Periodontitis is one of the most prevalent chronic inflammatory diseases worldwide, affecting nearly 50% of adults, with about 10% suffering from its severe form (Janakiram and Dye, 2020). Beyond its well-recognized role in tooth loss and impaired oral function, periodontitis has been increasingly associated with systemic disorders, including cardiovascular disease, diabetes, and inflammatory bowel disease (Kim and Pang, 2025; Hajishengallis and Chavakis, 2021). The emerging concept of the “oral-gut axis” suggests that oral dysbiosis and periodontal inflammation may influence gut homeostasis, but the precise molecular mediators remain poorly understood (Li et al., 2021; Qian et al., 2022; Bao et al., 2022).

Recent studies have highlighted the gut microbiota as a key link between oral inflammation and intestinal pathology (Xi et al., 2024). Periodontitis-associated microbial dysbiosis can extend beyond the oral cavity, altering gut microbial composition and metabolites, thereby modulating host immune responses (Bao et al., 2022; Qian et al., 2023). However, the downstream molecular targets through which the gut microbiota mediates these effects in the intestine remain unclear (Wang et al., 2024).

GPR109A is a member of the epithelial G-protein-coupled receptor (GPCR) family that functions as a metabolic sensor for microbial- and diet-derived metabolites, thereby linking luminal metabolic cues to host barrier regulation (Feng et al., 2022). Similar to other short-chain fatty acid (SCFA)–responsive receptors such as GPR41 and GPR43, as well as epithelial lipid-sensing GPCRs including GPR120 (Rubbino et al., 2022), GPR109A enables epithelial cells to sense commensal-derived butyrate, β-hydroxybutyrate, and dietary fermentation products (Chen et al., 2018; Thangaraju et al., 2009). Activation of GPR109A has been shown to strengthen epithelial barrier function, promote anti-inflammatory signaling, and protect against colonic inflammation (Macia et al., 2015). Conversely, reduced GPR109A activity is associated with heightened intestinal inflammation and susceptibility to colitis (Singh et al., 2014). Whether periodontitis and its associated microbiota influence GPR109A expression in the colon has not yet been investigated.

In this study, we hypothesized that periodontitis promotes intestinal inflammation through gut microbiota–mediated suppression of GPR109A. We first established a ligature-induced periodontitis model to examine colonic GPR109A expression. Next, we investigated whether probiotic supplementation could mitigate the impact of periodontitis on GPR109A. We then performed fecal microbiota transplantation from periodontitis mice to germ-free recipients to assess causality. Finally, we tested whether pharmacological activation of GPR109A could attenuate periodontitis-associated colonic inflammation. Collectively, our work uncovers a novel oral–gut axis mechanism whereby periodontitis impairs intestinal homeostasis through GPR109A suppression, suggesting new therapeutic opportunities targeting this pathway.

In this study, we provide systematic evidence that periodontitis disturbs intestinal homeostasis through gut microbiota-mediated suppression of colonic GPR109A. Using a ligature-induced periodontitis model, we confirmed typical periodontal tissue destruction and alveolar bone loss. Importantly, we demonstrated that colonic GPR109A expression was significantly reduced in periodontitis mice, concomitant with disruption of epithelial barrier integrity. Probiotic supplementation alleviated these pathological changes, while fecal microbiota transplantation from periodontitis mice transmitted the phenotype of reduced colonic GPR109A, barrier dysfunction, and enhanced inflammation to germ-free recipients. Furthermore, pharmacological modulation of GPR109A signaling revealed that receptor activation attenuated intestinal inflammation.

Our previous work demonstrated that periodontitis induces low-grade intestinal inflammation and alters gut microbial composition (Li et al., 2021), and that transplantation of dysbiotic microbiota from periodontitis mice transfers this inflammatory phenotype to recipient mice (Li et al., 2022). However, the precise mechanisms by which gut microbiota disrupts the intestinal epithelial barrier and the key molecular targets involved have remained unclear. Given that we previously observed significant alterations in butyrate-producing bacteria that played a crucial role in mediating hyperglycemia associated with periodontitis (Li et al., 2021), we hypothesized that the butyrate receptor GPR109A might serve as a critical mediator in this process. In the present study, we tested this hypothesis using complementary approaches, including probiotic supplementation to correct gut dysbiosis, fecal microbiota transplantation, and pharmacological activation of GPR109A. These findings provide direct evidence that GPR109A is a central link between periodontitis-associated gut dysbiosis, epithelial barrier dysfunction, and intestinal inflammation.

