Role of Probiotics for the Treatment of Peri-Implant Mucositis in Patients With and Without Type 2 Diabetes Mellitus

Probiotics, such as Lactobacillus reuteri (L reuteri), are living bacteria that benefit the host when consumed in suitable dosage and quantity.¹  Probiotic therapy (PT) offers protective effects in the oral cavity against cariogenic microbes and bacteria associated with periodontal diseases.²  Shimauchi et al³  showed that PT using L. reuteri reduces periodontal soft-tissue inflammation by decreasing the scores of the gingival index (GI) and plaque index (PI) in patients with periodontal diseases. With reference to implant dentistry, outcomes of a short-term follow-up triple-blinded randomized clinical trial (RCT) in patients with peri-implant mucositis (PM) showed that mechanical debridement (MD) with adjunctive PT enhances the overall anti-inflammatory effect of MD as compared with MD alone. Peña et al⁴  documented that PT is unsuccessful in delivering any supplementary antimicrobial or/and clinical assistance as compared with MD with the aid of 0.12% chlorhexidine gluconate oral rinse.⁴  These results indicate that there is still controversy regarding the effectiveness of PT for managing PM.^3,4 

Diabetes mellitus (or diabetes) is an endocrine disease associated with a partial or absolute insulin insufficiency.⁵  The most common form of diabetes is type 2 diabetes.⁵  Chronic hyperglycemia is a risk factor of oral diseases such as PM.^6–10  Moreover, outcomes of MD are compromised in terms of reduction in GI and PI and probing depth (PD) in patients with poorly controlled type 2 diabetes in contrast to individuals with glycemic levels within normal limits.^11–13  Abduljabbar^14,15  reported that uncontrolled diabetes is associated with compromised therapeutic outcomes in patients with peri-implant diseases. Nevertheless, when glycemic levels are well managed, patients with type 2 diabetes demonstrate oral and peri-implant health statuses that are similar to those of systemically healthy individuals.^6,16  The alternate hypothesis was that PT does not offer additional benefits to MD for the treatment of diabetic subjects with PM.

The aim of this study was to assess the influence of PT as an adjunct to MD for the treatment of PM in patients with and without type 2 diabetes over a 12-month follow-up period.

This trial (No. OR/RCT 2022-174) was performed in Karachi, Pakistan, and was registered by the Institutional Review Board (OR/COD/01917-2A). All procedures were performed following the guidelines recognized by the Declaration of Helsinki as revised in 2013 for experimentation involving human patients. All volunteering individuals were also invited to ask questions. Individuals who agreed to participate were asked to endorse an informed consent form. Consenting individuals reserved the right of withdrawal with no consequences. Verbal and written information regarding the (1) significance of oral health and glycemic maintenance and (2) deleterious effects of impaired glycemic status on overall health was provided at recruitment and at follow-up visits. The methodology of the present study was reviewed by an independent statistician.

Inclusion criteria included (1) patients who had undergone dental implant placement for partial edentulism, (3) patients with PM (gingival hemorrhage on mild probing with erythema in the gingival tissues),¹⁷  (3) patients medically diagnosed with type 2 diabetes, and (4) patients who signed the consent form. Patients with the following characteristics were not sought: (1) tobacco smokers and chewers; (2) patients with self-reported systemic diseases other than type 2 diabetes including type 1 diabetes, individuals with heart-, liver-, and kidney-related diseases, hepatic disorders, and renal diseases; (3) patients who self-reported as infected with viruses such as herpes and HIV infection; (4) patients who self-reported that they had undergone an oral surgical and/or nonsurgical intervention such as scaling and root planning within the past 6 months; (5) patients taking medications such as bisphosphonates, antibiotics, and steroids; (6) lactating and/or pregnant females; and (6) patients with a history of or ongoing periodontitis.

In the present study, a parallel-arm trial design was used as described by Nair.¹⁸  Trained personnel (A.M.) established the patient's eligibility after evaluating the baseline and screening information. Randomization was performed using a site-specific randomization assignment sequence generated before initiation the present RCT, and allocation to the study groups was done via block randomization.¹⁹  Treatment wise, PM patients with and without type 2 diabetes were divided into the following groups: (1) nonsurgical MD with adjunct PT and (2) nonsurgical MD alone. Randomization was done using a computer program (www.random.org, Randomness and Integrity Services Ltd., Dublin, Ireland).

