Microbiological and Clinical Effects of Pre- and Probiotics in Non-Surgical Periodontal Therapy

NCT07443410 | Recruiting

• 1 other identifier: S-477/2024
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Periodontitis is a prevalent chronic inflammatory disease driven by a dysbiotic oral biofilm and a dysregulated host immune response. Standard non-surgical periodontal therapy (NSPT) is primarily mechanical and, in selected cases, may be accompanied by antiseptics or systemic antibiotics. Targeted modulation of the oral microbiome ("microbiome engineering") is currently not part of routine periodontal care due to limited high-quality evidence. PROPARO is a single-center, randomized, controlled pilot study designed to assess whether adjunctive oral supplementation with a probiotic containing Limosilactobacillus reuteri (commercial dietary supplement lozenge) alone or combined with vitamin B12 (commercial dietary supplement drops) is associated with changes in supragingival and subgingival oral microbiome composition during guideline-concordant NSPT compared with standard care alone. Participants with Stage III or IV periodontitis will be randomized 1:1:1 to: (1) NSPT/SPT without supplementation (control), (2) NSPT/SPT plus probiotic lozenges for 3 months, or (3) NSPT/SPT plus probiotic lozenges and vitamin B12 drops for 3 months. The primary outcome is change in oral microbiome composition and structure (supragingival and subgingival), assessed using 16S rDNA-based profiling and metagenomic sequencing approaches. Secondary outcomes include clinical periodontal parameters (e.g., probing depth, clinical attachment level, bleeding on probing), oral hygiene/gingival indices, dental status, and participant-level ecological covariates (diet quality, perceived stress, physical activity). Sampling and assessments are aligned with routine care time points from baseline through supportive periodontal therapy follow-up (up to 12 months). This pilot trial aims to generate feasibility and effect-size estimates to inform future confirmatory studies and potential translation into guideline-based periodontal care.

Conditions

Periodontitis, Adult; Periodontitis (Stage 3); Periodontitis Stage IV

Keywords

Periodontitis; Non-surgical periodontal treatment; Probiotics; Prebiotics; Oral Microbiome

Outcome Measures

Primary Outcomes (1)

• Change in oral microbiome composition (supragingival and subgingival)

  Changes in supragingival and subgingival microbial community structure and taxonomic profiles, assessed by 16S rDNA-based profiling and metagenomic sequencing (as applicable), including diversity metrics and relative abundance of microbial taxa/features.

  Baseline through 12 months (assessed at baseline, NSPT instrumentation visit, ~3 months, ~6 months, and ~12 months).

Study Arms (3)

Control

ACTIVE COMPARATOR

Guideline-concordant non-surgical periodontal therapy including mechanical subgingival instrumentation and risk-factor-oriented oral hygiene instruction, followed by supportive periodontal therapy (maintenance) as part of routine care. No placebo is used.

Procedure: Non-surgical periodontal therapy (NSPT) and supportive periodontal therapy (SPT)

Test A - Probiotic

EXPERIMENTAL

Procedure: Non-surgical periodontal therapy (NSPT) and supportive periodontal therapy (SPT); Dietary Supplement: Probiotic lozenge (Limosilactobacillus reuteri; GUM® PerioBalance®)

Test B - Synbiotic-like: Probiotic + Vitamin B12

EXPERIMENTAL

Procedure: Non-surgical periodontal therapy (NSPT) and supportive periodontal therapy (SPT); Dietary Supplement: Probiotic lozenge (Limosilactobacillus reuteri; GUM® PerioBalance®); Dietary Supplement: Vitamin B12 drops (natural elements)

Interventions

Probiotic lozenge (Limosilactobacillus reuteri; GUM® PerioBalance®) DIETARY_SUPPLEMENT

Commercial dietary supplement lozenge containing Limosilactobacillus reuteri (GUM® PerioBalance®, Sunstar Deutschland GmbH, Schönau, Germany). Administered orally according to manufacturer instructions for 3 months starting with NSPT.

