Background: This review synthesizes the role of Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) in modulating immune responses through citrullination and assesses its impact on periodontitis and systemic conditions. Methods: A systematic review was conducted on preclinical and clinical studies focusing on P. gingivalis- and A. actinomycetemcomitans-induced citrullination and its effects on immune responses, particularly inflammatory pathways, and systemic diseases. The search included PubMed, Scopus, Google Scholar, Web of Science, and gray literature. Quality and risk of bias were assessed using OHAT Rob Toll and QUIN-Tool. The review is registered in PROSPERO (ID: CRD42024579352). Results: 18 articles published up to August 2024 were included. Findings show that P. gingivalis and A. actinomycetemcomitans citrullination modulates immune responses, leading to neutrophil dysfunction and chronic inflammation. Key mechanisms include citrullination of antimicrobial peptides, CXCL10, histone H3, α-enolase, and C5a, impairing neutrophil activation and promoting NET formation. Conclusions: This review suggests that P. gingivalis and A. actinomycetemcomitans citrullination modulates immune responses and may influence periodontitis and systemic conditions like RA. Beyond ACPA production, these pathogens affect key proteins such as H3, C5a, and CXCL10, as well as antimicrobial peptides, NET formation, and phagocytosis. These interactions lead to neutrophil dysfunction and potentially affect other cells, subsequently disrupting local and systemic inflammatory responses.

Introduction: Peri‐implantitis, characterized by inflammatory bone loss, is a leading cause of dental implant failure. Current regenerative strategies face limitations due to the persistent inflammatory microenvironment. Mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) have emerged as promising acellular therapeutics with dual osteogenic and immunomodulatory capacities, offering a novel approach to address the complexity of peri‐implant bone defects. Methods: This narrative review synthesizes preclinical evidence on MSC‐EVs for peri‐implant bone regeneration. It examines methods for EV isolation from various sources. Furthermore, it analyzes advanced engineered delivery systems, such as peptide‐functionalized implant surfaces and bioactive scaffolds, designed to enhance local retention and therapeutic efficacy. Results: MSC‐EVs orchestrate bone regeneration through multifaceted mechanisms. They directly stimulate osteogenesis by transferring pro‐osteogenic miRNAs and proteins, activating key pathways like PI3K/AKT and Wnt/β‐catenin. Crucially, they modulate the osteoimmune environment by reprogramming macrophages toward a reparative M2 phenotype, suppressing pro‐inflammatory Th1/Th17 responses, and expanding regulatory T cells (Tregs). Concurrently, MSC‐EVs inhibit bone resorption by favorably modulating the RANKL/OPG balance and directly interfering with osteoclast differentiation. They also promote neovascularization, a critical factor for healing in ischemic zones. Preclinical models demonstrate that localized delivery via engineered systems significantly enhances osseointegration, bone‐implant contact, and regeneration of functional bone‐vessel units. Conclusion: MSC‐EVs represent a promising and multifaceted therapeutic strategy for bone regeneration in peri‐implantitis, simultaneously targeting inflammation, bone resorption, and osteogenesis. While robust preclinical evidence supports their role in halting bone loss and promoting structured regeneration, successful clinical translation requires further standardization, optimization of delivery, and validation in human trials.

Objectives: This study aimed to, first, determine the prevalence of periodontitis in patients diagnosed with colorectal cancer (CRC) through a comprehensive clinical periodontal evaluation, and second, to analyze the relationship between periodontitis and different tumor severity variables. Materials and methods: In a cross-sectional and analytical study in patients with CRC, we divided the patients into two groups, periodontitis and non-periodontitis, based on a complete periodontal assessment (clinical attachment loss, probing pocket depth, bleeding on probing, plaque index, number of present teeth, and a periodontal severity index). In both groups, in addition to sociodemographic variables, 12 histopathological tumor severity variables were compared. Results: Out of 59 patients diagnosed with CRC, 41 (69.5%, 95% CI: 56.1–80.8) were diagnosed with periodontitis. The mean values in ng/mL of baseline and peak carcinoembryonic antigen (CEA) in the periodontitis patient group, mean ± SD (0.44 ± 0.39, 0.69 ± 0.49), were much higher compared to the non-periodontitis group (0.11 ± 0.29, 0.35 ± 0.45), 95% CI: 0.12–0.54, p < 0.001 and 95% CI: 0.06–0.62, p = 0.005, respectively. The rest of the comparisons between the different characteristics and histopathological variables of the tumor showed very similar results between both groups. Conclusions: The 69.5% prevalence of periodontitis in patients with colorectal cancer highlights the relationship between both diseases. Furthermore, the association between periodontitis and elevated CEA levels suggests a possible role of chronic inflammation in tumor susceptibility. However, the absence of an association with other histopathological variables suggests that periodontitis is not related to cancer severity. Clinical relevance: Recognizing periodontitis as a potential field cancerization highlights the importance of periodontal management as a possible strategy to reduce CRC susceptibility.

