The Oral–Gut Microbiome Axis in Gastrointestinal and Systemic Diseases

1. Introduction

The human body is colonized by complex microbial communities that occupy distinct ecological niches, most prominently the oral cavity and the gastrointestinal tract. The oral microbiome encompasses diverse bacteria, fungi, viruses, archaea, and their collective genomes inhabiting oral surfaces, including the teeth, gingival crevice, tongue, saliva, palate, and buccal mucosa. It is one of the most taxonomically and functionally diverse microbial ecosystems in the body and exists predominantly as structured, surface-attached biofilms shaped by salivary flow, dietary inputs, oxygen gradients, host immunity, and mechanical perturbation [1,2,3]. In contrast, the gut microbiome represents a densely populated microbial community distributed along the gastrointestinal tract, with maximal biomass and metabolic activity in the colon. This ecosystem plays central roles in host physiology, including nutrient metabolism, vitamin synthesis, immune homeostasis, epithelial barrier maintenance, and colonization resistance against exogenous microbes [4,5,6,7].

Historically, the oral and gut microbiomes were studied as independent systems. However, growing evidence supports the existence of an oral–gut microbiome axis, a bidirectional network linking these ecosystems through microbial transfer, immune signaling, and metabolic exchange [8,9]. The oral cavity continuously seeds the gastrointestinal tract through daily swallowing of saliva - estimated at 10¹¹ to 10¹² microbial cells per day - along with biofilm fragments and planktonic bacteria shed from oral surfaces [8,10]. Under homeostatic conditions, multiple ecological barriers - including gastric acidity, bile exposure, antimicrobial peptides, and competition from established gut microbiota - limit the persistence of oral microbes in the intestine. This phenomenon reflects colonization resistance, whereby resident microbial communities and host factors restrict the establishment of incoming organisms through nutrient competition, niche exclusion, and immune-mediated clearance [7,11]. However, these barriers are not absolute. Perturbations such as antibiotic exposure, proton-pump inhibitor use, inflammation, dietary shifts, or immunosuppression can disrupt colonization resistance and create permissive niches for microbial invasion [7,12,13]. Within this altered ecological landscape, oral-derived organisms may transition from transient passengers to stable colonizers, a process often referred to as ectopic colonization [13,14]. This distinction between transient passage and true engraftment is critical, as only the latter is likely to drive sustained functional and immunological consequences in the gut. Indeed, experimental studies have demonstrated that oral pathobionts, including Klebsiella species, can colonize the intestine and induce T helper 1 (Th1)-mediated inflammation under dysbiosis conditions [13].

A central mechanistic feature of the oral–gut axis is microbial translocation, defined as the movement of viable microorganisms or their molecular products from their original niche to distal anatomical sites. In this context, translocation may occur via multiple routes, including ingestion of oral microbes, hematogenous dissemination through inflamed periodontal tissues, or systemic circulation of microbial-associated molecular patterns such as lipopolysaccharide, peptidoglycan, bacterial DNA, and extracellular vesicles [8,15,16,17]. These processes enable oral microbial signals to influence distal mucosal and systemic immune responses, effectively linking localized oral dysbiosis to broader inflammatory states. From an ecological perspective, the oral–gut axis can be understood through principles of niche theory, ecological filtering, and community resilience. The gut environment imposes strong selective pressures that typically exclude non-adapted oral taxa. However, disruption of ecological stability through inflammation or microbiome perturbation reduces system resilience, allowing invasion by opportunistic organisms [18,19]. In this framework, certain oral microbes function as pathobionts or even keystone pathogens, capable of disproportionately altering host-microbe interactions and community structure despite relatively low abundance [20,21].

Importantly, the oral–gut axis is not restricted to bacterial interactions. The oral and gut mycobiome and virome, including bacteriophages, also contribute to community dynamics and host responses, although their roles remain less well defined. Fungal species such as Candida and phage-mediated modulation of bacterial populations may influence colonization dynamics, immune activation, and microbial competition across sites [22,23,24]. While bacterial mechanisms dominate current understanding, incorporating these additional microbial components is essential for a comprehensive view of cross-ecosystem interactions. The clinical relevance of the oral–gut axis is increasingly recognized across a wide spectrum of gastrointestinal and systemic diseases. Oral dysbiosis and periodontal inflammation have been associated with inflammatory bowel disease, colorectal cancer, cardiovascular disease, metabolic disorders, autoimmune conditions, and neurodegenerative diseases [25,26,27,28,29]. Notably, these associations often reflect ecological and functional disruption rather than the presence of a single causative pathogen, involving shifts in microbial composition, altered metabolite production, impaired epithelial barriers, and chronic immune activation. At the same time, systemic diseases can reciprocally influence the oral microbiome through changes in immune function, salivary composition, medication exposure, and inflammatory status, underscoring the bidirectional nature of this axis [30].

A particularly important implication of this framework is its ability to help explain the persistent clinic-laboratory disconnect observed in infectious and inflammatory diseases, where microbial behavior in vivo does not always align with in vitro expectations. Microbiome context, interspecies interactions, and host responses can fundamentally reshape microbial phenotypes, highlighting the limitations of reductionist models that isolate individual organisms from their ecological environment. Host factors further modulate the oral–gut axis. Genetic variation in immune pathways, epithelial barrier function, and inflammatory responsiveness influences susceptibility to microbial translocation and disease progression. Thus, the impact of oral dysbiosis on gut and systemic health is not uniform but depends on the interplay between microbial exposure and host predisposition [31]. Together, these findings support a conceptual model in which the oral cavity functions as a microbial reservoir that can influence intestinal ecology and systemic inflammation through swallowed oral microbes, barrier disruption, immune signaling, and loss of colonization resistance (Figure 1). 

2. The Oral Microbiome

The oral microbiome is a highly diverse and spatially structured microbial ecosystem distributed across multiple anatomical niches, including the teeth, gingival sulcus, tongue dorsum, buccal mucosa, palate, tonsils, and saliva. Rather than functioning as a single homogeneous community, it comprises distinct, site-specialized microbial consortia shaped by local environmental conditions such as oxygen tension, pH, nutrient availability, host immune factors, salivary flow, and surface characteristics [1,2,3]. More than 600 prevalent bacterial taxa have been identified in the human oral cavity, with substantial inter-individual variability but consistent ecological organization within niche-specific communities [1]. This biogeographical structuring is a defining feature of the oral microbiome and underlies both its resilience in health and its susceptibility to dysbiosis under perturbation [2,32]. From a systems perspective, the oral microbiome functions as a dynamic, multi-habitat ecosystem, in which microbial communities are interconnected through physical proximity, fluid flow, and metabolic exchange. These communities contribute to colonization resistance, modulation of host immunity, nitrate metabolism, and maintenance of ecological stability [33,34]. At the same time, the oral cavity serves as a major reservoir for microbial dissemination, with implications for both gastrointestinal and systemic health [8,15].

