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Review

From Dysbiosis to Tissue Destruction: Periodontal Pathogens as Inducers of Gingival Epithelial–Mesenchymal Transition (A Narrative Review)

by
Hadeel Mazin Akram
* and
Saif Sehaam Saliem
College of Dentistry, University of Baghdad, Baghdad 5421, Iraq
*
Author to whom correspondence should be addressed.
J. Mol. Pathol. 2026, 7(1), 11; https://doi.org/10.3390/jmp7010011
Submission received: 17 January 2026 / Revised: 14 February 2026 / Accepted: 2 March 2026 / Published: 4 March 2026
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Abstract

Periodontitis is a dysbiosis-driven inflammatory disease in which a pathogenic subgingival biofilm disrupts the host–microbe equilibrium and promotes progressive loss of tooth-supporting tissues. While periodontal destruction has traditionally been explained mainly through the host immune response, increasing experimental and clinical evidence suggests that epithelial–mesenchymal transition (EMT)-like changes in the gingival epithelium may contribute to barrier failure and tissue remodeling during disease progression. EMT is characterized by reduced epithelial adhesion and polarity, alongside a shift toward a mesenchymal-like phenotype with enhanced motility and impaired epithelial barrier function. This narrative review focuses on how periodontal pathogens, particularly red complex organisms and keystone species, may trigger gingival EMT through virulence factors such as gingipains, fimbriae, lipopolysaccharide, and outer membrane vesicles. These microbial signals can hijack host pathways including TGF-β/Smad, Wnt/β-catenin, and Notch to drive EMT-associated transcriptional changes and downstream functional consequences. Collectively, pathogen-induced gingival EMT may facilitate deeper microbial invasion, perpetuate chronic inflammation, impair wound healing, and contribute to fibrotic remodeling, ultimately linking microbial dysbiosis to connective tissue destruction. Understanding these mechanisms may support the development of EMT-related biomarkers and targeted interventions aimed at preserving epithelial barrier stability in periodontitis.

1. Introduction

Periodontitis is one of the most common chronic inflammatory diseases in the world, resulting in the loss of the periodontal ligament and alveolar bone [1,2]. It is initiated by subgingival biofilm accumulation, which promotes dysbiosis and disrupts the normal homeostatic relationship between the host and the oral microbiome [3,4]. The gingival epithelium, particularly the junctional epithelium, serves as the major physical and biological defense against microorganisms, yet it is not simply a wall; rather, it is a highly dynamic tissue that senses and reacts to microbial insult via numerous and complex signaling pathways [5,6,7].
More recently, EMT-like changes have been proposed as part of periodontitis pathogenesis [7,8]. Under chronic inflammatory conditions, characterized by repeated acute inflammatory episodes, epithelial cells lose their epithelial characteristics (such as E-cadherin) and acquire mesenchymal characteristics (such as vimentin and N-cadherin) [9]. Loss of epithelial characteristics, and therefore disruption of the gingival epithelial barrier [10], occurs due to epithelial cells losing apical-basal polarity and intercellular junctions [11].
EMT occurs in three types: developmental (Type 1), inflammation/repair (Type 2), and cancer-related (Type 3). In periodontitis, EMT-like epithelial plasticity represents a Type 2 EMT-like response driven by inflammation and microbial factors, manifesting as partial or reversible remodeling [7]. Since wound repair and fibrosis signaling overlap with EMT pathways, references to “fibrosis” or “myofibroblast-related” outcomes describe downstream remodeling responses rather than definitive epithelial-to-myofibroblast transition in periodontal tissues [11].
EMT-like changes in periodontal tissues appear to be strongly influenced by interactions of periodontal pathogens with the host epithelium [1]. Periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis) are able to utilize numerous virulence factors to promote both the invasion and colonization of host cells [3]. Through these virulence factors, pathogens cause an EMT resulting in bacterial invasion, thus allowing bacteria to migrate beyond the host’s initial immune defenses and into the connective tissue [5]. Most evidence comes from in vitro models and long-term infection experiments. However, direct causality in human periodontitis remains difficult to prove due to tissue heterogeneity, mixed biofilms, and confounding inflammation. This narrative review summarizes the mechanisms by which periodontal pathogens can promote EMT-like changes and disrupt epithelial barrier function. It also discusses how these events may contribute to downstream tissue destruction in periodontitis.
While the mechanistic pathways discussed here are strongly supported by in vitro models and, to a lesser extent, animal studies, the evidence base in human periodontitis is often observational (histopathology, expression studies, and association with disease severity). For that reason, we explicitly indicate throughout the review whether a finding comes primarily from experimental systems or from human tissues, and we treat causal language in human disease as inference unless directly supported by clinical or histological data.
A schematic overview summarizing pathogen-induced EMT-like remodeling and its proposed contribution to junctional epithelial instability, apical migration, pocket formation, and clinical attachment loss is provided in Figure 1.

