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Periodontitis is a chronic inflammatory disease induced by oral dysbiosis that induces a progressive loss of periodontal attachment, leading to the destruction of hard and soft tissues surrounding the tooth.1 This destructive process is associated with the presence of subgingival microbial communities and an intense immuno-inflammatory infiltrate in the periodontium in a susceptible host.2 The inflammatory host response to microbiota dysbiosis results in tissue destruction and the development of periodontitis.3 Although dysbiotic biofilm is necessary as a primary etiologic factor for periodontitis, it is actually the host response that results in the destruction of periodontal tissues.
Nonsurgical periodontal therapy, including the use of antimicrobials, has traditionally focused on biofilm disruption. Such therapy has been used as a first-line treatment for periodontitis. However, this approach is generally not considered definitive care in patients with more severe and/or rapidly progressing forms of periodontitis (eg, Stages III or IV and/or Grade C periodontitis).4 Biofilm dysbiosis contributes only 20% of the risk of developing periodontitis, and the remainder of the risk is associated with other patient-related factors. Further, longitudinal data confirm that bacteria are necessary but insufficient for disease development.5 The uncontrolled inflammation and immune response are responsible for hard and soft tissue destruction and disease progression seen in periodontitis.6
Treatment strategies solely targeting oral microbiota do not achieve favorable outcomes in all periodontal patients. Current and emerging therapeutic approaches that focus on modulating destructive aspects of the host inflammatory response strive to achieve better long-term clinical outcomes.7 The adjunctive use of host modulatory agents can have a positive impact on the progression of periodontal disease, especially in patients who demonstrate a chronic hyperinflammatory response to dysbiotic biofilm associated with genetic, systemic, or environmental factors.8
The host's immune and inflammatory response to microbial challenges plays a pivotal role in initiating the degradation of periodontal tissues and advancing the pathological progression of periodontitis.9 Many categories of therapies for the host-modulation response have been studied. The substances that modulate the host's pathologic collagenolytic response in the soft tissue and alveolar bone will be assessed in this article.
This review investigates the complex mechanisms and applications of host modulation strategies in the context of periodontitis, with a particular focus on doxycycline, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and probiotics. By exploring these pivotal agents and their impact on the host response, this article aims to elucidate their promising outcomes and therapeutic potential in managing periodontal disease.
Doxycycline
Doxycycline has the ability to inhibit matrix metalloproteinases (MMPs), particularly collagenase. Such inhibition can help preserve the integrity of periodontal connective tissues and prevent further destruction.10 Furthermore, doxycycline contributes to promoting collagen cross-linking, which can enhance collagen stabilization within periodontal tissues.7 It is the only drug approved by the FDA as a modulator of the host response in periodontitis. Doxycycline is a third-generation tetracycline showing enhanced properties compared to early-generation tetracyclines, including improved absorption, protein binding, diffusion into tissue structure, and prolonged action.11 When it is used as an adjunct with periodontal therapy, it is administered in a subantimicrobial dosage and does not contribute to bacterial antibiotic resistance. The recommended dosage of subantimicrobial dose doxycycline (SDD) is 20 mg twice daily as adjunctive treatment with nonsurgical periodontal therapy and/or ongoing periodontal maintenance for 3 to 9 months.12 Doxycycline exhibits anti-inflammatory actions by suppressing the production of proinflammatory cytokines such as IL-1, IL-6, and TNF-ɑ by immune cells like macrophages and neutrophils.9 The downregulation of these proinflammatory mediators can mitigate the exaggerated immune response in periodontal inflammation.7,9
Many studies investigate the use of SDD as an adjunction therapy for patients with systemic disease or smokers. Patients with diabetes mellitus treated with doxycycline present a significant reduction of probing deep pockets, but no improvement in clinical attachment loss.4 Other studies have demonstrated that the adjunctive use of SDD with nonsurgical periodontal therapy demonstrates improvements in clinical attachment loss and probing depths at sites with 7 mm and greater probing pocket depths for up to 9 months.13 Furthermore, the combination of SDD with other adjunctive therapies has also shown clinical benefit. For example, application of local statin medications at intrabony defects combined with the use of systemic SDD and delivery of nonsurgical periodontal therapy can result in clinical improvements at deep periodontal pockets.12 In addition, a recent review demonstrated that the use of local doxycycline as an adjuvant to non-surgical therapy significantly improved clinical attachment levels in smokers with periodontitis after 3 or 6 months.14
Omega-3 Fatty Acids (PUFAs)
Promoting the resolution of inflammation with lipid mediators has been proposed to manage inflammatory diseases.7 Polyunsaturated omega-3 fatty acids (PUFAs), found abundantly in certain fish, flaxseeds, and walnuts, have been identified for their potential anti-inflammatory properties and their role in host modulation response to periodontitis.15 These essential fatty acids can be metabolized into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both of which demonstrate anti-inflammatory properties, and have been shown to reduce proinflammatory mediators, such as cytokines (IL-1 and IL-6), and TNF-ɑ.16 In addition, immune cells demonstrate altered behavior in the presence of PUFAs. Omega-3 fatty acids can shift the polarization of macrophages from the inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. This pivot is crucial for resolving inflammation and tissue repair.15 Studies have shown that when nonsurgical periodontal therapy is performed with the adjunctive use of omega-3 fatty acids, patients demonstrate significantly better probing pocket depth and clinical attachment loss reduction compared to nonsurgical therapy alone.17