2.1. Core Microbial Taxa

The healthy oral microbiome is dominated by bacterial members of the phyla Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Fusobacteria, and Spirochaetes, although their relative abundances vary across oral niches and host conditions [1]. Prominent genera include Streptococcus, Actinomyces, Veillonella, Neisseria, Haemophilus, Rothia, Prevotella, Fusobacterium, Porphyromonas, Capnocytophaga, Leptotrichia, and Treponema [1]. Streptococcus species act as early colonizers, initiating biofilm formation by adhering to the acquired enamel pellicle and enabling subsequent microbial succession through coaggregation and metabolic cross-feeding [35,36]. Secondary colonizers, particularly Fusobacterium nucleatum, function as bridging organisms, facilitating interactions between early and late colonizers and supporting the development of complex multispecies communities [36]. In health, oral microbial communities exhibit functional redundancy and metabolic cooperation, which enhances ecological resilience and stability. For example, commensal bacteria participate in nitrate reduction pathways that influence systemic nitric oxide production and vascular function [33,34,37]. However, many oral microbes can act as pathobionts, transitioning to disease-associated states under ecological disruption. Key examples include Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, which are strongly associated with periodontitis, as well as acidogenic organisms such as Streptococcus mutans linked to dental caries [21,38]. Importantly, oral disease reflects community-level dysbiosis, rather than the action of a single pathogen, with shifts in microbial composition and function driving inflammation and tissue destruction [20,21].

2.2. Ecological Organization: Biofilms, Saliva, and Mucosa

A defining feature of the oral microbiome is its organization into biofilms, structured microbial communities embedded within an extracellular polymeric matrix. Dental plaque develops through a sequential process involving pellicle formation, attachment of pioneer species, coaggregation, and maturation into complex multispecies communities [36,39]. Within biofilms, microbes are arranged in spatially organized microenvironments characterized by gradients in oxygen, pH, and nutrient availability. These gradients enable the coexistence of aerobic, facultative anaerobic, and obligate anaerobic organisms within close proximity, facilitating metabolic cooperation and niche partitioning [2,32]. The extracellular matrix enhances resistance to mechanical disruption, antimicrobial agents, and host immune defenses [39].

Saliva plays a dual ecological role as both a regulatory and dispersal medium. It contains antimicrobial peptides, secretory IgA, enzymes, mucins, and nutrients that shape microbial growth, while simultaneously transporting microbes throughout the oral cavity and into the gastrointestinal tract [40]. Microbial densities in saliva can reach approximately 10⁸ cells per milliliter, with organisms shed from multiple oral niches, including the tongue dorsum, tooth surfaces, gingival crevice, and buccal mucosa [3,41]. The oral mucosa provides additional ecological niches. The tongue dorsum supports dense microbial communities due to its papillary structure and oxygen gradients, whereas non-keratinized surfaces, such as the buccal mucosa, experience rapid epithelial turnover, leading to more transient microbial populations [3,42,43]. This site-specific ecological differentiation, often described as the “site-specialist hypothesis,” highlights the role of environmental filtering in shaping microbial community composition [32]. The spatial organization of oral microbial communities across teeth, the gingival sulcus, the tongue dorsum, saliva, and the buccal mucosa is summarized in Figure 2, highlighting how local ecological conditions shape niche-specific microbial composition.

2.3. Major Drivers of Oral Dysbiosis

Oral dysbiosis refers to the disruption of microbial composition and function that promotes inflammation and disease. One of the primary drivers is periodontitis, a chronic inflammatory condition characterized by a shift toward anaerobic, proteolytic, and inflammation-adapted microbial communities within subgingival biofilms [16,21]. The polymicrobial synergy and dysbiosis model posits that keystone pathogens such as P. gingivalis can subvert host immune responses and reshape the microbial community, leading to a self-sustaining cycle of inflammation and dysbiosis [20,21]. Periodontal inflammation increases gingival crevicular fluid flow and releases host-derived nutrients, further selecting for dysbiotic organisms [16]. Poor oral hygiene contributes to plaque accumulation and biofilm maturation. As biofilms thicken, oxygen levels decrease, favoring anaerobic organisms associated with gingivitis and periodontitis [39]. Dietary factors also play a significant role, with frequent consumption of fermentable carbohydrates promoting acid production and selection of acid-tolerant species involved in caries [38,44].

Systemic and environmental factors further influence oral microbial ecology. Smoking, diabetes, aging, xerostomia, immunosuppression, and medication use - including antibiotics and proton-pump inhibitors - have all been associated with shifts in oral microbiome composition and function [12,45,46]. These factors act by altering host immunity, salivary composition, and the physicochemical environment of the oral cavity. Importantly, oral dysbiosis extends beyond local pathology. Inflammation-associated disruption of the gingival epithelium facilitates hematogenous dissemination of bacteria and microbial products, while saliva continuously delivers oral microbes into the gastrointestinal tract. Thus, the dysbiotic oral microbiome functions as both a source of systemic inflammatory signals and a reservoir of organisms capable of colonizing distal sites under permissive conditions [8,16]. Several oral and gut microbial taxa are repeatedly implicated in oral–gut microbiome interactions. Some organisms, such as Streptococcus, Veillonella, Prevotella, F. nucleatum, and P. gingivalis, are primarily associated with the oral cavity but may influence intestinal and systemic disease under dysbiotic conditions. In contrast, gut-associated organisms such as Faecalibacterium prausnitzii, Akkermansia muciniphila, Bacteroides, and Escherichia/Shigella reflect intestinal ecological balance or disruption. Representative taxa relevant to the oral–gut axis are summarized in Table 1.

3. Mechanisms Linking the Oral and Gut Microbiomes

The oral–gut microbiome axis is mediated by interconnected biological processes that enable communication between the oral and gut ecosystems. These mechanisms extend beyond simple microbial transfer and include ecological invasion, immune signaling, metabolite exchange, and disruption of epithelial barriers. Together, they form a multilayered network through which oral dysbiosis can influence intestinal homeostasis and systemic disease. Importantly, these interactions are bidirectional, with gut-derived signals also shaping oral microbial ecology, reinforcing the concept of an integrated mucosal system rather than isolated microbial compartments. These pathways are not mutually exclusive and may operate simultaneously, depending on host susceptibility, oral inflammatory status, gut barrier integrity, medication exposure, and baseline gut microbiome composition. As summarized in Figure 3, oral dysbiosis may affect intestinal and systemic health through five interconnected pathways: microbial migration, immune-mediated communication, metabolite-mediated effects, epithelial barrier disruption, and inflammatory feedback loops.

3.1. Major Drivers of Oral Dysbiosis

A fundamental connection between the oral cavity and the gastrointestinal tract is the continuous migration of microorganisms via saliva. Humans swallow substantial volumes of saliva daily, which contains large numbers of microbial cells shed from oral biofilms and mucosal surfaces; estimates suggest that approximately 10¹² oral bacteria may enter the gastrointestinal tract each day [8]. Under physiological conditions, most of these organisms behave as transient passengers that are cleared by gastric acidity, bile salts, digestive enzymes, and competition from resident gut microbiota. This reflects the principle of colonization resistance, whereby established microbial communities and host defenses prevent the stable establishment of incoming organisms through nutrient competition, niche exclusion, and immune-mediated clearance [7,11].

However, this barrier is not absolute. Disruption of colonization resistance - such as through antibiotic exposure, proton-pump inhibitor use, inflammation, immunosuppression, or dietary changes - can create permissive ecological conditions that allow oral-derived microbes to persist within the gut [8,12,13,64]. In this context, a critical distinction emerges between transient passage and stable engraftment. While most oral microbes pass through the gastrointestinal tract without consequence, a subset can establish functional niches under dysbiotic conditions, leading to sustained ecological and immunological effects. Experimental studies support this model, demonstrating that orally derived bacteria, such as Klebsiella species, can colonize the intestine and induce T helper 1–mediated inflammation [13]. Similarly, oral-associated taxa, including F. nucleatum, Porphyromonas, and Prevotella, have been identified in the gut microbiota of patients with inflammatory bowel disease and colorectal cancer, suggesting that oral microbes can contribute to disease-associated intestinal communities [25,26,27].