Details were collected regarding the duration of implants in function, participant gender, quantity of placed implants, and participant age. All participants were also asked if they had attained graduate-level (postcollege) education.

All patients underwent peri-implant nonsurgical MD (ImplantProphy Plastic Dental Instrument System Kit, Tess Corporation, Eau Claire, Wis). In group 1, PT was performed as described elsewhere.²⁰  In summary, PT started at the onset of NSMD. Probiotics (GumPerioBalance^, Sunstar, Etoy, Switzerland) were given in the form of lozenges that contained active units of 2 Lactobacillus reuteri strains (1 × 10⁸ colony-forming units (CFU) of ATCC PTA 5289, and 1 × 10⁸ CFU of DSM 17938).^21,22  The patients were advised to use one lozenge every 12 hours for 21 days, after brushing their teeth.²³ 

In all patients, hemoglobin A1c (HbA1c) levels were measured as described elsewhere.^24,25  When the HbA1c levels were <5.6%, glycemic status was considered normal, and values >5.6% were indicative of hyperglycemia.^26,27  These measurements were done at baseline and at 6 and 12 months.

In all groups, peri-implant PI and GI were measured using the protocol reported by Löe.²⁸  The peri-implant PD²⁹  was measured to the nearest millimeter using a plastic graded probe (UNC15 periodontal-probe, Hu, Friedy, Chicago, Ill).⁶  All measurements were obtained by a skilled researcher (Kappa = 0.95). These measurements were performed on 6 surfaces of each implant. In all patients, digital radiographs were taken to gauge crestal bone loss (CBL).

The methodology and results were assessed by an independent statistician. Statistics was carried using SPSS version 21 software (SPSS Inc, Chicago, Ill), and the following tests were done: (1) Kolmogrov-Smirnov test, (2) analysis of variance, and (3) Bonferroni post hoc adjustment tests. A P value less than 0.01 was considered as an indicator of statistical significance. Power analysis was done considering dental implants with mucositis, and it was established that the inclusion of 20 individuals with and 20 individuals without type 2 diabetes would provide a statistical power of 96% to detect a real difference in the mean GI of 0.78 between treatment groups with a standard deviation of 1.58 and an alpha value of 0.05.³⁰ 

In total, 40 (20 participants with and 20 participants without type 2 diabetes) individuals with PM were included. In the patient population, most of the participants were male. In patients with and without type 2 diabetes, 10 and 10 patients underwent MD with and without adjunct PT, respectively. There was no statistically significant difference in age among all patients, and all implants were in function for nearly 2 years. Tooth brushing once daily was reported by most of the individuals in all groups. None of the patients reported having ever used dental floss (Table 1).

The mean HbA1c levels were significantly higher at baseline among patients with type 2 diabetes (8.8% ± 0.4%) as compared with individuals without type 2 diabetes (4.4% ± 0.3%; P < .01). Among patients with type 2 diabetes who underwent MD with and without PT, the mean HbA1c levels were 8.6% ± 0.3% and 9.1% ± 0.2%, respectively. There was no statistically significant difference in the mean HbA1c levels among patients without type 2 diabetes who underwent MD with (4.2% ± 0.1%) and without PT (4.6% ± 0.2%). At 6- and 12-month follow-up, the HbA1c levels were significantly higher in patients with type 2 diabetes (8.5% ± 0.2% and 8.6% ± 0.3%, respectively) as compared with individuals without type 2 diabetes (4.3% ± 0.1% and 4.4% ± 0.2%) who underwent MD with and without adjunct PT, respectively (P < .001).

At baseline, peri-implant, PI, GI, PD, and CBL (on mesial and distal surfaces) were comparable among individuals in all groups (Table 2). Among patients with type 2 diabetes who underwent MD with and without PT, there was no statistically significant difference in PI, GI, PD, or CBL at 6- and 12-month follow-up. In patients without type 2 diabetes, there was a statistically significant reduction in peri-implant PI (P < 0.01), GI (P < 0.01), and PD (P < 0.01) at 6- and 12-month follow-up as compared with their respective baseline values. There was no statistically significant difference in peri-implant PI, GI, CBL, or PD among nondiabetic patients who underwent MD with and without PT (Table 3).

