Microbial mechanisms and therapeutic interventions in the periodontitis-inflammatory bowel disease axis: a comprehensive review

Abstract

Background

Periodontitis and inflammatory bowel disease (IBD) are chronic inflammatory conditions of the oral and gastrointestinal tracts that exhibit bidirectional microbial and immunological crosstalk.

Objective

Aimed at elucidating the bidirectional crosstalk between periodontitis and IBD at both microbiological and immunological levels and evaluate related therapeutic interventions, this review comprehensively summarizes recent evidence on their interaction via the oral-gut-bone axis, focusing on microbial ecology, host responses, and innovative therapies.

Design

Distinct yet overlapping dysbiotic signatures are observed in both diseases, with periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum capable of translocating to the gut and perturbing intestinal homeostasis, while gut inflammation reciprocally reshapes the oral microbiome. Mechanistic links include a spectrum of convergent pathways: (i) microbial metabolites—short-chain fatty acids, choline metabolites, indole derivatives, polyamines, and bile acids—that modulate barrier integrity and immune responses; (ii) shared immune cells and inflammatory mediators driving mucosal damage at both sites; (iii) bacterial extracellular vesicles (BEVs) and lysine lactylation (Kla)-mediated signaling; and (iv) oxidative stress, iron metabolism dysregulation, and ferroptosis contributing to tissue destruction.

Results

Therapeutic strategies targeting this axis encompass bidirectional interventions: periodontal and IBD treatments that mutually influence oral and gut health, natural anti-inflammatory and antimicrobial compounds, probiotics and prebiotics, oral and fecal microbiota transplantation, and emerging bacteriophage therapy. Critically, the clinical translation of collaborative dentistry-gastroenterology management is highlighted as a promising avenue for integrated care.

Conclusions

By integrating findings across microbial ecology, host response, and therapeutic innovation, this review provides a comprehensive framework for understanding and targeting the periodontitis-IBD axis.

Introduction

Periodontitis is a chronic inflammatory disease driven by dysbiotic dental plaque biofilms, leading to progressive destruction of tooth-supporting tissues and affecting over one billion people globally [1]. Beyond local tissue damage, periodontitis is increasingly recognised as a source of systemic inflammation, with strong epidemiological and mechanistic links to conditions such as diabetes, rheumatoid arthritis, and inflammatory bowel disease (IBD) [2,3]. Recent clinical studies further illustrate this systemic dimension: non-surgical periodontal therapy has been associated with improved arterial stiffness and endothelial function [4], while periodontal microRNAs (e.g. miR-200b-3p, miR-200b-5p) have emerged as dynamic regulators of local tissue remodelling that carry potential systemic implications [5]. Critically, periodontal pathogens can translocate to distant sites via hematogenous or alimentary routes, and growing evidence supports their role in exacerbating intestinal inflammation through immune activation along the oral-gut axis [6,7] (Table 1). IBD—encompassing Crohn’s disease and ulcerative colitis (UC)—is a chronic immune-mediated disorder of the gut, marked by recurrent intestinal inflammation and a rising global prevalence [8]. Notably, both periodontitis and IBD are characterised by microbial dysbiosis and aberrant host immune responses, suggesting potential shared pathophysiological mechanisms (Figure 1a). Accumulating clinical and experimental data now support a bidirectional relationship between these conditions, where each may influence the onset and progression of the other [3,7]. Epidemiological studies consistently report a higher prevalence and severity of periodontitis in IBD patients, supporting this bidirectional association [9,10].

Table 1.

Major oral-derived pathobionts linking Periodontitis-IBD: mechanisms of action and supporting evidence.

Major pathogens	Mechanisms of action	Evidence source	References
Porphyromonas gingivalis	Activates FFAR2, downregulates Smad1, and inhibits osteogenic differentiation of PDLSCs	In vitro (human PDLSCs)	[11]
	PPAD enzyme expands Th17 cells (↑IL-17) and reduces Tregs (↓IL-10), exacerbating colitis	C57BL/6 mice, DSS-induced UC	[12]
	Secreted EVs activate FADD-RIPK1-caspase-3 signalling, impair bile acid metabolism, reduce IL-10, and disrupt gut barrier	C57BL/6 mice, DSS-induced UC	[13]
	Activates CARD3 to upregulate IL-1β, IL-6, IL-17F, and TNF-α via IL-17F pathway, promoting intestinal inflammation	In vitro (C57BL/6 mice, IEC cells)	[14]
	EVs internalised by IECs activate AIM2 inflammasome, triggering pyroptosis and barrier dysfunction	C57BL/6 mice, DSS-induced UC	[15]
	Stimulates macrophage glycolysis and H3K18 lactylation, inducing Aβ expression and activating Syk/ROS signalling	In vitro (Human monocytes U937)	[16]
	Promotes H4K12 lactylation and ADAM17 expression; suppresses TGF-βR1 and MerTK in macrophages, impairing osteogenesis and immune function	In vitro (MEPM cells)	[17]
	Induces ferroptosis via SLC7A11/GSH/GPX4 inhibition, disrupting oral epithelial barrier integrity	SD male rats, ligature/P.gingivalis-induced periodontitis	[18]
	FadA adhesin binds PEBP1, activating Raf1-MAPK and IKK-NF-κB pathways, increasing IL-1β, IL-6, and IL-8	In vitro (human PDLSCs)	[19]
	EVs induce ferroptosis in intestinal epithelium, increasing permeability	C57BL/6 mice, DSS-induced UC	[20]
Enterococcus faecalis	Induces macrophage apoptosis and dampens inflammation via NF-κB/MAPK modulation	In vitro (E. faecalis OG1RF ATCC 47,077)	[21]

Figure 1.

Bidirectional Microbial and Functional crosstalk in periodontitis and IBD. a. Dysbiosis along the oral-gut axis: shifts in oral microbiota observed in IBD patients (e.g. Leptotrichia, Atopobium) and gut microbiota changes in periodontitis (e.g. Fusobacterium, Prevotella). b. Key mechanisms mediating interactions between periodontitis and IBD via the oral-gut axis, including microbial metabolites (e.g. Bile acids, Choline metabolites), immune cells and mediators, oxidative stress, iron metabolism (e.g. ferroptosis), microbial effectors (e.g. BEVs) and epigenetic regulation (e.g. Kla) and other factors.

A key mediator of this interaction is the oral-gut microbial axis. Oral microbiota, either free-living or in keratinocyte-associated complexes, typically enters the digestive tract via dietary ingestion; salivary components (water, lipids, mucins) protect these microbes and enable them to survive gastric stress and persist in the gut [7,22]. In periodontitis, this process facilitates the translocation of periodontal pathogens to the gut, where they can colonise and disrupt intestinal homoeostasis [23]. Animal models further support this link: induction of periodontitis alters gut structure and immune infiltration [24], while oral administration of saliva from periodontitis patients exacerbates colitis and enriches IBD-associated taxa such as Blautia, Helicobacter, and Ruminococcus[25]. Conversely, gut-derived microbial signals may influence alveolar bone metabolism via immune and metabolic pathways, suggesting a reciprocal gut-bone axis.

