiology as well as a useful marker for diagnosis and prognosis in PDAC pathogenesis.
In addition to oral dysbiosis, PDAC patients showed a distinct shift in the oral microbiome compared to the healthy subjects [196,199]. Notably, Fusobacterium, a well-known oral bacterial group, has been detected in human PDAC tissues, although its relationship with prognosis of PDAC is controversial [196,200]. Moreover, the pancreatic microbiome was highly overlapped with the intestinal microbiome in PDAC patients [85]. Both pancreatic and intestinal microbiomes exhibited the relative abundance of the oral taxa Fusobacterium and Porphyromonas [85]. Thus, it is plausible that certain types of oral microbes can migrate to the gut and even further to the pancreas, which can promote PDAC pathogenesis through the coordinated modulation of the intestinal and pancreatic microbiomes. In support of this notion, a correlation has been found between oral, intestinal, and pancreatic microbiomes in PDAC patients, particularly coabundance of oral-originated F. nucleatum subsp. vincentii [76]. Taken together, these data suggest that the oral–gut microbiome axis can modulate PDAC pathogenesis, even further creating the oral–gut–pancreatic microbial route.

5. Perspectives

It has been well-appreciated that the gut and oral dysbioses are associated with numerous diseases [5,8,55,56]. To date, most of the research on microbiome-associated diseases have been conducted with respect to a single organ-specific microbiome, with less concern for an interorgan microbial communication. The oral cavity and gut are the two largest microbial habitats in the human body [9]. Cumulative evidence supports that the oral microbiota can change the overall gut microbial ecosystem through direct translocation and/or rather indirectly, by secretomes of oral bacteria [12,201,202]. Gut-to-oral microbial transmission can occur as well, particularly under certain circumstances, such as poor hygienic and immunocompromised conditions [14,90,92]. Collectively, the bidirectional crosstalk between oral and gut microbiomes can develop the oral–gut microbiome axis, which plays a crucial role in regulating pathogenesis of various human diseases, primarily in the GI system (see Table 1, Table 2 and Table 3).
It is noteworthy that the oral–gut microbiome axis improves prediction of pathogenesis and prognosis in the GI system. The meta-analysis has shown that oral microbiome changes are associated with the risk of GI cancer, including CRC, PDAC, and HCC, which can be a potential index for early detection [203]. Farrell et al. have validated PDAC-specific oral microbial patterns as a PDAC biomarker [199]. The concomitant enrichment of two oral bacterial species, Neisseria elongata and Streptococcus mitis, can specifically distinguish PDAC patients from healthy subjects [199]. In convergence with the coordinated modulation of oral and gut microbiomes, the oral dysbiotic pattern can provide more consolidated information on the pathogenesis. In CRC patients, combining oral and gut microbiome data can significantly increase the sensitivity to predict and detect polyps and/or tumors [68]. Although it is challenging to uncover the causal relationship between the microbiome and disease, integration of oral and gut microbiomes might be helpful to overcome this hurdle.
Furthermore, the oral cavity is highly accessible than the intestine, since it is open to the outside of body. For gut microbiome analysis, the samples are primarily collected from stool and mucosal biopsy [204]. The fecal samples are noninvasive and cost-effective, but can be contaminated with urine and bring unpleasant feelings to the sample donor [204,205]. However, the biopsy sampling is invasive and not suitable for healthy individuals, while it can generate more accurate data [204]. In case of the oral microbiome analysis, the samples can be obtained from cotton swabbing, saliva, and mouth-rinse [4,206]. Compared to sampling methods for gut microbiota, oral microbiota collection is practically more convenient and available regardless of the health status, without any invasion or hygienic issues. Thus, in conjunction with the gut microbiome, the oral microbiome further provides feasible merits as a diagnostic/prognostic tool as well as a therapeutic target. Moreover, the modification of oral microbiome simply by improvement of dental hygiene and/or supplementation with probiotics can modulate the pathogenesis of disease [47,207].

6. Conclusions

Taken together, it is evident that the oral–gut microbiome axis is strongly associated with diseases in the GI system. Understanding the correlation of the oral–gut microbiome axis in pathogenesis confers an advantage for precise diagnosis/prognosis and effective treatment. Thus, integrative research on the interorgan microbial network will shed light on novel strategies to better control microbiome-associated diseases.

Author Contributions

N.-Y.S. contributed to study conception. S.-Y.P., B.-O.H., M.L., S.-H.O., S.-K.L., K.-S.C., K.-K.P., Y.H., W.-Y.C., and N.-Y.S. performed literature review and analysis and revised the manuscript. N.-Y.S., S.-Y.P. and B.-O.H. drafted the manuscript, figures, and tables. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by National Research Foundation of Korea (NRF) Grants funded by the Korean Government (grant numbers NRF-2020R1C1C1003338 and NRF-2016R1A5A2008630 to N.-Y.S.) and by the Yonsei University Research Fund of 2021 (Yonsei Signature Research Cluster Program 2021-22-0017).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors are especially grateful to Young-Joon Surh (College of Pharmacy, Seoul National University, Seoul, Korea) for his inspiring insights and invaluable advice during preparation of this review.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Turnbaugh, P.J.; Ley, R.E.; Hamady, M.; Fraser-Liggett, C.M.; Knight, R.; Gordon, J.I. The human microbiome project. Nature 2007, 449, 804–810. [Google Scholar] [CrossRef] [PubMed]
  2. Lozupone, C.A.; Stombaugh, J.I.; Gordon, J.I.; Jansson, J.K.; Knight, R. Diversity, stability and resilience of the human gut microbiota. Nature 2012, 489, 220–230. [Google Scholar] [CrossRef] [Green Version]
  3. The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012, 486, 207–214. [Google Scholar] [CrossRef] [Green Version]
  4. The Human Microbiome Project Consortium. A framework for human microbiome research. Nature 2012, 486, 215–221. [Google Scholar] [CrossRef] [Green Version]
  5. Lynch, S.V.; Pedersen, O. The Human Intestinal Microbiome in Health and Disease. N. Engl. J. Med. 2016, 375, 2369–2379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Round, J.L.; Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 2009, 9, 313–323. [Google Scholar] [CrossRef]
  7. Roy, S.; Trinchieri, G. Microbiota: A key orchestrator of cancer therapy. Nat. Rev. Cancer 2017, 17, 271–285. [Google Scholar] [CrossRef]
  8. Sekirov, I.; Russell, S.L.; Antunes, L.C.; Finlay, B.B. Gut microbiota in health and disease. Physiol. Rev. 2010, 90, 859–904. [Google Scholar] [CrossRef] [Green Version]
  9. Group, N.H.W.; Peterson, J.; Garges, S.; Giovanni, M.; McInnes, P.; Wang, L.; Schloss, J.A.; Bonazzi, V.; McEwen, J.E.; Wetterstrand, K.A.; et al. The NIH Human Microbiome Project. Genome Res. 2009, 19, 2317–2323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Cryan, J.F.; O’Riordan, K.J.; Cowan, C.S.M.; Sandhu, K.V.; Bastiaanssen, T.F.S.; Boehme, M.; Codagnone, M.G.; Cussotto, S.; Fulling, C.; Golubeva, A.V.; et al. The Microbiota-Gut-Brain Axis. Physiol. Rev. 2019, 99, 1877–2013. [Google Scholar] [CrossRef] [PubMed]
  11. Wypych, T.P.; Wickramasinghe, L.C.; Marsland, B.J. The influence of the microbiome on respiratory health. Nat. Immunol. 2019, 20, 1279–1290. [Google Scholar] [CrossRef] [PubMed]
  12. Olsen, I.; Yamazaki, K. Can oral bacteria affect the microbiome of the gut? J. Oral Microbiol. 2019, 11, 1586422. [Google Scholar] [CrossRef] [Green Version]