3.2. Immune-Mediated Communications

Beyond direct microbial migration, the oral–gut axis is strongly mediated by the host immune system, which integrates microbial signals across mucosal sites. Oral inflammation, particularly in periodontitis, results in the release of pro-inflammatory cytokines and microbial-associated molecular patterns into systemic circulation [16,17]. These signals are recognized by pattern recognition receptors such as Toll-like receptors and nucleotide-binding oligomerization domain-like receptors, leading to activation of innate immune pathways and modulation of adaptive immune responses [65,66]. A key consequence of this signaling is the polarization of T helper cell responses, particularly T helper 1 (Th1) and T helper 17 (Th17) pathways, which play essential roles in mucosal immunity but are also implicated in chronic inflammatory disease [67]. Oral pathobionts can promote these inflammatory responses, contributing to intestinal immune activation and barrier dysfunction [13,14]. At the same time, gut inflammation can influence oral immunity through systemic cytokine signaling and immune cell redistribution, highlighting the bidirectional nature of immune communication along the oral–gut axis. This interconnected immune landscape underscores how localized dysbiosis can propagate inflammatory responses across distant mucosal sites.

3.3. Metabolite-Mediated Interaction

Microbial metabolites represent another critical layer of communication linking the oral and gut microbiomes. Both ecosystems produce a wide array of bioactive compounds that can influence host physiology and microbial community dynamics. Among these, short-chain fatty acids such as acetate, propionate, and butyrate play central roles in maintaining epithelial barrier integrity, regulating immune responses, and suppressing inflammation [58,59]. Although these metabolites are primarily associated with gut microbiota, their systemic effects extend beyond the intestinal environment. In contrast, dysbiotic oral communities - particularly those associated with periodontitis - are characterized by increased proteolytic metabolism, generating compounds such as ammonia, hydrogen sulfide, phenols, and biogenic amines. These metabolites contribute to tissue damage, inflammation, and altered microbial selection both locally and systemically [68]. In addition, endotoxins, such as lipopolysaccharide (LPS) derived from Gram-negative oral bacteria, can enter the systemic circulation, promoting low-grade inflammation and endothelial dysfunction [16,69]. These circulating microbial products can influence gut immune responses and may contribute to shifts in intestinal microbial composition, linking the two ecosystems through metabolite-driven signaling pathways.

3.4. Effects on Barrier Integrity

Epithelial barrier integrity represents a critical interface in the oral–gut axis, regulating interactions between microbial communities and host tissues. In the oral cavity, periodontal inflammation compromises the gingival epithelium, increasing vascular permeability and facilitating the entry of bacteria and microbial products into systemic circulation [16,17]. This provides a pathway for the dissemination of oral-derived inflammatory signals beyond the local environment. In the gastrointestinal tract, inflammatory processes can disrupt tight junctions between epithelial cells, leading to increased intestinal permeability and allowing luminal microbes and their products to translocate into underlying tissues and the bloodstream [70,71]. Barrier dysfunction is both a cause and consequence of microbial dysbiosis. Oral inflammation may contribute to gut barrier disruption through systemic inflammatory mediators, while gut inflammation can alter oral microbial composition by influencing immune tone and host defenses [14,72]. Together, these processes establish a self-reinforcing cycle in which dysbiosis, barrier disruption, microbial translocation, and inflammation perpetuate one another across anatomical sites. Such feedback loops are likely central to the persistence and progression of chronic inflammatory diseases associated with the oral–gut microbiome axis.

The clinical relevance of the oral–gut microbiome axis varies across diseases. Evidence is strongest for inflammatory bowel disease (IBD) and colorectal cancer (CRC), where oral-associated taxa have been repeatedly detected in intestinal or tumor-associated microbial communities and supported by mechanistic studies. Evidence for cardiovascular, metabolic, autoimmune, and neurodegenerative diseases is biologically plausible but remains more indirect, often involving systemic inflammation, microbial products, barrier disruption, and immune signaling. In irritable bowel syndrome (IBS), celiac disease, and some forms of colitis, current findings are still emerging and should be interpreted cautiously. A simplified overview of these disease associations, proposed mechanisms, and clinical implications is provided in Table 2.

4. Oral Dysbiosis and Gastrointestinal Disorders

Oral dysbiosis is increasingly recognized as a biologically meaningful contributor to gastrointestinal disease, rather than a process confined to the oral cavity. Current oral–gut axis models propose that the mouth can serve as a reservoir of pathobionts, inflammatory mediators, and disrupted microbial communities that reach the intestine through swallowed saliva, shed oral biofilms, transient bacteremia, and immune-mediated signaling [8,55,63,87]. This model has gained attention because many gastrointestinal disorders are marked by impaired epithelial barrier integrity, weakened colonization resistance, and chronic immune activation, creating conditions that may allow oral taxa to persist, engraft, or influence intestinal physiology [14,88]. Importantly, the oral–gut relationship is bidirectional. Intestinal inflammation can alter oral microbial communities, salivary composition, and mucosal immune responses, while periodontal inflammation may increase systemic inflammatory burden and reshape the gut microbial ecosystem [87,89]. This bidirectionality argues against a simplistic one-way causal model. Instead, oral dysbiosis is best understood as part of a dynamic mucosal network in which microbial imbalance may function as a cause, consequence, biomarker, or amplifier of gastrointestinal disease.

4.1. Inflammatory Bowel Disease (IBD)

Among gastrointestinal disorders, inflammatory bowel disease (IBD) provides some of the strongest evidence for a clinically relevant connection between the oral and gut microbiomes. Recent reviews report that oral manifestations, including aphthous ulcers, gingival inflammation, periodontitis, and other mucosal abnormalities, are more common in individuals with IBD and may correlate with intestinal disease activity and systemic inflammatory status [55,63]. In parallel, oral microbiome profiling studies show that patients with IBD often have altered oral microbial communities, while the intestinal microbiome may show increased “oralization,” suggesting microbial translocation, ecological convergence, or shared inflammatory pressures across oral and intestinal niches [63,90]. Mechanistically, IBD research supports several overlapping pathways through which oral dysbiosis may influence intestinal inflammation. Periodontitis increases the burden of swallowed oral bacteria and inflammatory products, while intestinal inflammation weakens epithelial barrier defenses and colonization resistance, potentially allowing oral taxa to persist ectopically in the gut [55,63]. Organisms frequently implicated include F. nucleatum, P. gingivalis, Klebsiella spp., Campylobacter concisus, and selected oral streptococci. These taxa have been associated with epithelial barrier disruption, innate immune activation, altered cytokine signaling, and pathogenic T-cell polarization in experimental and translational studies [13,87,91,92].

F. nucleatum is one of the most extensively studied examples because it links microbial ecology to host immunopathology. Its enrichment in IBD-associated samples, together with its ability to invade epithelial cells, disrupt tight junction integrity, and activate inflammatory pathways, such as Toll-like receptor (TLR)/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling, supports its potential role in mucosal injury [55,63]. Its adhesins and outer membrane vesicles may further enhance epithelial attachment, immune modulation, and cooperative interactions within polymicrobial communities. These findings suggest that F. nucleatum may act not only as a marker of inflammation but also as an active contributor to mucosal damage [55]. P. gingivalis provides a complementary model. Although best known as a periodontal pathogen, it can have systemic effects even without stable or dominant gut colonization. Experimental studies summarized in recent reviews suggest that oral exposure to P. gingivalis can alter gut microbial composition, reduce tight-junction protein expression, modify host metabolic pathways, and promote Th17-skewed inflammatory responses [55,63]. These findings indicate that oral bacteria may affect intestinal disease through both direct colonization and indirect ecological reprogramming of the gut environment.