This review centres on the microbial and immunological mechanisms governing the crosstalk between periodontitis and IBD, encompassing pathogen translocation, dysbiosis propagation, and host responses modulated by microbial metabolites and immune mediators (Figure 1b). It further consolidates existing evidence linking the two disorders via the oral-gut-bone axis, and explores corresponding bidirectional interventions: therapeutic strategies for periodontitis and IBD that mutually shape oral and gut health, natural anti-inflammatory and antimicrobial agents, probiotics, prebiotics, oral and faecal microbiota transplantation, as well as emerging bacteriophage therapy. Ultimately, this review seeks to establish a conceptual framework for deciphering the oral-gut-bone connection and facilitating the development of coordinated management regimens for periodontitis and IBD.

Differences and connections between periodontitis and IBD microbiota

Periodontitis and IBD share a bidirectional pathogenic relationship rooted in disrupted microbe-immune homoeostasis. Dysbiosis in one site can exacerbate inflammation at the other through microbial translocation and immune crosstalk [7]. Periodontal pathogens not only damage the intestinal epithelial barrier but also modulate host immunity, contributing to systemic inflammation [7,9]. Once translocated to the gut, these bacteria disrupt the balance between commensals and opportunistic pathogens, promoting dysbiosis [24]. Conversely, gut-derived microbes and metabolites can act as antigens, compromising oral mucosal integrity and driving autoimmune responses in the context of IBD [26]. This reciprocal inflammation-dysbiosis cycle underpins the clinical association between periodontitis and IBD (Figure 1a, b; Table 1).

Dysbiotic microbial profiles in periodontitis and IBD

The dysbiotic microbial profiles in periodontitis and IBD share striking similarities. In periodontitis, the microbiota shifts from facultative anaerobes to Gram-negative obligate anaerobes, with enrichment of pathobionts such as Porphyromonas gingivalis, Fusobacterium nucleatum, Tannerella forsythia, Treponema denticola, Aggregatibacter actinomycetemcomitans and Prevotella intermedia [27,28]. In contrast, the gut microbiome supports barrier integrity and immune regulation under homoeostasis. In IBD, however, dysbiosis manifests as reduced diversity, increased Proteobacteria and Bacteroidetes, and decreased Firmicutes and Lactobacillus [29,30]. Notably, a variety of periodontal pathogens including F. nucleatum, Peptostreptococcus, Staphylococcus and Streptococcus were enriched in the colonic biopsy tissues of IBD patients, indicating niche-specific microbial alterations [31].

Regulatory effects of periodontal pathogens on gut microecology

The regulatory effects of periodontal pathogens on gut microecology involve specific mechanisms supported by evidence from both animal models and human studies. Given the enrichment of periodontal pathogens in the saliva of periodontitis patients, these microbes can reach the gut directly or via systemic circulation following barrier disruption, thus altering gut microbial composition compared to that of healthy individuals [24,32]. In the dual mouse model of periodontitis combined with DSS treatment, oral pathobionts such as Klebsiella and Enterobacter were synchronously enriched in both the oral cavity and the intestine [33]. Gavage of salivary microbiota from periodontitis patients into mice with periodontitis-associated colitis induced marked alterations in the IBD-linked gut microbiota—specifically, reduced Blautia and Helicobacter and enrichment of Aerococcus—and exacerbated intestinal inflammation, whereas microbiota from healthy individuals did not elicit these effects [25]. Periodontal therapy improves gut barrier function in murine models, reducing Alistipes, Barnesiella, and Sporobacter, while increasing beneficial taxa such as Turicibacter and Bifidobacterium [34]. Oral pathogens including F. nucleatum and Veillonella parvula are frequently detected in the intestines of IBD patients [9,35]. Clinical studies have also demonstrated that the similarity between the gut microbiota and oral microbiota in IBD patients complicated with periodontitis is significantly higher than that in healthy controls, indicating an increased ectopic intestinal colonisation of oral bacteria in IBD patients [36]. This translocation is facilitated by gut inflammation, which creates a permissive niche for oral pathobionts, thereby establishing a feed-forward loop of dysbiosis [37]. Gastric acid suppression further promotes ectopic oral bacterial colonisation, thus accelerating IBD progression [38]. Notably, P. gingivalis, F. nucleatum, Streptococcus spp., and Veillonella spp. are enriched in the gut microbiota of IBD patients, preferentially colonise inflamed tissues, and correlate positively with disease activity, implicating them in pathogenesis [39]. For example, F. nucleatum, a keystone periodontal pathogen, not only promotes alveolar bone loss but also—when co-aggregated with Enterococcus faecalis—exhibits enhanced survival under alkaline, hyperosmotic, nutrient-deficient, and antimicrobial conditions, while significantly inducing macrophage apoptosis and attenuating pro-inflammatory responses by regulating the NF-κB/MAPK signalling pathway [21,40]. However, the role of F. nucleatum may be context-dependent: it exists at low levels in healthy individuals, exhibits subspecies-specific virulence, and under certain conditions may even skew immune responses toward tolerance rather than inflammation [41]. Prevotella spp. and Aggregatibacter actinomycetemcomitans have been detected in intestinal biopsies, and these pathogens show marked expansion in the guts of patients with IBD and colorectal cancer, which underscores the role of the oral-gut microbiota axis in the pathogenesis of intestinal diseases [42,43] (Figure 1a).

Gut inflammation reshapes the oral microbiome

Conversely, IBD-associated gut inflammation reshapes the oral microbiome. Clinically, IBD patients display elevated oral-gut microbial similarity, indicating heightened susceptibility to oral dysbiosis [10,43]. In IBD patients, both salivary and subgingival microbiota show reduced levels of Neisseria, Gemella, Haemophilus, and Lactobacillus, with enrichment of Bacteroides, Campylobacter, Fusobacterium, Porphyromonas, Veillonella, Leptotrichia, Prevotella, Granulicatella, Capnocytophaga, and Saccharibacteria (formerly TM7); these dysbiotic changes normalise following successful IBD therapy [44–46]. This remodelling is likely mediated by systemic inflammation, altered salivary composition, and immune cell trafficking from the gut to oral mucosal sites. In murine colitis models (dextran sulphate sodium [DSS]-induced or Citrobacter rodentium-infected models), salivary and oral mucosal microbiota dysbiosis was consistently observed: Proteobacteria, Actinobacteria, Klebsiella, and Enterobacter were increased, whereas Firmicutes (especially Streptococcus) and Bacteroidetes were decreased [33,47]. These findings demonstrate bidirectional crosstalk between the oral and gut microbiomes and suggest that certain periodontal pathogens may serve as biomarkers for IBD activity (Figure 1a). This reciprocal modulation highlights the interconnectedness of oral and gut ecosystems in systemic inflammatory conditions.

Periodontitis-IBD interactions via the gut-bone axis

The gut microbiota plays a crucial role in regulating systemic physiology, particularly through the gut-bone axis—a signalling pathway increasingly recognised for its influence on skeletal homoeostasis, including alveolar bone integrity [9] (Figures 1b and 2). Microbial metabolites such as short-chain fatty acids (SCFAs), choline metabolites, indole derivatives, polyamines, and bile acids form a complex network that regulates host immune responses and metabolic functions. By influencing the balance between osteoclasts and osteoblasts, these gut-derived signals contribute to the regulation of alveolar bone remodelling [48]. Emerging evidence further implicates additional mediators—such as bacterial extracellular vesicles (BEVs), lysine lactylation (Kla), oxidative stress, and iron metabolism—in the modulation of this gut-bone crosstalk during periodontitis-IBD comorbidity (Table 1).

Figure 2.

