Oral microbiome dysbiosis and gastrointestinal diseases: a narrative review

Mouth is the gateway to the total body wellness. Accordingly, oral microbiome influences overall health of an individual. Oral microbiome plays a key role in shaping up the host’s health profile. Obvious differences have been reported between patients with gastrointestinal diseases and healthy controls. 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. Oral bacteria can disseminate to the distal gut via enteral or hematogenous routes. The translocation of oral microbes to the gut may give rise to a variety of gastrointestinal diseases including Helicobacter -induced diseases, irritable bowel syndrome, inflammatory bowel disease, celiac disease, and colorectal cancer. Understanding the role of the oral-to-gut microbial translocation in the pathogenesis will contribute to precise diagnosis and effective treatment. In this review, we aim to highlight the role of oral microbiota dysfunction in various gastrointestinal disorders.


Introduction
More than 10 14 symbiotic microorganisms colonize the human body referred to as the human microbiota [1,2].Oral microorganisms are identified as a constituent of the oral microbiome with the aid of using the Human Oral Microbiome Database (http:// www.homd.org/) and feature a better abundance in the oral cavity than in the gut samples of healthy individuals based on the NIH Human Microbiome Project (HMP1; https:// hmpda cc.org/ hmp/) [3].The oral cavity is the preliminary gateway of the human digestive system and has the second-biggest and maximum various microbiota after the intestine, harboring extra than 770 species of bacteria [4].From 12 international locations worldwide, salivary oral microbiota outcomes confirmed person specificities with few geographic variations among these subjects [5].Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria confirmed the very best abundance [6].Oral microbes can spread through the body and have been found in a variety of systemic diseases, whether in sterile organs such as cardiovascular diseases and rheumatoid arthritis or in non-sterile organs such as the digestive tract [7,8].
The oral microbiome plays a pivotal role in human health.Both inflammatory and anti-inflammatory responses may be induced in the host tissues by members of the oral microbiota [9].The benefits to the host include resistance to infections mediated by inhibition of colonization by pathogenic microorganisms [10], maturation of both the innate and adaptive host immune systems, and fine-tuning of its reaction patterns to achieve a balance between inflammatory and anti-inflammatory reactions [11][12][13][14][15][16].Oral microbial dysbiosis is the major causative factor of oral diseases such as dental caries and periodontal diseases [7], and it is also closely associated with systemic diseases such as asthma and atopic diseases, inflammatory bowel diseases, autoimmune disease, obesity and metabolic syndrome, colon cancer, peripheral vascular disease and hypertension, aberrant responses to drugs, depression, and autism [17].
Although millions of oral and salivary microbiomes are swallowed daily with our food, their persistence and passage to the gut are affected by many factors including gastric acidity, bile acids production (BAs), digestive enzymes and antimicrobial proteins in the duodenum and beyond, intestinal architecture, peristalsis, and transit times [18].The concentration gradient of microbes is found along the small intestine, as microbial abundance in oral samples was found to be 1000-fold higher than that of duodenal aspirates [19] (Fig. 1).
Oral pathogens had been found abnormally enriched in the gut mucosal tissues and the luminal contents in patients with gut diseases [20,21].Therefore, it is suggestive that the ectopic gut colonization of oral pathogens is partially responsible for the pathogenesis of gut diseases: oral-gut axis microbiota.

Gut colonization by oral bacteria
Two routes had been suggested for the oral bacteria to reach the gut: hematogenous and/or enteral.

Hematogenous route
Oral mechanical injuries caused by daily dental activity, e.g., hard mastication and brushing, and dental procedures, e.g., orthodontics and extraction, enable oral bacteria to spread into the systemic circulation [22,23].Oral bacteria invade and survive inside immune cells, such as dendritic cells and macrophages.These cells help dissemination of the oral bacteria from the oral to the gut mucosa [7].