  13. Schmidt, T.S.; Hayward, M.R.; Coelho, L.P.; Li, S.S.; Costea, P.I.; Voigt, A.Y.; Wirbel, J.; Maistrenko, O.M.; Alves, R.J.; Bergsten, E.; et al. Extensive transmission of microbes along the gastrointestinal tract. Elife 2019, 8. [Google Scholar] [CrossRef]
  14. Shaffer, M.; Lozupone, C. Prevalence and Source of Fecal and Oral Bacteria on Infant, Child, and Adult Hands. mSystems 2018, 3. [Google Scholar] [CrossRef] [Green Version]
  15. Avila, M.; Ojcius, D.M.; Yilmaz, O. The oral microbiota: Living with a permanent guest. DNA Cell Biol. 2009, 28, 405–411. [Google Scholar] [CrossRef] [PubMed]
  16. Dewhirst, F.E.; Chen, T.; Izard, J.; Paster, B.J.; Tanner, A.C.; Yu, W.H.; Lakshmanan, A.; Wade, W.G. The human oral microbiome. J. Bacteriol. 2010, 192, 5002–5017. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Sharma, N.; Bhatia, S.; Sodhi, A.S.; Batra, N. Oral microbiome and health. AIMS Microbiol. 2018, 4, 42–66. [Google Scholar] [CrossRef] [PubMed]
  18. Sultan, A.S.; Kong, E.F.; Rizk, A.M.; Jabra-Rizk, M.A. The oral microbiome: A Lesson in coexistence. PLoS Pathog. 2018, 14, e1006719. [Google Scholar] [CrossRef] [Green Version]
  19. Aas, J.A.; Paster, B.J.; Stokes, L.N.; Olsen, I.; Dewhirst, F.E. Defining the normal bacterial flora of the oral cavity. J. Clin. Microbiol. 2005, 43, 5721–5732. [Google Scholar] [CrossRef] [Green Version]
  20. Segata, N.; Haake, S.K.; Mannon, P.; Lemon, K.P.; Waldron, L.; Gevers, D.; Huttenhower, C.; Izard, J. Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples. Genome Biol. 2012, 13, R42. [Google Scholar] [CrossRef] [Green Version]
  21. Chattopadhyay, I.; Verma, M.; Panda, M. Role of Oral Microbiome Signatures in Diagnosis and Prognosis of Oral Cancer. Technol. Cancer Res. Treat. 2019, 18, 1533033819867354. [Google Scholar] [CrossRef] [Green Version]
  22. Baker, J.L.; Edlund, A. Exploiting the Oral Microbiome to Prevent Tooth Decay: Has Evolution Already Provided the Best Tools? Front. Microbiol. 2018, 9, 3323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Kilian, M.; Chapple, I.L.; Hannig, M.; Marsh, P.D.; Meuric, V.; Pedersen, A.M.; Tonetti, M.S.; Wade, W.G.; Zaura, E. The oral microbiome—An update for oral healthcare professionals. Br. Dent. J. 2016, 221, 657–666. [Google Scholar] [CrossRef]
  24. Hooper, L.V.; Gordon, J.I. Commensal host-bacterial relationships in the gut. Science 2001, 292, 1115–1118. [Google Scholar] [CrossRef] [PubMed]
  25. Arumugam, M.; Raes, J.; Pelletier, E.; Le Paslier, D.; Yamada, T.; Mende, D.R.; Fernandes, G.R.; Tap, J.; Bruls, T.; Batto, J.M.; et al. Enterotypes of the human gut microbiome. Nature 2011, 473, 174–180. [Google Scholar] [CrossRef]
  26. Qin, J.; Li, R.; Raes, J.; Arumugam, M.; Burgdorf, K.S.; Manichanh, C.; Nielsen, T.; Pons, N.; Levenez, F.; Yamada, T.; et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010, 464, 59–65. [Google Scholar] [CrossRef] [Green Version]
  27. Rinninella, E.; Raoul, P.; Cintoni, M.; Franceschi, F.; Miggiano, G.A.D.; Gasbarrini, A.; Mele, M.C. What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases. Microorganisms 2019, 7, 14. [Google Scholar] [CrossRef] [Green Version]
  28. Valdes, A.M.; Walter, J.; Segal, E.; Spector, T.D. Role of the gut microbiota in nutrition and health. BMJ 2018, 361, k2179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Martinsen, T.C.; Bergh, K.; Waldum, H.L. Gastric juice: A barrier against infectious diseases. Basic Clin. Pharmacol. Toxicol. 2005, 96, 94–102. [Google Scholar] [CrossRef]
  30. Ridlon, J.M.; Kang, D.J.; Hylemon, P.B.; Bajaj, J.S. Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 2014, 30, 332–338. [Google Scholar] [CrossRef] [Green Version]
  31. Leonard, J.; Marshall, J.K.; Moayyedi, P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am. J. Gastroenterol. 2007, 102, 2047–2056, quiz 2057. [Google Scholar] [CrossRef] [PubMed]
  32. McDonald, E.G.; Milligan, J.; Frenette, C.; Lee, T.C. Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection. JAMA Intern. Med. 2015, 175, 784–791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Imhann, F.; Bonder, M.J.; Vich Vila, A.; Fu, J.; Mujagic, Z.; Vork, L.; Tigchelaar, E.F.; Jankipersadsing, S.A.; Cenit, M.C.; Harmsen, H.J.; et al. Proton pump inhibitors affect the gut microbiome. Gut 2016, 65, 740–748. [Google Scholar] [CrossRef] [Green Version]
  34. Begley, M.; Gahan, C.G.; Hill, C. The interaction between bacteria and bile. FEMS Microbiol. Rev. 2005, 29, 625–651. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Merritt, M.E.; Donaldson, J.R. Effect of bile salts on the DNA and membrane integrity of enteric bacteria. J. Med. Microbiol. 2009, 58, 1533–1541. [Google Scholar] [CrossRef] [Green Version]
  36. Belkaid, Y.; Hand, T.W. Role of the microbiota in immunity and inflammation. Cell 2014, 157, 121–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Kho, Z.Y.; Lal, S.K. The Human Gut Microbiome—A Potential Controller of Wellness and Disease. Front. Microbiol. 2018, 9, 1835. [Google Scholar] [CrossRef] [Green Version]
  38. Al-Asmakh, M.; Zadjali, F. Use of Germ-Free Animal Models in Microbiota-Related Research. J. Microbiol. Biotechnol. 2015, 25, 1583–1588. [Google Scholar] [CrossRef] [Green Version]
  39. Kostic, A.D.; Howitt, M.R.; Garrett, W.S. Exploring host-microbiota interactions in animal models and humans. Genes Dev. 2013, 27, 701–718. [Google Scholar] [CrossRef] [Green Version]
  40. Hoverstad, T.; Midtvedt, T. Short-chain fatty acids in germfree mice and rats. J. Nutr. 1986, 116, 1772–1776. [Google Scholar] [CrossRef]
  41. Rabot, S.; Membrez, M.; Bruneau, A.; Gerard, P.; Harach, T.; Moser, M.; Raymond, F.; Mansourian, R.; Chou, C.J. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 2010, 24, 4948–4959. [Google Scholar] [CrossRef] [Green Version]
  42. Backhed, F.; Ding, H.; Wang, T.; Hooper, L.V.; Koh, G.Y.; Nagy, A.; Semenkovich, C.F.; Gordon, J.I. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. USA 2004, 101, 15718–15723. [Google Scholar] [CrossRef] [Green Version]
  43. Ding, S.; Chi, M.M.; Scull, B.P.; Rigby, R.; Schwerbrock, N.M.; Magness, S.; Jobin, C.; Lund, P.K. High-fat diet: Bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS ONE 2010, 5, e12191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Cebra, J.J. Influences of microbiota on intestinal immune system development. Am. J. Clin. Nutr. 1999, 69, 1046S–1051S. [Google Scholar] [CrossRef] [PubMed]
  45. El Aidy, S.; van Baarlen, P.; Derrien, M.; Lindenbergh-Kortleve, D.J.; Hooiveld, G.; Levenez, F.; Dore, J.; Dekker, J.; Samsom, J.N.; Nieuwenhuis, E.E.; et al. Temporal and spatial interplay of microbiota and intestinal mucosa drive establishment of immune homeostasis in conventionalized mice. Mucosal Immunol. 2012, 5, 567–579. [Google Scholar] [CrossRef]
  46. Hansen, C.H.; Nielsen, D.S.; Kverka, M.; Zakostelska, Z.; Klimesova, K.; Hudcovic, T.; Tlaskalova-Hogenova, H.; Hansen, A.K. Patterns of early gut colonization shape future immune responses of the host. PLoS ONE 2012, 7, e34043. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Zarco, M.F.; Vess, T.J.; Ginsburg, G.S. The oral microbiome in health and disease and the potential impact on personalized dental medicine. Oral Dis. 2012, 18, 109–120. [Google Scholar] [CrossRef]
  48. Darveau, R.P.; Hajishengallis, G.; Curtis, M.A. Porphyromonas gingivalis as a potential community activist for disease. J. Dent. Res. 2012, 91, 816–820. [Google Scholar] [CrossRef] [Green Version]
  49. Forssten, S.D.; Bjorklund, M.; Ouwehand, A.C. Streptococcus mutans, caries and simulation models. Nutrients 2010, 2, 290–298. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Mager, D.L.; Haffajee, A.D.; Devlin, P.M.; Norris, C.M.; Posner, M.R.; Goodson, J.M. The salivary microbiota as a diagnostic indicator of oral cancer: A descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects. J. Transl. Med. 2005, 3, 27. [Google Scholar] [CrossRef] [Green Version]