2. Materials and Methods

Literature Search and Study Selection

This paper is a narrative review. A structured literature search was completed using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, published up to January 2026, to find studies for this review. The searches were designed to look at both “dysbiosis” and “epithelial–mesenchymal transition (EMT)” and contained (but are not limited to) the following terms: periodontitis, subgingival dysbiosis, gingival epithelium, epithelial–mesenchymal transition (EMT), Porphyromonas gingivalis, Fusobacterium nucleatum, gingipains, fimbriae, lipopolysaccharide (LPS), outer membrane vesicles, and transcription factors associated with EMT such as E-cadherin, vimentin, Snail, Twist, and ZEB.
In selecting studies to link periodontal pathogens (and/or their virulence factors) to EMT-like epithelial changes or barrier disruption, we prioritized articles from peer-reviewed journals, and we also reviewed recently published reviews on the topic so that we would not miss important mechanisms. Since it is often very difficult to establish causation in human periodontitis, we evaluated evidence from all three areas of study (animal studies, in vitro models, human tissue/clinical studies) and discussed the limitations of each in the relevant sections.

3. Subgingival Dysbiosis and Keystone Periodontal Pathogens

3.1. Characterization of the Red Complex and Keystone Pathogens

The ‘red complex’ classically comprises P. gingivalis, Treponema denticola, and Tannerella forsythia [12]. These species are frequently isolated from deep periodontal pockets and are associated with greater disease severity [13]. While the association between these taxa and disease severity is supported by clinical and microbiological studies in humans, many of the mechanistic links discussed in the following sections (adhesion, invasion, EMT-marker shifts, and pathway activation) come primarily from in vitro systems and, to a lesser extent, animal models. For clarity, we indicate when evidence is experimental versus human-based, and we avoid implying direct causality in human periodontitis when the available data are largely associative.
P. gingivalis, as identified as a “keystone pathogen”, has the capability to cause inflammatory bone loss at low levels through structural changes to the oral microbiota [14]. Pathogenicity of these microbes is due to the presence of multiple virulence factors. P. gingivalis uses several cysteine proteases referred to as gingipains that are divided into two types based on specificity; RgpA/RgpB are arginine-specific, and Kgp is lysine-specific [15] and work together to degrade extracellular factors such as cytokines and cell-surface receptors to alter the host’s immune response and disrupt tissue architecture [16]; the bacterial surface is also typically modified with carbohydrates-glycans, this modification may enhance host–pathogen interaction and promote bacterial survival [17].
Treponema denticola, the oral spirochete, contributes to its virulence through motility and the production of dentilisin, a protease that degrades the extracellular matrix and impairs cell-to-cell communication [18,19], while the S-layer of T. forsythia promotes the evasion of the host immune response and the adhesion to host cells [20]. The collective presence of both the red complex species and other members of the orange complex, including Fusobacterium nucleatum, produces a biofilm environment that maintains a chronic infection [21].

3.2. Mechanisms of Bacterial Attachment and Intracellular Invasion

The ability of periodontal pathogens to cause epithelial cells to undergo a change from an epithelial phenotype to a mesenchymal phenotype (EMT) has been shown to correlate with how well those pathogens can adhere to and enter into gingival epithelial cells [5]. It is worth noting that this correlation is best established in experimental models; in humans, invasion-related findings are more difficult to interpret directly because tissues are heterogeneous, and biofilms are polymicrobial (Figure 2). An example of this would be P. gingivalis using its fimbriae; long and thin extensions of itself, to come into close proximity with the host cell’s outer layer, or cell membrane [22]. The primary structure of the fimbriae used by P. gingivalis to attach to the host cell is called FimA [22]. FimA will selectively bind to the conformations of the α5β1-integrin receptors found on epithelial cells, causing an inside-out signaling pathway that ultimately allows the bacteria to enter the epithelial cell [23]. In experimental models, these interactions appear to precede cytoskeletal remodeling and the induction of EMT-related genes [6].
After attaching to a host cell, pathogens can enter via receptor-mediated endocytosis pathways [24]. P. gingivalis will initially be in endocytic vacuoles after internalization, but they may escape into the cytoplasm or be directed to lytic compartments [25]. Some intracellular bacteria can even exit cell via endocytic recycling pathways to neighboring cells without immediately lysing the host cell [26]. This trans-cellular movement is a mechanism for invading more substantive tissue layers [27].
In addition to a whole-cell invasion, periodontal pathogens also release outer membrane vesicles (OMVs), spherical nanostructures, that contain various virulence factors, including gingipains and lipopolysaccharides (LPS) [28]. The advantage of OMVs is that they can cross the epithelial barrier easily compared to the parent bacteria, and are internalized by host cells via endocytic pathways [29]. OMVs will release their cargo once inside the host cell, and have the ability to directly interfere with cellular activity and/or even stimulate the host signaling cascade for inducing EMT [30]. Chronic exposure of the gingival epithelium to these bacterial products causes persistent impairment of cellular function and barrier integrity [31].

