The Clinical, Microbiological, and Immunological Effects of Probiotic Supplementation on Prevention and Treatment of Periodontal Diseases: A Systematic Review and Meta-Analysis

Abstract

(1) Background: Periodontal diseases are a global health concern. They are multi-stage, progressive inflammatory diseases triggered by the inflammation of the gums in response to periodontopathogens and may lead to the destruction of tooth-supporting structures, tooth loss, and systemic health problems. This systematic review and meta-analysis evaluated the effects of probiotic supplementation on the prevention and treatment of periodontal disease based on the assessment of clinical, microbiological, and immunological outcomes. (2) Methods: This study was registered under PROSPERO (CRD42021249120). Six databases were searched: PubMed, MEDLINE, EMBASE, CINAHL, Web of Science, and Dentistry and Oral Science Source. The meta-analysis assessed the effects of probiotic supplementation on the prevention and treatment of periodontal diseases and reported them using Hedge's g standardized mean difference (SMD). (3) Results: Of the 1883 articles initially identified, 64 randomized clinical trials were included in this study. The results of this meta-analysis indicated statistically significant improvements after probiotic supplementation in the majority of the clinical outcomes in periodontal disease patients, including the plaque index (SMD = 0.557, 95% CI: 0.228, 0.885), gingival index, SMD = 0.920, 95% CI: 0.426, 1.414), probing pocket depth (SMD = 0.578, 95% CI: 0.365, 0.790), clinical attachment level (SMD = 0.413, 95% CI: 0.262, 0.563), bleeding on probing (SMD = 0.841, 95% CI: 0.479, 1.20), gingival crevicular fluid volume (SMD = 0.568, 95% CI: 0.235, 0.902), reduction in the subgingival periodontopathogen count of P. gingivalis (SMD = 0.402, 95% CI: 0.120, 0.685), F. nucleatum (SMD = 0.392, 95% CI: 0.127, 0.658), and T. forsythia (SMD = 0.341, 95% CI: 0.050, 0.633), and immunological markers MMP-8 (SMD = 0.819, 95% CI: 0.417, 1.221) and IL-6 (SMD = 0.361, 95% CI: 0.079, 0.644). (4) Conclusions: The results of this study suggest that probiotic supplementation improves clinical parameters, and reduces the periodontopathogen load and pro-inflammatory markers in periodontal disease patients. However, we were unable to assess the preventive role of probiotic supplementation due to the paucity of studies. Further clinical studies are needed to determine the efficacy of probiotic supplementation in the prevention of periodontal diseases.

Keywords: clinical parameters; gingivitis; oral health; periodontal disease; periodontitis; prevention; probiotic; therapeutics.

Figure 1

Etiology and pathogenesis of periodontal diseases. Periodontal disease is initiated by disrupting the commensal oral microbiome–host homeostasis. (A). Both modifiable and nonmodifiable risk factors impact the oral microbiome composition and disrupt homeostasis between the host and microbiome. Modifiable risk factors include diet, smoking, oral hygiene, and comorbidities (such as type 2 diabetes), while genetics, age, and sex are nonmodifiable risk factors. (B). Disrupted homeostasis provides appropriate conditions for the growth of periodontopathogens and biofilm formation on the tooth surfaces extending sub-gingivally. There are no clinical symptoms in this stage. (C). These bacteria penetrate and grow in the gingival epithelium. Host–bacteria interactions cause a chemotactic gradient that attracts innate immune cells, including neutrophils, macrophages, and NK cells, to the affected sites. In addition, the outgrowth of bacteria progressively destroys the tissue and provides enough nutrients for more pathogen growth, followed by increased activity of innate immune cells and the secretion of pro-inflammatory cytokines, including IL-1, IL-8, and TNF. Early clinical symptoms in this stage are redness, swelling, mild inflammation, and bleeding of the gingiva, which are diagnosed by measuring the PlI, GI, and BOP. (D). Then, Antigen-Presenting Cells (APC), including dendritic cells, present bacterial antigens to lymphocytes and trigger adaptive immune system activity and antibody and cell-mediated immune responses, resulting in a pro-inflammatory response with high expression of IL-4, 6, 8, 10, 12, TGF-β, and IFN-γ. (E). High levels of these inflammatory mediators stimulate more inflammatory mediators, causing periodontal tissue destruction and leading to the loss of the gingival attachment to the tooth, and causing deep pockets around the teeth that provide appropriate conditions for the growth and colonization of other anaerobic periodontopathogens. Untreated, these pathophysiological changes can lead to alveolar bone resorption and, ultimately, tooth loss in the most advanced stage of the disease. (F). Probiotics may have therapeutic benefits in periodontal disease treatment when used as an adjuvant to standard periodontal care. Various mechanisms of action have been considered for the role of probiotics in periodontal disease improvement. Probiotics interact directly with periodontopathogens through colonization resistance, which includes competition for binding sites and nutrients, and the production of antibacterial agents inhibiting pathogen growth. Probiotics can play a role in periodontal disease improvement indirectly via the modulation of innate and adaptive immunity and through the gut–oral microbiome axis. PlI, Plaque Index; GI, Gingival Index; BOP, Bleeding on Probing; IL, Interleukin; TGF-β, Tumor Growth Factor-β; and IFN-γ, Interferon-γ.