Systemic regulation of alveolar bone remodelling in periodontitis via the gut-bone axis.​​ Gut-derived and host-derived mediators—including microbial metabolites (e.g. SCFAs, bile acids), BEVs, and dysregulated host processes (e.g. iron metabolism, ferroptosis, Kla)—act systemically to disrupt osteoimmune homoeostasis. These signals converge on key signalling pathways in the periodontium, tipping the balance from osteoblast-mediated bone formation to osteoclast-driven bone resorption, ultimately leading to alveolar bone loss.

Microbial metabolites

Microbial metabolites serve as critical mediators of the oral-gut-bone axis, linking dysbiosis in periodontitis and IBD to systemic inflammation and tissue destruction. While their molecular mechanisms and effects have been extensively characterised in vitro and in rodent models, direct clinical evidence demonstrating their causal roles in human comorbid periodontitis-IBD remains limited. The following subsections synthesise current knowledge on key metabolite classes, highlighting conserved pathways that may provide insights for future translational research.

SCFAs

SCFAs—primarily acetate, propionate, and butyrate—are key fermentation products of gut microbiota. They play essential roles in maintaining intestinal epithelial barrier integrity and serve as signalling molecules that modulate immune responses, metabolism, and endocrine functions [49]. SCFAs can enter the systemic circulation and exert effects on distant tissues. Butyrate enhances mineral solubility and calcium absorption by lowering luminal pH and promoting mucosal proliferation via mTOR and Wnt/β-catenin signalling, which increases villus height and epithelial surface area, thereby upregulating calcium-binding protein expression and intestinal calcium uptake [50]. In a murine model of chronic kidney disease, Lactobacillus johnsonii and its metabolite cyclo (Pro-Trp) significantly reduced parathyroid hormone (PTH) levels. This suppression enhances calcium influx into intestinal epithelial cells (IECs) through calcium-sensing receptors (CaSR) and transient receptor potential vanilloid 4 (TRPV4) channels, further promoting intestinal calcium absorption [51]. Additionally, butyrate inhibits histone deacetylase (HDAC) activity, facilitating the differentiation and function of regulatory T cells (Tregs), thus contributing to immune homoeostasis [52]. In contrast, SCFAs derived from periodontal pathogens exhibit context-dependent pathogenic effects. P. gingivalis, F. nucleatum, P. intermedia, and T. forsythia produce substantial amounts of butyrate and propionate during amino acid fermentation [48]. Elevated levels of these SCFAs are detected in the gingival crevicular fluid (GCF) of periodontitis patients compared to healthy individuals, and this elevation correlates with disease severity [53]. In vitro, butyrate compromises gingival epithelial integrity, induces ROS production, and disrupts cell cycle progression in gingival fibroblasts. It also inhibits osteogenic differentiation of periodontal ligament stem cells by activating free fatty acid receptor 2 (FFAR2) and downregulating Smad1 expression [11,49]. Propionate similarly impairs adhesion, proliferation, and protein synthesis in gingival fibroblasts in vitro [48]. Collectively, these SCFAs exert cytotoxic effects on periodontal tissues, contributing to tissue destruction. Notably, non-surgical periodontal therapy significantly reduces GCF concentrations of propionate and butyrate, concurrent with clinical improvement, suggesting their potential as biomarkers of disease activity [54].

Choline metabolites

Choline metabolites, produced during the metabolism of choline in the body, primarily include trimethylamine (TMA), trimethylamine N-oxide (TMAO), and acetylcholine. TMA is produced by gut microbiota from choline and is subsequently oxidised in the liver to form TMAO, which modulates gut microbial composition, systemic immunity, and periodontal inflammation [55].

In a murine model of periodontitis, elevated hepatic interleukin-6 (IL-6) and flavin-containing monooxygenase 3 (FMO3) levels were observed, along with increased plasma lipopolysaccharide (LPS) and TMAO; notably, non-surgical periodontal treatment reduced circulating TMAO levels [56]. Experimental TMAO administration in drinking water activates the NF-κB pathway, disrupts gut microbial balance by decreasing Bacteroidetes and increasing Firmicutes, and upregulates osteoclast-related genes via the NF-κB/NFATc1 signalling axis, ultimately promoting alveolar bone loss [57]. This dysbiosis further enhances TMAO production, creating a feed-forward loop that exacerbates inflammation and bone resorption. Gold nanospheres can significantly reduce the relative abundance of Firmicutes and increase the relative abundance of Proteobacteria, thereby lowering TMAO levels and reducing the production of pro-inflammatory cytokines (e.g. IL-6 and TNF-α), thus regulating bone metabolism [58].

Indole derivatives

Indole derivatives, microbial metabolites of tryptophan, enhance antimicrobial peptide and mucin production, stimulate intestinal epithelial proliferation, and suppress pathogen expansion, thereby preserving gut barrier integrity. Dietary indole-3-propionic acid (IPA) in rat pups activates the PXR/ACBP pathway, modulates the gut microbiota, and upregulates tight junction proteins, mucins, and interleukin-10 (IL-10) in IECs, while suppressing IL-8 expression [59]. These changes strengthen the intestinal barrier and may indirectly influence bone homoeostasis.

5-Hydroxytryptamine (5-HT), a key indole derivative, exerts opposing effects on alveolar bone remodelling based on its site of action. Central 5-HT activates calmodulin-dependent kinases (CaMKKβ/CaMKIV), leading to CREB phosphorylation, reduced sympathetic nervous system activity, and enhanced osteogenesis [60]. In contrast, peripheral 5-HT stimulates IL-6 secretion in bone cells via 5-HT₂B and ERK1/2 signalling, which in turn promotes osteoclastogenesis and bone resorption [61]. Thus, gut-derived indole derivatives may impact periodontal health through the gut-bone axis and direct regulation of alveolar bone turnover.

Polyamines

Polyamines are essential molecules involved in cell growth, proliferation, differentiation, and survival and are synthesised and released by the gut microbiota [62]. For example, putrescine produced by Escherichia coli in the mouse colon is absorbed by IECs and subsequently converted to spermidine, which accelerates epithelial renewal and increases the population of anti-inflammatory macrophages in the colon, thereby contributing to gut homoeostasis [63]. In obese or type 2 diabetic mice, dietary supplementation with polyamines promotes the polarisation of macrophages toward an anti-inflammatory phenotype, reduces the levels of pro-inflammatory cytokines (e.g. TNF-α and IL-6), and upregulates the expression of IL-10—effects that help restore systemic immune homoeostasis [64]. Furthermore, polyamines can regulate intestinal flora, repair the intestinal barrier, inhibit the differentiation and maturation of osteoclasts, and reduce bone loss in the weightlessness-induced bone loss (WIBL) model, suggesting that they exert a protective effect against pathological bone resorption [65]. Given that periodontitis-associated alveolar bone loss is also driven by chronic inflammation and excessive osteoclast activity, polyamines may similarly protect against periodontal tissue destruction through systemic immunomodulation.

Bile acids

Bile acids are signalling molecules that regulate lipid metabolism, bone homoeostasis, and energy balance; they can also inhibit the overgrowth of the gut microbiota [66]. They exist in two forms: 1) Primary bile acids: Synthesised in the liver as bile salts and subsequently secreted into the small intestine; 2) Secondary bile acids: Generated via gut microbiota metabolism of primary bile acids, such as 3-oxolithocholic acid (3-oxoLCA), they can directly bind to the RORγt receptor, inhibiting Th17 cell differentiation. Isolithocholic acid (isoLCA) can promote Treg differentiation by inducing mitochondrial ROS levels, thereby participating in the regulation of bone metabolism and affecting alveolar bone health [67].

