Effects of a Composition on the Oral Microbiome, pH, Nitrite/Nitrate Ratio, Elastases and Inflammation in Oral Dysbiosis

Effects of a Composition Delivered Via Toothpaste on the Oral Microbiome, pH, Nitrite/Nitrate Ratio, Elastases, and Inflammation in Patients With Oral Dysbiosis: A Controlled, Randomized, Double-blind Study. Part of Stop Dysbiosis Project

Dysbiosis is a condition in which the normal function of an ecological net is altered. In dysbiosis a state of inflammation, a loss of hydration, a change in pH, a loss of the barrier function are all allies of key pathogens that initiate invasion and cytokine and pro-inflammatory mediators release that target other tissues and organs resulting in chronic inflammatory conditions.

In health there is a cross-talk between the host and the microbiota in order to maintain and promote a state of eubiosis with a local and general health gain. Dysbiosis reversion has not been solved with the use of antibacterials, antiseptics nor antibiotics.

Stop dysbiosis project is focussed on different aspects of human dysbiosis such as oral dysbiosis, skin dysbiosis, vaginal dysbiosis and cancer dysbiosis, between others including the current prospective interventional double-blind randomised clinical trial.

One of the most common oral dysbiosis is periodontal and mucosa dysbiosis that courses with inflammation of the gingiva (gingivitis). This inflammation induces specific enzymes that in a later stage destroy connective tissue. The current clinical trial analyzes the effect of a composition (Saliactive ®) delivered to the oral cavity via a daily use toothpaste (YOTUEL® microbiome toothpaste) in a group of patients with oral dysbiosis.

Study Overview

• Status: Completed
• Conditions: Oral Dysbiosis
• Intervention / Treatment: Drug: Test composition Saliactive® (olive product, betaine and xylitol); Drug: Placebo; Drug: Control

Detailed Description

Oral microbiota is the most diverse of the human body. It consists of mainly commensal bacteria, archea, protozoos, yeast and funghi. More than 700 species of bacteria have been identified in the mouth. In conditions of health these bacteria live in equilibrium. In inflammatory conditions, balance is lost, due to changes in microbiota or in the ecosystem with lost of the mucosa barrier function. If dysbiosis appears pathogen or fragments of these or toxic agents penetrate the body orchestrating a deep alteration of vital functions such as immune defense, nitric oxide pathways, cell cycle regulation and redox balance.

Periodontal dysbiosis is the consequence of the accumulation of plaque and the increase of gram negative species capable of releasing virulence factors that maintain inflammation and bleeding that perpetuate a disease-promoting ecosystem.

Oral hygiene is a daily personal protocol for effective delivery of active substances to the tissues of the oral cavity, mainly fluoride and antiseptics. The standard of care in the oral compound is toothpaste used 2-3 times a day.

The test toothpaste including Saliactive® (an olive product, betaine and xylitol) does not contain any antimicrobial agent nor antiseptic. A randomized, double-blind controlled clinical trial in 100 patients will evaluate the efficacy to reverse oral dysbiosis. Microbiota profile through genetic sequenciation of the rDNA16s, inflammatory markers, nitrate reducing bacteria abundance, nitrite/nitrate ratio, pH, plaque and bleeding index will be evaluated at baseline, after 2 months and 4 months of exposure to the assigned composition. Two controls will be analysed, one fluoridated placebo but without the 3 active ingredients olive product, betaine and xylitol (Saliactive®), and a fluoridated commercial toothpaste for gingivitis with zinc citrate. Assignation of the 100 subjects will be randomized and the products are blind for the subjects and the researcher.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Spain
  • Granada, Spain, 18071
    • Departamento de Estomatología, Facultad de Odontología

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinical diagnose of gingivitis.
• At least 20 teeth (3rd molars excluded).
• Must Accept informed consent.