Test A - Probiotic; Test B - Synbiotic-like: Probiotic + Vitamin B12

Vitamin B12 drops (natural elements) DIETARY_SUPPLEMENT

Commercial dietary supplement vitamin B12 drops (natural elements GmbH, Düsseldorf, Germany). Administered orally according to manufacturer instructions for 3 months, in addition to the probiotic regimen, starting with NSPT.

Test B - Synbiotic-like: Probiotic + Vitamin B12

Non-surgical periodontal therapy (NSPT) and supportive periodontal therapy (SPT) PROCEDURE

Guideline-concordant non-surgical periodontal therapy including mechanical subgingival instrumentation and risk-factor-oriented oral hygiene instruction, followed by supportive periodontal therapy (maintenance) as part of routine care. No placebo is used.

Control; Test A - Probiotic; Test B - Synbiotic-like: Probiotic + Vitamin B12

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Stage III or IV periodontitis (localized or generalized)
• Ability to provide informed consent
• Written informed consent including data protection consent

You may not qualify if:

• Pregnancy or breastfeeding
• Conditions/medications likely to substantially confound the oral microbiome or periodontal healing (e.g., uncontrolled diabetes mellitus, systemic immunosuppression, chronic steroid use)
• Antibiotic use within the last 3 months
• Use of oral pre-/probiotic supplements within the last 3 months
• Recent subgingival instrumentation within the last 6 months
• Need for obligatory adjunctive systemic antibiotic prophylaxis/therapy for NSPT
• Severe active systemic infection or other conditions judged by investigators to pose undue risk
• Regular use of antiseptic mouthrinses during the study period (unless medically required)
• Strict diets likely to substantially alter baseline microbiome trajectories (e.g., ketogenic, strict vegan) per protocol definition
• Chronic bowel diseases (for systemic confounding considerations)

Sponsors & Collaborators

• University Hospital Heidelberg: lead

Study Sites (1)

Heidelberg University Hospital

Heidelberg, Baden-Wurttemberg, 69120, Germany

RECRUITING

Related Publications (14)

• Zong G, Holtfreter B, Scott AE, Volzke H, Petersmann A, Dietrich T, Newson RS, Kocher T. Serum vitamin B12 is inversely associated with periodontal progression and risk of tooth loss: a prospective cohort study. J Clin Periodontol. 2016 Jan;43(1):2-9. doi: 10.1111/jcpe.12483. Epub 2016 Jan 18.

  PMID: 26613385 BACKGROUND

• Slomka V, Hernandez-Sanabria E, Herrero ER, Zaidel L, Bernaerts K, Boon N, Quirynen M, Teughels W. Nutritional stimulation of commensal oral bacteria suppresses pathogens: the prebiotic concept. J Clin Periodontol. 2017 Apr;44(4):344-352. doi: 10.1111/jcpe.12700. Epub 2017 Feb 18.

  PMID: 28128467 BACKGROUND

• Ince G, Gursoy H, Ipci SD, Cakar G, Emekli-Alturfan E, Yilmaz S. Clinical and Biochemical Evaluation of Lozenges Containing Lactobacillus reuteri as an Adjunct to Non-Surgical Periodontal Therapy in Chronic Periodontitis. J Periodontol. 2015 Jun;86(6):746-54. doi: 10.1902/jop.2015.140612. Epub 2015 Mar 5.

  PMID: 25741580 BACKGROUND

• Tekce M, Ince G, Gursoy H, Dirikan Ipci S, Cakar G, Kadir T, Yilmaz S. Clinical and microbiological effects of probiotic lozenges in the treatment of chronic periodontitis: a 1-year follow-up study. J Clin Periodontol. 2015 Apr;42(4):363-72. doi: 10.1111/jcpe.12387. Epub 2015 Apr 10.