  51. Pushalkar, S.; Mane, S.P.; Ji, X.; Li, Y.; Evans, C.; Crasta, O.R.; Morse, D.; Meagher, R.; Singh, A.; Saxena, D. Microbial diversity in saliva of oral squamous cell carcinoma. FEMS Immunol. Med. Microbiol. 2011, 61, 269–277. [Google Scholar] [CrossRef] [Green Version]
  52. Zhang, Z.; Yang, J.; Feng, Q.; Chen, B.; Li, M.; Liang, C.; Li, M.; Li, Z.; Xu, Q.; Zhang, L.; et al. Compositional and Functional Analysis of the Microbiome in Tissue and Saliva of Oral Squamous Cell Carcinoma. Front. Microbiol. 2019, 10, 1439. [Google Scholar] [CrossRef]
  53. Zhao, H.; Chu, M.; Huang, Z.; Yang, X.; Ran, S.; Hu, B.; Zhang, C.; Liang, J. Variations in oral microbiota associated with oral cancer. Sci. Rep. 2017, 7, 11773. [Google Scholar] [CrossRef]
  54. Stashenko, P.; Yost, S.; Choi, Y.; Danciu, T.; Chen, T.; Yoganathan, S.; Kressirer, C.; Ruiz-Tourrella, M.; Das, B.; Kokaras, A.; et al. The Oral Mouse Microbiome Promotes Tumorigenesis in Oral Squamous Cell Carcinoma. mSystems 2019, 4. [Google Scholar] [CrossRef] [Green Version]
  55. Gao, L.; Xu, T.; Huang, G.; Jiang, S.; Gu, Y.; Chen, F. Oral microbiomes: More and more importance in oral cavity and whole body. Protein Cell 2018, 9, 488–500. [Google Scholar] [CrossRef] [Green Version]
  56. Wade, W.G. The oral microbiome in health and disease. Pharmacol. Res. 2013, 69, 137–143. [Google Scholar] [CrossRef] [PubMed]
  57. Sureda, A.; Daglia, M.; Arguelles Castilla, S.; Sanadgol, N.; Fazel Nabavi, S.; Khan, H.; Belwal, T.; Jeandet, P.; Marchese, A.; Pistollato, F.; et al. Oral microbiota and Alzheimer’s disease: Do all roads lead to Rome? Pharmacol. Res. 2020, 151, 104582. [Google Scholar] [CrossRef] [PubMed]
  58. Tsai, C.; Hayes, C.; Taylor, G.W. Glycemic control of type 2 diabetes and severe periodontal disease in the US adult population. Community Dent. Oral Epidemiol. 2002, 30, 182–192. [Google Scholar] [CrossRef] [PubMed]
  59. Mesa, F.; Magan-Fernandez, A.; Castellino, G.; Chianetta, R.; Nibali, L.; Rizzo, M. Periodontitis and mechanisms of cardiometabolic risk: Novel insights and future perspectives. Biochim. Biophys. Acta Mol. Basis Dis. 2019, 1865, 476–484. [Google Scholar] [CrossRef]
  60. Liu, X.X.; Jiao, B.; Liao, X.X.; Guo, L.N.; Yuan, Z.H.; Wang, X.; Xiao, X.W.; Zhang, X.Y.; Tang, B.S.; Shen, L. Analysis of Salivary Microbiome in Patients with Alzheimer’s Disease. J. Alzheimers Dis. 2019, 72, 633–640. [Google Scholar] [CrossRef]
  61. Bathini, P.; Foucras, S.; Dupanloup, I.; Imeri, H.; Perna, A.; Berruex, J.L.; Doucey, M.A.; Annoni, J.M.; Auber Alberi, L. Classifying dementia progression using microbial profiling of saliva. Alzheimers Dement. 2020, 12, e12000. [Google Scholar] [CrossRef] [PubMed]
  62. de Groot, P.F.; Belzer, C.; Aydin, O.; Levin, E.; Levels, J.H.; Aalvink, S.; Boot, F.; Holleman, F.; van Raalte, D.H.; Scheithauer, T.P.; et al. Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study. PLoS ONE 2017, 12, e0188475. [Google Scholar] [CrossRef] [PubMed]
  63. Fak, F.; Tremaroli, V.; Bergstrom, G.; Backhed, F. Oral microbiota in patients with atherosclerosis. Atherosclerosis 2015, 243, 573–578. [Google Scholar] [CrossRef] [PubMed]
  64. Jia, L.; Han, N.; Du, J.; Guo, L.; Luo, Z.; Liu, Y. Pathogenesis of Important Virulence Factors of Porphyromonas gingivalis via Toll-Like Receptors. Front. Cell Infect. Microbiol. 2019, 9, 262. [Google Scholar] [CrossRef] [PubMed]
  65. Kleinstein, S.E.; Nelson, K.E.; Freire, M. Inflammatory Networks Linking Oral Microbiome with Systemic Health and Disease. J. Dent. Res. 2020, 99, 1131–1139. [Google Scholar] [CrossRef] [PubMed]
  66. Chu, H.; Mazmanian, S.K. Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat. Immunol. 2013, 14, 668–675. [Google Scholar] [CrossRef]
  67. Yu, J.C.; Khodadadi, H.; Baban, B. Innate immunity and oral microbiome: A personalized, predictive, and preventive approach to the management of oral diseases. EPMA J. 2019, 10, 43–50. [Google Scholar] [CrossRef]
  68. Flemer, B.; Warren, R.D.; Barrett, M.P.; Cisek, K.; Das, A.; Jeffery, I.B.; Hurley, E.; O’Riordain, M.; Shanahan, F.; O’Toole, P.W. The oral microbiota in colorectal cancer is distinctive and predictive. Gut 2018, 67, 1454–1463. [Google Scholar] [CrossRef] [Green Version]
  69. Gaiser, R.A.; Halimi, A.; Alkharaan, H.; Lu, L.; Davanian, H.; Healy, K.; Hugerth, L.W.; Ateeb, Z.; Valente, R.; Fernandez Moro, C.; et al. Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer. Gut 2019, 68, 2186–2194. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Poole, S.; Singhrao, S.K.; Kesavalu, L.; Curtis, M.A.; Crean, S. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J. Alzheimers Dis. 2013, 36, 665–677. [Google Scholar] [CrossRef] [PubMed]
  71. Dominy, S.S.; Lynch, C.; Ermini, F.; Benedyk, M.; Marczyk, A.; Konradi, A.; Nguyen, M.; Haditsch, U.; Raha, D.; Griffin, C.; et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci. Adv. 2019, 5, eaau3333. [Google Scholar] [CrossRef] [Green Version]
  72. Ilievski, V.; Zuchowska, P.K.; Green, S.J.; Toth, P.T.; Ragozzino, M.E.; Le, K.; Aljewari, H.W.; O’Brien-Simpson, N.M.; Reynolds, E.C.; Watanabe, K. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS ONE 2018, 13, e0204941. [Google Scholar] [CrossRef] [Green Version]
  73. Chhibber-Goel, J.; Singhal, V.; Bhowmik, D.; Vivek, R.; Parakh, N.; Bhargava, B.; Sharma, A. Linkages between oral commensal bacteria and atherosclerotic plaques in coronary artery disease patients. NPJ Biofilms Microbiomes 2016, 2, 7. [Google Scholar] [CrossRef]
  74. Huh, J.W.; Roh, T.Y. Opportunistic detection of Fusobacterium nucleatum as a marker for the early gut microbial dysbiosis. BMC Microbiol. 2020, 20, 208. [Google Scholar] [CrossRef] [PubMed]
  75. Strauss, J.; Kaplan, G.G.; Beck, P.L.; Rioux, K.; Panaccione, R.; Devinney, R.; Lynch, T.; Allen-Vercoe, E. Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm. Bowel Dis. 2011, 17, 1971–1978. [Google Scholar] [CrossRef]
  76. Chung, M.; Zhao, N.; Meier, R.; Koestler, D.C.; Del Castillo, E.; Wu, G.J.; Paster, B.J.; Charpentier, K.; Izard, J.; Kelsey, K.T.; et al. Oral, intestinal, and pancreatic microbiomes are correlated and exhibit co-abundance in patients with pancreatic cancer and other gastrointestinal diseases. Cancer Res. 2020, 80, 52. [Google Scholar]
  77. Tennant, S.M.; Hartland, E.L.; Phumoonna, T.; Lyras, D.; Rood, J.I.; Robins-Browne, R.M.; van Driel, I.R. Influence of gastric acid on susceptibility to infection with ingested bacterial pathogens. Infect. Immun. 2008, 76, 639–645. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Nagpal, R.; Mainali, R.; Ahmadi, S.; Wang, S.; Singh, R.; Kavanagh, K.; Kitzman, D.W.; Kushugulova, A.; Marotta, F.; Yadav, H. Gut microbiome and aging: Physiological and mechanistic insights. Nutr. Healthy Aging 2018, 4, 267–285. [Google Scholar] [CrossRef] [Green Version]
  79. Sovran, B.; Hugenholtz, F.; Elderman, M.; Van Beek, A.A.; Graversen, K.; Huijskes, M.; Boekschoten, M.V.; Savelkoul, H.F.J.; De Vos, P.; Dekker, J.; et al. Age-associated Impairment of the Mucus Barrier Function is Associated with Profound Changes in Microbiota and Immunity. Sci. Rep. 2019, 9, 1437. [Google Scholar] [CrossRef] [PubMed]
  80. Makino, H. Bifidobacterial strains in the intestines of newborns originate from their mothers. Biosci. Microbiota Food Health 2018, 37, 79–85. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Toda, K.; Hisata, K.; Satoh, T.; Katsumata, N.; Odamaki, T.; Mitsuyama, E.; Katayama, T.; Kuhara, T.; Aisaka, K.; Shimizu, T.; et al. Neonatal oral fluid as a transmission route for bifidobacteria to the infant gut immediately after birth. Sci. Rep. 2019, 9, 8692. [Google Scholar] [CrossRef]