Immune cells and mediators in oral-gut inflammatory crosstalk

Role of immune cells in periodontal and IBD-associated intestinal inflammation

In the context of periodontitis and IBD, immune cell trafficking from oral-draining lymph nodes to the intestine occurs under physiological conditions, establishing a cellular basis for oral-gut immune crosstalk [9]. Shared immunoinflammatory mechanisms between these two chronic inflammatory diseases enable their bidirectional interaction. In experimental periodontitis-colitis models, periodontal pathogens activate oral-derived CD4⁺ T cells expressing the gut-homing integrin α₄β₇, which migrate to and accumulate in inflamed intestinal tissues; in contrast, homoeostatic gut microbiota do not elicit this response [33]. The ectopic colonisation of periodontal pathogens (e.g. P. gingivalis) in the gut enables their secreted virulence factor—peptidylarginine deiminase (PPAD)—to exacerbate intestinal inflammation by increasing the number of Th17 cells and the production of IL-17, while reducing the count of Tregs and the secretion of IL-10 in the spleen of UC mice [12].

Strains isolated from CD patients exhibit higher invasiveness and more potently upregulate MUC2 and TNF expression compared to those from healthy individuals [68]. Atarashi et al. [69] demonstrated that Klebsiella pneumoniae isolated from the salivary microbiota of CD patients activates dendritic cells (DCs) and epithelial cells through the Toll-like receptor 4 (TLR4) signalling pathway, inducing IL-18 secretion, Th1 cell recruitment, and subsequent intestinal inflammation. F. nucleatum binds inhibitory receptors to suppress natural killer cell cytotoxicity and survives within macrophages to evade lymphocyte-mediated clearance, while its virulence factors—including outer membrane proteins Fap2 and RadD—inhibit T cell function and induce lymphocyte apoptosis [70]. Paradoxically, it also promotes CD4⁺ T cell differentiation into pro-inflammatory Th1 and Th17 subsets, thereby exacerbating experimental colitis in mice [71].

Gut dysbiosis further disrupts immune homoeostasis by suppressing Treg differentiation, promoting Th17 polarisation, expanding the pool of osteoclast precursors, and enhancing RANKL expression in stromal cells, collectively facilitating osteoclastogenesis and bone resorption [72,73]. Neutrophils are central effector cells in periodontal tissue destruction. Peripheral neutrophils from patients with active IBD exhibit significantly elevated metabolic activity compared to those from patients with inactive IBD, who in turn display higher activity than neutrophils from healthy controls [74]. Notably, Wolinella species isolated from the periodontal microbiota of IBD patients can potently modulate neutrophil chemotaxis in vitro, suggesting a functional link between periodontal dysbiosis and systemic innate immune dysregulation [75,76].

Role of immune mediators in periodontal and IBD-associated intestinal inflammation

Periodontitis and IBD, two chronic inflammatory disorders, share common immune mediators, which lay the foundation for their bidirectional crosstalk. Periodontal pathogen virulence factors trigger adaptive immune responses in the oral cavity, activating periodontal ligament fibroblasts, gingival fibroblasts, and infiltrating inflammatory cells to sustain inflammation; these cells secrete pro-inflammatory mediators, including cytokines, chemokines, and matrix metalloproteinases (MMPs), and upregulate osteoclastogenic genes, driving tissue destruction (Figure 2). Key cytokines such as TNF-α, IL-1β, and IL-6 directly promote periodontal tissue degradation and bone resorption and serve as biomarkers of disease severity [7,9,76]. Furthermore, F. nucleatum can modulate the activation of caspase recruitment domain 3 (CARD3) to upregulate the expression of pro-inflammatory cytokines (including IL-1β, IL-6, IL-17F, and TNF-α) and induce intestinal inflammation via the IL-17F signalling pathway [13,14]. Notably, elevated levels of IL-1β, IL-6, IL-21, sCD40L, IL-23, and IFN-γ in the periodontium correlate with the severity of IBD-associated intestinal inflammation, supporting the existence of an oral-gut inflammatory axis [37].

In DSS-induced colitis models, TNF-α, IL-6, and IL-1β are upregulated—findings that underscore the central role of TNF-α in IBD pathogenesis [72,73,77]. Clinically, anti-TNF-α monoclonal antibodies reduce inflammation and promote mucosal healing [78]. IL-6 signalling via its receptor drives inflammation, and IL-6R blockade inhibits leucocyte recruitment and ameliorates colitis in preclinical models [79]. TNF-α also stimulates MMP secretion, and these proteases contribute to the pathogenesis of both periodontitis and IBD [37]. Elevated levels of TNF-α, IL-2, IL-6, and IL-8 in IBD patients correlate with disease activity, and the combined detection of these cytokines may facilitate the early diagnosis and assessment of disease progression [9,79].

BEVs

BEVs are 50-250 nm spherical nanostructures secreted by bacteria, encapsulating LPS, phospholipids, peptidoglycan, outer membrane proteins, enzymes, and signalling molecules [80]. Their nanoscale size and bilayer membrane confer resistance to degradation and enable systemic dissemination. BEVs often exhibit greater pathogenicity than their parent bacteria, penetrating deep tissues and potently activating host inflammatory pathways [81]. These distinct features enable BEVs to act as potent vectors mediating the crosstalk between periodontitis and IBD. Periodontal pathogen-derived BEVs (e.g. Filifactor alocis BEVs) contribute to biofilm formation and, upon binding to immune cell receptors, activate inflammatory signalling, induce osteoclast differentiation, and drive alveolar bone loss, thereby accelerating periodontitis progression [82]. Critically, BEVs deliver virulence factors to distant sites; they can be internalised by intestinal epithelial cells and initiate gut inflammation via immune activation [13,15,83].

In IBD patients, translocation of periodontal pathogens alters gut microbiota composition and shifts the gut-derived BEV profile—increasing BEVs derived from Proteobacteria and decreasing those from Firmicutes [84]. Pathogenic enteric bacteria (e.g. E. coli, Pseudomonas aeruginosa) produce BEVs containing cytotoxins that disrupt protein synthesis, trigger macrophage mitochondrial apoptosis, and stimulate pro-inflammatory cytokine production [85]. Conversely, Bifidobacterium fragilis and Bacteroides thetaiotaomicron BEVs modulate bone metabolism indirectly by influencing SCFA and enzyme metabolism in intestinal cells [86], while Lactobacillus animalis BEVs promote bone formation by enhancing endothelial cell activity, stimulating mesenchymal stem cell osteogenic differentiation, and facilitating angiogenic-osteogenic paracrine signalling [87]. Notably, Akkermansia muciniphila BEVs exert systemic osteoprotective effects, accumulating in bone tissue and rebalancing bone remodelling through enhanced osteoblast activity and suppressed osteoclastogenesis in osteoporotic models [88]. While these findings highlight the potential of BEVs as therapeutic targets, direct clinical evidence in human patients with periodontitis or IBD remains limited.

Kla

Lactic acid, a central glycolytic metabolite, functions as both an energy substrate and a signalling molecule [89]. Its signalling role is largely mediated through Kla, a novel post-translational modification where lactyl groups are covalently attached to lysine residues, thereby modulating gene expression and cellular function [90]. Kla serves as a key link between microbial activity and host responses, offering novel therapeutic directions for periodontitis and IBD.

