In Vivo Effectiveness and Safety of Probiotics on Prophylaxis and Treatment of Oral Candidiasis

A Systematic Review and Meta-analysis

Lijun Hu; Mimi Zhou; Andrew Young; Weiwei Zhao; Zhimin Yan

BMC Oral Health. 2019;19(140)

Abstract and Introduction

Abstract

Background: To systematically review and assess the in vivo effectiveness and safety of probiotics for prophylaxis and treating oral candidiasis.

Methods: A literature search for studies published in English until August 1, 2018 was conducted in the following databases: PubMed, EMBASE, Cochrane Library, and Web of Science. Randomized controlled clinical trials and experimental mouse animal model studies comparing probiotics (at any dosage and in any form) with control groups (placebo, blank control or other agents) and reporting outcomes of the prophylactic and therapeutic effects were considered for inclusion. A descriptive study and, potentially, a meta-analysis were planned.

Results: Six randomized controlled clinical trials and 5 controlled experiments of mouse animal models were included in the systematic review. Four randomized controlled clinical trials comparing a probiotics group with a placebo/blank control group in 480 elderly and denture wearers were included in the meta-analysis. The overall combined odds ratio of the (random effects) meta-analysis was 0.24 (95% CI =0.09–0.63, P < 0.01). The overall combined odds ratio of the (fixed effects) sensitivity analysis was 0.39 (95% CI =0.25–0.60, P < 0.01) by excluding a study with the smallest sample size. These analyses showed that there was a statistically significant difference in the effect of probiotics compared with the control groups in elderly and denture wearers. The remaining 2 studies compared probiotics with other agents in a population aged 18–75 years and children aged 6–14 years respectively, and were analyzed descriptively. Meta-analysis and descriptive analyses indicated that probiotics were potentially effective in reducing morbidity, improving clinical symptoms and reducing oral Candida counts in oral candidiasis. The biases of the included studies were low or uncertain. The relatively common complaints reported were gastrointestinal discomfort and unpleasant taste, and no severe adverse events were reported.

Conclusions: Probiotics were superior to the placebo and blank control in preventing and treating oral candidiasis in the elderly and denture wearers. Although probiotics showed a favorable effect in treating oral candidiasis, more evidence is required to warrant their effectiveness when compared with conventional antifungal treatments. Moreover, data on the safety of probiotics are still insufficient, and further research is needed.

1 2 3 4 5 6

Next Section

Abstract and Introduction
Background
Methods
Results
Discussion
Conclusions
References

Table 1. Characteristics of the included clinical studies
Author and publication year	Probiotics group				Control group				Follow-up time (weeks)	Outcome indicators
Author and publication year	Age (Average)	Gender (M:F)	Sample size	Interventions	Age (Average)	Gender (M:F)	Sample size	Interventions	Follow-up time (weeks)	Outcome indicators
Hatakka et al., 2007 [25]	58.7–95.2	36:100	92 (Baseline 136)	The combination of L. rhamnosus and P. freudenreichii	65.4–94.7	30:110	100 (Baseline 140)	Blank control	16	Candida counts; hyposalivation; salivary buffering capacity; dry mouth; mucosal lesions; oral pain; decayed teeth
Ishikawa et al., 2015 [27]	61.6 ± 7.8	6:24	30	The combination of L. rhamnosus HS111, L. acidophilus HS101 and B. bifidum	62.1 ± 9.4	8:17	25	Placebo	5	Candida counts
Kraft-Bodi et al., 2015 [26]	88.3 ± 5.7	35:60	84 (Baseline 95)	L. reuteri	87.7 ± 7.7	42:61	90 (Baseline 103)	Placebo	12	Candida counts; oral hygiene; gingival inflammation
Miyazima et al., 2017 [30]	66.1 ± 11.6	4:15	19	L. acidophilus	65.5 ± 10.5	3:17	20	Blank control	8	Candida counts
Miyazima et al., 2017 [30]	61.7 ± 14.1	3:17	20	L. rhamnosus	65.5 ± 10.5	3:17	20	Blank control	8	Candida counts
Li et al., 2014 [31]	62.72 ± 9.57	5:29	34	The combination of B. longum, L. bulgaricus, S. thermophiles, 2% Sodium bicarbonate solution and 2% Nysfungin cataplasm	64.84 ± 11.92	7:24	31	2% Sodium bicarbonate solution + 2% Nysfungin cataplasm	4	Candida counts; pain level; hyperaemia
Mishra et al., 2016 [32]	8.65	9:11	20	Probiotics mint tablet (unknown the types of probiotics)	8.90	11:9	20	0.2% Chlorhexidine digluconate	1	Candida counts
Mishra et al., 2016 [32]	8.65	9:11	20	Probiotics mint tablet (unknown the types of probiotics)	9.70	12:8	20	Herbal gargle	1	Candida counts