  82. Iwauchi, M.; Horigome, A.; Ishikawa, K.; Mikuni, A.; Nakano, M.; Xiao, J.Z.; Odamaki, T.; Hironaka, S. Relationship between oral and gut microbiota in elderly people. Immun. Inflamm. Dis. 2019, 7, 229–236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Odamaki, T.; Kato, K.; Sugahara, H.; Hashikura, N.; Takahashi, S.; Xiao, J.Z.; Abe, F.; Osawa, R. Age-related changes in gut microbiota composition from newborn to centenarian: A cross-sectional study. BMC Microbiol. 2016, 16, 90. [Google Scholar] [CrossRef] [Green Version]
  84. Li, B.; Ge, Y.; Cheng, L.; Zeng, B.; Yu, J.; Peng, X.; Zhao, J.; Li, W.; Ren, B.; Li, M.; et al. Oral bacteria colonize and compete with gut microbiota in gnotobiotic mice. Int. J. Oral Sci. 2019, 11, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Del Castillo, E.; Meier, R.; Chung, M.; Koestler, D.C.; Chen, T.; Paster, B.J.; Charpentier, K.P.; Kelsey, K.T.; Izard, J.; Michaud, D.S. The Microbiomes of Pancreatic and Duodenum Tissue Overlap and Are Highly Subject Specific but Differ between Pancreatic Cancer and Noncancer Subjects. Cancer Epidemiol. Biomark. Prev. 2019, 28, 370–383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Gevers, D.; Kugathasan, S.; Denson, L.A.; Vazquez-Baeza, Y.; Van Treuren, W.; Ren, B.; Schwager, E.; Knights, D.; Song, S.J.; Yassour, M.; et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 2014, 15, 382–392. [Google Scholar] [CrossRef] [Green Version]
  87. Nakatsu, G.; Li, X.; Zhou, H.; Sheng, J.; Wong, S.H.; Wu, W.K.; Ng, S.C.; Tsoi, H.; Dong, Y.; Zhang, N.; et al. Gut mucosal microbiome across stages of colorectal carcinogenesis. Nat. Commun. 2015, 6, 8727. [Google Scholar] [CrossRef]
  88. Ding, T.; Schloss, P.D. Dynamics and associations of microbial community types across the human body. Nature 2014, 509, 357–360. [Google Scholar] [CrossRef]
  89. de Graaf, M.; Beck, R.; Caccio, S.M.; Duim, B.; Fraaij, P.; Le Guyader, F.S.; Lecuit, M.; Le Pendu, J.; de Wit, E.; Schultsz, C. Sustained fecal-oral human-to-human transmission following a zoonotic event. Curr. Opin. Virol. 2017, 22, 1–6. [Google Scholar] [CrossRef]
  90. Ayele, B.H.; Geleto, A.; Ayana, D.A.; Redi, M. Prevalence of feco-oral transmitted protozoan infections and associated factors among university students in Ethiopia: A cross-sectional study. BMC Infect. Dis. 2019, 19, 499. [Google Scholar] [CrossRef]
  91. Reid, B.; Orgle, J.; Roy, K.; Pongolani, C.; Chileshe, M.; Stoltzfus, R. Characterizing Potential Risks of Fecal-Oral Microbial Transmission for Infants and Young Children in Rural Zambia. Am. J. Trop. Med. Hyg. 2018, 98, 816–823. [Google Scholar] [CrossRef] [Green Version]
  92. Gaetti-Jardim, E., Jr.; Jardim, E.C.G.; Schweitzer, C.M.; da Silva, J.C.L.; Oliveira, M.M.; Masocatto, D.C.; Dos Santos, C.M. Supragingival and subgingival microbiota from patients with poor oral hygiene submitted to radiotherapy for head and neck cancer treatment. Arch. Oral Biol. 2018, 90, 45–52. [Google Scholar] [CrossRef] [Green Version]
  93. Schuurhuis, J.M.; Stokman, M.A.; Witjes, M.J.; Langendijk, J.A.; van Winkelhoff, A.J.; Vissink, A.; Spijkervet, F.K. Head and neck intensity modulated radiation therapy leads to an increase of opportunistic oral pathogens. Oral Oncol. 2016, 58, 32–40. [Google Scholar] [CrossRef]
  94. Ciocca, M. Clinical course and consequences of hepatitis A infection. Vaccine 2000, 18 (Suppl. 1), S71–S74. [Google Scholar] [CrossRef]
  95. Tahaei, S.M.; Mohebbi, S.R.; Zali, M.R. Enteric hepatitis viruses. Gastroenterol. Hepatol. Bed Bench 2012, 5, 7–15. [Google Scholar] [PubMed]
  96. Kotwal, G.; Cannon, J.L. Environmental persistence and transfer of enteric viruses. Curr. Opin. Virol. 2014, 4, 37–43. [Google Scholar] [CrossRef] [PubMed]
  97. Karst, S.M. The influence of commensal bacteria on infection with enteric viruses. Nat. Rev. Microbiol. 2016, 14, 197–204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Sehgal, R.; Bedi, O.; Trehanpati, N. Role of Microbiota in Pathogenesis and Management of Viral Hepatitis. Front. Cell Infect. Microbiol. 2020, 10, 341. [Google Scholar] [CrossRef]
  99. Wu, J.; Huang, F.; Ling, Z.; Liu, S.; Liu, J.; Fan, J.; Yu, J.; Wang, W.; Jin, X.; Meng, Y.; et al. Altered faecal microbiota on the expression of Th cells responses in the exacerbation of patients with hepatitis E infection. J. Viral Hepat. 2020, 27, 1243–1252. [Google Scholar] [CrossRef]
  100. Kreuzer, S.; Machnowska, P.; Assmus, J.; Sieber, M.; Pieper, R.; Schmidt, M.F.; Brockmann, G.A.; Scharek-Tedin, L.; Johne, R. Feeding of the probiotic bacterium Enterococcus faecium NCIMB 10415 differentially affects shedding of enteric viruses in pigs. Vet. Res. 2012, 43, 58. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Bui, D.; Brown, H.E.; Harris, R.B.; Oren, E. Serologic Evidence for Fecal-Oral Transmission of Helicobacter pylori. Am. J. Trop. Med. Hyg. 2016, 94, 82–88. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. De Schryver, A.; Van Winckel, M.; Cornelis, K.; Moens, G.; Devlies, G.; De Backer, G. Helicobacter pylori infection: Further evidence for the role of feco-oral transmission. Helicobacter 2006, 11, 523–528. [Google Scholar] [CrossRef] [PubMed]
  103. Manichanh, C.; Rigottier-Gois, L.; Bonnaud, E.; Gloux, K.; Pelletier, E.; Frangeul, L.; Nalin, R.; Jarrin, C.; Chardon, P.; Marteau, P.; et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 2006, 55, 205–211. [Google Scholar] [CrossRef] [Green Version]
  104. Ott, S.J.; Musfeldt, M.; Wenderoth, D.F.; Hampe, J.; Brant, O.; Folsch, U.R.; Timmis, K.N.; Schreiber, S. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut 2004, 53, 685–693. [Google Scholar] [CrossRef] [Green Version]
  105. Prosberg, M.; Bendtsen, F.; Vind, I.; Petersen, A.M.; Gluud, L.L. The association between the gut microbiota and the inflammatory bowel disease activity: A systematic review and meta-analysis. Scand. J. Gastroenterol. 2016, 51, 1407–1415. [Google Scholar] [CrossRef] [PubMed]
  106. Walker, A.W.; Sanderson, J.D.; Churcher, C.; Parkes, G.C.; Hudspith, B.N.; Rayment, N.; Brostoff, J.; Parkhill, J.; Dougan, G.; Petrovska, L. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 2011, 11, 7. [Google Scholar] [CrossRef] [Green Version]
  107. Kleessen, B.; Kroesen, A.J.; Buhr, H.J.; Blaut, M. Mucosal and invading bacteria in patients with inflammatory bowel disease compared with controls. Scand. J. Gastroenterol. 2002, 37, 1034–1041. [Google Scholar] [CrossRef] [PubMed]
  108. Mylonaki, M.; Rayment, N.B.; Rampton, D.S.; Hudspith, B.N.; Brostoff, J. Molecular characterization of rectal mucosa-associated bacterial flora in inflammatory bowel disease. Inflamm. Bowel Dis. 2005, 11, 481–487. [Google Scholar] [CrossRef]
  109. Seedorf, H.; Griffin, N.W.; Ridaura, V.K.; Reyes, A.; Cheng, J.; Rey, F.E.; Smith, M.I.; Simon, G.M.; Scheffrahn, R.H.; Woebken, D.; et al. Bacteria from diverse habitats colonize and compete in the mouse gut. Cell 2014, 159, 253–266. [Google Scholar] [CrossRef] [Green Version]
  110. Peeters, M.; Geypens, B.; Claus, D.; Nevens, H.; Ghoos, Y.; Verbeke, G.; Baert, F.; Vermeire, S.; Vlietinck, R.; Rutgeerts, P. Clustering of increased small intestinal permeability in families with Crohn’s disease. Gastroenterology 1997, 113, 802–807. [Google Scholar] [CrossRef]
  111. Schmitz, H.; Barmeyer, C.; Fromm, M.; Runkel, N.; Foss, H.D.; Bentzel, C.J.; Riecken, E.O.; Schulzke, J.D. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 1999, 116, 301–309. [Google Scholar] [CrossRef]
  112. Brennan, C.A.; Garrett, W.S. Fusobacterium nucleatum—Symbiont, opportunist and oncobacterium. Nat. Rev. Microbiol. 2019, 17, 156–166. [Google Scholar] [CrossRef]
  113. Gu, X.; Song, L.J.; Li, L.X.; Liu, T.; Zhang, M.M.; Li, Z.; Wang, P.; Li, M.; Zuo, X.L. Fusobacterium nucleatum Causes Microbial Dysbiosis and Exacerbates Visceral Hypersensitivity in a Colonization-Independent Manner. Front. Microbiol. 2020, 11, 1281. [Google Scholar] [CrossRef] [PubMed]
  114. Atarashi, K.; Suda, W.; Luo, C.; Kawaguchi, T.; Motoo, I.; Narushima, S.; Kiguchi, Y.; Yasuma, K.; Watanabe, E.; Tanoue, T.; et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science 2017, 358, 359–365. [Google Scholar] [CrossRef] [PubMed]