Metabolites and immune mediators add further complexity. IBD is associated with depletion of short-chain fatty acid-producing gut commensals, while oral dysbiosis may favor proteolytic microbial communities and inflammatory metabolites that intensify epithelial stress and weaken barrier maintenance [63,90]. Overall, oral dysbiosis is unlikely to be a universal primary cause of IBD. However, current evidence supports its role as a disease-modifying factor that may influence susceptibility, inflammatory severity, and extraintestinal manifestations in biologically predisposed individuals [55,63,90].

4.2. Irritable Bowel Syndrome (IBS)

The relationship between oral dysbiosis and irritable bowel syndrome (IBS) is less clearly defined than in IBD. IBS is classified as a disorder of gut-brain interaction and does not involve the overt tissue-destructive inflammation characteristic of Crohn’s disease or ulcerative colitis, limiting direct mechanistic comparisons [73,74]. An exploratory study of the buccal mucosal microbiome in IBS identified compositional differences between IBS participants and healthy controls and reported associations between specific oral taxa and visceral pain severity, particularly among overweight individuals with IBS. Some oral microbial patterns resembled previously described fecal findings, suggesting that the oral microbiome may reflect broader host-microbiome disturbances relevant to IBS pathophysiology [73]. However, because the study was small, cross-sectional, and exploratory, its findings should be interpreted as hypothesis-generating rather than mechanistically conclusive. Current hypotheses, therefore, remain cautious. Low-grade inflammation may alter autonomic signaling, dietary patterns, stress-related biology, salivary changes, intestinal permeability, and motility, which may, in turn, shape oral microbial ecology in IBS [73,74]. At present, there is insufficient evidence to conclude that specific oral taxa are established causal drivers of IBS, as oral pathobionts are increasingly implicated in IBD and colorectal cancer [73].

4.3. Celiac Disease, Colitis, and Colorectal Cancer (CRC)

Beyond IBD and IBS, evidence linking oral dysbiosis to other gastrointestinal disorders is variable but increasingly suggestive. Broad oral-systemic reviews and oral–gut axis studies indicate that oral microbial disturbances may accompany celiac disease, non-IBD colitis, and colorectal cancer (CRC), although the depth and quality of evidence differ substantially across these conditions [74,75]. In celiac disease, oral microbial involvement remains an emerging area of investigation. Current literature suggests that celiac disease may be associated with oral manifestations and altered oral microbial ecology, but the field has not yet established a validated disease-specific oral microbial signature or a mechanistic framework comparable to that available for IBD [75]. The term “colitis” also requires careful distinction because it includes infectious, ischemic, microscopic, and immune-mediated forms. Much of the mechanistic evidence relevant to the oral–gut axis comes from experimental colitis models rather than from all forms of human colitis. These studies suggest that oral taxa such as F. nucleatum, P. gingivalis, Klebsiella spp., and oral streptococci may aggravate epithelial injury, inflammatory cytokine production, and pathological immune polarization [55,63].

CRC represents the most mature translational field within oral–gut axis research. Multiple studies have reported enrichment of oral-associated taxa, particularly F. nucleatum, in adenomas, colorectal tumors, and tumor-associated mucosal communities, supporting the hypothesis that oral bacteria may contribute to tumor-promoting inflammation, dysregulated epithelial signaling, and immune evasion [93,94,95]. CRC literature is especially compelling because it integrates ecological association studies, mechanistic work on virulence factors such as FadA and Fap2, and translational research evaluating salivary or oral microbial signatures as non-invasive biomarkers [93,94,96]. Importantly, oral microbiome research in CRC has moved beyond association toward potential clinical application. Rezasoltani et al. (2023) reported that salivary microbiota could differentiate early CRC from healthy controls and suggested that saliva-based microbial profiling may outperform fecal profiling in some classification models. Other studies have similarly proposed oral dysbiosis as a non-invasive biomarker for CRC detection and highlighted the recurrent diagnostic relevance of taxa such as Fusobacterium, Dialister, Catonella, and related oral genera [94,95]. More recent evidence also suggests that oral microbiota signatures may have prognostic value, indicating that the oral compartment could eventually contribute not only to screening but also to disease stratification [96].

5. Systemic Diseases Influenced by the Oral–Gut Axis

5.1. Cardiovascular Disease

According to the World Health Organization (WHO), approximately 19.8 million people died from cardiovascular diseases [97]. A meta-analysis of five case-control studies showed a 1.14-fold increased risk of coronary heart disease in patients with periodontal disease [79,98]. The oral microbiota harbors approximately 750 microbial species, including viruses, fungi, protozoa, and archaea. In oral dysbiosis and periodontal disease, this balance is disturbed, increasing the abundance of pathogenic or inflammatory microbial communities [99]. Recent studies on the oral spirochete T. denticola in atherosclerosis models and human vascular lesions have shown that dissemination into organs such as the heart can stimulate cytokine release and modify inflammatory pathways [100,101,102].

P. gingivalis, a bacterial pathogen commonly associated with adult periodontitis, can enter circulation through blood vessels and invade heart endothelial cells. It increases aortic plaque formation and inflammatory gene expression [56,103]. P. gingivalis disrupts endothelial homeostasis through TLR-NF-κB signaling, promotes endothelial-mesenchymal transition, and induces apoptosis [104]. In atherosclerosis, P. gingivalis also increases mitochondrial reactive oxygen species (ROS) levels and decreases adenosine triphosphate (ATP) via Drp1-dependent fission [105]. These findings indicate how periodontal pathogens may contribute to endothelial injury and cardiovascular disease. Long-term infection with P. gingivalis LPS in C57BL/6.KOR-Apoeshl mice reduced serum high-density lipoprotein (HDL) and increased very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and total cholesterol. In this way, it disrupts cholesterol and lipid metabolism, worsening existing atherosclerosis and contributing to the development of coronary heart disease [106]. P. gingivalis also induces lipid peroxidation, modifies plasma lipoproteins, and depletes antioxidant capacity, suggesting a mechanistic link between periodontal infection, oxidative stress, and atherogenesis [107].

Human evidence supports an association but remains less definitive than animal and cell-culture evidence. Periodontopathic bacterial DNA, including P. gingivalis DNA, has been detected in coronary and carotid atheromatous plaques from patients with vascular disease, but detection of bacterial DNA does not prove that oral pathogens initiate plaque formation [108]. Therefore, oral dysbiosis is biologically plausible as a cardiovascular risk modifier, but the causal relationship in humans remains unresolved because periodontitis and cardiovascular disease share risk factors such as age, smoking, diabetes, socioeconomic status, diet, and systemic inflammation [81,109].

5.2. Metabolic Disorders

Metabolic disease is strongly connected to both oral and gut dysbiosis because metabolic syndrome, obesity, type 2 diabetes, hypertension, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD) are all characterized by chronic low-grade inflammation and altered host-microbe interactions [110]. Periodontitis has been associated with metabolic syndrome and diabetes, while metabolic disease can worsen periodontal inflammation and reshape the salivary and subgingival microbiome [110,111]. One of the most important experimental studies for the oral–gut-metabolic pathway showed that oral administration of P. gingivalis in mice altered gut microbiota composition, increased systemic inflammation, impaired glucose and insulin tolerance, tended to increase circulating endotoxin, and reduced expression of ileal tight junction genes. This study supports a model in which swallowed periodontal pathogens disturb gut ecology and intestinal barrier integrity, producing metabolic endotoxemia and systemic inflammation [61].