Figure 2

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram detailing the study selection.

Figure 3

Pooled meta-analysis examining the effects of probiotic supplementation on clinical outcomes. 1. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the plaque index (P1I) using a random-effects model. Note that we detected publication bias and/or small study effects, and the adjusted Hedge’s g SMD = 0.557, 95% CI: 0.228, 0.885, and p-value ≤ 0.05 [14,41,43,53,58,60,62,67,69,70,80,86,91,105]. 2. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the mean plaque percentage (MPP) using a random-effects model [54,66,68,72,77,82,88,89,92,107,109]. 3. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the gingival index (GI) using a random-effects model [14,41,43,53,58,60,69,70,75,80,89,91,92,105,110]. 4. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the probing pocket depth (PPD) using a random-effects model [10,34,41,53,54,55,58,60,62,64,66,67,68,69,74,75,76,77,80,81,82,85,89,92,102,103,109,110]. 5. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the clinical attachment level (CAL) using a random-effects model [10,34,54,58,62,66,68,76,77,80,82,85,92,102,103,109]. 6. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on bleeding on probing (BOP) using a random-effects model. Note that we detected publication bias and/or small study effects, and the adjusted Hedge’s g SMD = 0.841, 95% CI: 0.479, 1.200, and p-value ≤ 0.05 [10,34,41,53,56,66,67,69,70,72,74,76,77,88,89,102,103,107,109]. 7. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the gingival crevicular fluid (GCF) using a random-effects model [42,67,72,74,75,106].

Figure 3

Pooled meta-analysis examining the effects of probiotic supplementation on clinical outcomes. 1. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the plaque index (P1I) using a random-effects model. Note that we detected publication bias and/or small study effects, and the adjusted Hedge’s g SMD = 0.557, 95% CI: 0.228, 0.885, and p-value ≤ 0.05 [14,41,43,53,58,60,62,67,69,70,80,86,91,105]. 2. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the mean plaque percentage (MPP) using a random-effects model [54,66,68,72,77,82,88,89,92,107,109]. 3. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the gingival index (GI) using a random-effects model [14,41,43,53,58,60,69,70,75,80,89,91,92,105,110]. 4. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the probing pocket depth (PPD) using a random-effects model [10,34,41,53,54,55,58,60,62,64,66,67,68,69,74,75,76,77,80,81,82,85,89,92,102,103,109,110]. 5. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the clinical attachment level (CAL) using a random-effects model [10,34,54,58,62,66,68,76,77,80,82,85,92,102,103,109]. 6. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on bleeding on probing (BOP) using a random-effects model. Note that we detected publication bias and/or small study effects, and the adjusted Hedge’s g SMD = 0.841, 95% CI: 0.479, 1.200, and p-value ≤ 0.05 [10,34,41,53,56,66,67,69,70,72,74,76,77,88,89,102,103,107,109]. 7. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the gingival crevicular fluid (GCF) using a random-effects model [42,67,72,74,75,106].

Figure 3

Pooled meta-analysis examining the effects of probiotic supplementation on clinical outcomes. 1. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the plaque index (P1I) using a random-effects model. Note that we detected publication bias and/or small study effects, and the adjusted Hedge’s g SMD = 0.557, 95% CI: 0.228, 0.885, and p-value ≤ 0.05 [14,41,43,53,58,60,62,67,69,70,80,86,91,105]. 2. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the mean plaque percentage (MPP) using a random-effects model [54,66,68,72,77,82,88,89,92,107,109]. 3. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the gingival index (GI) using a random-effects model [14,41,43,53,58,60,69,70,75,80,89,91,92,105,110]. 4. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the probing pocket depth (PPD) using a random-effects model [10,34,41,53,54,55,58,60,62,64,66,67,68,69,74,75,76,77,80,81,82,85,89,92,102,103,109,110]. 5. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the clinical attachment level (CAL) using a random-effects model [10,34,54,58,62,66,68,76,77,80,82,85,92,102,103,109]. 6. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on bleeding on probing (BOP) using a random-effects model. Note that we detected publication bias and/or small study effects, and the adjusted Hedge’s g SMD = 0.841, 95% CI: 0.479, 1.200, and p-value ≤ 0.05 [10,34,41,53,56,66,67,69,70,72,74,76,77,88,89,102,103,107,109]. 7. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the gingival crevicular fluid (GCF) using a random-effects model [42,67,72,74,75,106].

Figure 4

Pooled meta-analysis examining the effects of probiotic supplementation on microbiological outcomes in periodontal disease patients. 1. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the subgingival P. gingivalis bacterial count using a random-effects model [14,43,76,77,102]. 2. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the subgingival F. nucleatum bacterial count using a random-effects model [14,43,76,77,102]. 3. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the subgingival T. forsythia bacterial count using a random-effects model [14,43,76,102].

Figure 5

Pooled meta-analysis examining the effects of probiotic supplementation on immunological outcomes in periodontal disease patients; 1. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the gingival crevicular fluid (GCF) level of matrix metalloproteinase-8 (MMP-8) using a random-effects model [59,67,78]. 2. Forest plot of the Hedge’s g SMD comparing the effects of probiotic supplementation to control groups on the GCF level of interleukin-6 (IL-6) using a random-effects model [42,72,95,106].