4. Gingival EMT in Periodontitis: Core Concepts and Molecular Markers

4.1. Molecular Markers and Phenotypic Changes in Gingival Epithelium

EMT has been divided into three subcategories of biological relevance: Type 1 is associated with embryonic development; Type 2 is associated with chronic wound/chronic inflammation; and Type 3 is associated with tumor progression [1]. With regard to the biology of periodontitis, the primary EMT observed is that of Type 2, due to the constant presence of a pro-inflammatory environment as well as microbial challenge [10]. The hallmark of EMT is termed the “cadherin switch” and is defined by the downregulation of the epithelial cell marker E-cadherin (also known as cadherin-1) and its replacement with the mesenchymal cell marker called N-cadherin [32].
The most important role of the loss of E-cadherin is its ability as the key component of adherens junctions to maintain cellular adhesion, and therefore, the polarity of epithelial cells [33]. When E-cadherin expression decreases, and cells lose their cobblestone-like shape, they begin to look like spindle-shaped, fibroblast-like cells [34]. In addition to the change in phenotype, vimentin, an important intermediate filament protein, will be overexpressed, giving the cells the flexibility required for a migratory phenotype [35]. Additionally, the transformation of cells will also be identified by the production of fibronectin, and matrix metalloproteinases (MMPs) to degrade the basement membrane and to allow the transformed cells to migrate into connective tissue [36].
These molecular changes profoundly affect the gingival barrier. As junctional proteins decrease, paracellular permeability increases and allows bacterial toxins and metabolic by-products to penetrate deeper into periodontal tissues [10]. Furthermore, the migratory phenotype acquired by the epithelial cells could allow an apical migration of the junctional epithelium that is a classic clinical feature of periodontal pocketing [1].

4.2. Core Signaling Pathways: TGF-β, Wnt/β-Catenin, and Notch

EMT induction is governed by a complex network of signaling pathways in response to cell surface stimuli [11]. The transforming growth factor-beta (TGF-β) pathway is widely regarded as the master regulator of EMT [37]. The Smad-dependent canonical pathway sees TGF-β1 bind to its receptors to phosphorylate Smad2 and Smad3, which form a complex with Smad4 and translocate to the nucleus [38]. The complex activates transcription of EMT-inducing factors Snail, Slug, and Twist that repress E-cadherin expression [39].
Periodontal pathogens have been shown to hijack the TGF-β axis. For example, P. gingivalis was shown to elicit host-derived TGF-β1 and activate Smad signaling in human gingival epithelial cells [40,41,42]. Activation is often compounded by the inflammatory milieu in which cytokines such as TNF-α and IL-1β provide additional signals that promote mesenchymal differentiation [43]. TGF-β signaling can also contribute to the anti-inflammatory response during wound healing; however, chronic activation by pathogens can lead to pathological fibrosis [41,44].
The Wnt/β-catenin pathway is also important and plays a direct role in periodontal EMT [45]. In the absence of Wnt signals, β-catenin is degraded by a cytoplasmic destruction complex. When the Wnt pathway is activated, β-catenin is stabilized and translocates to the nucleus, acting as a co-activator for mesenchymal state-promoting genes [45]. Wnt signaling was significantly activated in gingival tissues from experimental periodontitis [46]. There is also extensive crosstalk between Wnt/β-catenin and TGF-β signaling as well as with NF-κB pathway, that collectively drive EMT marker expression such as ZEB2 [47].
Notch signaling once again is a critical pathway involved in cell fate determination and EMT [48]. Activation of the Notch pathway in epithelial cells leads to upregulation of Snail, followed by reduced expression of E-cadherin [49]. In the periodontium, Notch signaling also interacts with other signaling pathways such as periostin, which is strongly expressed in the periodontal ligament, and is involved in both tissue remodeling/regeneration [50]. All three signaling pathways, TGF-β, Wnt, and Notch ultimately result in a self-reinforcing feedback loop and has been shown to support the maintenance of EMT during a chronic microbial challenge [51].
The integration of Wnt, TGF-β and Notch signaling is further complicated by epigenetic modification and changes induced in the hypoxic microenvironment associated with deep periodontal pockets [52]. Hypoxia-inducible factors (HIFs) directly activate EMT transcription factors, as well as synergize with Wnt signaling to promote a mesenchymal phenotype [53]. In summary, collectively these signaling pathways have helped provide a basis for how periodontal pathogens reprogram the host epithelium to elicit the structural and functional failures observed in periodontitis [53].