  115. Curtis, M.A.; Diaz, P.I.; Van Dyke, T.E. The role of the microbiota in periodontal disease. Periodontology 2000 2020, 83, 14–25. [Google Scholar] [CrossRef]
  116. Flak, M.B.; Colas, R.A.; Munoz-Atienza, E.; Curtis, M.A.; Dalli, J.; Pitzalis, C. Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis. JCI Insight 2019, 4. [Google Scholar] [CrossRef]
  117. Nakajima, M.; Arimatsu, K.; Kato, T.; Matsuda, Y.; Minagawa, T.; Takahashi, N.; Ohno, H.; Yamazaki, K. Oral Administration of P. gingivalis Induces Dysbiosis of Gut Microbiota and Impaired Barrier Function Leading to Dissemination of Enterobacteria to the Liver. PLoS ONE 2015, 10, e0134234. [Google Scholar] [CrossRef] [Green Version]
  118. Kobayashi, R.; Ogawa, Y.; Hashizume-Takizawa, T.; Kurita-Ochiai, T. Oral bacteria affect the gut microbiome and intestinal immunity. Pathog. Dis. 2020, 78. [Google Scholar] [CrossRef]
  119. Kato, T.; Yamazaki, K.; Nakajima, M.; Date, Y.; Kikuchi, J.; Hase, K.; Ohno, H.; Yamazaki, K. Oral Administration of Porphyromonas gingivalis Alters the Gut Microbiome and Serum Metabolome. mSphere 2018, 3. [Google Scholar] [CrossRef] [Green Version]
  120. Arimatsu, K.; Yamada, H.; Miyazawa, H.; Minagawa, T.; Nakajima, M.; Ryder, M.I.; Gotoh, K.; Motooka, D.; Nakamura, S.; Iida, T.; et al. Oral pathobiont induces systemic inflammation and metabolic changes associated with alteration of gut microbiota. Sci. Rep. 2014, 4, 4828. [Google Scholar] [CrossRef] [Green Version]
  121. Maekawa, T.; Krauss, J.L.; Abe, T.; Jotwani, R.; Triantafilou, M.; Triantafilou, K.; Hashim, A.; Hoch, S.; Curtis, M.A.; Nussbaum, G.; et al. Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe 2014, 15, 768–778. [Google Scholar] [CrossRef] [Green Version]
  122. She, Y.Y.; Kong, X.B.; Ge, Y.P.; Liu, Z.Y.; Chen, J.Y.; Jiang, J.W.; Jiang, H.B.; Fang, S.L. Periodontitis and inflammatory bowel disease: A meta-analysis. BMC Oral Health 2020, 20, 67. [Google Scholar] [CrossRef] [Green Version]
  123. Lorenzo-Pouso, A.I.; Castelo-Baz, P.; Rodriguez-Zorrilla, S.; Perez-Sayans, M.; Vega, P. Association between periodontal disease and inflammatory bowel disease: A systematic review and meta-analysis. Acta Odontol. Scand. 2020, 1–15. [Google Scholar] [CrossRef]
  124. Said, H.S.; Suda, W.; Nakagome, S.; Chinen, H.; Oshima, K.; Kim, S.; Kimura, R.; Iraha, A.; Ishida, H.; Fujita, J.; et al. Dysbiosis of salivary microbiota in inflammatory bowel disease and its association with oral immunological biomarkers. DNA Res. 2014, 21, 15–25. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Rautava, J.; Pinnell, L.J.; Vong, L.; Akseer, N.; Assa, A.; Sherman, P.M. Oral microbiome composition changes in mouse models of colitis. J. Gastroenterol. Hepatol. 2015, 30, 521–527. [Google Scholar] [CrossRef] [PubMed]
  126. Rawla, P.; Sunkara, T.; Barsouk, A. Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors. Prz. Gastroenterol. 2019, 14, 89–103. [Google Scholar] [CrossRef] [PubMed]
  127. Triantafillidis, J.K.; Nasioulas, G.; Kosmidis, P.A. Colorectal cancer and inflammatory bowel disease: Epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer Res. 2009, 29, 2727–2737. [Google Scholar]
  128. Brennan, C.A.; Garrett, W.S. Gut Microbiota, Inflammation, and Colorectal Cancer. Annu. Rev. Microbiol. 2016, 70, 395–411. [Google Scholar] [CrossRef] [Green Version]
  129. Sun, J.; Kato, I. Gut microbiota, inflammation and colorectal cancer. Genes Dis. 2016, 3, 130–143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  130. Ahn, J.; Sinha, R.; Pei, Z.; Dominianni, C.; Wu, J.; Shi, J.; Goedert, J.J.; Hayes, R.B.; Yang, L. Human gut microbiome and risk for colorectal cancer. J. Natl. Cancer Inst. 2013, 105, 1907–1911. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  131. Wang, T.; Cai, G.; Qiu, Y.; Fei, N.; Zhang, M.; Pang, X.; Jia, W.; Cai, S.; Zhao, L. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J. 2012, 6, 320–329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Wirth, U.; Garzetti, D.; Jochum, L.M.; Spriewald, S.; Kuhn, F.; Ilmer, M.; Lee, S.M.L.; Niess, H.; Bazhin, A.V.; Andrassy, J.; et al. Microbiome Analysis from Paired Mucosal and Fecal Samples of a Colorectal Cancer Biobank. Cancers 2020, 12, 3702. [Google Scholar] [CrossRef]
  133. Son, J.S.; Khair, S.; Pettet, D.W., 3rd; Ouyang, N.; Tian, X.; Zhang, Y.; Zhu, W.; Mackenzie, G.G.; Robertson, C.E.; Ir, D.; et al. Altered Interactions between the Gut Microbiome and Colonic Mucosa Precede Polyposis in APCMin/+ Mice. PLoS ONE 2015, 10, e0127985. [Google Scholar] [CrossRef] [PubMed]
  134. Zackular, J.P.; Baxter, N.T.; Iverson, K.D.; Sadler, W.D.; Petrosino, J.F.; Chen, G.Y.; Schloss, P.D. The gut microbiome modulates colon tumorigenesis. mBio 2013, 4, e00692-13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Arthur, J.C.; Perez-Chanona, E.; Muhlbauer, M.; Tomkovich, S.; Uronis, J.M.; Fan, T.J.; Campbell, B.J.; Abujamel, T.; Dogan, B.; Rogers, A.B.; et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 2012, 338, 120–123. [Google Scholar] [CrossRef] [Green Version]
  136. Wong, S.H.; Zhao, L.; Zhang, X.; Nakatsu, G.; Han, J.; Xu, W.; Xiao, X.; Kwong, T.N.Y.; Tsoi, H.; Wu, W.K.K.; et al. Gavage of Fecal Samples From Patients With Colorectal Cancer Promotes Intestinal Carcinogenesis in Germ-Free and Conventional Mice. Gastroenterology 2017, 153, 1621–1633.e1626. [Google Scholar] [CrossRef] [Green Version]
  137. Castellarin, M.; Warren, R.L.; Freeman, J.D.; Dreolini, L.; Krzywinski, M.; Strauss, J.; Barnes, R.; Watson, P.; Allen-Vercoe, E.; Moore, R.A.; et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 2012, 22, 299–306. [Google Scholar] [CrossRef] [Green Version]
  138. Kostic, A.D.; Gevers, D.; Pedamallu, C.S.; Michaud, M.; Duke, F.; Earl, A.M.; Ojesina, A.I.; Jung, J.; Bass, A.J.; Tabernero, J.; et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 2012, 22, 292–298. [Google Scholar] [CrossRef] [Green Version]
  139. Kostic, A.D.; Chun, E.; Robertson, L.; Glickman, J.N.; Gallini, C.A.; Michaud, M.; Clancy, T.E.; Chung, D.C.; Lochhead, P.; Hold, G.L.; et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 2013, 14, 207–215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  140. Grivennikov, S.I.; Wang, K.; Mucida, D.; Stewart, C.A.; Schnabl, B.; Jauch, D.; Taniguchi, K.; Yu, G.Y.; Osterreicher, C.H.; Hung, K.E.; et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 2012, 491, 254–258. [Google Scholar] [CrossRef] [Green Version]
  141. Soler, A.P.; Miller, R.D.; Laughlin, K.V.; Carp, N.Z.; Klurfeld, D.M.; Mullin, J.M. Increased tight junctional permeability is associated with the development of colon cancer. Carcinogenesis 1999, 20, 1425–1431. [Google Scholar] [CrossRef] [Green Version]
  142. Polak, D.; Shapira, L.; Weiss, E.I.; Houri-Haddad, Y. The role of coaggregation between Porphyromonas gingivalis and Fusobacterium nucleatum on the host response to mixed infection. J. Clin. Periodontol. 2012, 39, 617–625. [Google Scholar] [CrossRef]
  143. Polak, D.; Wilensky, A.; Shapira, L.; Halabi, A.; Goldstein, D.; Weiss, E.I.; Houri-Haddad, Y. Mouse model of experimental periodontitis induced by Porphyromonas gingivalis/Fusobacterium nucleatum infection: Bone loss and host response. J. Clin. Periodontol. 2009, 36, 406–410. [Google Scholar] [CrossRef]
  144. Mu, W.; Jia, Y.; Chen, X.; Li, H.; Wang, Z.; Cheng, B. Intracellular Porphyromonas gingivalis Promotes the Proliferation of Colorectal Cancer Cells via the MAPK/ERK Signaling Pathway. Front. Cell Infect. Microbiol. 2020, 10, 584798. [Google Scholar] [CrossRef] [PubMed]
  145. Ahn, J.; Segers, S.; Hayes, R.B. Periodontal disease, Porphyromonas gingivalis serum antibody levels and orodigestive cancer mortality. Carcinogenesis 2012, 33, 1055–1058. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Li, W.; Xu, J.; Zhang, R.; Li, Y.; Wang, J.; Zhang, X.; Lin, L. Is periodontal disease a risk indicator for colorectal cancer? A systematic review and meta-analysis. J. Clin. Periodontol. 2020. [Google Scholar] [CrossRef]