Diabetes and periodontitis show a clinically important bidirectional relationship. Poor glycemic control impairs immune function, increases inflammatory responses, delays tissue repair, and favors periodontal pathogen expansion. In the opposite direction, periodontal inflammation increases systemic pro-inflammatory mediators that can worsen insulin resistance and metabolic control [111]. Reviews of metabolic syndrome and periodontitis suggest that lipids, inflammatory cytokines, altered host response, and microbiome changes jointly explain this interaction [110]. Obesity adds another layer to the oral–gut axis. The oral microbiome may influence obesity and metabolic disease through local effects on taste perception, dietary preference, nitrate metabolism, systemic inflammation, and downstream effects on the gut microbiome [112]. Salivary microbiome data also associate oral dysbiosis with hypertension and metabolic syndrome biomarkers, although the direction of causality remains uncertain [113]. The oral-liver axis is particularly relevant to metabolic disease because nonalcoholic fatty liver disease is considered the hepatic manifestation of metabolic syndrome [114]. Periodontal disease may contribute to NAFLD and nonalcoholic steatohepatitis through two routes: hematogenous dissemination of bacteria, inflammatory mediators, and reactive oxygen species, and enteral disruption of gut microbiota and gut barrier function, increasing hepatic exposure to microbial products through enterohepatic circulation [82,114].

5.3. Neurodegenerative Diseases

The oral–gut-brain axis is an emerging extension of the microbiota-gut-brain axis. Oral and gut dysbiosis may influence neurodegenerative disease through systemic inflammation, altered microbial metabolites, blood-brain barrier permeability, microglial activation, microbial amyloids, LPS signaling, and possible dissemination of oral microbes or microbial products to neural tissues [115,116]. Alzheimer’s disease is the most frequently discussed neurodegenerative condition in relation to oral dysbiosis. Oral microbial dysbiosis and periodontitis are common in older adults and may contribute to Alzheimer’s disease risk by increasing systemic pro-inflammatory cytokines, compromising blood-brain barrier integrity, and promoting neuroinflammatory cascades [117]. Reviews have reported the detection of oral-associated microbial signatures in Alzheimer’s disease brain tissue and have discussed P. gingivalis as a candidate contributor to neuroinflammation, amyloid pathology, and cognitive decline [118,119]. The causal status of periodontal pathogens in Alzheimer’s disease remains uncertain. A critical review concluded that P. gingivalis and other periodontal microorganisms may contribute to Alzheimer’s-related inflammatory and pathological changes, but human clinical evidence is insufficient to establish a direct causal relationship [119]. Therefore, the most accurate wording is that oral dysbiosis may act as a modifiable inflammatory risk factor or disease amplifier rather than an established primary cause of Alzheimer’s disease [117].

Gut dysbiosis also contributes to neurodegenerative diseases by increasing intestinal permeability, systemic inflammation, and neuroinflammation [120]. Microbiota-derived metabolites, including short-chain fatty acids, bile acid derivatives, neurotransmitter precursors, and inflammatory metabolites, can regulate microglia, astrocytes, oligodendrocytes, and peripheral immune responses [116]. Parkinson’s disease provides another important example because oral and gut dysbiosis have both been observed in patients. A shotgun metagenomic study found significant differences in the oral and gut microbiomes between patients with Parkinson’s disease and controls, with oral Lactobacillus associated with opportunistic gut pathogens and functional microbial changes in glutamate and arginine biosynthesis, as well as antimicrobial resistance genes [62]. Parkinson’s disease reviews also emphasize gut inflammation, impaired barrier function, neuroinflammation, changes in microbial metabolites, and possible α-synuclein propagation via the enteric nervous system and vagal pathways [83]. Evidence for multiple sclerosis is less developed but supports inclusion under inflammatory neuroimmune conditions. One study found that oral microbial communities differed between patients with multiple sclerosis (MS) and healthy controls, with higher abundances of genera including Staphylococcus, Actinomyces, Fusobacterium, Bacteroides, Porphyromonas, Prevotella, and Veillonella in MS patients [49]. Gut microbiome reviews in MS propose that intestinal dysbiosis can influence immune tolerance and central nervous system demyelination, but the oral–gut contribution requires more direct study [84].

5.4. Autoimmune and Inflammatory Conditions

Autoimmune and inflammatory diseases are highly relevant to the oral–gut axis because mucosal microbiomes shape immune tolerance, Th17 differentiation, neutrophil recruitment, cytokine signaling, and autoantigen exposure [121]. Oral microbiota dysbiosis has been linked to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome, and other systemic autoimmune diseases [86]. The main proposed mechanisms include microbial translocation, molecular mimicry, local and systemic cytokine amplification, autoantigen overproduction, and disruption of mucosal immune homeostasis [121]. Prevotella species are particularly relevant because increased Prevotella abundance at mucosal sites has been linked to periodontitis, rheumatoid arthritis, metabolic disease, Th17-mediated inflammation, and systemic dissemination of inflammatory mediators [50].

Rheumatoid arthritis is the most developed autoimmune example. Periodontitis and RA share inflammatory tissue destruction, immune dysregulation, and risk factors such as smoking [122]. P. gingivalis has been proposed as a mechanistic link because it expresses peptidylarginine deiminase activity that can contribute to citrullinated antigen formation, potentially intersecting with anti-citrullinated protein antibody (ACPA) biology [57]. Clinical evidence supports an association between periodontitis and RA severity. In a study comparing RA patients with osteoarthritis controls, periodontitis was more common in RA and ACPA-positive RA, and periodontal disease was associated with swollen joint counts, disease activity, radiographic damage, anti-cyclic citrullinated peptide-2 (anti-CCP-2), and rheumatoid factor [85]. Oral microbiome studies in early RA and at-risk individuals show enrichment of potentially pro-inflammatory taxa, including Prevotella and Veillonella, suggesting that oral microbial alterations may appear early in RA-associated autoimmunity [48].

Animal evidence directly connects oral bacteria, gut microbiota, and arthritis. Oral administration of P. gingivalis aggravated collagen-induced arthritis in mice, changed gut microbial composition, increased serum endotoxin and inflammatory markers, impaired gut barrier function, and increased Th17 responses. This study is among the strongest mechanistic evidence for an oral–gut-immune axis in systemic inflammatory disease [123]. Systemic lupus erythematosus is also associated with differences in the oral microbiome. A large tongue-coating study found increased oral microbial diversity and distinct microbial composition in treatment-naive SLE patients, with enrichment of Prevotella and Veillonella and reduction of Streptococcus and Porphyromonas. The same study developed oral microbial classifiers with high diagnostic performance, suggesting possible non-invasive biomarker applications, although independent validation and mechanistic work remain needed [51].

6. Cancer Connections

Cancer is one of the clearest areas where oral–gut microbial interactions have translational potential. Oral and gut microbes can influence carcinogenesis through chronic inflammation, genotoxic metabolites, DNA damage, immune evasion, epithelial barrier disruption, biofilm formation, altered cell proliferation, and modulation of therapy response [124,125]. The oral cavity is particularly important because it can serve as a reservoir for bacteria that later appear in colorectal, gastric, pancreatic, and other gastrointestinal tumors [9,126].