Enteral route
A human being swallows about 600 times a day, and ~ 1.5 L of saliva contains numerous resident oral bacteria [24,25].Most of the ingested oral bacteria do not reach and/or colonize the healthy gut because of the barrier functions along the gastrointestinal tract.The gut resident microbiota is the major barrier that prevents the ectopic colonization by swallowed oral bacteria, so, gut dysbiosis is a prerequisite for the ectopic colonization of oral pathobionts.

Gut barriers dysbiosis
Gut dysbiosis-inducing factors include gut inflammation, and diets such as high fat, low-fiber diet, and artificial sweeteners are the main factors.Other possible factors include immune depression as aging, smoking, drugs, virus infection, or immune compromization as HIV [26].The inappropriate use of antibiotic and the long-term use of proton-pump inhibitors that reduce the gastric acidity facilitate opportunistic gut colonization by oral bacteria.Other examples of the effect of impaired gastric acidity include individuals who have gastritis and gastric surgery (e.g., gastric bypass or gastrectomy) [27,28].These individuals have significant increase in the level of resident oral bacteria and altered bacterial composition.Worth mentioning, certain types of oral bacteria, such as Porphyromonas gingivalis, can tolerate the acidic environment in the stomach and consequently may pass through the stomach barrier [29].

Role of oral bacteria in Helicobacter-induced gastric pathology
Helicobacter pylori can be detected in the mouth and gut.The number of H. pylori in the mouth is actually lower than in the stomach constituting roughly 42-97% of the total gastric bacterial community [30].Because the oral microbiome is the main source of gastric microbes, it is intimately related to the infection and transmission of H. pylori [31,32].
Interactions between H. pylori and oral microbiome may take one or further of three main forms: co-aggregation, symbiotic biofilm formation, and endosymbiosis [33].Fusobacterium nucleatum and Porphyromonas gingivalis which might be vital microorganism in periodontal infection can mixture with H. pylori cells promoting oral to gastric colonization by oral bacteria [34].
Streptococcus mutans, the fundamental cariogenic bacterium, can shape a symbiotic biofilm with H. pylori to increase its survival in the unsuitable atmosphere of the mouth [35].H. pylori can anchor on the surface of the Candida albicans and mixture with C. albicans to form a mixed biofilm.Also, H. pylori plan to enter C. albicans yeast cells in the oral cavity and vagina [36,37].
The interaction between H. pylori and members of the oral microbial community in H. pylori-positive people with oral complaints differs from those with gastrointestinal complaints.P. gingivalis has been established as a pathogenic agent of periodontitis and positively associated with H. pylori indicating that H. pylori infection may aggravate periodontal disease [38].The transmission of oral-to-gut and gut-to-oral microorganisms can affect the ecosystem in both territories and hence regulate the pathogenesis of different diseases [39].

Role of oral bacteria in gut pathology
The presence of nearly half of the microbial species in both the mouth and gut gives evidence of oral-gut translocation even in healthy individuals [40].This is known to modulate host immunity [41].Hence, ectopic colonization by oral bacteria in the healthy gut may in part contribute to the physiologic development and/or maintenance of gut immunity.On the other hand and under certain conditions, gut colonization by specific oral bacteria might be linked to the pathogenesis of diseases in the gastrointestinal tract.The dissemination of oral microbes to the intestine may also exacerbate diverse gastrointestinal diseases, including irritable bowel syndrome (IBS) [42], inflammatory bowel disease (IBD) [43], celiac disease [44], and colorectal cancer (CRC) [45] (Fig. 2).