  147. Xuan, K.; Jha, A.R.; Zhao, T.; Uy, J.P.; Sun, C. Is periodontal disease associated with increased risk of colorectal cancer? A meta-analysis. Int. J. Dent. Hyg. 2021, 19, 50–61. [Google Scholar] [CrossRef]
  148. Dowman, J.K.; Tomlinson, J.W.; Newsome, P.N. Pathogenesis of non-alcoholic fatty liver disease. QJM 2010, 103, 71–83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Caussy, C.; Tripathi, A.; Humphrey, G.; Bassirian, S.; Singh, S.; Faulkner, C.; Bettencourt, R.; Rizo, E.; Richards, L.; Xu, Z.Z.; et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat. Commun. 2019, 10, 1406. [Google Scholar] [CrossRef] [PubMed]
  150. Loomba, R.; Seguritan, V.; Li, W.; Long, T.; Klitgord, N.; Bhatt, A.; Dulai, P.S.; Caussy, C.; Bettencourt, R.; Highlander, S.K.; et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2017, 25, 1054–1062.e1055. [Google Scholar] [CrossRef] [PubMed]
  151. Zhu, L.; Baker, S.S.; Gill, C.; Liu, W.; Alkhouri, R.; Baker, R.D.; Gill, S.R. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH. Hepatology 2013, 57, 601–609. [Google Scholar] [CrossRef]
  152. Qin, N.; Yang, F.; Li, A.; Prifti, E.; Chen, Y.; Shao, L.; Guo, J.; Le Chatelier, E.; Yao, J.; Wu, L.; et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014, 513, 59–64. [Google Scholar] [CrossRef]
  153. Mouzaki, M.; Comelli, E.M.; Arendt, B.M.; Bonengel, J.; Fung, S.K.; Fischer, S.E.; McGilvray, I.D.; Allard, J.P. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013, 58, 120–127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Le Roy, T.; Llopis, M.; Lepage, P.; Bruneau, A.; Rabot, S.; Bevilacqua, C.; Martin, P.; Philippe, C.; Walker, F.; Bado, A.; et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2013, 62, 1787–1794. [Google Scholar] [CrossRef] [PubMed]
  155. Giannelli, V.; Di Gregorio, V.; Iebba, V.; Giusto, M.; Schippa, S.; Merli, M.; Thalheimer, U. Microbiota and the gut-liver axis: Bacterial translocation, inflammation and infection in cirrhosis. World J. Gastroenterol. 2014, 20, 16795–16810. [Google Scholar] [CrossRef]
  156. Jungst, C.; Berg, T.; Cheng, J.; Green, R.M.; Jia, J.; Mason, A.L.; Lammert, F. Intrahepatic cholestasis in common chronic liver diseases. Eur. J. Clin. Investig. 2013, 43, 1069–1083. [Google Scholar] [CrossRef] [PubMed]
  157. Welsh, F.K.; Ramsden, C.W.; MacLennan, K.; Sheridan, M.B.; Barclay, G.R.; Guillou, P.J.; Reynolds, J.V. Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice. Ann. Surg. 1998, 227, 205–212. [Google Scholar] [CrossRef]
  158. White, J.S.; Hoper, M.; Parks, R.W.; Clements, W.D.; Diamond, T. Patterns of bacterial translocation in experimental biliary obstruction. J. Surg. Res. 2006, 132, 80–84. [Google Scholar] [CrossRef]
  159. Kuzu, M.A.; Kale, I.T.; Col, C.; Tekeli, A.; Tanik, A.; Koksoy, C. Obstructive jaundice promotes bacterial translocation in humans. Hepatogastroenterology 1999, 46, 2159–2164. [Google Scholar]
  160. Wu, T.; Zhang, Z.; Liu, B.; Hou, D.; Liang, Y.; Zhang, J.; Shi, P. Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study. BMC Genom. 2013, 14, 669. [Google Scholar] [CrossRef] [Green Version]
  161. Dubinkina, V.B.; Tyakht, A.V.; Odintsova, V.Y.; Yarygin, K.S.; Kovarsky, B.A.; Pavlenko, A.V.; Ischenko, D.S.; Popenko, A.S.; Alexeev, D.G.; Taraskina, A.Y.; et al. Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease. Microbiome 2017, 5, 141. [Google Scholar] [CrossRef]
  162. Bajaj, J.S.; Cox, I.J.; Betrapally, N.S.; Heuman, D.M.; Schubert, M.L.; Ratneswaran, M.; Hylemon, P.B.; White, M.B.; Daita, K.; Noble, N.A.; et al. Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function. Am. J. Physiol. Gastrointest. Liver Physiol. 2014, 307, G951–G957. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Bajaj, J.S.; Betrapally, N.S.; Hylemon, P.B.; Heuman, D.M.; Daita, K.; White, M.B.; Unser, A.; Thacker, L.R.; Sanyal, A.J.; Kang, D.J.; et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology 2015, 62, 1260–1271. [Google Scholar] [CrossRef] [Green Version]
  164. Alazawi, W.; Bernabe, E.; Tai, D.; Janicki, T.; Kemos, P.; Samsuddin, S.; Syn, W.K.; Gillam, D.; Turner, W. Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease. PLoS ONE 2017, 12, e0185902. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Gronkjaer, L.L. Periodontal disease and liver cirrhosis: A systematic review. SAGE Open Med. 2015, 3, 2050312115601122. [Google Scholar] [CrossRef] [Green Version]
  166. Gronkjaer, L.L.; Holmstrup, P.; Schou, S.; Kongstad, J.; Jepsen, P.; Vilstrup, H. Periodontitis in patients with cirrhosis: A cross-sectional study. BMC Oral Health 2018, 18, 22. [Google Scholar] [CrossRef] [PubMed]
  167. Guggenheimer, J.; Eghtesad, B.; Close, J.M.; Shay, C.; Fung, J.J. Dental health status of liver transplant candidates. Liver Transpl. 2007, 13, 280–286. [Google Scholar] [CrossRef] [PubMed]
  168. Yoneda, M.; Naka, S.; Nakano, K.; Wada, K.; Endo, H.; Mawatari, H.; Imajo, K.; Nomura, R.; Hokamura, K.; Ono, M.; et al. Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease. BMC Gastroenterol. 2012, 12, 16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Nagao, Y.; Kawahigashi, Y.; Sata, M. Association of Periodontal Diseases and Liver Fibrosis in Patients With HCV and/or HBV infection. Hepat. Mon. 2014, 14, e23264. [Google Scholar] [CrossRef]
  170. Nakahara, T.; Hyogo, H.; Ono, A.; Nagaoki, Y.; Kawaoka, T.; Miki, D.; Tsuge, M.; Hiraga, N.; Hayes, C.N.; Hiramatsu, A.; et al. Involvement of Porphyromonas gingivalis in the progression of non-alcoholic fatty liver disease. J. Gastroenterol. 2018, 53, 269–280. [Google Scholar] [CrossRef]
  171. Nagasaki, A.; Sakamoto, S.; Chea, C.; Ishida, E.; Furusho, H.; Fujii, M.; Takata, T.; Miyauchi, M. Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation. Sci. Rep. 2020, 10, 4134. [Google Scholar] [CrossRef] [Green Version]
  172. Ramakrishna, G.; Rastogi, A.; Trehanpati, N.; Sen, B.; Khosla, R.; Sarin, S.K. From cirrhosis to hepatocellular carcinoma: New molecular insights on inflammation and cellular senescence. Liver Cancer 2013, 2, 367–383. [Google Scholar] [CrossRef]
  173. Dapito, D.H.; Mencin, A.; Gwak, G.Y.; Pradere, J.P.; Jang, M.K.; Mederacke, I.; Caviglia, J.M.; Khiabanian, H.; Adeyemi, A.; Bataller, R.; et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012, 21, 504–516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Mizutani, T.; Mitsuoka, T. Effect of intestinal bacteria on incidence of liver tumors in gnotobiotic C3H/He male mice. J. Natl. Cancer Inst. 1979, 63, 1365–1370. [Google Scholar] [PubMed]
  175. Ren, Z.; Li, A.; Jiang, J.; Zhou, L.; Yu, Z.; Lu, H.; Xie, H.; Chen, X.; Shao, L.; Zhang, R.; et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut 2019, 68, 1014–1023. [Google Scholar] [CrossRef] [PubMed]
  176. Ni, J.; Huang, R.; Zhou, H.; Xu, X.; Li, Y.; Cao, P.; Zhong, K.; Ge, M.; Chen, X.; Hou, B.; et al. Analysis of the Relationship Between the Degree of Dysbiosis in Gut Microbiota and Prognosis at Different Stages of Primary Hepatocellular Carcinoma. Front. Microbiol. 2019, 10, 1458. [Google Scholar] [CrossRef]
  177. Grat, M.; Wronka, K.M.; Krasnodebski, M.; Masior, L.; Lewandowski, Z.; Kosinska, I.; Grat, K.; Stypulkowski, J.; Rejowski, S.; Wasilewicz, M.; et al. Profile of Gut Microbiota Associated With the Presence of Hepatocellular Cancer in Patients With Liver Cirrhosis. Transplant. Proc. 2016, 48, 1687–1691. [Google Scholar] [CrossRef]
  178. Lapidot, Y.; Amir, A.; Nosenko, R.; Uzan-Yulzari, A.; Veitsman, E.; Cohen-Ezra, O.; Davidov, Y.; Weiss, P.; Bradichevski, T.; Segev, S.; et al. Alterations in the Gut Microbiome in the Progression of Cirrhosis to Hepatocellular Carcinoma. mSystems 2020, 5. [Google Scholar] [CrossRef] [PubMed]