The biosynthesis of resolvins and SPMs in inflamed tissues influences the activity of enzymes, including asprin-induced cyclooxygenase 2 (COX-2)/acetylated COX-2 function. SPMs act as receptor agonists and upregulate COX-2 function. This increased activity initiates pro-resolving pathways, promoting the termination of inflammation to facilitate the restoration of tissue homeostasis.18 Animal studies show that topical application of SPMs reverses inflammatory gene expression, decreases inflammatory infiltrate, and promotes a host-mediated shift in the subgingival microflora, reversing dysbiosis. SPMs can modulate the adaptive immune response, prevent alveolar bone resorption, and regenerate lost bone due to periodontal inflammation. Previous studies have demonstrated their direct immunoregulatory actions on human periodontal ligament cells and bone cell differentiation and activation.19,20
The combination of omega-3 PUFAs and aspirin has the potential to increase endogenous COX-2 mediated synthesis of resolving molecules and subsequently aid resolution of inflammation in periodontal tissues.7,21 In addition, in an experimental periodontitis model adjunctive administration of PUFA and aspirin reduced bone resorption and suppressed proinflammatory cytokines (TNF-ɑ and IL-1) and RANK-L mediated expression of MMP genes.21 Although omega-3 use alone has not been shown to enhance clinical outcomes of nonsurgical periodontal therapy, when combined with low-dose aspirin, it notably enhanced both the reduction in probing pocket depth and the gain in clinical attachment loss at 3 to 6 months intervals after nonsurgical periodontal treatment.13 The range of omega-3 PUFA dosages was heterogenous in most studies that evaluated their use, from 300mg to 500mg and was combined with low dose (<325mg) asprin.13 The most common combined dosage studies was 180mg eicosapentaenoic acid (EPA) and 120mg docosahexaenoic acid (DHA) with 81mg aspirin over a course of 3-6 months.13
Specialized Pro-resolving Mediators (SPM)
Specialized pro-resolving mediators (SPMs) are lipid molecules that suppress chronic tissue imbalance, aid in repair, and promote regeneration.22 Some examples of SMPs include lipoxins, protectins, resolvins, maresins, and annexins. These mediators have been shown to reduce inflammation, improve inflammatory product clearance, and restore tissue function. Endogenous lipid mediators, classified as lipoxins (LX) and aspirin-triggered lipoxins (ATL), are generated from omega-6 fatty acids during late-stage inflammation.23 Leukocytes, platelets, and stem cells generate lipoxins, which then interact with receptors to inhibit inflammation. Lipoxins enable phagocytosis in monocytes and macrophages while suppressing proinflammatory activity.24
Resolvins and maresins are metabolites of omega-3 polyunsaturated fatty acids (PUFAs) with anti-inflammatory and pro-resolving properties. Resolvins have been shown to promote the elimination of periodontal infection, prevent disease recurrence, promote the proliferation and differentiation of mesenchymal stem cells necessary for tissue repair and regeneration, and reverse oral dysbiosis.22 Resolvin use has also been associated with reduced bone resorption, which has been attributed to RANKL suppression and/or enhanced osteoprotegerin synthesis; these effects result in the inhibition of osteoclastogenesis and upregulation of periodontal ligament fibroblast proliferation. Maresins are macrophage inflammatory mediators that inhibit the expression of proinflammatory cytokines. They also block fibroblast phenotypic transition and reduce reactive oxygen species (ROS), promoting collagen fibrillogenesis and osteoblast, fibroblast, and stem cell migration.23
There are promising preclinical data using resolvins as a treatment demonstrating inhibition of the inflammatory process and alveolar bone loss in laboratory-induced periodontitis.22 Clinical data evaluating the adjunctive use of omega-3 PUFAs dietary supplements and aspirin with nonsurgical periodontal therapy have demonstrated beneficial effects including significant improvements in probing depth reduction and gain in clinical attachment levels in both systemically healthy25 and Type 2 diabetic patients.26 In particular, the addition of aspirin promotes acetylation and changes the enzymatic function of COX2, triggering the production of E- and D-resolvins instead of prostaglandins.27
The effects of SPM oral rinse on gingival inflammation have been evaluated in a recent clinical trial. Oral rinse containing lipoxin notably decreased the modified gingival index when compared with both the placebo and no-rinse control groups. The data also indicated a consistent and more pronounced reduction in metrics such as bleeding on probing, probing depth, and clinical attachment gain, although these findings did not reach statistical significance.28
The utilization of SPM as a therapeutic approach is an emerging area that holds great potential for managing the degradation of periodontal tissues and facilitating the restoration of lost tissues. As research endeavors delve deeper into the mechanisms responsible for resolving inflammation through SPMs, it becomes increasingly evident that this therapy holds the most promise, primarily due to its track record of being free from any observed adverse effects during its application. Currently, downstream clinical trials assessing ideal dosages of SPM for oral and/or topical use are not available and future research should focus on the clinical applications and ideal clinical dosages and modes of use for optimal outcomes.