Irritable bowel syndrome
IBS is one of the most common disorder occurring in up to 4.8% of the population worldwide [46].IBS is described as chronically recurring abdominal pain related to altered bowel habits in the absence of detectable organic disease.Recent evidence suggests the presence of IBS subgroups based on gut microbial community structure, with groups not differing from healthy controls despite GI symptoms [47,48].The most effective treatments for IBS and other disorders of oral-gut axis interactions include personalized diet approaches, behavioral therapies, and a few number of pharmacologic treatments to improve bowel function.As a common feature in IBS, there is an increase in the families Enterobacteriaceae and Lactobacillaceae and a decrease in the genera Clostridium, Faecalibacterium, and Bifidobacterium, as compared with controls [49].The gut of patients with IBS showed enrichment of certain types of typical oral bacteria such as Streptococcus spp.and family Veillonellaceae [50][51][52][53].Veillonellaceae was found abundantly in the gut of overweight patients with IBS who have significantly higher induced visceral pain scores than normal-weight patients with IBS.Veillonellaceae were also responsible for gastrointestinal colics in infants caused by the accumulation of lactate, hydrogen, or hydrogen sulfide [54].Vervier et al. in 2022 [55] were able to stratify patients with IBS according to their gut microbiota species.Gut microbiota subtype with an enhanced clinical response to a low FODMAP diet compared with other subjects with IBS was identified.Microbiota signatures reported to be useful as biomarkers to guide IBS treatment.Recently, Tanaka and his colleagues [56] reported that colonic hostmicrobial interactions are altered in IBS-D patients during exacerbation of symptoms.However, there were no overlaps between feces and oral microbiomes.Tang and his colleagues [57] showed that the oral and fecal microbiota composition in IBS-D patients differed significantly from that in the normal population.The imbalance of Firmicutes/Bacteroidetes ratio in the oral microbiota of IBS-D patients, as compared to fecal microbiota, is of much concern.Additionally, the decrease in oral microbial richness was more directly connected to IBS-D [58].

Inflammatory bowel disease
The specific etiology of IBD stays poorly understood despite the identity of relevant risk factors, which include individual genetic susceptibility, environmental triggers, and disruption of immune homeostasis.Dysbiosis of the gut microbiota is thought to exacerbate the development of IBD.An imbalance of the gut microbiota appears to be an essential factor in the pathogenesis of IBD [59].Gut dysbiosis in IBD is characterized by a decrease in the bacterial diversity and species richness of the microbiota.Docktor et al. [60] found a significant decrease in the overall microbial diversity of pediatric CD.Fusobacteria and Firmicutes were significantly reduced in CD, whereas Bacteroidetes were increased in UC compared with healthy controls.Said et al. [61] found that the salivary microbiota in adult IBD was significantly different from that of healthy controls, characterized by increased Bacteroidetes, Prevotella, and Veillonella, with decreased Proteobacteria, Streptococcus, and Haemophilus.Zhe et al. [62] revealed enrichment of Streptococcaceae and Enterobacteriaceae in UC, and Veillonellaceae in CD, while depletion of Lachnospiraceae and Prevotellain UC and Neisseriaceae in CD.Oral biofilm-forming bacteria were significantly increased in the salivary microbiota of IBD patients.Moreover, TM7 and SR1 showed a positive correlation to inflammatory cytokines associated with IBD, indicating that alterations in oral microbiota are related to altered inflammatory immune responses [63].
The best-described mechanisms of the oral microbiota in IBD occurrence are the destruction of the intestinal epithelial barrier, excessive secretion of inflammatory cytokines, disruption of the host immune system, and induction of immune escape.Oral bacteria-mediated destruction of the intestinal epithelial barrier may increase intestinal permeability and mucosal degradation, leading to the impairment of intestinal resistance to pathogens and intestinal inflammation.Ectopic colonization of oral bacteria disrupts the ecological balance among the oral microbiota, host, and immune system, leading to continuous intestinal inflammation [64].Kitamoto et al. [65] show that the oral pathobionts during periodontitis aggravate gastrointestinal pathology via two mechanisms.Specific oral pathobionts are able to colonize the colitic gut and enhance IL-1β production.Also, oral pathobiont-reactive Th17 cells, primed in oral mucosa-draining lymph nodes, trafficked to the gut and became reactivated by periodontal microbiota traveling to the gastrointestinal tract through ingestion.