6.1. Colorectal Cancer

Colorectal cancer has the strongest evidence base for an oral–gut cancer axis. Early genomic studies found enrichment of Fusobacterium sequences in colorectal carcinoma tissue compared with matched normal tissue, establishing F. nucleatum as a central organism in CRC microbiome research [52,76]. Fusobacterium has also been associated with colorectal adenomas, suggesting that enrichment of oral-associated bacteria may begin before invasive carcinoma [127]. Oral-associated communities are not restricted to Fusobacterium. A mucosal microbiome study across colorectal tumorigenesis found that a metacommunity dominated by oral microbiome members was primarily associated with CRC [127]. A high-resolution bacterial 16S meta-analysis found that species from the Human Oral Microbiome Database were highly enriched in CRC and that overlapping bacterial consortia appeared in a large proportion of CRC cases [128]. CRC-associated gut microbiomes also show enrichment of oral-associated species such as F. nucleatum, Peptostreptococcus stomatis, Gemella morbillorum, and Parvimonas micra [129].

Oral microbiota may also have diagnostic value in CRC. Flemer et al. profiled oral swabs, colonic mucosa, and stool samples and concluded that oral microbiota in CRC is distinctive and predictive, supporting the possibility that oral microbiome profiling could contribute to non-invasive CRC screening [26]. A systematic review of oral microbiome biomarkers for CRC concluded that oral microbiota-based biomarkers are promising but require larger validation studies and mechanistic clarification [78]. Mechanistically, F. nucleatum contributes to colorectal carcinogenesis through adhesion, invasion, inflammation, immune modulation, DNA damage, altered epithelial signaling, and therapy resistance [130]. FadA adhesin promotes DNA damage and tumor progression by modulating E-cadherin and β-catenin signaling, leading to downstream upregulation of Chk2 [131]. F. nucleatum can also promote chemoresistance to 5-fluorouracil through Toll-like receptor 4 (TLR4)/NF-κB-mediated upregulation of baculoviral IAP repeat-containing 3 (BIRC3) [53].

Recent strain-level work has refined this field by showing that a distinct F. nucleatum subspecies animalis clade, Fna C2, dominates the CRC tumor niche. This clade exhibits CRC-enriched genetic features consistent with gastrointestinal colonization and metabolic adaptation, and Fna C2-treated mice develop more intestinal adenomas and show altered metabolites. This finding is important because it suggests that cancer relevance may depend on strain-level traits rather than species-level presence alone [54]. CRC is therefore best described as a polymicrobial, context-dependent disease ecosystem rather than a single-pathogen cancer [60]. Oral-associated bacteria may contribute to tumorigenesis by forming biofilms, stimulating inflammatory pathways, interacting with host immune responses, altering local metabolites, and cooperating with other CRC-associated bacteria such as enterotoxigenic Bacteroides fragilis and colibactin-producing Escherichia coli [60,77].

6.2. Pancreatic and Gastric Cancers

Pancreatic cancer is a high-priority area because early detection remains difficult, and non-invasive biomarkers are urgently needed. A prospective nested case-control study found associations between pre-diagnostic oral microbiota and subsequent pancreatic cancer risk, indicating that oral microbial differences can precede clinical diagnosis rather than merely reflecting cancer treatment or late-stage disease. This makes pancreatic cancer one of the most important non-CRC examples for oral microbiome biomarker research [132]. Salivary microbiome studies also show differences between pancreatic cancer patients and controls. Torres et al. reported that salivary bacterial profiles differed in pancreatic cancer and found a higher Leptotrichia to Porphyromonas ratio in pancreatic cancer patients compared with healthy and disease controls [133]. Vogtmann et al. found that oral microbial community composition differed between pancreatic cancer cases and controls in an Iranian case-control study, especially in beta diversity [134]. Evidence also suggests that oral-associated bacteria may be present in pancreatic tissues or precursor lesions. Gaiser et al. found bacterial DNA, including oral-associated taxa, in pancreatic cystic neoplasms and reported associations with cyst severity and inflammatory features [135]. Reviews of the oral microbiome and pancreatic cancer conclude that oral microbial shifts may occur years before diagnosis and that oral microbes may influence pancreatic carcinogenesis through inflammation, immune modulation, metabolism, and tumor microenvironment effects, but mechanisms remain incompletely proven [136,137].

Fecal microbiome studies may currently outperform saliva alone for pancreatic cancer classification. Kartal et al. developed fecal metagenomic classifiers that identified pancreatic ductal adenocarcinoma with high accuracy, and performance improved further when combined with serum carbohydrate antigen 19-9 (CA19-9). This suggests that future pancreatic cancer screening may use integrated oral, fecal, serum, and clinical markers rather than a single microbial specimen type [138]. Gastric cancer differs from pancreatic cancer because Helicobacter pylori remain the dominant microbial carcinogen. However, gastric carcinogenesis is increasingly understood as a broader dysbiosis process in which non-H. pylori microbes and oral-associated organisms may contribute to inflammation, nitrosation, acetaldehyde production, and mucosal transformation [47]. Gastric mucosal microbiome studies show stage-associated dysbiosis across superficial gastritis, atrophic gastritis, intestinal metaplasia, and gastric cancer [139]. Shotgun metagenomic work also shows that the gastric microbiome is perturbed in advanced gastric adenocarcinoma, with potential diagnostic and prognostic relevance [140].

The oral-gastric axis is especially plausible because the stomach is directly exposed to swallowed oral microbes. A recent review concluded that oral microbes are closely related to gastric microbes and gastric lesions, including gastric atrophy, intestinal metaplasia, and gastric cancer. The same review noted that oral-associated microbes such as Streptococcus anginosus and Prevotella melaninogenica may contribute to gastric inflammation or carcinogenesis, and that microbial metabolites such as lactate, nitrite, and acetaldehyde may promote malignant transformation [47]. Oral and tongue microbiome profiles have also been investigated as gastric cancer screening tools. Sun et al. reported that oral bacterial profiles in saliva and plaque were more complex in gastric cancer patients and proposed a microbial scoring system with high sensitivity in a small cohort [141]. Tongue-coating microbiota has also been associated with gastric cancer risk, supporting the idea that accessible oral surfaces may contain signals of upper gastrointestinal disease [142].

6.3. Oral Microbiome Biomarkers for Cancer Risk

Oral microbiome biomarkers are attractive because saliva, oral rinse, tongue coating, plaque, and mucosal swabs are non-invasive, repeatable, inexpensive, and compatible with population screening [3,143]. Saliva is particularly useful because it contains microbial DNA, host RNA, proteins, metabolites, extracellular vesicles, and immune mediators that can reflect both oral and systemic disease states [144,145]. In colorectal cancer, oral microbiome biomarkers are promising but not yet clinically validated. One study showed that oral microbiota in CRC is distinctive and predictive [26]. A systematic review concluded that oral microbiota-based biomarkers could become useful non-invasive tools for CRC detection, but larger cohorts, standardized protocols, and external validation are needed [78]. Microbiome-based screening may be most powerful when combined with existing clinical tests. A fecal microbiota-based random forest model improved sensitivity for detecting colonic lesions when combined with fecal immunochemical testing (FIT), detecting more cancers and adenomas than FIT alone in that cohort. This supports an adjunctive model in which microbial biomarkers complement rather than replace established screening methods [146].