In our experimental design, we introduced a high-fructose diet to capture both clinical relevance and mechanistic plausibility. High-sugar diets are highly prevalent in modern societies and represent a widespread suboptimal lifestyle that affects large segments of the population (Ge et al., 2025; Lara-Castor et al., 2025). Such diets are well recognized to induce low-grade systemic inflammation and to destabilize the gut microbiota and intestinal epithelial barrier (Zhang et al., 2024; Satokari, 2020). Under these conditions of impaired homeostasis, periodontal inflammation is more likely to exert pronounced systemic effects, including further disruption of the gut barrier. This interaction is particularly pertinent to metabolically compromised populations, where the burden of periodontitis may be amplified (Reytor-González et al., 2024). By modeling periodontitis in the context of a high-fructose diet, our study reflects real-world dietary exposures and enhances translational relevance, especially given the strong association of high-sugar intake with metabolic syndrome, obesity, and diabetes.

The oral–gut axis has emerged as an important research focus, as accumulating evidence suggests that oral dysbiosis can influence gut microbiota composition and intestinal inflammation (Azzolino et al., 2025). Epidemiological studies have linked periodontitis with an increased risk of inflammatory bowel disease (IBD) (Park et al., 2025), metabolic disorders (Saito et al., 2024), and systemic low-grade inflammation (Cecoro et al., 2020; Pink et al., 2023). However, the molecular mediators underpinning this association remain poorly understood. Our findings extend current knowledge by demonstrating that GPR109A, a receptor for niacin and short-chain fatty acids such as butyrate, is a crucial target suppressed in the colonic mucosa of periodontitis mice.

As a key member of the epithelial metabolite-sensing GPCR family, GPR109A serves as a central regulator linking microbial and dietary metabolites to the maintenance of mucosal barrier integrity and immune balance (Chang, 2024). Activation of GPR109A by microbiota-derived butyrate or ketone bodies not only strengthens epithelial tight-junction assembly and mucus layer organization, but also modulates epithelial–immune crosstalk by promoting anti-inflammatory signaling and restraining excessive NF-κB– and inflammasome-driven responses (Gong et al., 2020; Chen et al., 2018). This places GPR109A alongside other SCFA-responsive receptors and lipid-sensing GPR120 as part of a coordinated signaling network that translates luminal metabolic activity into protective epithelial programs, including reinforcement of barrier function, regulation of goblet cell differentiation, and control of cytokine and antimicrobial peptide production (Dias Nirello et al., 2025; Takakuwa et al., 2019; Rubbino et al., 2022). Thus, GPR109A has been established as an important regulator of mucosal immunity and epithelial integrity (Liu et al., 2022; Gong et al., 2020). Previous studies have shown that GPR109A deficiency leads to increased susceptibility to colitis and colorectal carcinogenesis (Singh et al., 2014). In line with these findings, we observed that colonic GPR109A expression was markedly reduced in periodontitis, accompanied by diminished expression of the tight junction proteins ZO-1 and Occludin(Figures 2D, F). Notably, this epithelial barrier dysfunction precedes overt inflammatory pathology, as hematoxylin–eosin staining of colonic tissues revealed no apparent histological damage or inflammatory cell infiltration in periodontitis mice (Figure 2A). These findings indicate that disruption of epithelial tight junctions occurs at an early stage and is not a secondary consequence of established inflammation. Consistent with this interpretation, pharmacological activation of GPR109A significantly attenuated inflammatory responses in periodontitis mice (Figure 5), supporting a functional role for GPR109A signaling in maintaining epithelial barrier integrity. In this context, suppression of GPR109A may primarily compromise epithelial tight junction organization, thereby increasing mucosal permeability and creating a permissive environment for subsequent inflammatory activation.

Interestingly, we found that the GPR109A antagonist mepenzolate bromide did not further exacerbate intestinal tight junction disruption or induce a broad increase in inflammatory cytokine expression in periodontitis-challenged mice. Mepenzolate bromide is a well-characterized functional antagonist of GPR109A that primarily inhibits receptor signaling rather than directly downregulating receptor expression, which may partly explain the absence of additional suppression of GPR109A levels. Consistent with this mechanism, previous studies have shown that pharmacological inhibition of GPR109A with mepenzolate bromide effectively blocks receptor activity without reducing GPR109A protein expression (Yang et al., 2024). Moreover, because periodontitis itself markedly downregulates colonic GPR109A expression, GPR109A-mediated protective signaling is likely already substantially compromised, thereby limiting the residual receptor pool available for further pharmacological antagonism. This interpretation is supported by prior studies demonstrating that, in disease contexts characterized by reduced GPR109A expression or function, genetic deletion or pharmacological antagonism of GPR109A does not further worsen pathological indices, but instead primarily abolishes the protective effects conferred by receptor activation (Snelson et al., 2020; Kang et al., 2022).