Probiotics
Probiotics can be described as living bacteria that, when supplied in adequate quantities, provide a health advantage to the host.29 Such bacteria often compete with pathogenic species and may enhance a shift from dysbiosis to eubiosis within biofilm. Probiotics have been studied as adjuvant periodontal treatment, demonstrating antibacterial and immuno-modulatory activities. However, the mechanisms behind these effects are not yet fully understood.30
Lactobacillus brevis aids in the reduction of clinical gingival inflammation by competing with arginase and nitric oxide synthase for the substrate arginine, reducing the production of the potent proinflammatory mediator nitric oxide in gingival crevicular fluid.3 Probiotics' antibacterial activity is caused by altered microbial signaling and the host's subsequent immunological response. Lactobacilli, particularly the most commonly studied probiotic, L. reuteri, have been found to influence the immune response to periodontopathogens such Porphyromonas gingivalis. In mice with artificially induced periodontitis, probiotic treatment also reduced alveolar bone loss. Probiotics, in addition to their antibacterial properties, can help enhance the immune system. Lactobacillus acidophilus, for example, has been found to boost immunity against P. gingivalis and Fusobacterium nucleatum.31
Some human clinical trials have investigated the efficacy of Lactobacillus- and Bifidobacterium genera-based probiotics as adjuncts to nonsurgical periodontal therapy. In patients with gingivitis and high initial gingival index scores, the use of probiotics and mechanical plaque removal in gingivitis demonstrate enhanced resolution of probing pocket depth and decreased bleeding on probing when compared to mechanical plaque removal alone.32 Further, a recent randomized controlled trial reports significant improvements in probing pocket depth and clinical attachment loss at sites with moderate or deep pockets.32
Probiotics may improve clinical outcomes, including decreased probing pocket depth, clinical attachment loss, and bleeding on probing, but they do not change plaque indices and, therefore, may be most indicated for use in combination with enhanced oral hygiene measures.33 Probiotics are not associated with significant adverse effects and may have benefits for both gingivitis and periodontitis patients.33 Typical dosages vary based on the product, but common dosages range from 5 to 10 billion colony-forming units (CFUs) per day for children, and from 10 to 20 billion CFUs per day for adults, but in adults L. reuteri has been administered in high doses of 100 billion CFU and found to be safe with minimal to no reported side effects.30 These findings suggest that probiotics may hold promise in managing periodontal disease. However, further research, especially randomized controlled clinical trials with larger sample sizes and longer follow-ups, is needed to understand their effectiveness and optimal use.30
Conclusion
While mechanical means of biofilm control have a well-established positive effect on periodontal health, the use of adjunctive medicaments, particularly those that allow for modulation of the host response, are emerging as a tool for enhanced therapeutic outcomes. While combining host modulation therapy with periodontal treatment improves periodontal health metrics, monitoring potential systemic and/or adverse effects is essential. A deeper understanding of how current and emerging host modulation therapeutic agents function and their specific targets would be advantageous in periodontal therapy. Periodontitis is a bacterially initiated, chronic inflammatory condition. As a result of the role of the host immune-inflammatory response in disease progression, it may be possible to mitigate tissue destruction by modulating the host's immune response with bioactive compounds possessing protective properties, such as anti-inflammatory and antioxidant effects. Such host modulation may be particularly impactful for individuals who demonstrate hyper-inflammatory conditions, including nicotine users, individuals with dysglycemia, or other systemic conditions. Further investigations could reveal more impactful host modulation therapy agents and allow clinical practitioners to better stratify patients based upon disease activity to better target adjunctive therapies for patient-centered care. Therefore, future clinical investigations are necessary to confirm the significant role of host modulation therapy agents in managing periodontitis.
About the Authors
Felipe D. Ouriques, DDS, MS
Periodontology Resident
University of Alabama at Birmingham
Department of Periodontology
Birmingham, Alabama
Maria L. Geisinger, DDS, MS
Professor
University of Alabama at Birmingham
Department of Periodontology
Birmingham, Alabama
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