Digestive cancer reviews show that oral microbiota composition differs between patients with and without gastrointestinal cancers, but they also emphasize that oral–gut microbial transmission patterns and carcinogenic mechanisms require further validation [126]. The main biomarker challenges include heterogeneity in sampling sites, sequencing platforms, DNA extraction, bioinformatics pipelines, geography, diet, smoking, oral hygiene, periodontal status, antibiotic exposure, tumor stage, and treatment history [86,126]. Therefore, oral microbiome biomarkers should currently be considered promising risk-stratification and screening adjuncts, not standalone diagnostic replacements [78]. Future clinical translation will require multi-center validation, reproducible laboratory pipelines, longitudinal pre-diagnostic cohorts, integration with host biomarkers, and evidence that microbial markers add value beyond existing screening tools [147,148].

7. Therapeutic and Preventive Implications

The therapeutic significance of the oral–gut microbiome axis lies in a broader conceptual shift: the oral cavity should no longer be viewed solely as a localized anatomical niche, but as a modifiable upstream contributor to microbial dissemination, systemic inflammatory burden, and mucosal immune signaling. Although microbiome-guided therapies are not yet ready for routine clinical implementation across gastrointestinal diseases, current evidence increasingly supports incorporating oral ecology into prevention strategies, risk assessment, and adjunctive therapeutic frameworks, particularly in inflammatory bowel disease (IBD) and colorectal cancer (CRC) [75,90].

7.1. Oral Health as A Systemic Intervention

Among the proposed interventions, optimization of oral health is the most immediately actionable in clinical practice. Periodontal inflammation increases the burden of oral pathobionts and inflammatory mediators, while studies of the oral–gut axis suggest that periodontal disease may both exacerbate intestinal inflammation and reflect broader systemic dysregulation [55,63,90]. Consequently, plaque control, periodontal therapy, reduction of gingival inflammation, and regular dental surveillance may reasonably be viewed not only as oral care measures but also as potential adjunctive approaches to the management of systemic inflammation. This concept is particularly relevant in IBD. Recent reviews suggest that monitoring and correcting oral dysbiosis may improve disease control, although robust randomized interventional evidence remains limited [75,149]. At present, the most evidence-supported conclusion is appropriately cautious: optimization of oral health represents a low-risk, biologically plausible, and readily implementable systems-level intervention whose broader clinical relevance may currently be underestimated. Importantly, this perspective does not imply that periodontal therapy alone can reverse complex immune-mediated gastrointestinal disease. Rather, oral health should be considered one component of a broader ecological and inflammatory management strategy that may complement conventional therapies.

7.2. Probiotics, Prebiotics, and Synbiotics

Microbiome-modifying strategies, including probiotics, prebiotics, and synbiotics, remain central to discussions surrounding oral–gut therapeutics, although the supporting evidence remains heterogeneous and, in many cases, preliminary [75]. Because both oral and intestinal microbial ecosystems are interconnected, there is increasing rationale for integrated oral–gut ecological modulation rather than interventions directed exclusively at a single anatomical site. In IBD, the strongest evidence does not support the notion that probiotics can independently reverse complex immune-mediated pathology. Instead, selected microbial interventions may function as adjuncts to conventional anti-inflammatory therapy by supporting epithelial barrier integrity, reducing pathogen burden, and reshaping metabolite networks [75,90]. However, therapeutic responses are likely influenced by multiple interacting variables, including strain specificity, dosage, host diet, baseline microbiome architecture, medication exposure, and inflammatory context. Accordingly, broad claims regarding universal efficacy should be avoided.

An additional challenge is ecological resistance within dysbiotic microbial communities. Established inflammatory microbiomes may resist colonization by beneficial organisms, while inflammatory conditions themselves may impair microbial engraftment or alter nutrient availability in ways that reduce probiotic persistence and function [55,75]. These observations suggest that future synbiotic strategies may need to combine substrate support, inflammation control, and targeted pathogen reduction rather than relying on single-strain supplementation alone. More broadly, the field is gradually moving away from simplistic “good-versus-bad bacteria” models toward ecological frameworks that emphasize microbial networks, metabolite interactions, and host context. Future therapeutic approaches will likely depend less on introducing isolated organisms and more on restoring resilient microbial community structure and mucosal homeostasis.

7.3. Microbiome-Based Diagnostics and Screening

Microbiome-based diagnostics represent one of the most immediately translatable applications of oral–gut axis research. The oral cavity is highly accessible for sampling, repeated collections are feasible, and saliva or oral swabs provide a non-invasive biological matrix that is often more acceptable to patients than biopsy procedures and more convenient than stool collection [94,95]. In IBD, emerging evidence suggests that oral microbial signatures may contribute to early diagnosis, assessment of disease activity, and potentially prognostic classification [63,90]. In CRC, however, biomarker development is considerably more advanced. Multiple studies report that salivary and oral microbiota-based models can differentiate CRC from healthy controls and, in some cohorts, identify early-stage disease or precancerous lesions with promising discriminative performance [94,95].

Recent evidence also suggests that oral microbial signatures may carry prognostic value, expanding the potential utility of oral sampling beyond screening toward disease stratification and surveillance. This is particularly important because it positions the oral microbiome not merely as a passive reflection of disease state, but as a potentially informative component of precision oncology workflows. Despite this promise, substantial translational barriers remain. Cohort variability, sequencing-platform effects, confounding by oral hygiene, diet, smoking, medication exposure, and the absence of standardized sampling and analytical workflows all complicate interpretation and limit reproducibility [93,94,96]. Consequently, oral microbiome diagnostics are currently best viewed as adjunctive or risk-enrichment tools rather than replacements for established screening modalities such as colonoscopy or validated stool-based tests. Future progress will require large longitudinal cohorts, standardized laboratory pipelines, external validation across populations, and integration with host, clinical, and imaging biomarkers. The greatest clinical value may ultimately emerge from multimodal diagnostic models rather than microbiome signatures alone.

7.4. Opportunities for Personalized Medicine

The promise of personalized medicine within the oral–gut microbiome axis is rooted in biological heterogeneity. The clinical significance of oral dysbiosis likely depends on numerous host-specific variables, including periodontal status, host genetics, immune phenotype, diet, medication exposure, gastric acidity, epithelial barrier integrity, and the pre-existing structure of the gut microbiome [63,75]. As a result, the same oral microorganism may behave as a benign passenger in one individual, a biomarker in another, and a disease-modifying factor in a third. Accordingly, the most credible future strategies will likely integrate multisite microbial profiling with clinical phenotyping, immune characterization, and mechanistic biomarkers. In IBD, this could involve identifying patients with pronounced oralization of the gut microbiome, persistent periodontal inflammation, or reproducible enrichment of taxa such as Fusobacterium or Klebsiella, followed by targeted interventions including intensified dental management or ecological modulation [55,63,90]. In CRC, oral microbial signatures may eventually contribute to individualized screening intensity, prognostic assessment, and surveillance strategies when integrated with tumor and host characteristics [93,94,96]. More broadly, advances in metagenomics, metabolomics, transcriptomics, and machine learning may allow future models to move beyond static taxonomic descriptions toward dynamic prediction of disease trajectories and therapeutic responsiveness, consistent with broader microbiome-driven precision medicine frameworks [150]. Nevertheless, caution remains essential. Personalized microbiome medicine remains constrained by incomplete mechanistic understanding, limited longitudinal validation, and uncertainty about causality versus association. At present, the strongest translational value of the oral–gut microbiome axis lies not in replacing established medical frameworks but in expanding them through a more integrated understanding of mucosal ecology, inflammation, and systemic disease.