5. Mechanisms of Pathogen-Induced EMT in Periodontitis

The movement of gingival epithelial cells from a static, polarized state to a migratory, mesenchymal-like state is not just a passive effect of tissue loss but a highly regulated process driven by a few periodontal pathogens [9,11]. These pathogens utilize their own virulence factors to co-opt the host signaling pathways and effectively “reprogram” the epithelial barrier for their own survival and deeper interaction with the tissues. In this section, we will consider the specific roles of various keystone pathogens and the complex intracellular cascades activated by the bacteria [5].

5.1. Porphyromonas gingivalis as a Key Driver of EMT

As a key pathogen in the subgingival biofilm, Porphyromonas gingivalis (P. gingivalis) disproportionately shapes the periodontal environment by modulating the host immune response and cellular homeostasis [3]. Several studies have found that P. gingivalis is a very potent inducer of epithelial–mesenchymal transition (EMT) in gingival epithelial cells [10,54,55]. P. gingivalis uses many of the tools in its arsenal to induce the morphological transformation of the gingival epithelium [7]. The key pathways through which P. gingivalis induces EMT are based on the expression of the cysteine proteases gingipain (Rgp and Kgp) and the expression of fimbriae, which both contribute to adherence and signaling to the host cells. P. gingivalis-induced EMT has been characterized by the down-regulation of epithelial proteins, with a corresponding increase in the expression of mesenchymal proteins [53]. In addition to degrading the structure of the gingival epithelium, P. gingivalis also promoted the generation of TGF-β1 from within the host cells [7]. This produced an autocrine/paracrine signaling pathway that stabilized the mesenchymal phenotype and allowed the bacteria to avoid the initial physical barrier to the periodontium [54].
In addition to the aforementioned effects, P. gingivalis also has the ability to enter the host epithelial cells [54]. This allows the pathogen to affect host gene expression. Once internalized, P. gingivalis can persist intracellularly and modulate host transcriptional responses that favor EMT-associated changes [54]. Its intracellular presence would maintain an EMT stimulus, which may in part explain the strong association between P. gingivalis chronic infection, irreversible attachment loss and periodontal pockets [56].

5.2. Role of Fusobacterium nucleatum and Synergistic Biofilm Effects

While P. gingivalis acts as a primary orchestrator, F. nucleatum serves as a critical “bridge” organism in terms of creating the pathogenic biofilm, and will directly induce EMT [57]. F. nucleatum has the FadA adhesin (Fusobacterium adhesin A) which is a key virulence factor based on its interaction with host epithelial cells [57]. FadA binds specifically to E-cadherin within the apical membrane of epithelial cells, which does more than anchor the bacteria, it initiates intracellular signaling cascades [57].
After binding E-cadherin, FadA disrupts the stability of the adherens junctions between epithelial cells, which leads to the internalization and eventual degradation of E-cadherin [58]. Due to the loss of E-cadherin, β-catenin is released to the cytoplasm and can then translocate to the nucleus to initiate transcription of genes associated with cellular proliferation and mesenchymal transformation [3]. Additionally, there is evidence that F. nucleatum directly induces expression of mesenchymal markers, and increases the migration capacity of oral epithelial cells, supporting its role as a direct contributor to EMT-associated epithelial remodeling [59].
The effect of these bacteria is compounded by the multispecies biofilm [59]. For example, P. gingivalis has been shown to invade epithelial cells at higher levels when F. nucleatum was present, and the bacteria produced metabolites (e.g., hydrogen sulfide) that stress the epithelium, furthering the possibilities for phenotypic shifting [60]. The species Fusobacterium periodonticum can also promote phenotypic shifting within the epithelium (e.g., EMT subtype) through Wnt signaling. It is likely that multiple periodontal bacteria have this plasticity in the epithelium [60].

