Table of Contents
- Key Points
- Background: Why This Research Matters
- How the Research Was Conducted
- What Studies Were Included
- Key Findings: Oral Mucositis
- Key Findings: Oral Candidiasis
- Key Findings: Xerostomia (Dry Mouth)
- Tolerability and Side Effects
- Study Quality Assessment
- How Biotics May Work
- Clinical Implications for Patients
- Limitations of the Research
- Recommendations
- Frequently Asked Questions
- Source Information
Key Points
- In 12 randomized trials with 885 patients, probiotics did not significantly reduce how often oral mucositis occurred.
- Probiotics significantly reduced the severity of oral mucositis, cutting severe cases by 38%.
- Bifidobacterium-containing products reduced severe mucositis more than Lactobacillus or Streptococcus blends in this analysis.
- Probiotics did not significantly reduce xerostomia (dry mouth); the reduction was about 8% and not statistically significant.
- Side effects were generally mild to moderate; six of eight studies reporting tolerability found no adverse effects.
Background: Why This Research Matters
Head and neck cancers (HNCs) are cancers that start in the lining of the upper aerodigestive tract, which includes the mouth, throat, and related structures. These cancers are a major global health problem. Each year, about 890,000 new cases are diagnosed worldwide, and about 450,000 people die from these cancers. That represents roughly 4.5% of all cancer cases, making head and neck cancers the seventh most common cancer type.
Treating head and neck cancers usually requires a team-based approach. Most patients need surgery combined with radiation therapy and chemotherapy. Treatment may also include specialized radiation techniques such as high-dose-rate brachytherapy, stereotactic body radiation therapy, and intensity-modulated radiotherapy.
These treatments save lives, but they often cause painful oral complications. Common problems include candidiasis (fungal infection in the mouth), mucositis (painful inflammation and ulcers in the mouth), salivary gland dysfunction, taste dysfunction, and radiation caries (tooth decay caused by radiation).
Oral mucositis (OM) is one of the most common and troubling side effects. It causes acute inflammation, redness, pain, and ulcerative sores in the mouth. About 90% of head and neck cancer patients treated with standard regimens develop oral mucositis. Nearly all patients treated with altered fractionation radiotherapy develop it as well.
These mouth sores are not just uncomfortable. They can force doctors to interrupt treatment, change radiation doses, or delay therapy. When treatment is interrupted, the cancer may be less well controlled. Altered fractionation radiotherapy causes even more cases of severe (grade 3 or 4) oral mucositis than standard radiotherapy. It also increases the need for feeding tubes during cancer treatment.
Xerostomia (dry mouth from reduced saliva production) and oral candidiasis are other common complications. Xerostomia occurs in about 80% of thyroid and head and neck cancer patients, and oral candidiasis occurs in about 53.5%. Because salivary glands absorb radioiodine (131I), patients with thyroid cancer face a higher risk of temporary or permanent xerostomia.
When saliva production drops, the mouth becomes inflamed more easily. This opens the door to secondary infections such as candidiasis and other fungal infections. These problems make it harder for patients to stick with their treatment.
Cancer treatment can disturb the balance of bacteria in the mouth, a condition called oral microbial dysbiosis. Tissue oxidation and inflammation drive this imbalance. The disturbed microbiome then causes more inflammation, creating a vicious cycle. Radiation therapy may shift the mouth's bacterial mix toward more gram-negative bacteria and Candida (yeast). Reduced saliva flow can further change the oral microbiome and make radiation-induced mucositis and candidiasis worse.
Recent studies suggest that probiotics may help restore the balance of mouth bacteria and ease oral complications in thyroid and head and neck cancer patients. Probiotics appear helpful for oral mucositis in cancer patients. However, researchers have not well studied other biotics, such as synbiotics and prebiotics. The effect of biotics on other oral complications also remains unclear. This study aimed to evaluate how effective and tolerable biotics are for oral complications caused by cancer treatment in patients with thyroid and head and neck cancers.
How the Research Was Conducted
The researchers followed the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) throughout the entire review process. These guidelines set international standards for conducting and reporting systematic reviews.
The team searched three major scientific databases: PubMed, Web of Science, and Scopus. The search covered all studies published up to April 2024. They also checked the reference lists of included studies to find additional relevant articles. The search was limited to English-language publications. The researchers managed references using EndNote v.20 software.
Two independent authors screened all articles by reviewing titles and abstracts first. They then reviewed the full text of selected articles. A third researcher resolved any disagreements between the two reviewers.
To be included, studies had to meet three criteria:
- Article type: The study had to be a randomized controlled trial (a study where participants are randomly assigned to treatment or placebo groups).
- Participants: The study had to include individuals receiving treatment for head and neck cancers or thyroid cancer. Participants had to have developed at least one type of oral complication.