Exclusion Criteria:

• Clinical diagnose of periodontitis.
• With orthodontics.
• With removable dentures.
• With upper incisors restorated.
• Tumours in soft or hard tissues of the mouth.
• More than 5 caries lesions with immediate restorative need
• Antibiotics intake less than one month ago.
• Pregnant women.
• Other clinic assay at the moment.
• Dental prophylaxis less than 2 weeks before starting the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo product; Toothpaste with the same composition as the test product but without olive product, betaine and xylitol.	Drug: Placebo; Fluoridated toothpaste without Saliactive®.; Other Names: Placebo fluoridated toothpaste without the test composition
Active Comparator: Control product; Toothpaste marketed for gingivitis with zinc mineral with antimicrobial activity.	Drug: Control; Commercial Fluoridated toothpaste for gingivitis with zinc citrate.; Other Names: Control commercial Fluoridated toothpaste for gingivitis with zinc citrate.
Experimental: Test product; Toothpaste including an olive product, betaine and xylitol (Saliactive®).	Drug: Test composition Saliactive® (olive product, betaine and xylitol); Fluoridated toothpaste with Saliactive®.; Other Names: Saliactive®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oral microbiota profile at baseline and after 4 months	16s rDNA genetic sequencing	4 months
Oral pH at baseline and after 4 months	pH meter	4 months
Nitrite/Nitrate ratio at baseline and after 4 months	Ionic chromatography	4 months
Elastase at baseline at 2 months and at 4 months	ELISA	4 months
Bleeding index at baseline, at 2 months and at 4 months	Ainamo and Bay bleeding index indicating the percentage of bleeding from 0 (no bleeding) to 100 (maximum bleeding)	4 months
Plaque index at baseline, at 2 months and at 4 months	Tonetti plaque index	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Salivary flow rate at baseline, 2 months and at 4 months	Unstimulated salivary flow rate recovery as per Navazesh	4 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tooth colour at baseline and at 4 months	VITA Easyshade® V	4 months

Collaborators and Investigators

• Sponsor: Mucosa Innovations, S.L.
• Collaborators: Universidad de Granada
• Investigators: Principal Investigator: Francisco Luis Mesa Aguado, Departamento de Estomatología, Facultad de Odontología

Publications and helpful links

General Publications

• Ainamo J, Bay I. Problems and proposals for recording gingivitis and plaque. Int Dent J. 1975 Dec;25(4):229-35.
• Navazesh M. Methods for collecting saliva. Ann N Y Acad Sci. 1993 Sep 20;694:72-7. doi: 10.1111/j.1749-6632.1993.tb18343.x. No abstract available.
• Tonetti MS. The future of periodontology: new treatments for a new era. J Int Acad Periodontol. 2002 Jul;4(3):110-4.
• Barbadoro P, Ponzio E, Coccia E, Prospero E, Santarelli A, Rappelli GGL, D'Errico MM. Association between hypertension, oral microbiome and salivary nitric oxide: A case-control study. Nitric Oxide. 2021 Jan 1;106:66-71. doi: 10.1016/j.niox.2020.11.002. Epub 2020 Nov 10.
• Bescos R, Ashworth A, Cutler C, Brookes ZL, Belfield L, Rodiles A, Casas-Agustench P, Farnham G, Liddle L, Burleigh M, White D, Easton C, Hickson M. Effects of Chlorhexidine mouthwash on the oral microbiome. Sci Rep. 2020 Mar 24;10(1):5254. doi: 10.1038/s41598-020-61912-4.

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2021
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): July 15, 2023

Study Registration Dates

• First Submitted: July 7, 2022
• First Submitted That Met QC Criteria: July 18, 2022
• First Posted (Actual): July 19, 2022

Study Record Updates

• Last Update Posted (Actual): July 8, 2024
• Last Update Submitted That Met QC Criteria: July 4, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Gum inflammation; Periodontal Dysbiosis; Oral Dysbiosis
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Dysbiosis; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Gastrointestinal Agents; Hypolipidemic Agents; Lipid Regulating Agents; Lipotropic Agents; Betaine
• Other Study ID Numbers: 02-2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No