5.3. Activation of Transcription Factors and Protease-Driven Signaling

EMT is a distinctly molecular exercise, involving the activation of core transcription factors, including Snail (SNAI1), Slug (SNAI2), and Twist, that repress epithelial gene expression by binding to promoters, while activating mesenchymal gene expression [11]. Transcription factor activation is accomplished via multiple mechanisms, including direct bacterial signaling and the secondary inflammatory response related to periodontitis [11].
Protease-driven signaling, particularly within host tissues, is thought to be a pivotal process involved in the various downstream effects of EMT [11]. Matrix metalloproteinases (MMPs) have been shown to be significantly upregulated in periodontal pathogen infections, with MMP-2 and MMP-9 thought to be important actors [36]. MMPs degrade the structural components of the ECM and basement membranes and the degradation of these structural components creates a cascade that can alter how cells are signaled [61].
The inhibition of the ECM by MMPs can also release bound and sequestered growth factors (e.g., TGF-β), which then bind to host receptors to stimulate the Smad dependent pathway and increase levels of Snail and Slug in the host cells [62]. An additional mechanism of action is through the activation of protease activated receptors (PAR), and specifically, PAR-2 [63]. Gingipains, which are virulence factors produced by bacteria, cleave/activate PAR-2 at the surface of gingival epithelial cells, creating a signal transduction pathway that leads to the activation of mitogen-activated protein kinases (MAPKs) and increases expression of EMT markers [63]. This mechanism demonstrates the close association between bacterial enzyme activity and the host cell’s genetic reprogramming [64]. With multiple pathways (i.e., bacterial adhesion to host inflammatory cytokines), there is an increased potential for the epithelial layer to undergo a phenotypic transformation into a mesenchymal layer and maintain that transformed state throughout the periodontal disease process [64].

6. From Gingival EMT to Tissue Destruction: Barrier Breakdown and Remodeling

The effects of EMT go beyond being simply a cell biological process; it plays a significant role as one of the main reasons for the development of the clinical features associated with periodontitis [11]. In terms of the gingival epithelium, through the process of EMT, the cellular “identity” and the functional capabilities of the gingival epithelial cells are changed and compromised, thereby initiating an inflammatory response which can be either immune or non-immune mediated as well as creating a cascade of destructive events [1]. This area of discussion will look at the possible effect of EMT on breaking down the epithelial barrier and ultimately resulting in the production of chronic inflammation and fibrotic tissue [10].

6.1. Junctional Epithelium Barrier Breakdown

The Junctional Epithelium (JE) is the main barrier between the oral cavity and the supporting connective tissue [7]. Unlike other forms of oral epithelium, the JE has a distinct molecular profile and a greater degree of permeability that allows for the movement of select immune cells and gingival crevicular fluid through it [7]. While this increased permeability could have provided an opportunity for enhanced immune surveillance of the bacterial environment, it also created a number of challenges for the JE itself [65]. The JE’s susceptibility to the myriad effects of EMT resulted in its being considered as “leaky” as a direct consequence [65]. In addition to creating a breach in immune cell permeability through the JE when bacteria cause EMT, the barrier is compromised at many different levels of function [66]. One of the significant effects of barrier compromise is the dissolution of intercellular junctions, which include tight junctions (TJ), adherens junctions (AJ), and desmosomes [66]. TJ play a key role in controlling paracellular permeability, and consist of proteins such as claudins and occludins that are dramatically reduced or eliminated during the EMT process [66], thereby leading to a loss of molecular “sewing,” and an increase in the permeability of the epithelium that would allow bacterial toxins, enzymes, and pathogens to invade the periodontal ligament and alveolar bone [67].
In addition to the loss of E-cadherin in the AJ that results in the loss of physical adhesion between cells, there is also a loss of contact inhibition of movement [68]. As a result of undergoing EMT, the epithelial cells that line the junctional epithelium will develop a migratory phenotype and undergo a reorganization of their actin cytoskeleton and express vimentin [69]. The reorganized actin cytoskeleton and expression of vimentin will facilitate the apical migration of these epithelial cells along the root surface-a clinical manifestation of the apical migration of the epithelial attachment and subsequent formation of the periodontal pocket [69]. The ability of the junctional epithelium cells to migrate apically is one of the hallmarks of periodontitis, and represents a permanent loss of biological seal [69,70].

6.2. Fostering Chronic Inflammation and Alveolar Bone Resorption

EMT serves as a link between the bacterial insult and the sustained chronic inflammation that advances periodontitis pathology [71]. Cells undergoing EMT do not only change their morphology but also their secretome. The embryonic-like cells will become active sources of pro-inflammatory cytokines (i.e., interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF α) [71]. This creates a self-sustaining inflammatory environment in which these reformed epithelial cells aid in perpetuating cytokine signaling and recruiting and activating immune cells (i.e., macrophages and neutrophils) into the inflammatory site [71].
The inflammatory signaling molecules released during EMT also contribute to alveolar bone homeostasis [71]. Pro-inflammatory cytokines (i.e., TNF α and IL-1β) are well known stimulators of Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) expression [72,73,74]. RANKL is the primary driver of osteoclastogenesis, and osteoclasts are responsible for bone resorption [74]. The shift in the RANKL/osteoprotegerin (OPG) ratio promotes bone resorption from the signaling pathways of EMT [71].
Additionally, the presence of the mesenchymal-like cells at the inflammatory site can produce extracellular vimentin [70]. Extracellular vimentin has been shown to enhance the inflammatory response and worsen the injury [70]. Together, increased epithelial permeability, osteoclastogenic signaling, and cytokine amplification create a self-reinforcing cycle in which repeated EMT activation accelerates periodontal breakdown unless therapeutically interrupted [75].