Background: Rheumatoid arthritis and periodontitis are chronic inflammatory diseases linked to systemic complications, including increased cardiovascular risk. The impact of glycemia, lipid profile and atherogenic cardiovascular risk indices in patients with rheumatoid arthritis (RA) and periodontitis, compared to controls, has not yet been evaluated. We aimed to analyze whether periodontitis acts as an aggravating factor in this relationship. Methods: In a case–control study, we assessed biochemical, RA-related markers and four atherogenic indices (Atherogenic Index of Plasma, Castelli Risk Index I, Castelli Risk Index II, and Triglyceride–Glucose Index). Periodontitis was evaluated using a gingival inflammation index (BOP) and a periodontal severity index (PIRIM). Multiple linear regression models were used to analyze whether periodontitis had a differential effect in RA cases versus controls. Results: A total of 46 participants were included (32 RA cases, 14 controls). Periodontitis was more prevalent among cases (62.5% vs. 28.5%). BOP was significantly higher in RA patients (p < 0.001) and associated with LDLC (p = 0.031). Both BOP and PIRIM correlated with higher CRI-1 and CRI-2 values across groups. PIRIM was also linked to increased LDLC (p = 0.018) and decreased HDLC (p = 0.003). Conclusions: RA and periodontitis appear to interact synergistically and are associated with a more atherogenic profile. These findings highlight periodontal health as a potentially modifiable factor in reducing cardiovascular risk in RA patients.

Chronic periodontitis has emerged as a potential modifiable risk factor for several tumors, yet its role remains underexplored beyond epidemiological associations. This perspective review examines the immunological and molecular interplay between periodontitis and various cancers—including prostate, colorectal, oral squamous cell carcinoma, and oral potentially malignant disorders—highlighting shared inflammatory mediators and immune dysregulation. Special attention is given to immune cell profiles, cytokine expression, dysbiosis, and common miRNA signatures. Recent evidence suggests that periodontitis may act not only as a co-factor in tumor development but also, in some contexts, as a marker of therapeutic response, particularly in patients undergoing immune checkpoint inhibitor therapy. In our view, future research should prioritize mechanistic studies to define common immune–inflammatory pathways and clarify whether periodontitis functions as a field cancerization process or as a facilitator of malignant transformation in already compromised tissues. The relationship between cancer and periodontitis underscores the need to integrate oral health into oncologic care and immunotherapy management.

This review synthesizes the role of Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (A.a) in modulating immune responses through citrullination and assesses its impact on periodontitis and systemic conditions. A systematic review was conducted on preclinical and clinical studies focusing on Pg- and A.a- induced citrullination and its effects on immune responses, particularly inflammatory pathways and on systemic diseases. The search included PubMed, Scopus, Google Scholar, Web of Science, and gray literature. Quality and risk of bias were assessed using OHAT Rob Toll and QUIN-Tool. The review is registered in PROSPERO (ID: CRD42024579352). 18 articles published up to August 2024 were included. Findings show that Pg and A.a citrullination modulates immune responses, leading to neutrophil dysfunction and chronic inflammation. Key mechanisms include citrullination of antimicrobial peptides, CXCL10, histone H3, α-enolase, and C5a, impairing neutrophil activation and promoting NET formation. This review suggests that Pg and A.a citrullination modulates immune responses and may influence periodontitis and systemic conditions like RA. Beyond ACPA production, these pathogens affect key proteins such as H3, C5a, and CXCL10, as well as antimicrobial peptides, NET formation, and phagocytosis. These interactions lead to neutrophil dysfunction and potentially affect other cells, subsequently disrupting local and systemic inflammatory responses.