Periodontitis patients exhibit elevated lactate levels in GCF, which normalise after treatment, paralleled by increased Kla levels in periodontal epithelial and inflammatory cells [91]. High lactate concentrations (e.g. 10 mmol/L) can upregulate the expression of integrin α5, IL-6, IL-8, adhesion molecules, and RANKL in periodontal tissues, damaging junctional epithelial cells [92]. Furthermore, P. gingivalis infection stimulates macrophage glycolysis and H3K18la modification, induces the expression of amyloid-β (Aβ), which in turn triggers the Syk/ROS signalling pathway, thereby accelerating osteoclastogenesis and bone loss [16,93]. Transgenerationally, maternal P. gingivalis can promote glycolysis and the expression of H4K12la and ADAM17 in offspring. This reduces TGF-β receptor 1 in mouse embryonic palatal mesenchymal cells (MEPM) and Mer tyrosine kinase in macrophages, consequently inhibiting osteogenic differentiation and macrophage function, and leading to aberrant bone formation [17].

In colitis, B-cell adaptor for phosphoinositide 3-kinase (BCAP)-deficient macrophages display impaired glycolysis, resulting in reduced lactate production, diminished histone Kla levels, and suppressed tissue-repair gene expression [94]. Exogenous lactate supplementation restores Kla levels and promotes the transition of macrophages from a pro-inflammatory to a reparative phenotype. At inflammatory sites, lactate also reprograms Th17 cells via a ROS-dependent mechanism that suppresses IL-17A and enhances Foxp3 expression, thereby driving Th17-to-Treg conversion and ameliorating colitis [95]. Gut-derived lactate from Saccharomyces cerevisiae further attenuates inflammation by reducing IL-6/IL-1β production, inhibiting M1 macrophage polarisation, and elevating H3K18la levels [96]. Collectively, these findings establish Kla as a critical metabolic-immune interface linking microbial activity to host responses, revealing novel therapeutic targets for periodontitis and IBD.

Oxidative stress

Oxidative stress, characterised by an imbalance between ROS production and antioxidant defenses, leads to excessive ROS accumulation and can exacerbate both periodontitis and IBD. In periodontitis, neutrophils recruited to periodontal tissues release ROS to clear pathogens but also induce oxidative stress, promoting inflammasome formation, gingival fibroblast apoptosis, and inhibition of periodontal ligament cell activity [97]. Clinically, periodontal disease patients exhibit elevated salivary biomarkers such as malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), which correlate with disease severity and bleeding on probing [98]. Excessive ROS not only stimulate matrix metalloproteinases (MMPs) release at infection sites but also upregulate the RANKL/OPG ratio, thereby promoting osteoclast differentiation and alveolar bone resorption. Antioxidants significantly alleviate alveolar bone resorption and attachment loss in rat models of periodontal disease [99].

Similarly, gut microbiota dysbiosis drives persistent ROS generation, disrupting systemic redox balance and causing oxidative damage that compromises intestinal cell homoeostasis and microbial diversity [100]. Colonic enterococci can rapidly generate substantial amounts of substantial ROS, inducing localised oxidative stress and illustrating shared oxidative mechanisms linking oral and gut pathologies. Under the dual effects of gut microbiota disruption and oxidative stress, intestinal mucosal damage and inflammation propagate through a self-perpetuating cycle involving goblet cell depletion, crypt hyperplasia, reduced mucus production, and ulceration. This compromises epithelial barrier function and facilitates pathogen penetration, thereby exacerbating IBD [100]. Antioxidants have shown promise in alleviating intestinal mucosal damage and improving outcomes in IBD patients.

Ye et al. [101] demonstrated that nano-selenium particles combined with Eucommia ulmoides (EUP-SeNP) inhibit the activation of the TLR4/NF-κB signalling pathway, enhancing colon antioxidant capacity and regulating gut microbiota composition, thus alleviating DSS-induced colitis in mice. Probiotics like engineered Lactobacillus lactis directly target inflammatory sites by releasing superoxide dismutase (SOD) to scavenge ROS and reduce oxidative damage [102]. These findings support the therapeutic potential of combined antioxidant-probiotic formulations for managing both oxidative stress and microbial dysbiosis in IBD and periodontitis.

Iron metabolism and ferroptosis

Iron is essential for oxygen transport, storage, and cellular energy metabolism, and its metabolic dysregulation can exacerbate both periodontitis and IBD. Physiologically, Fe³⁺ is internalised via transferrin receptor (TFRC)-mediated endocytosis, reduced to Fe²⁺ by STEAP3, and transported into the cytosol by DMT1 for use in enzymes or storage in ferritin, maintaining intracellular iron homoeostasis [103]. Dysregulation of iron metabolism leads to Fe²⁺ accumulation, driving Fenton reactions that generate ROS and cause oxidative damage to lipids, proteins, and DNA, ultimately inducing ferroptosis [104].

Patients with gingivitis or periodontitis exhibit elevated iron levels in gingival crevicular fluid and serum [105]. Periodontal pathogens disrupt iron homoeostasis by: (i) cleaving iron-binding proteins to release free iron; (ii) inducing erythrocyte lysis; and (iii) inhibiting osteoblast function via iron-mediated pathways [106]. P. gingivalis induces ferroptosis by inhibiting the SLC7A11/GSH/GPX4 axis, thereby disrupting the oral mucosal barrier integrity [18]. Concurrently, periodontitis impairs antioxidant defenses, depleting glutathione (GSH) and increasing susceptibility to lipid peroxidation (LPO) and ferroptosis [107]. Glutathione peroxidase 4 (GPX4), a key ferroptosis inhibitor, shows reduced activity in periodontitis, which in turn exacerbates the release of inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-18) [108]. F. nucleatum infection in human periodontal ligament stem cells (PDLSCs) suppresses proliferation, promotes apoptosis and ferroptosis, and upregulates iron metabolism genes (e.g. Ferritin) while downregulating antioxidant genes (e.g. GPX4), thus linking microbial challenge to ferroptotic damage [19]. In colitis models, F. nucleatum activates the ferroptosis pathway to disrupt the intestinal barrier—consistent with its pathogenic role in periodontal tissues—characterised by elevated Fe²⁺ and MDA levels, glutathione depletion, dysregulated GPX4/FTH1/ACSL4 expression, reduced mitochondrial membrane potential, and ROS accumulation in mouse colonic tissues [20].

In both colitis models and IBD patients, ferroptosis markers are elevated, including PTGS2 and LPO indicators (ROS, COX2, ACSL4), alongside reduced GPX4 expression and impaired NF-κB p65 phosphorylation—normally protective against endoplasmic reticulum (ER) stress-induced ferroptosis [109,110]. Iron chelators reduce intestinal ROS and disease severity, highlighting their therapeutic potential [111]. High dietary iron intake increases IBD risk by reducing SCFA production, impairing probiotic growth, and promoting macrophage iron accumulation during infections (e.g. with B. fragilis) [112,113]. Thus, iron dysregulation represents a mechanistic link between periodontitis and IBD, with ferroptosis regulators emerging as promising therapeutic targets.

Other factors

Emerging evidence implicates endocrine dysregulation, neuro-immune crosstalk, and genetic susceptibility in the shared pathogenesis of periodontitis and IBD, offering new insights into their bidirectional relationship. Collectively, these factors contribute to the complex interplay between periodontitis and IBD (Figure 2).