6.3. Contributing to Gingival Fibrosis and Impaired Wound Healing

Although periodontitis is typically discussed in terms of connective tissue loss, disease progression can also involve pathological remodeling and fibrosis [76]. EMT may contribute to these changes by generating myofibroblast-like cells that promote excessive collagen deposition and tissue contraction [76]. These profibrotic features likely reflect pathway convergence during chronic repair rather than a distinct EMT subtype operating in periodontal epithelium. Furthermore, the gingival epithelial cells during the latter stages of chronic inflammation, or chronic exposure to certain medications, can transition to a fully mesenchymal state [11].
The result of the fully mesenchymal state is to fully transform to myofibroblasts [10]. These myofibroblasts that arise via EMT are characterized by increased expression of alpha-smooth muscle actin (α-SMA) and improved Type I collagen production. In the case of drug-induced gingival overgrowth, those patients had higher levels of EMT markers that correlated with the extent of gingival thickening and abundance of dense fibrotic extracellular matrix [77,78]. Of note, this fibrotic response is different than wound healing; it is excessive and disorganized, which interferes with the normal structure and function of the gingiva [79].
The presence of EMT-like cells in the periodontal pocket severely limits the possibility of regenerative wound healing [11]. Given the nature of these cells, as they have lost their epithelial identity and gained a migratory pro-inflammatory phenotype, they do not re-establish a functional junctional epithelium post therapy [1]. These cells do not work toward the restoration of the biological seal and continue to build the fibrotic environment that prevents re-attachment of the periodontal ligament to the root surface [80]. This is why contemporary regenerative therapies continually fail to achieve complete restitution ad integrum at sites with chronic inflammatory conditions that resulted in extensive epithelium phenotypic reprogramming [81].

7. Clinical Implications and Future Directions

Viewing periodontitis through the lens of gingival EMT shifts attention from bacterial presence alone toward how pathogens reprogram epithelial behavior and barrier function. This perspective may support the development of EMT-related biomarkers and targeted therapies aimed at stabilizing the gingival epithelium and improving regenerative outcomes [82].

7.1. Potential Utility of EMT Markers for Periodontal Disease Diagnosis

Current diagnostic measures, including clinical attachment loss (CAL) and radiographic bone loss, are largely retrospective and reflect past destruction rather than real-time disease activity [83]. At this juncture in the field of periodontitis, “real-time” biomarkers favored, especially ones that identify active disease sites or the risk for future progression of disease [84]. Because EMT markers are representative of an early cellular change in the disease process, their utility is significant [1].
EMT associated molecules found in gingival crevicular fluid (GCF) or saliva would offer a non-invasive diagnostic methodology [85]. Several research designs have mentioned their candidates for the use as potential biomarkers, including transcription factors like Slug and Snail, or mesenchymal markers such as vimentin and N-cadherin [86]. Elevated levels of these markers in GCF have shown a direct correlation to clinical parameters of disease severity, suggesting these might be practical to determine the activity of a periodontal pocket [87,88].
In addition to protein markers, non-coding RNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are new and provide great potential for sensitive biomarkers for EMT in periodontitis. One example of work is miRNA panels related to EMT and angiogenesis that have been isolated from chronic periodontitis patients, which provide for an interesting potential molecular signature for periodontal disease [89]. Furthermore, lncRNAs such as Malat1 and Neat1 have been associated with the dysbiotic microbiome and/or expression of EMT markers in diseased periodontal tissues [86].