The oral–gut microbiome axis also offers several translational opportunities, particularly in non-invasive diagnostics, disease risk prediction, periodontal intervention, and personalized microbiome-based therapy. However, most applications remain investigational because of variability in sampling methods, host factors, sequencing platforms, and limited clinical validation. Translation of oral microbiome research requires a structured pipeline that connects sample collection, multi-omics analysis, biomarker discovery, risk prediction, and intervention design, consistent with broader microbiome-driven precision medicine approaches [150]. This workflow is summarized in Figure 4.

While Figure 4 summarizes the translational workflow, Table 3 outlines specific applications, current limitations, and future directions for oral microbiome-based diagnostics and interventions.

8. Challenges and Future Directions

Despite rapid growth in oral–gut microbiome research, the field still faces major conceptual, methodological, and translational challenges. The most important limitation is that many studies remain cross-sectional and cannot determine whether microbial dysbiosis is a cause, a consequence, a biomarker, or a bystander of disease [80,86].

8.1. Causality Versus Correlation

Causality is difficult to establish because oral dysbiosis, gut dysbiosis, and systemic disease share many confounders, including age, diet, smoking, medication use, antibiotics, proton-pump inhibitors, diabetes, obesity, socioeconomic status, immune function, oral hygiene, and access to dental care [81,154]. The disease itself can also alter the microbiome through inflammation, altered diet, reduced salivary flow, immune dysfunction, medication exposure, and treatment effects [151]. Future work should follow a layered causality framework. Prospective cohorts are needed to show that oral or gut microbial changes precede disease onset [147]. Longitudinal sampling is needed to determine whether microbial shifts track disease flares, treatment response, or progression [155]. Mechanistic models are needed to test whether candidate organisms or metabolites can reproduce disease-relevant immune, metabolic, barrier, or tumor phenotypes [156].

8.2. Need for Longitudinal and Mechanistic Studies

A longitudinal study design is essential because microbiomes are dynamic communities that can change abruptly after perturbations and may settle into alternative stable states [155]. Oral–gut studies need repeated oral, fecal, blood, metabolite, and immune sampling to identify whether oral dysbiosis precedes gut dysbiosis, follows gut inflammation, or fluctuates with systemic disease activity [157]. Mechanistic studies should distinguish oral microbial passage from true colonization. Many oral bacteria are swallowed daily, but only some survive gastric acidity, resist bile acids, overcome colonization resistance, adhere to intestinal mucus, invade tissue, or participate in biofilm communities [9]. Future studies should therefore combine strain tracking, culture-based validation, spatial imaging, metagenomics, metatranscriptomics, and host immune profiling to show where oral microbes are located and what they are doing [152]. Cancer studies show why strain-level resolution matters. Species-level detection of F. nucleatum is useful, but CRC-associated behavior may depend on specific clades with genetic adaptations for tumor colonization and intestinal survival. This means future oral–gut cancer studies should move beyond genus-level and species-level 16S profiling toward shotgun metagenomics, isolate sequencing, and functional assays [54].

8.3. Integrating Oral–Gut Multi-Omics

Multi-omics integration is needed because taxonomic profiling alone cannot explain mechanisms. Shotgun metagenomics can identify species, strains, virulence genes, and metabolic pathways [152]. Metatranscriptomics can reveal which microbial genes are actively expressed during disease [158]. Metabolomics can identify functional mediators, including short-chain fatty acids (SCFAs), bile acids, amino acid metabolites, nitrite, acetaldehyde, lactate, polyamines, and inflammatory lipids [153]. Host transcriptomics and proteomics can reveal epithelial barrier responses, immune activation, cytokine signaling, oxidative stress, and tissue remodeling [152].

8.4. Personalized Intervention Strategies

Personalized intervention is the translational goal of oral–gut microbiome research. Potential strategies include oral hygiene optimization, periodontal therapy, dietary modification, probiotics, prebiotics, synbiotics, postbiotics, targeted antimicrobials, bacteriocins, microbiota transplantation, host-response modulation, and engineered bacteria [159,160]. Oral health interventions could become systemic prevention strategies if future trials show that treating oral dysbiosis reduces gut dysbiosis, systemic inflammation, or disease-specific endpoints. Periodontal therapy is particularly relevant for cardiometabolic disease, rheumatoid arthritis, NAFLD, and inflammatory bowel disease, as these conditions share inflammatory pathways with periodontitis [82,102]. Microbiome-based interventions must also account for ecological resilience. Antibiotics can perturb microbiome diversity, resistance genes, and colonization resistance, and recovery depends on age, diet, baseline microbiome composition, antibiotic spectrum, treatment duration, and host health. This is relevant to oral–gut studies because broad antimicrobial approaches may reduce pathobionts but also damage beneficial microbial networks [161]. Probiotics, prebiotics, synbiotics, and dietary interventions are promising, but disease-specific evidence remains uneven. In type 2 diabetes, microbiome-targeted approaches include diet, probiotics, metformin-mediated gut effects, bariatric surgery-associated microbiome shifts, targeted propionate delivery, fecal microbiota transplantation, and genetically modified bacteria, but human causal evidence is still limited [162]. In NAFLD linked to periodontitis, periodontal treatment and microbiome-targeted approaches have been proposed, but robust clinical trials are needed [82].

9. Conclusions

The oral–gut microbiome axis provides an important framework for understanding how microbial communities at anatomically distinct mucosal sites can influence gastrointestinal and systemic health. The oral cavity is not only a local microbial niche but also a potential upstream source of microbes, metabolites, and inflammatory signals that may reach the gut and systemic circulation. Through microbial migration, immune-mediated communication, metabolite-mediated effects, epithelial barrier disruption, and inflammatory feedback loops, oral dysbiosis may contribute to altered gut ecology, chronic inflammation, and disease susceptibility. However, these mechanisms should not be interpreted as linear or mutually exclusive; they likely operate together and are shaped by host genetics, oral inflammatory status, medication exposure, epithelial barrier integrity, diet, and baseline gut microbiome composition. Current evidence is strongest for inflammatory bowel disease and colorectal cancer, where oral-associated taxa and oral microbial signatures have been repeatedly linked with intestinal inflammation, tumor-associated microbiota, and potential biomarker development. Evidence for cardiovascular disease, metabolic disorders, neurodegenerative diseases, and autoimmune conditions is biologically plausible but remains more indirect and requires further mechanistic and longitudinal validation. Therefore, oral dysbiosis should currently be viewed as a potential disease modifier, biomarker source, or inflammatory amplifier rather than a universal primary cause of systemic disease.

From a translational perspective, the oral microbiome offers promising opportunities because saliva, oral rinse, tongue coating, and oral swabs are accessible, repeatable, and patient-friendly sample types. Oral microbiome profiling may eventually support risk stratification, CRC screening, IBD monitoring, periodontal intervention, microbiome modulation, and personalized prevention strategies. However, clinical implementation remains limited by cohort heterogeneity, differences in sequencing platforms, confounding factors, incomplete causal evidence, and the need for standardized protocols. Future studies should prioritize longitudinal sampling, multi-center validation, mechanistic models, strain-level analysis, and integration of microbiome data with host immune, metabolic, and clinical biomarkers. Ultimately, the greatest value of the oral–gut microbiome axis may lie not in replacing existing diagnostic or therapeutic approaches, but in expanding them through a more integrated understanding of mucosal ecology, inflammation, and precision medicine.