Estrogen deficiency promotes alveolar bone resorption by activating the RANKL/RANK/OPG pathway and impairing periodontal tissue homoeostasis [114]. It also disrupts gut microbiota composition, reducing beneficial Bifidobacterium and Lactobacillus while enriching pro-inflammatory Enterobacteriaceae, thereby amplifying intestinal inflammation via TNF-α and IL-1β [115]. Similarly, parathyroid hormone (PTH)-driven bone loss involves gut microbiota-dependent Th17 activation, with Segmented Filamentous Bacteria enhancing TNF production and osteoclastogenesis [116].

Neuroendocrine pathways, including the brain-gut-bone axis, regulate skeletal integrity. Dopamine promotes osteoblast activity via the Wnt/β-catenin signalling pathway; leptin modulates bone metabolism through hormonal cross-talk; and serotonin influences bone homoeostasis via corticotropin-releasing hormone (CRH) regulation [117]. In Parkinson’s disease models, systemic LPS elevation activates the TLR4/MyD88/NF-κB signalling pathway in the gut and brain, triggering inflammation that secondarily impairs bone homoeostasis [118].

Genetic polymorphisms in immune sensors like TLRs and nucleotide-binding oligomerization domain 2 (NOD2) increase susceptibility to both diseases. NOD2 variants impair recognition of microbial components (e.g. muramyl dipeptide [MDP] from P. gingivalis), leading to defective host responses in periodontitis and disrupted gut immune homoeostasis in IBD—including reduced antimicrobial peptide production and compromised pathogen containment [74,118,119]. This shared genetic vulnerability positions NOD2 as a molecular link between oral and intestinal inflammation, suggesting its pathway as a potential dual-target therapeutic strategy.

Therapeutic modulation of the microbiome in periodontitis and IBD

Emerging microbiome-targeted strategies—including probiotic and prebiotic supplementation, faecal microbiota transplantation (FMT), and dietary interventions—hold therapeutic promise for both periodontitis and IBD. Clinical evidence indicates that specific probiotic strains (e.g. Bifidobacterium and Lactobacillus spp.) modulate oral-gut microbial crosstalk and fine-tune local immune responses [120]. These approaches have been translated into diverse formulations, including oral tablets, functional beverages, and topical agents (e.g. mouthwashes and toothpastes), laying the groundwork for integrated, system-wide therapies focused on microbiome regulation (Figure 3; Table 2).

Figure 3.

Bidirectional Crosstalk Between Periodontitis and IBD via the Oral-Gut Axis: Therapeutic Strategies and Implications for Bone Metabolism. The core crosstalk mechanisms illustrate key pathological signalling pathways linking the oral cavity and gut. Therapeutic strategies aim to restore oral-gut microbial and immune homoeostasis, interrupt inflammatory cascades, and thereby ameliorate comorbid outcomes in periodontitis and IBD, including alveolar and systemic bone loss.

Table 2.

Therapeutic Interventions Targeting the Periodontitis-IBD Axis: Modalities, Mechanisms, and Evidence Levels.

Modalities	Target site(s)	Mechanism of action	Model system	References
Quercetin	Oral	Activates NRF2 in PDLSCs, reduces oxidative stress, and alleviates alveolar bone loss	C57BL/6 mice, Ligature-induced periodontitis	[121]
	Oral	Inhibits P. gingivalis virulence (gingipains, hemagglutinins) and biofilm formation	In vitro (P. gingivalis ATCC 33277)	[122]
	Oral/Gut	Downregulates miR-147-5p to promote Clip3 activation, suppressing Th17 differentiation and alveolar bone repair	SD rats, Ligature-induced periodontitis	[123]
Baicalin	Oral/Systemic	Restores Firmicutes/Bacteroidetes ratio, enriches SCFA-producing taxa, and ameliorates alveolar bone loss and gut barrier dysfunction	C57BL/6 mice, Ligature-induced periodontitis	[124]
	Gut	Modulates bile acid metabolism and suppresses NF-κB/PPARα signalling to reduce mucosal inflammation	C57BL/6 mice, DSS-induced UC	[125]
Lacticaseibacillus rhamnosus GG	Oral/Gut/Systemic	Improves alveolar bone parameters, modulates gut microbiota, and elevates selenomethionine to promote osteogenesis	SD rats, Periodontitis with hyperlipidemia	[126]
Clostridium butyricum	Gut	Enhances tight junctions, increases goblet cells and MUC2, and reduces pro-inflammatory cytokines	C57BL/6 mice, DSS-induced UC	[127]
Escherichia coli NISSLE 1917	Gut	Scavenges ROS, down-regulate pro-inflammatory cytokine levels, regulates gut microbiota, and repairs epithelial barrier	C57BL/6 mice, DSS-induced UC	[128]
Inulin	Gut	Scavenges ROS, down-regulate pro-inflammatory cytokine levels, and promote epithelial barrier repair	SD rats or C57BL/6 mice, DSS-induced UC or TNBS-induced CD	[129]
Faecal Microbiota Transplantation (FMT)	Gut	Reduces Eubacterium hallii and F. nucleatum enrichment, enhances SCFAs synthesis and secondary bile acid levels	Human, double-blind RCT in UC patients	[130]
	Gut	Downregulates the peroxidase family, increases IL-10 secretion, and elevates the abundance of SCFA-producing and secondary bile acid-producing bacteria	C57BL/6 mice, DSS-induced UC	[131]
	Gut	Promotes Foxp3⁺/RORγt⁺ Tregs expansion, induces IL-10 and SCFAs production, suppresses mucosal inflammation	C57BL/6 mice, DSS-induced UC	[132]
	Gut	Upregulates occludin and claudin-1, reduces the proportion of CD4⁺RORγt⁺ Th17 cells, and increases the proportion of CD4⁺Foxp3⁺ Treg cells	Human, clinical trial	[133]

Bidirectional effects of periodontal and IBD treatments on intestinal and oral health

Periodontal therapy not only targets local oral biofilms but also exerts systemic effects on gut homoeostasis. The expression of periodontitis-related biomarkers exhibits stage-specific dynamic evolutionary characteristics, which are closely correlated with disease progression, treatment response and prognostic outcome [28]. The active phase of the disease is characterised by abnormally elevated levels of pro-inflammatory factors and tissue degradation markers (e.g. TNF-α, IL-6, IL-1, ROS, and MMPs), reflecting active periodontal tissue destruction and intense inflammatory responses [7,9]. Following standardised periodontal supportive therapy, levels of pro-inflammatory markers decrease significantly, while anti-inflammatory and repair-regulating factors (e.g. IL-10 and Tregs) tend to increase or restore balance, leading to a restoration of immune homoeostasis. Concurrently, clinical parameters including bleeding on probing, probing depth, clinical attachment level, and full-mouth plaque index shift toward a healthy status [34,45]. Notably, recent evidence highlights that the efficacy of such care is protocol-dependent. Supportive Periodontal Care (SPC) incorporating subgingival instrumentation yields superior outcomes in reducing bleeding on probing compared to supragingival cleaning alone, although deep pockets and smoking habits remain negative predictors of treatment response [134]. Furthermore, adjunctive chemical therapies are being optimised; for instance, chlorhexidine formulations supplemented with sodium DNA maintain antimicrobial efficacy against oral bacteria while significantly attenuating host cytotoxicity and metabolic stress, offering a refined strategy to control dysbiosis without compromising tissue compatibility [135]. Scaling and root planing (SRP), the gold-standard treatment for periodontitis, mechanically removes subgingival biofilm, calculus, and bacterial toxins, and is often combined with local antimicrobials (e.g. metronidazole, chlorhexidine, minocycline) to enhance efficacy. In preclinical models, hyperlipidemic apolipoprotein E-deficient (apoE⁻/⁻) mice with periodontitis treated with SRP showed restored intestinal barrier function and enrichment of butyrate-producing taxa, accompanied by reduced abundances of Alistipes, Barnesiella, and Sporobacter and increased abundances of Turicibacter and Bifidobacterium[34]. Consistent with these findings, clinical studies demonstrate that periodontal therapy induces significant remodelling of the gut microbiota in patients, including increased Actinobacteria and reduced Bacteroidetes and Verrucomicrobia; in advanced cases, decreases in Bacteroides, Faecalibacterium, and Lachnospiraceae are observed [136].