7.2. Therapeutic Targeting of EMT Pathways for Tissue Regeneration

The overall objective of periodontal treatment is to restore damaged connective tissue structures that support teeth (periodontal ligament, cementum, and alveolar bone) [90]. However, the transformation of cells from an epithelial to a mesenchymal state at sites of injury during wound healing typically leads to scarring, and not to the restoration of native tissue architecture. Thus, either preventing the onset of epithelial–mesenchymal transition (EMT) or promoting the reverse process of mesenchymal to epithelial transition (MET) may significantly improve regenerative success in periodontal treatments. A promising method for blocking EMT involves using pharmacological agents that inhibit the action of small molecules that signal the onset of EMT or using neutralizing antibodies to prevent the activation of EMT pathways [91]. Inhibiting the TGF-β1/Smad axis or the Wnt/β-catenin pathway may block the conversion of junctional epithelium to a mesenchymal phenotype [92]. Additionally, the inhibition of certain matrix metalloproteinases (MMPs), such as MMP-9, has been found to inhibit EMT or completely suppress it [93]; this inhibition could be used in combination with scaling and root planing to promote regeneration [93].
Another novel way to treat EMT and the subsequent reprogramming of the host epithelium to a bacterial-friendly disease state is through the application of miRNA-based therapeutics to reset the cellular phenotype. Due to their ability to simultaneously regulate multiple genes within a single signaling pathway, miRNAs are ideal candidates for the modulation of complex biological processes like EMT. It has recently been demonstrated that miR-34 can inhibit Wnt signaling, thereby suppressing EMT [92], and thus miR-34 is a candidate for the prevention of epithelial instability and the reversal of disease caused by bacteria. Moreover, the development of new methods to deliver miRNA locally to the site of the periodontal pocket, including hydrogels or self-assembling peptide scaffolds, will provide a means of delivering miR-34 inhibitors to the affected area, while minimizing systemic side effects, improving the local delivery of the inhibitor, and increasing the effectiveness of the treatment [94]. For these reasons, EMT-pathway modulation is best viewed as a promising research direction at present, but one that still requires careful validation of delivery feasibility, safety, and clinically relevant endpoints before it can be considered clinically actionable [95].

Translational Considerations and Current Limitations

Although EMT-targeted strategies are conceptually appealing, the translation to routine periodontal care is not straightforward. Most pathway modulators would need local delivery (gels, fibers, hydrogels, or scaffolds), but periodontal pockets are challenging due to the dynamic environment of crevicular fluid flow and constant presence of biofilm leading to possible instability or washout of dosing [96]. Safety is also an issue because EMT-related signaling crosstalks with regular epithelial turnover and wound healing; thus, it may impair repair or compromise barrier recovery in susceptible individuals if broadly inhibited. Proving a positive result will require coupling pathway modulation to clinically relevant endpoints (CAL, probing pocket depth (PPD)) along with barrier-related readouts (junctional markers, permeability/inflammation resolution) [97]. From a regulatory standpoint, repurposing agents with known safety profiles may be more realistic than developing new EMT-specific inhibitors for periodontitis.

8. Conclusions

Framing periodontitis progression as a dysbiosis-driven process that includes gingival EMT provides a useful mechanistic bridge between microbial challenge and tissue destruction. Beyond direct enzymatic damage, keystone pathogens such as P. gingivalis and bridging organisms such as F. nucleatum can reshape epithelial signaling, weaken junctional integrity, and promote persistent inflammation and remodeling. EMT-related markers in saliva or gingival crevicular fluid may improve real-time assessment of disease activity, while therapeutic strategies targeting EMT-associated pathways could enhance periodontal healing and regenerative predictability.

Author Contributions

Conceptualization, H.M.A. and S.S.S.; methodology, H.M.A.; software, H.M.A.; validation, H.M.A. and S.S.S.; formal analysis, H.M.A.; investigation, H.M.A.; resources, H.M.A.; data curation, H.M.A.; writing—original draft preparation, H.M.A.; writing—review and editing, H.M.A. and S.S.S.; visualization, H.M.A.; supervision, S.S.S.; project administration, H.M.A.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable. This study is a narrative review and did not require ethical approval as it does not involve human participants, patient data, or animal research.

Informed Consent Statement

Not applicable. No new human data were collected for this review.

Data Availability Statement

No new experimental data were generated. The illustrative figures created for this review are available from the corresponding author upon reasonable request.

Acknowledgments

During the preparation of this review, the authors used Paperpal V.5.43.3 and Quilbot V.40.77.9 for the purposes of checking grammar and improving writing. The authors have reviewed and edited the output and take full responsibility for the content of this publication.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AJ, adherens junctions; α-SMA, alpha-smooth muscle actin; CAL, clinical attachment loss; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; EMT-TFs, epithelial–mesenchymal transition transcription factors; FadA, Fusobacterium adhesin A; FGF, fibroblast growth factor; GCF, gingival crevicular fluid; HGF, hepatocyte growth factor; HIF, hypoxia-inducible factor; IL-1β, interleukin-1 beta; IL-6, interleukin-6; JE, junctional epithelium; Kgp, lysine-specific gingipain; lncRNA, long non-coding RNA; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MET, mesenchymal–epithelial transition; miRNA, microRNA; MMP, matrix metalloproteinase; NF-κB, nuclear factor kappa B; Notch, Notch signaling pathway; OMVs, outer membrane vesicles; OPG, osteoprotegerin; PAR-2, protease-activated receptor-2; PCR, polymerase chain reaction; RANKL, receptor activator of nuclear factor kappa-B ligand; Rgp, arginine-specific gingipain; RTK, receptor tyrosine kinase; Smad, suppressor of mothers against decapentaplegic; TGF-β, transforming growth factor-beta; TJ, tight junctions; TNF-α, tumor necrosis factor-alpha; Wnt, Wingless/Int signaling pathway.