  179. Fox, J.G.; Feng, Y.; Theve, E.J.; Raczynski, A.R.; Fiala, J.L.; Doernte, A.L.; Williams, M.; McFaline, J.L.; Essigmann, J.M.; Schauer, D.B.; et al. Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens. Gut 2010, 59, 88–97. [Google Scholar] [CrossRef]
  180. Garcia, A.; Zeng, Y.; Muthupalani, S.; Ge, Z.; Potter, A.; Mobley, M.W.; Boussahmain, C.; Feng, Y.; Wishnok, J.S.; Fox, J.G. Helicobacter hepaticus—Induced liver tumor promotion is associated with increased serum bile acid and a persistent microbial-induced immune response. Cancer Res. 2011, 71, 2529–2540. [Google Scholar] [CrossRef] [Green Version]
  181. Huang, Y.; Fan, X.G.; Wang, Z.M.; Zhou, J.H.; Tian, X.F.; Li, N. Identification of helicobacter species in human liver samples from patients with primary hepatocellular carcinoma. J. Clin. Pathol. 2004, 57, 1273–1277. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  182. Avenaud, P.; Marais, A.; Monteiro, L.; Le Bail, B.; Bioulac Sage, P.; Balabaud, C.; Megraud, F. Detection of Helicobacter species in the liver of patients with and without primary liver carcinoma. Cancer 2000, 89, 1431–1439. [Google Scholar] [CrossRef]
  183. Rao, B.C.; Lou, J.M.; Wang, W.J.; Li, A.; Cui, G.Y.; Yu, Z.J.; Ren, Z.G. Human microbiome is a diagnostic biomarker in hepatocellular carcinoma. Hepatobiliary Pancreat. Dis. Int. 2020, 19, 109–115. [Google Scholar] [CrossRef] [PubMed]
  184. Li, D.; Xi, W.; Zhang, Z.; Ren, L.; Deng, C.; Chen, J.; Sun, C.; Zhang, N.; Xu, J. Oral microbial community analysis of the patients in the progression of liver cancer. Microb. Pathog. 2020, 149, 104479. [Google Scholar] [CrossRef]
  185. Lu, H.; Ren, Z.; Li, A.; Zhang, H.; Jiang, J.; Xu, S.; Luo, Q.; Zhou, K.; Sun, X.; Zheng, S.; et al. Deep sequencing reveals microbiota dysbiosis of tongue coat in patients with liver carcinoma. Sci. Rep. 2016, 6, 33142. [Google Scholar] [CrossRef] [Green Version]
  186. Tamaki, N.; Takaki, A.; Tomofuji, T.; Endo, Y.; Kasuyama, K.; Ekuni, D.; Yasunaka, T.; Yamamoto, K.; Morita, M. Stage of hepatocellular carcinoma is associated with periodontitis. J. Clin. Periodontol. 2011, 38, 1015–1020. [Google Scholar] [CrossRef]
  187. Wei, M.Y.; Shi, S.; Liang, C.; Meng, Q.C.; Hua, J.; Zhang, Y.Y.; Liu, J.; Zhang, B.; Xu, J.; Yu, X.J. The microbiota and microbiome in pancreatic cancer: More influential than expected. Mol. Cancer 2019, 18, 97. [Google Scholar] [CrossRef]
  188. Geller, L.T.; Barzily-Rokni, M.; Danino, T.; Jonas, O.H.; Shental, N.; Nejman, D.; Gavert, N.; Zwang, Y.; Cooper, Z.A.; Shee, K.; et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 2017, 357, 1156–1160. [Google Scholar] [CrossRef] [Green Version]
  189. Maekawa, T.; Fukaya, R.; Takamatsu, S.; Itoyama, S.; Fukuoka, T.; Yamada, M.; Hata, T.; Nagaoka, S.; Kawamoto, K.; Eguchi, H.; et al. Possible involvement of Enterococcus infection in the pathogenesis of chronic pancreatitis and cancer. Biochem. Biophys. Res. Commun. 2018, 506, 962–969. [Google Scholar] [CrossRef]
  190. Riquelme, E.; Zhang, Y.; Zhang, L.; Montiel, M.; Zoltan, M.; Dong, W.; Quesada, P.; Sahin, I.; Chandra, V.; San Lucas, A.; et al. Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. Cell 2019, 178, 795–806.e12. [Google Scholar] [CrossRef] [PubMed]
  191. Pushalkar, S.; Hundeyin, M.; Daley, D.; Zambirinis, C.P.; Kurz, E.; Mishra, A.; Mohan, N.; Aykut, B.; Usyk, M.; Torres, L.E.; et al. The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Cancer Discov. 2018, 8, 403–416. [Google Scholar] [CrossRef] [Green Version]
  192. Thomas, R.M.; Gharaibeh, R.Z.; Gauthier, J.; Beveridge, M.; Pope, J.L.; Guijarro, M.V.; Yu, Q.; He, Z.; Ohland, C.; Newsome, R.; et al. Intestinal microbiota enhances pancreatic carcinogenesis in preclinical models. Carcinogenesis 2018, 39, 1068–1078. [Google Scholar] [CrossRef] [PubMed]
  193. Maisonneuve, P.; Amar, S.; Lowenfels, A.B. Periodontal disease, edentulism, and pancreatic cancer: A meta-analysis. Ann. Oncol. 2017, 28, 985–995. [Google Scholar] [CrossRef]
  194. Zhang, Y.; Sun, C.; Song, E.J.; Liang, M.; Shi, T.; Min, M.; Sun, Y. Is periodontitis a risk indicator for gastrointestinal cancers? A meta-analysis of cohort studies. J. Clin. Periodontol. 2020, 47, 134–147. [Google Scholar] [CrossRef] [PubMed]
  195. Michaud, D.S.; Izard, J.; Wilhelm-Benartzi, C.S.; You, D.H.; Grote, V.A.; Tjonneland, A.; Dahm, C.C.; Overvad, K.; Jenab, M.; Fedirko, V.; et al. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut 2013, 62, 1764–1770. [Google Scholar] [CrossRef] [PubMed]
  196. Fan, X.; Alekseyenko, A.V.; Wu, J.; Peters, B.A.; Jacobs, E.J.; Gapstur, S.M.; Purdue, M.P.; Abnet, C.C.; Stolzenberg-Solomon, R.; Miller, G.; et al. Human oral microbiome and prospective risk for pancreatic cancer: A population-based nested case-control study. Gut 2018, 67, 120–127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Chen, S.M.; Hsu, L.J.; Lee, H.L.; Lin, C.P.; Huang, S.W.; Lai, C.J.; Lin, C.W.; Chen, W.T.; Chen, Y.J.; Lin, Y.C.; et al. Lactobacillus Attenuate the Progression of Pancreatic Cancer Promoted by Porphyromonas Gingivalis in K-ras(G12D) Transgenic Mice. Cancers 2020, 12, 3522. [Google Scholar] [CrossRef]
  198. Gnanasekaran, J.; Binder Gallimidi, A.; Saba, E.; Pandi, K.; Eli Berchoer, L.; Hermano, E.; Angabo, S.; Makkawi, H.A.; Khashan, A.; Daoud, A.; et al. Intracellular Porphyromonas gingivalis Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells. Cancers 2020, 12, 2331. [Google Scholar] [CrossRef]
  199. Farrell, J.J.; Zhang, L.; Zhou, H.; Chia, D.; Elashoff, D.; Akin, D.; Paster, B.J.; Joshipura, K.; Wong, D.T. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut 2012, 61, 582–588. [Google Scholar] [CrossRef]
  200. Mitsuhashi, K.; Nosho, K.; Sukawa, Y.; Matsunaga, Y.; Ito, M.; Kurihara, H.; Kanno, S.; Igarashi, H.; Naito, T.; Adachi, Y.; et al. Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget 2015, 6, 7209–7220. [Google Scholar] [CrossRef] [Green Version]
  201. Ray, K. The oral-gut axis in IBD. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 532. [Google Scholar] [CrossRef]
  202. du Teil Espina, M.; Gabarrini, G.; Harmsen, H.J.M.; Westra, J.; van Winkelhoff, A.J.; van Dijl, J.M. Talk to your gut: The oral-gut microbiome axis and its immunomodulatory role in the etiology of rheumatoid arthritis. FEMS Microbiol. Rev. 2019, 43, 1–18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  203. Chen, Y.; Chen, X.; Yu, H.; Zhou, H.; Xu, S. Oral Microbiota as Promising Diagnostic Biomarkers for Gastrointestinal Cancer: A Systematic Review. OncoTargets Ther. 2019, 12, 11131–11144. [Google Scholar] [CrossRef] [Green Version]
  204. Tang, Q.; Jin, G.; Wang, G.; Liu, T.; Liu, X.; Wang, B.; Cao, H. Current Sampling Methods for Gut Microbiota: A Call for More Precise Devices. Front. Cell Infect. Microbiol. 2020, 10, 151. [Google Scholar] [CrossRef]
  205. Vandeputte, D.; Tito, R.Y.; Vanleeuwen, R.; Falony, G.; Raes, J. Practical considerations for large-scale gut microbiome studies. FEMS Microbiol. Rev. 2017, 41, S154–S167. [Google Scholar] [CrossRef]
  206. Jo, R.; Nishimoto, Y.; Umezawa, K.; Yama, K.; Aita, Y.; Ichiba, Y.; Murakami, S.; Kakizawa, Y.; Kumagai, T.; Yamada, T.; et al. Comparison of oral microbiome profiles in stimulated and unstimulated saliva, tongue, and mouth-rinsed water. Sci. Rep. 2019, 9, 16124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  207. Jia, G.; Zhi, A.; Lai, P.F.H.; Wang, G.; Xia, Y.; Xiong, Z.; Zhang, H.; Che, N.; Ai, L. The oral microbiota—A mechanistic role for systemic diseases. Br. Dent. J. 2018, 224, 447–455. [Google Scholar] [CrossRef] [PubMed]
Cancers 13 02124 g001 550
Figure 1. Local and systemic effects of oral microbiome. The oral dysbiosis can regulate the pathological processes in the oral cavity, such as dental caries, periodontitis, and OSCC. The altered oral microbiota profiles can further modulate systemic diseases, including Alzheimer’s disease, diabetes, and cardiovascular disease, beyond the local impacts.