Colorectal cancer
CRC has a distinct gut microbial composition as compared with healthy individuals.Many of the bacteria enriched in colonic adenomas and carcinomas are related to the typical resident oral bacteria, including the families Streptococcaceae and Neisseriaceae and the genera Staphylococcus, Porphyromonas, Veillonella, and Fusobacterium [66,67] with validation from three recent large cohort studies [21,68,69].The transmission rates of bacteria from the mouth to the gut are higher in patients with CRC when compared with healthy individuals in particular the transmission of Fusobacterium nucleatum, Parvimonas micra, and Peptostreptococcus stomatis supporting the potential link between the oral and gut microbiome in patients with CRC [70].
Porphyromonas gingivalis and Fusobacterium nucleatum are two famous CRC-related oral pathogens.Both of them can cause CRC through a different pathogenic pathway.
Porphyromonas gingivalis A gram-negative anaerobic bacteria was found to be responsible for both the occurrence of periodontitis [71] and was enriched in CRC patients [72].It was positively associated with poor prognosis in CRC patients.It stimulates cellular senescence via butyrate secretion and accelerates the onset of colorectal tumors [73].It can promote colorectal tumorigenesis by recruiting tumor-infiltrating myeloid cells and creating a proinflammatory tumor microenvironment via activation of the hematopoietic NOD-like receptor protein 3 inflammasomes [72].It has the antiapoptotic ability of epithelial cells through inhibition of caspase 3 [74] and caspase 9 [75].It inhibits the suppressor of cytokine signaling 3 causing apoptosis via STAT3 [76].In addition, P. gingivalis contributes to accelerating epithelial cell proliferation through regulating the activity of PI3K, p53 [77], and cyclins [78], as well as activation of the WNT/β-catenin [79] and MAPK/ERK [80] pathways.
Fusobacterium nucleatum Similar strains of F. nucleatum are detected in both the saliva and colonic tumors of patients with CRC, indicating that F. nucleatum colonized in the colonic tumors originates in the oral microbiota [81].F. nucleatum is highly adhesive to the gut epithelium through Fap2 adhesin promoting the proliferation of tumor cells by activation of the Wnt/β-catenin pathway [82].The abundance of F. nucleatum is gradually increased from normal tissues to adenoma tissues and to adenocarcinoma tissues in colorectal carcinogenesis [83,84].F. nucleatum is increased in CRC patients after chemotherapy with recurrence, compared with those with nonrecurrence.It becomes evident that F. nucleatum directly promotes CRC chemoresistance to oxaliplatin and 5-fluorouracil through the activation of the autophagy pathway [85].The high abundance of F. nucleatum in CRC is associated with poorer survival [81,86].Accordingly, F. nucleatum promotes the occurrence and development of CRC through localization, proliferation, immune suppression, metastasis, and chemoresistance.

Celiac disease
Patients who have celiac disease have oral flora dysbiosis.The initial metabolism of gliadin in the oral cavity may be related to the genus of Rothia, Actinomyces, Neisseria, and Streptococcus that colonized the oral cavity [87].There is a significant increase in Lactobacillus species in the saliva of patients with celiac disease.This may be one of the reasons to explain gluten degradation and its higher rate in comparison to healthy people [88].Although α-gliadin peptide could be completely degraded by dental plaque bacteria to reduce immunogenicity [88,89], still, others report oral microbial enzymes to degrade part of gluten, which in turn increases immunogenic small molecule peptides and further induces intestinal inflammation [88].
Panelli et al. [90] investigated 52 adult patients affected with celiac disease and 31 patients with functional dyspepsia, to characterize the salivary, duodenal, and fecal microbiota composition.In addition to a general reduction of the microbial diversity in all analyzed samples from celiac disease patients, this study showed a significant abundance of Proteobacteria in active celiac disease and, importantly, confirmed the expansion of Neisseria spp.Moreover, they reported a better correspondence of the bacterial microbiota in the saliva with duodenal mucosa microbiome, rather than with fecal samples.