Conversely, systemic IBD therapies can modulate oral inflammation and immunity. Standard pharmacotherapy for IBD includes aminosalicylates, corticosteroids, immunosuppressants, and biologics such as anti-TNF antibodies, anti-IL-12/23 agents, and leucocyte trafficking inhibitors [137]. Although direct mechanistic studies in animal models of periodontitis are limited, human evidence indicates that anti-TNF-α agents confer ancillary benefits on oral health: IBD patients with periapical periodontitis treated with these biologics exhibit accelerated healing compared to those receiving dental treatment alone, along with elevated salivary IgA and myeloperoxidase (MPO) levels [98].

Together, these findings indicate that interventions targeting either condition exert reciprocal regulatory effects across the oral-gut axis: periodontal therapy improves gut microbial composition and mucosal integrity, while IBD treatment ameliorates oral inflammation. This bidirectional benefit underscores the potential for integrated clinical management. Nevertheless, robust interventional trials are still lacking—particularly those assessing whether periodontal treatment improves IBD activity or vice versa—warranting further investigation. In the meantime, routine oral health monitoring remains essential for IBD patients, as oral inflammation may serve as an indicator of systemic disease activity.

Natural compounds with anti-inflammatory and antimicrobial activities in periodontitis and IBD

Natural bioactive compounds show promise in modulating inflammation and microbial dysbiosis in both periodontitis and IBD [138]. Quercetin inhibits P. gingivalis virulence factors, including gingipains and hemagglutinins, and activates the Nrf2 pathway in oxidatively stressed PDLSCs, enhancing antioxidant defenses and osteogenic differentiation [121,122]. In murine periodontitis models, quercetin suppresses pro-inflammatory mediators (IL-1β, TNF-α, IL-17), miR-147-5p/Clip3 axis, and osteoclastogenic signalling (RANKL), significantly attenuating alveolar bone resorption [123].

Baicalin exhibits broad antimicrobial activity against periodontal pathogens such as S. salivarius, P. gingivalis, A. actinomycetemcomitans, and F. nucleatum, and reduces IL-1β-induced PGE₂ production, thereby mitigating periodontal inflammation and bone loss [124]. In IBD models, baicalin normalises the Firmicutes/Bacteroidetes ratio, enhances SCFA-producing taxa, and restores intestinal barrier function. When combined with magnesium, it improves solubility, modulates bile acid metabolism, and suppresses NF-κB and PPARα signalling, reducing oxidative stress and mucosal damage [125]. In addition, a nanocomposite of carboxymethyl chitosan, infliximab (IFX), and chondroitin sulphate (CS) resists gastric enzymatic degradation and pH variability, enhancing intestinal drug availability [139]. Notably, this nanocomposite can be co-delivered with natural compounds to synergistically improve therapeutic efficacy.

Conventional drugs face limitations including poor bioavailability, drug resistance, and systemic toxicity, prompting the development of advanced delivery systems to improve solubility, stability, and targeted tissue-specific delivery. Given that blind use of antibiotics may disrupt the balance of intestinal symbiotic flora, exacerbate dysbiosis, and conversely promote the growth and colonisation of pathogenic bacteria such as P. gingivalis and F. nucleatum, future therapeutic strategies are likely to combine natural compounds with both anti-inflammatory and antibacterial activities with novel drug delivery systems to achieve targeted therapy; nevertheless, this strategy remains in the experimental stage. It is worth noting that further studies are needed to clarify the optimal combination ratios and safety profiles of these natural compounds—as well as their synergistic mechanisms with drug delivery systems.

Probiotics and prebiotics in periodontitis and IBD

Probiotics and prebiotics can ameliorate IBD and exert osteoprotective effects via the gut-bone axis. Probiotic supplementation is an emerging adjunct to standard periodontal therapy. In hyperlipidemic rats with periodontitis, administration of Lacticaseibacillus rhamnosus (LGG) improved alveolar bone parameters—including bone mineral density (BMD), bone volume (BV), and trabecular thickness (Tb.Th)—and increased gut abundance of Staphylococcus, Corynebacterium, and Collinsella. FMT from LGG-treated donors to diseased recipients elevated levels of osteogenic metabolites such as selenomethionine (SeMet), promoting osteogenic differentiation of bone marrow mesenchymal stem cells [126]. Clinical studies demonstrate that probiotics significantly improve outcomes of SRP, enhancing clinical attachment level (CAL), reducing bleeding on probing (BOP), and improving gingival and plaque indices [140].

Probiotic, prebiotic, and synbiotic interventions modulate gut microbiota and inflammation in IBD, offering safe adjunctive therapy. Clostridium butyricum enhances intestinal barrier function in murine colitis by strengthening tight junctions, increasing goblet cells and MUC2 production, and shifting the Firmicutes/Bacteroidetes ratio—collectively attenuating inflammation [127,141]. Engineered probiotics, such as CS-sodium alginate-coated ECN-pE(C/A)₂, improve gastrointestinal survival, colonise efficiently, scavenge ROS via catalase and SOD expression, suppress pro-inflammatory cytokines (IL-1β, TNF-α), enhance anti-inflammatory mediators (IL-10, TGF-β), and upregulate ZO-1 and occludin to restore barrier integrity, while enriching SCFA-producing taxa like Lachnospiraceae NK4A136 [128]. Prebiotic composites, including olsalazine-inulin gels, modulate microbial ecology, reduce Proteobacteria expansion, and promote epithelial repair [129]. Emerging evidence indicates that these microbiome-targeted interventions exert systemic effects beyond the gut. Certain probiotics (e.g. L. reuteri ATCC PTA 6475) improve bone homoeostasis by correcting dysbiosis and reducing systemic inflammation [142], while others may inhibit bone resorption through metabolic modulation [143,144]. Prebiotics like inulin and fructooligosaccharides (FOS) enhance microbial diversity and SCFA production, contributing to reduced inflammation and bone loss [145].

These findings indicate that probiotics exert systemic benefits beyond the oral cavity, potentially mediating periodontal regeneration through gut microbiota-dependent metabolic signalling. Specifically, probiotics and prebiotics exhibit orally relevant systemic anti-inflammatory and osteoprotective potential by modulating the gut-bone axis. Although direct effects on alveolar bone resorption require further validation, the established role of gut microbiota in regulating systemic bone metabolism suggests potential benefits for periodontal bone preservation in IBD patients. Notably, probiotics and prebiotics have already been clinically applied in the treatment of both diseases, and their continued development is expected to become an important research direction for the future therapy of periodontitis and IBD.