Among patients with type 2 diabetes, at 6- and 12-month follow-up, 80% of individuals (n = 16) reported brushing once daily, and none reported having ever used dental floss. Among patients without type 2 diabetes, 17 (85%) and 12 (60%) individuals reported that they brushed teeth and flossed twice daily, respectively, at 6- and 12-month follow-up.

The present results showed no statistically significant influence of MD with and without adjunct PT for the treatment of PM in patients with type 2 diabetes, and the effect of MD with and without adjunct PT was comparable among PM patients without type 2 diabetes. Based on these results, it may be postulated that PT does not offer additional benefits in terms of reducing peri-implant soft-tissue inflammation in patients with PM. It is important to interpret these outcomes cautiously, as a number of factors could have influenced the reported results. First, it is notable that all patients with type 2 diabetes had uncontrolled diabetes throughout the duration of the study (12 months). It has been reported that a state of persistent hyperglycemia augments oxidative stress and the accumulation of advanced glycation end products in the tissues.^31,32  Moreover, impaired glycemic status has also been reported to compromise the outcomes of MD irrespective of whether adjunct therapies are used or not.⁹  In a study on rats with streptozotocin-induced diabetes, Kido et al³³  showed that hyperglycemia delays gingival wound healing by impairing the migration and proliferation of gingival fibroblasts. Furthermore, a state of chronic hyperglycemia also increases the expression of reactive oxygen species in gingival tissues.³³  These are possible explanations for the comparable outcomes (PD, PI, and GI) that were observed after MD with and without PT in patients with type 2 diabetes.

Beneficial effects of probiotics on oral health have been reported.^20,34  An interesting finding was that baseline PI, GI, and PD were similar among patients with and without type 2 diabetes. One reason for this is that if oral hygiene maintenance is not routinely performed, there is the possibility that patients with and without type 2 diabetes can demonstrate comparable oral inflammatory parameters. From an ethical standpoint, oral hygiene instructions and information related to the significance of glycemic control/maintenance were given verbally and in writing to participants at the initial visit (patient recruitment phase). Moreover, these instructions and recommendations were repeated and given to all patients at the 6- and 12-month follow-up visits. However, it is worth mentioning that at the 6- and 12-month follow-up, the mean HbA1c levels were significantly higher among patients with type 2 diabetes in contrast to nondiabetic individuals without type 2 diabetes who had PM. There is the possibility that patients with type 2 diabetes either neglected or made minimal efforts toward managing their serum glycemic levels. It has been reported that an underprivileged education status is a risk factor for a state of persistent hyperglycemia in patients with type 2 diabetes.³⁵  According to Kassahun et al,³⁶  patients with a poor education status are likely to have impaired glycemic status. In the present study, nearly 80% of patients without type 2 diabetes had attained a graduate-level education as compared with individuals with type 2 diabetes (20%). This factor could explain the persistent state of hyperglycemia observed in patients with type 2 diabetes throughout the study period. Although the present results showed comparable outcomes in terms of treatment of PM in nondiabetic patients who underwent MD with and without PT, it would be preliminary to presume that PT does not offer additional anti-inflammatory effects. The improved oral hygiene maintenance regimens adopted by nondiabetic patients could have played a positive role in improving the peri-implant health in these patients. This suggests that oral health education programs should be conducted routinely to educate the general public about the detrimental effect of hyperglycemia on health and at the same time illuminate the benefits of glycemic control and oral hygiene maintenance toward attainment of a superior quality of life.

One limitation of the present study is that tobacco smokers were excluded, and studies^37,38  have shown that tobacco smoking is a risk factor of peri-implant diseases. Moreover, it has also been reported that dental implants can function well in patients with diabetes that are routinely maintaining their glycemic levels.¹⁶  It is recommended that future studies focusing on the influence of glycemic control and tobacco habits be performed to assess the influence of MD (with or without adjunct PT) in patients with PM.

In patients without type 2 diabetes, MD with or without adjunct PT reduces soft-tissue inflammatory parameters in patients with PM.

Abbreviations

CBL:

crestal bone loss

CFU:

colony-forming units

GI:

gingival index

MD:

mechanical debridement

PD:

probing depth

PI:

plaque index

PM:

peri-implant mucositis

PT:

probiotic therapy

The authors thank Mr. Kashef Sulaimani for performing the statistical analysis of the methodology and results of the present study.

The authors declare no conflicts of interest.