Table 2. Bias assessment of the included clinical studies
Author and publication year	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Other bias
Hatakka et al., 2007 [25]	Low risk	Uncertain	Low risk	Uncertain	Low risk	Low risk	Uncertain
Ishikawa et al., 2015 [27]	Uncertain	Uncertain	Low risk	Low risk	Low risk	Low risk	Low risk
Kraft-Bodi et al., 2015 [26]	Low risk	Low risk	Low risk	Low risk	Uncertain	Low risk	Low risk
Miyazima et al., 2017 [30]	Uncertain	Uncertain	Low risk	Uncertain	Low risk	Low risk	Low risk
Li et al., 2014 [31]	Low risk	Uncertain	High risk	High risk	Low risk	Low risk	Low risk
Mishra et al., 2016 [32]	Uncertain	Uncertain	Low risk	Uncertain	Low risk	Low risk	Uncertain

Table 3. Characteristics of the included animal model experiments
Author and publication year	Strain	Gender	Age (week)	Sample sizes	Method of candida infection	Probiotic species	Method of drug administration	Intervention time	Control group	Outcome indicators
Matsubara et al., 2012 [33]	DBA/2	Male	6–8	152	–	The combination of L. acidophilusand L. rhamnosus	0.2 ml suspension (10⁹ probiotics)	Start 2 weeks before Candidainoculation, qd, 27d	Blank control	Candida counts
Matsubara et al., 2012 [33]	DBA/2	Male	6–8	152	–	The combination of L. acidophilusand L. rhamnosus	0.2 ml suspension (10⁹ probiotics)	Start 2 weeks before Candidainoculation, qd, 27d	Nystatin	Candida counts
Ishijima et al., 2012 [34]	ICR	Female	6	55	Candida cotton swab to wipe oral mucosa	S. salivariusK12	0.05 ml suspension	24 h, 3 h before Candida inoculation, 3 h, 24 h, 27 h after Candida inoculation	Blank control	Candida counts, Oral infection score, Histology
Ishijima et al., 2012 [34]	ICR	Female	6	55	Candida cotton swab to wipe oral mucosa	S. salivariusK12	0.05 ml suspension		Fluconazole	Candida counts, Oral infection score, Histology
Elahi et al., 2005 [35]	DBA/2, BALB/c (Test data not published)	Male	6–8	25	Candida cotton swab to wipe oral mucosa	The combination of L. acidophilusand L. fermentum	0.2 ml suspension (10⁹ probiotics)	Start 2 weeks before Candidainoculation, qd, 28d	Blank control	Candida counts, IL-4, IL-12, IFN-γ, NO
Ishijima et al., 2014 [36]	ICR	Female	6	73	Candida cotton swab to wipe oral mucosa	E. faecalis	0.05 ml suspension	24 h, 3 h before Candida inoculation, 3 h, 24 h, 27 h after Candida inoculation	Blank control	Candida counts, Oral infection score, Histology
Ishijima et al., 2014 [36]	ICR	Female	6	73	Candida cotton swab to wipe oral mucosa	E. faecalis	0.05 ml suspension		Fluconazole	Candida counts, Oral infection score, Histology
Leao et al., 2018 [37]	Wistar mice (immunosupp-ressed by intraperitoneal injection with dexamethasone (65 mg/kg))	Male	11–12	90	Candida cotton swab was left for 80 min under the tongue	L. rhamnosus	100 μL suspension (10⁹ cells/mL)	2 weeks before Candida inoculation; Probiotics intake when Candidainoculation	Blank control	Candida counts, Inflammatory infiltrate score, The cytokines levels (TNF-α, IL-1β, IL-4, IL-6, IL-10, IL-12, and INF-γ)

Table 4. Bias assessment of the included mouse animal model experiments
Author and publication year	Sample-size calculation	Randomization of treatment or control	Allocation concealment	Blinded assessment of outcome	Suitable animal model	Avoidance of anaesthetics with marked intrinsic properties	Statement of control of temperature	Statement of compliance with regulatory requirements	Publication in peer-reviewed journal	Statement regarding possible conflict of interest
Matsubara et al., 2012 [33]	–	✓	–	–	✓	–	–	✓	✓	–
Ishijima et al., 2012 [34]	–	✓	–	–	✓	✓	✓	✓	✓	–
Elahi et al., 2005 [35]	–	✓	–	–	✓	✓	✓	–	✓	–
Ishijima et al., 2014 [36]	–	✓	–	–	✓	✓	✓	✓	✓	✓
Leao et al., 2018 [37]	✓	–	–	–	✓	✓	✓	✓	✓	✓