The fecal microbiota transplantation experiments provide compelling evidence that gut microbiota is responsible for mediating the suppression of GPR109A. To further elucidate the microbial basis underlying the functional alterations observed after fecal microbiota transplantation, we performed 16S rRNA gene sequencing of donor fecal samples. Our results showed that periodontitis was associated with a pronounced restructuring of the gut microbial community, characterized by reduced microbial diversity, distinct compositional alterations, and significant shifts in multiple taxa implicated in short-chain fatty acid metabolism. Interestingly, Germ-free mice colonized with fecal microbiota from periodontitis donors recapitulated the phenotype of reduced GPR109A expression, impaired barrier function, and elevated pro-inflammatory cytokines. These findings highlight the causal role of dysbiotic microbiota in transmitting the pathological effects of periodontitis to the intestine. The decreased activation of this receptor subsequently compromises barrier integrity and enhances inflammation (Chen et al., 2018; Gong et al., 2020). In addition, dysbiotic microbiota may directly promote the expansion of pro-inflammatory bacterial taxa and trigger host immune responses that further downregulate GPR109A expression (Maciel-Fiuza et al., 2023).

Notably, our data show that supplementation with a butyrate-producing probiotic strain effectively restored colonic GPR109A expression and normalized tight junction protein localization. By specifically enhancing microbial butyrate output, this intervention targeted GPR109A activation, thereby underscoring the central role of this receptor in mediating periodontitis-associated intestinal pathology. These results highlight the potential of butyrate-producing probiotics to counteract dysbiosis and reinforce host–microbiota metabolic crosstalk critical for GPR109A signaling (Gong et al., 2020). Previous studies have reported beneficial effects of probiotics in reducing systemic inflammation and improving gut barrier integrity (Zheng et al., 2023; Ghorbani et al., 2025), and our findings extend this evidence by linking probiotic effects specifically to GPR109A activation. This suggests that therapeutic strategies aimed at the microbiota–butyrate–GPR109A axis may not only mitigate intestinal inflammation but also attenuate the systemic consequences of periodontitis.

Our findings have important implications for both periodontal and gastrointestinal health. First, they reinforce the concept that periodontitis is not merely an oral disease but may act as a driver of distal intestinal pathology through microbial and molecular pathways. This highlights the importance of comprehensive periodontal care in reducing the risk of systemic inflammatory diseases, including IBD (Madsen et al., 2023; Ozayzan et al., 2024). Second, identifying GPR109A as a key mediator provides a tangible molecular target for intervention, suggesting that restoring its signaling, such as via agonists like GSK256073 or supplementation with probiotics, could serve as a viable strategy to manage patients with both periodontal disease and intestinal inflammatory disorders.

Despite the strengths of our study, several limitations should be acknowledged. First, our findings are based on murine models, and translation to human physiology requires careful validation. Although ligature-induced periodontitis and fecal microbiota transplantation provide robust tools to study oral–gut interactions, human studies are essential to confirm whether similar mechanisms operate in clinical populations. Second, while we demonstrated the involvement of gut microbiota in GPR109A suppression, we did not identify specific bacterial taxa or metabolites responsible. Future work employing metagenomic sequencing and metabolomic profiling will be necessary to pinpoint the microbial drivers of this effect, with particular attention to butyrate-producing bacteria. Third, our study focused primarily on colonic outcomes, but systemic consequences of GPR109A modulation, including effects on cardiovascular or metabolic health, remain unexplored. Finally, although we used a selective agonist to probe GPR109A function, off-target effects cannot be fully excluded. Further studies using genetic knockout models may help validate these findings.

From a translational perspective, as a metabolic sensor for microbiota- and diet-derived short-chain fatty acids, particularly butyrate, GPR109A can be modulated through dietary interventions that enhance fermentable fiber intake and endogenous butyrate production. In parallel, microbiota-based approaches, including butyrate-producing probiotics or postbiotic formulations, may reinforce GPR109A-mediated epithelial protection, especially in individuals with impaired microbial fermentation capacity. Moreover, pharmacological activation of GPR109A could be explored as an adjunctive strategy in high-risk periodontitis patients with systemic inflammatory or metabolic comorbidities, thereby translating mechanistic insights into clinically actionable interventions. Additionally, monitoring GPR109A expression or fecal butyrate levels might offer a potential approach to assess gut barrier risks in periodontitis patients. Nevertheless, the clinical relevance of targeting GPR109A will require further validation in well-characterized human cohorts to establish its therapeutic potential.

In conclusion, this study demonstrates that periodontitis promotes intestinal inflammation through gut microbiota–mediated suppression of colonic GPR109A. We show that downregulation of this receptor disrupts epithelial barrier integrity and enhances pro-inflammatory responses, whereas its activation restores barrier function and attenuates inflammation. These findings not only advance our mechanistic understanding of the oral–gut axis but also highlight GPR109A as a promising therapeutic target for mitigating the intestinal consequences of periodontitis.