Oral and faecal microbiota transplantation

Microbiota transplantation can regulate microbial homoeostasis at both the oral and gut sites, demonstrating promising translationalapplication prospects. Oral microbiota transplantation (OMT) involves transferring health-associated oral microbial communities to restore microbial balance and suppress periodontal pathogens [146]. Preclinical studies in beagle dogs show that OMT significantly increases oral alpha diversity, reduces periodontal inflammation, and improves clinical outcomes compared to mechanical plaque removal alone [147]. While human trials are currently lacking, these findings support OMT as a promising strategy for patients unresponsive to conventional therapies, offering targeted microbiome restoration as a future direction in periodontitis management [148].

FMT has emerged as a clinically validated intervention for modulating gut microbiota composition and function, demonstrating significant efficacy in improving both clinical symptoms and endoscopic remission rates in IBD patients [149]. FMT promotes engraftment of beneficial taxa such as Faecalibacterium prausnitzii and Roseburia inulinivorans, enhancing SCFA and secondary bile acid production, while improving mucus metabolism and butyrate synthesis [130,131,150]. Its immunomodulatory effects include rebalancing intestinal T cell subsets—reducing CD4⁺ T cell abundance and promoting Tregs differentiation via strains like Bacteroides visceratus, which induce IL-10 secretion and suppress mucosal inflammation [132,133]. These systemic changes in microbial and immune homoeostasis suggest potential indirect benefits for extra-intestinal inflammatory conditions, including periodontitis.

Future therapeutic regimens may be designed to integrate natural compounds with both anti-inflammatory and antibacterial activities, along with probiotics or microbiota transplantation via novel targeted drug delivery systems. By modulating the microbial community balance at both ends of the oral-gut axis, such strategies aim to break the vicious cycle between chronic inflammation and dysbiosis; however, this requires further clinical validation.

Bacteriophage therapy

Bacteriophage therapy has emerged as a promising experimental strategy for IBD due to its high specificity for pathobionts such as adherent-invasive Escherichia coli, enabling their selective elimination while preserving commensal microbiota [151]. Advanced delivery systems, including dextran-based nanoparticles, enhance phage stability and targeting efficiency, potentially extending activity to other pro-inflammatory species like F. nucleatum—a bacterium linked to both periodontitis and colorectal inflammation [152]. By precisely modulating dysbiotic microbial communities, phage-based interventions represent a novel preclinical approach toward restoring gut homoeostasis in IBD. Although not yet advanced to clinical trials, this precision strategy offers a compelling rationale for future interdisciplinary collaboration between dentistry and gastroenterology in targeting shared microbial drivers of mucosal inflammation.

Clinical translation of collaborative management between dentistry and gastroenterology

Based on the oral-gut axis mechanism underlying periodontitis and IBD, the clinical translation of interdisciplinary collaboration between dentistry and gastroenterology relies on practical strategies that balance applicability and feasibility. First, a bidirectional referral system is essential: dentists should refer patients with moderate-to-severe periodontitis (especially those with elevated systemic inflammation) to gastroenterologists for intestinal mucosal screening and microbiota testing, while gastroenterologists should routinely arrange oral examinations for IBD patients to assess periodontal status. Second, an interdisciplinary combined monitoring system for inflammatory and immune biomarkers is required to evaluate the efficacy of co-therapy. For non-responsive patients, joint analysis by dentists and gastroenterologists—such as identifying incomplete eradication of oral pathogens or poor intestinal barrier repair—is critical for optimising interventions. Third, synergistic elimination of oral-derived pathogens is pivotal: basic periodontal therapy reduces oral pathogenic reservoirs, and targeted probiotics (guided by gut microbiota profiles) regulate intestinal microecology, preventing cross-site pathogen translocation that may occur with single-site treatment. Fourth, precision interventions targeting core pathobionts (e.g. P. gingivalis, F. nucleatum)—such as specific bacteriophages or vaccines—warrant animal and early-phase clinical studies. These studies should verify dual benefits (reducing oral pathogen load and ameliorating intestinal inflammation) to develop combined regimens of local periodontal targeting and intestinal microecological regulation. Finally, interdisciplinary patient education is indispensable: dentists should teach standardised oral hygiene practices (e.g. Bass technique, flossing) and highlight the impact of periodontal health on intestinal diseases, while gastroenterologists should guide diet and medication management and inform patients of the risk of oral infections exacerbating intestinal inflammation. Collectively, these strategies bridge basic research and clinical practice, providing a framework for the integrated management of periodontitis and IBD.

Conclusion and perspectives

This review establishes a systematic theoretical framework for the periodontitis-IBD regulatory axis by integrating perspectives from microbial ecology, host immunology, and innovative therapeutics. Core mechanisms driving this crosstalk are elucidated, including pathogen translocation, the propagation of dysbiosis, and the pivotal roles of microbial metabolites and immune mediators. Beyond mechanistic insights, current evidence on bidirectional interventions targeting the oral-gut-bone axis is summarised. These interventions range from reciprocal therapeutic regimens and natural anti-inflammatory compounds to advanced strategies such as microbiota transplantation (both oral and faecal) and phage therapy. Collectively, these findings advocate for a paradigm shift toward an integrated dental-gastroenterological model for diagnosis and treatment.

Despite these advances, critical knowledge gaps persist that must be addressed to translate this framework into clinical practice. First, epidemiological data on the baseline prevalence of periodontitis-IBD comorbidity across diverse populations remain scarce; future studies are essential to define risk modifiers related to disease subtype, demographics, and lifestyle factors to quantify the true burden of this comorbidity. Second, mechanistic understanding remains limited regarding pathway specificity and inter-individual heterogeneity. Integrating multi-omics approaches will be crucial to map the ‘oral-gut axis’ and pinpoint key molecular nodes. Crucially, the dynamic evolution of periodontitis-related biomarkers must be leveraged as a predictive tool. Future research should focus on correlating stage-specific shifts in inflammatory mediators (e.g. TNF-α, IL-6, MMPs) and repair factors (e.g. IL-10, Tregs) with intestinal outcomes, thereby establishing a longitudinal monitoring system to evaluate the efficacy of oral-gut targeted therapies. Of particular urgency is deciphering how immune tolerance imbalance drives cross-organ inflammation and how circulating oral-derived cytokines reshape the intestinal immune microenvironment. Furthermore, high-resolution characterisation of core pathobionts (e.g. P. gingivalis, F. nucleatum) at the strain level is needed to clarify their colonisation patterns. Finally, deeper investigation into microbial metabolites and their impact on intestinal barrier integrity will refine the ‘microbiota-metabolite-host’ paradigm, ultimately informing targeted interventional trials where biomarker trajectories serve as key endpoints for ameliorating IBD outcomes through periodontal therapy.

Funding Statement

This study was supported by the Guizhou Provincial Science and Technology Programme (QKHJC-MS[2026]895), Outstanding Young Talent Project of Zunyi Medical University (17zy-002). Pilot Construction Project of Rural Revitalisation from Guizhou Province Ministry of Education (QJJ[2022]037). Science and technology project of Zunyi city (ZSKH-HZ[2024]340, ZSKH-SYS[2025]1).

Disclosure statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

No datasets were generated or analysed during the current study.