Figure 1. Local and systemic effects of oral microbiome. The oral dysbiosis can regulate the pathological processes in the oral cavity, such as dental caries, periodontitis, and OSCC. The altered oral microbiota profiles can further modulate systemic diseases, including Alzheimer’s disease, diabetes, and cardiovascular disease, beyond the local impacts.
Cancers 13 02124 g001
Cancers 13 02124 g002 550
Figure 2. Oral–gut microbiome axis. The oral microbiota can translocate to the gut in conditions of the oral–gut barrier disruption. Likewise, the gut microbes transmit to the oral cavity in both intra- and interpersonal manners, particularly related to poor hygienic conditions. This bidirectional interaction between oral and gut microbiomes develops the microbial ecosystems in both habitats through either competition or cooperation, eventually regulating the pathophysiological processes in the gastrointestinal (GI) tract.
Figure 2. Oral–gut microbiome axis. The oral microbiota can translocate to the gut in conditions of the oral–gut barrier disruption. Likewise, the gut microbes transmit to the oral cavity in both intra- and interpersonal manners, particularly related to poor hygienic conditions. This bidirectional interaction between oral and gut microbiomes develops the microbial ecosystems in both habitats through either competition or cooperation, eventually regulating the pathophysiological processes in the gastrointestinal (GI) tract.
Cancers 13 02124 g002
Table
Table 1. Oral–gut microbiome axis in colon diseases.
Table 1. Oral–gut microbiome axis in colon diseases.
DiseaseAssociation with Oral and Gut MicrobiomesReferences
IBDAssociation with gut microbiome
• Gut dysbiosis in IBD patients[103,104,105,106]
Association with oral microbiome
• Altered salivary microbiome in IBD patients[124]
• Altered oral microbiome in colitis-induced mice[125]
• Periodontitis was associated with increased IBD risk[122,123]
• Oral administration of P. gingivalis altered the gut microbiome in mice[117,119]
• F. nucleatum-gavage altered gut microbiome in rat[113]
Prevalence of oral microbiota
• F. nucleatum in the gut microbiome of IBD patients[74,75]
• Klebsiella in the gut microbiome of GF mice transplanted with salivary microbiota from CD patients[114]
CRCAssociation with gut microbiome
• Gut dysbiosis in CRC patients[87,130,131,132]
• Altered gut microbiome in CRC mouse models[133,134]
Association with oral microbiome
• Periodontitis was associated with increased CRC risk[146,147]
• A positive correlation between P. gingivalis serum antibody level and mortality in CRC patients[145]
• Oral administration of F. nucleatum promoted colon carcinogenesis in mice[139]
Prevalence of oral microbiota
• Parvimonas, Peptostreptococcus, and Fusobacterium in the gut of CRC patients[87]
• F. nucleatum in tumors and feces of CRC patients[87,137,138,139]
Table
Table 2. Oral–gut microbiome axis in liver diseases.
Table 2. Oral–gut microbiome axis in liver diseases.
DiseaseAssociation with Oral and Gut MicrobiomesReferences
Chronic liver diseasesAssociation with gut microbiome
• Gut dysbiosis in NAFLD[149,150]
• Gut dysbiosis in NASH[151,152,153]
• Gut dysbiosis in cirrhosis[152]
Gut–liver microbiome axis
• Gut-to-liver translocation by biliary obstruction[158,159]
• Concomitant shifts in the biliary tract and gut microbiomes in gallstone patients[160]
Association with oral microbiome
• Concomitant shifts in the oral and gut microbiomes in cirrhosis[163]
• Periodontitis was associated with NASH, NAFLD, and cirrhosis[164,165,166,167]
• Oral administration of P. gingivalis accelerated progression of NAFLD and NASH in high fat diet-fed mice[170,171]
Prevalence of oral microbiota
• Colonization of oral bacteria in the gut of cirrhosis patients[152]
HCCAssociation with gut microbiome
• Gut dysbiosis in HCC patients[175]
• Prevalence of E. coli and Fusobacteria in the gut microbiome of HCC patients with cirrhosis[177,178]
Association with oral microbiome
• Altered oral microbiome in HCC patients[183,184,185]
• Prevalence of Fusobacterium and Oribacterium in the tongue microbiome of HCC patients with cirrhosis[185]
• Periodontitis was associate with advanced HCC stages[186]
Prevalence of oral microbiota
• Prevalence of Fusobacterium in both oral and gut microbiomes of HCC patients with cirrhosis[176,178,185]
Table
Table 3. Oral–gut microbiome axis in pancreatic disease.
Table 3. Oral–gut microbiome axis in pancreatic disease.
DiseaseAssociation with Oral and Gut MicrobiomesReferences
PDACAssociation with gut microbiome
• Gut dysbiosis in PDAC patients[85,188,190,191]
Gut–pancreatic microbiome axis
• Concomitant shifts in the gut, pancreatic, and tumor microbiomes of PDAC patients[188,190,191]
• Overlap between gut and pancreatic microbiomes[85]
Association with oral microbiome
• Altered oral microbiome in PDAC patients[196,199]
• Concomitant shifts in the oral, gut, and pancreatic microbiomes of PDAC patients[76]
• Periodontitis was associated with increased PDAC risk and mortality[193,194]
• Carriage of P. gingivalis was associated with increased PDAC risk and mortality[145,195,196]
• Oral administration of P. gingivalis accelerated progression of PDAC in mice[197]
Prevalence of oral microbiota
• Fusobacterium in the gut, pancreatic, and tumor microbiomes of PDAC patients[85,196,200]
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Park, S.-Y.; Hwang, B.-O.; Lim, M.; Ok, S.-H.; Lee, S.-K.; Chun, K.-S.; Park, K.-K.; Hu, Y.; Chung, W.-Y.; Song, N.-Y. Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer. Cancers 2021, 13, 2124. https://doi.org/10.3390/cancers13092124

AMA Style

Park S-Y, Hwang B-O, Lim M, Ok S-H, Lee S-K, Chun K-S, Park K-K, Hu Y, Chung W-Y, Song N-Y. Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer. Cancers. 2021; 13(9):2124. https://doi.org/10.3390/cancers13092124

Chicago/Turabian Style

Park, Se-Young, Byeong-Oh Hwang, Mihwa Lim, Seung-Ho Ok, Sun-Kyoung Lee, Kyung-Soo Chun, Kwang-Kyun Park, Yinling Hu, Won-Yoon Chung, and Na-Young Song. 2021. "Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer" Cancers 13, no. 9: 2124. https://doi.org/10.3390/cancers13092124

APA Style

Park, S.-Y., Hwang, B.-O., Lim, M., Ok, S.-H., Lee, S.-K., Chun, K.-S., Park, K.-K., Hu, Y., Chung, W.-Y., & Song, N.-Y. (2021). Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer. Cancers, 13(9), 2124. https://doi.org/10.3390/cancers13092124

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