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Figure 1. From Dysbiosis to Tissue Destruction: Pathogen-Induced Gingival Epithelial–Mesenchymal Transition (EMT) in Periodontitis. Schematic representation of the pathway from subgingival dysbiosis to periodontal tissue destruction via pathogen-induced EMT. Keystone periodontal pathogens release virulence factors that attach to and invade gingival epithelial cells, activating TGF-β/Smad, Wnt/β-catenin, and Notch signaling pathways. This triggers EMT, characterized by loss of epithelial markers (E-cadherin) and gain of mesenchymal markers (vimentin, N-cadherin), leading to junctional epithelial instability, apical migration, periodontal pocket formation, and clinical attachment loss (CAL). Downstream consequences include barrier breakdown with increased bacterial penetration, chronic inflammation with alveolar bone resorption, and tissue remodeling with profibrotic signaling that impairs regenerative healing.
Figure 1. From Dysbiosis to Tissue Destruction: Pathogen-Induced Gingival Epithelial–Mesenchymal Transition (EMT) in Periodontitis. Schematic representation of the pathway from subgingival dysbiosis to periodontal tissue destruction via pathogen-induced EMT. Keystone periodontal pathogens release virulence factors that attach to and invade gingival epithelial cells, activating TGF-β/Smad, Wnt/β-catenin, and Notch signaling pathways. This triggers EMT, characterized by loss of epithelial markers (E-cadherin) and gain of mesenchymal markers (vimentin, N-cadherin), leading to junctional epithelial instability, apical migration, periodontal pocket formation, and clinical attachment loss (CAL). Downstream consequences include barrier breakdown with increased bacterial penetration, chronic inflammation with alveolar bone resorption, and tissue remodeling with profibrotic signaling that impairs regenerative healing.
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Figure 2. Evidence Supporting Pathogen-Induced EMT-Like Changes in Periodontitis by Study Type. An evidence map detailing the present level of knowledge regarding pathogen-induced EMT in periodontitis across various research methods (in vitro, animal models, and humans). In vitro studies have demonstrated a high degree of mechanistic evidence for how certain pathogens associated with periodontitis can cause EMT marker changes and functional consequences in gingival epithelial cells. The application of animal models offers in vivo validation, demonstrating the relationship between infection- or ligature-induced periodontitis, activation of signaling pathways, and remodeling of epithelial tissue. While human studies have demonstrated an association between the expression of EMT-associated markers and the severity of the clinical disease, the causal relationship between the two in humans is indirect.
Figure 2. Evidence Supporting Pathogen-Induced EMT-Like Changes in Periodontitis by Study Type. An evidence map detailing the present level of knowledge regarding pathogen-induced EMT in periodontitis across various research methods (in vitro, animal models, and humans). In vitro studies have demonstrated a high degree of mechanistic evidence for how certain pathogens associated with periodontitis can cause EMT marker changes and functional consequences in gingival epithelial cells. The application of animal models offers in vivo validation, demonstrating the relationship between infection- or ligature-induced periodontitis, activation of signaling pathways, and remodeling of epithelial tissue. While human studies have demonstrated an association between the expression of EMT-associated markers and the severity of the clinical disease, the causal relationship between the two in humans is indirect.
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MDPI and ACS Style

Akram, H.M.; Saliem, S.S. From Dysbiosis to Tissue Destruction: Periodontal Pathogens as Inducers of Gingival Epithelial–Mesenchymal Transition (A Narrative Review). J. Mol. Pathol. 2026, 7, 11. https://doi.org/10.3390/jmp7010011

AMA Style

Akram HM, Saliem SS. From Dysbiosis to Tissue Destruction: Periodontal Pathogens as Inducers of Gingival Epithelial–Mesenchymal Transition (A Narrative Review). Journal of Molecular Pathology. 2026; 7(1):11. https://doi.org/10.3390/jmp7010011

Chicago/Turabian Style

Akram, Hadeel Mazin, and Saif Sehaam Saliem. 2026. "From Dysbiosis to Tissue Destruction: Periodontal Pathogens as Inducers of Gingival Epithelial–Mesenchymal Transition (A Narrative Review)" Journal of Molecular Pathology 7, no. 1: 11. https://doi.org/10.3390/jmp7010011

APA Style

Akram, H. M., & Saliem, S. S. (2026). From Dysbiosis to Tissue Destruction: Periodontal Pathogens as Inducers of Gingival Epithelial–Mesenchymal Transition (A Narrative Review). Journal of Molecular Pathology, 7(1), 11. https://doi.org/10.3390/jmp7010011

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