Gut microbiota therapeutic manipulation
Multiple substances can be used to modulate many physiologic functions within the body that constitute one of the risk factors in the pathogenesis of many diseases.
Prebiotics It is a selectively fermented ingredient that results in specific changes in the composition and activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health [91].It is safe, effective, and has a great therapeutic effect and minimal side effects in maintaining IBD [92].Fructo-oligosaccharides in CD patients increase mucosal Bifidobacteria and reduce the inflammation index [93].Prebiotics prevent CRC in patients with its high risk and improve their immunological response [94,95].
Probiotics These are live organisms that, when administered in adequate doses, confer a health benefit on the host [96].IBS is the main treatment indication [97].Butyrate-producing Faecalibacterium prausnitzii induces immune responses, has anti-inflammatory effects, and improves intestinal barrier function [98,99].
Fecal microbiota transplantation and fecal virome transplantation Whether liquefied or encapsulated, preprocessed stool from a healthy donor is transferred to the recipient's colon.It is successful in the treatment of recurrent C. difficile infection and colitis [100,101].Other indications for the use of FMT include the treatment of antibiotic-resistant bacteria (ARB) gut colonization [102] and acute gastrointestinal graft-versus-host disease [103][104][105].
A new version of FMT is fecal virome transplantation (FVT), which uses bacteriophages to restore gut microbiota dysbiosis.However, the prophage-encoded virulence factors remain a safety issue, which limits the use of phages in medicine [106].
Microbiota metabolites These not only produce diseases but also have a therapeutic role.It has a role in the prevention and treatment of CRC [107].The only metabolites that are anticarcinogenic are SCFAs [108] and polyphenol metabolites [109,110].Butyrate increases SCFAs and prevents the formation of harmful substances in the rectum [111].Butyrate enhances the efficacy of radiotherapy in CRC patients [112], suggesting that gut microbiota-derived metabolites could be associated with modalities in cancer treatment.
MiRNA Intestinal miRNAs respond to commensals, pathogens, and probiotics.In the human intestines, miRNAs are mainly synthesized in the intestinal epithelial cells.Any deficiency in the miRNA synthesis by those cells is associated with gut microbial dysbiosis [113].Intestinal miRNA may regulate responses to pathogenic and probiotic bacteria.Probiotic bacteria, Bifidobacterium bifidium, can alter intestinal miRNA in a species-and strain-specific manner [114].
Hyaluronan (HA) It is considered a novel tool for the development of novel therapeutic agents for the treatment of diseases underlying dysregulation of the microbiota-immune-gut axis [115].HA appeared to directly modulate the promotion and resolution of IBD by controlling the recruitment of immune cells, through the release of inflammatory cytokines, and by balancing homeostasis [116].The biological effects of HA are mediated by recruiting different receptors, such as CD44 [117], and by promoting the activation of toll-like receptors, particularly, TLR2 and TLR4, present in different cell types, including fibroblasts, smooth muscle cells, epithelial cells, immune cells, and neuronal cells [118,119].

Nanomedicine-based approaches and extracellular vesicles
These are experiments trying to shape nanomaterials able to alter the cancer-causing dysbiotic microorganisms as well as their metabolites found in the cancer microenvironment [120].Microbiota has the ability to interact with host cells and mitochondria, when needed, through extracellular vesicles, leading to the endocytosis of the extracellular vesicle and its content delivery [121][122][123].Exosomal microRNA derived from mesenchymal stem cells plays a strategic role in modulating the gut microbiota and inflammatory status.

Conclusion
The oral-gut axis microbiota plays an important role in maintaining homeostasis.The oral cavity is an easily accessed body site for the assessment of the microbial community, with convenient sampling, noninvasiveness, and effective interventions.Hence, the oral microbiota holds great promise for diagnostic tools.New therapeutic approaches targeting the oral microbiota by facilitating beneficial bacteria and eliminating pathogenic oral bacteria may be an innovative medical strategy to prevent and treat many gastrointestinal disorders.Beyond having the pre-or probiotics, which are the traditional and first-line choice of microbial therapies, other strategies are being clinically studied such as the FMT, metabolites, phages, and miRNAs.

Fig. 1
Fig. 1 Human microbiota composition in different locations.Predominant bacterial genera in the oral cavity, respiratory tract, skin, gut, and vagina.Published by Hou K. et al. in the Signal Transduction and Targeted Therapy (2022) 7:135