  PMID: 25728888 BACKGROUND

• Teughels W, Durukan A, Ozcelik O, Pauwels M, Quirynen M, Haytac MC. Clinical and microbiological effects of Lactobacillus reuteri probiotics in the treatment of chronic periodontitis: a randomized placebo-controlled study. J Clin Periodontol. 2013 Nov;40(11):1025-35. doi: 10.1111/jcpe.12155. Epub 2013 Sep 15.

  PMID: 24164569 BACKGROUND

• Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C, Swanson KS, Cani PD, Verbeke K, Reid G. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017 Aug;14(8):491-502. doi: 10.1038/nrgastro.2017.75. Epub 2017 Jun 14.

  PMID: 28611480 BACKGROUND

• Van der Weijden FA, Slot DE. Efficacy of homecare regimens for mechanical plaque removal in managing gingivitis a meta review. J Clin Periodontol. 2015 Apr;42 Suppl 16:S77-91. doi: 10.1111/jcpe.12359.

  PMID: 25597787 BACKGROUND

• Trombelli L, Franceschetti G, Farina R. Effect of professional mechanical plaque removal performed on a long-term, routine basis in the secondary prevention of periodontitis: a systematic review. J Clin Periodontol. 2015 Apr;42 Suppl 16:S221-36. doi: 10.1111/jcpe.12339.

  PMID: 25495875 BACKGROUND

• Needleman I, Nibali L, Di Iorio A. Professional mechanical plaque removal for prevention of periodontal diseases in adults--systematic review update. J Clin Periodontol. 2015 Apr;42 Suppl 16:S12-35. doi: 10.1111/jcpe.12341.

  PMID: 25495962 BACKGROUND

• Suvan J, Leira Y, Moreno Sancho FM, Graziani F, Derks J, Tomasi C. Subgingival instrumentation for treatment of periodontitis. A systematic review. J Clin Periodontol. 2020 Jul;47 Suppl 22:155-175. doi: 10.1111/jcpe.13245.

  PMID: 31889320 BACKGROUND

• Hajishengallis G, Chavakis T, Lambris JD. Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. Periodontol 2000. 2020 Oct;84(1):14-34. doi: 10.1111/prd.12331.

  PMID: 32844416 BACKGROUND

• Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015 Jan;15(1):30-44. doi: 10.1038/nri3785.

  PMID: 25534621 BACKGROUND

• Lang NP, Bartold PM. Periodontal health. J Periodontol. 2018 Jun;89 Suppl 1:S9-S16. doi: 10.1002/JPER.16-0517.

  PMID: 29926938 BACKGROUND

• Papapanou PN, Sanz M, Buduneli N, Dietrich T, Feres M, Fine DH, Flemmig TF, Garcia R, Giannobile WV, Graziani F, Greenwell H, Herrera D, Kao RT, Kebschull M, Kinane DF, Kirkwood KL, Kocher T, Kornman KS, Kumar PS, Loos BG, Machtei E, Meng H, Mombelli A, Needleman I, Offenbacher S, Seymour GJ, Teles R, Tonetti MS. Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Clin Periodontol. 2018 Jun;45 Suppl 20:S162-S170. doi: 10.1111/jcpe.12946.

  PMID: 29926490 BACKGROUND

MeSH Terms

Conditions

Chronic Periodontitis; Periodontitis

Condition Hierarchy (Ancestors)

Periodontal Diseases; Mouth Diseases; Stomatognathic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Diana Wolff, Prof. Dr.

CONTACT

00496221566002; diana.wolff@med.uni-heidelberg.de

Valentin Bartha, Dr.

CONTACT

004962215639888; valentin.bartha@med.uni-heidelberg.de

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor Dr. med. dent.

Study Record Dates

• First Submitted: February 24, 2026
• First Posted: March 2, 2026
• Study Start: October 25, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: March 2, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Beginning 6 months after publication of the primary results and ending 5 years thereafter.
• Access Criteria: Requests should include a brief proposal, analysis plan, and evidence of appropriate ethical approval (if required). Data will be provided to qualified researchers for non-commercial scientific purposes under a signed data use agreement. Contact: Diana.wolff@med.uni-heidelberg.de

Locations

DE (1)