- Intervention: The study had to compare any biotic components (probiotics, prebiotics, or synbiotics) against a placebo.
The researchers excluded reviews, book chapters, and other types of studies.
The team collected the following data from each included article: publication year and author, patient age, gender, country, and number of participants. The team also collected type of cancer, type of oral complication, type and ingredients of biotics, duration of treatment, and outcomes. Two authors extracted data independently, and a third researcher resolved any disagreements. All data were entered into Microsoft Excel.
The researchers grouped and analyzed each disease type separately: oral mucositis, oral candidiasis, and xerostomia. They also grouped studies by biotic type based on the formula used.
For quality assessment, all included articles were evaluated for potential bias. The researchers used the Cochrane Risk-of-Bias tool for randomized trials (ROB2) to evaluate the accuracy and quality of the included studies.
Statistical analysis was performed using Revman 5.1 software. The researchers used a random-effects model to calculate the risk ratio (RR) and 95% confidence interval (CI). The I² statistic was used to evaluate heterogeneity (how much the studies differed from each other) between included studies. Values of 25%, 50%, and 75% represent low, moderate, and high levels of heterogeneity, respectively. The researchers performed a subgroup meta-analysis based on the bacterial blend of biotics. This addressed the source of heterogeneity. It also aimed to determine the best bacterial blend for reducing the severity and incidence of oral mucositis.
What Studies Were Included
The literature search found a total of 2,403 studies. After removing 192 duplicate articles, the researchers reviewed the titles and abstracts of 2,211 studies. Through the full-text review, 12 studies were deemed suitable for inclusion.
Of these 12 studies, 11 assessed the role of probiotics, and one study by Manifar et al. assessed the effect of synbiotics. A total of 885 participants were included in the analysis. Of these, 367 were in the control group and 432 were in the intervention group.
The included studies came from several countries, including Italy, India, China, Iran, New Zealand, and the USA. The studies examined patients with head and neck cancer, thyroid cancer, nasopharyngeal carcinoma, and oral squamous cell carcinoma. Treatment durations ranged from 2 weeks to 8 weeks. The mean ages of participants ranged from about 31.5 to 60 years across the studies.
Key Findings: Oral Mucositis
Eight studies assessed how well biotics worked on the incidence (how often it occurred) and severity (how bad it became) of oral mucositis. This was the most studied outcome in the analysis.
For the incidence of oral mucositis, biotics showed a slight but statistically insignificant effect. The risk ratio was 0.90 (95% CI [0.79, 1.03]), with high heterogeneity between studies (I² = 89%). In plain language, this means biotics reduced the risk of developing oral mucositis by about 10%, but this result was not statistically significant. The high heterogeneity means the studies varied considerably in their results.
For the severity of oral mucositis, biotics had a significant effect. The risk ratio was 0.62 (95% CI [0.48, 0.80]), with moderate heterogeneity (I² = 39%). This means biotics reduced the risk of severe oral mucositis by 38%. This result was statistically significant, meaning it is unlikely to be due to chance.
The subgroup meta-analysis revealed important differences between types of biotics:
- Bifidobacterium-containing biotics significantly reduced the severity of oral mucositis (RR = 0.37, 95% CI [0.19, 0.71], I² = 39%).
- Lactobacillus-containing biotics also significantly reduced the severity of oral mucositis (RR = 0.57, 95% CI [0.37, 0.88], I² = 62%).
- Streptococcus-containing biotics did not significantly decrease the severity of oral mucositis (RR = 0.31, 95% CI [0.04, 2.63], I² = 78%).
None of the three types of biotics (Bifidobacterium, Lactobacillus, or Streptococcus) had a significant effect on preventing the incidence of oral mucositis.
An important finding was that Bifidobacterium-containing biotics were more effective in reducing the severity of oral mucositis than Lactobacillus-containing biotics. The risk ratio for Bifidobacterium was 0.37 (95% CI [0.19, 0.71]), compared to 0.57 (95% CI [0.37, 0.88]) for Lactobacillus.
Key Findings: Oral Candidiasis
Despite a comprehensive search through databases, only one study was eligible based on the inclusion criteria for oral candidiasis. This study assessed how well probiotics worked in the remission (reduction or clearing) of oral candidiasis.
The study demonstrated that a blend of Lactobacillus, Bifidobacterium, and Saccharomyces bacteria significantly decreased the colony count of various Candida species. These species included C. albicans, C. glabrata, and C. tropicalis. This effect occurred whether the blend was used in combination with antifungal therapies or alone.
Because only one study met the criteria, the researchers could not perform a meta-analysis for this outcome. More research is needed to draw firm conclusions about biotics for oral candidiasis.
Key Findings: Xerostomia (Dry Mouth)
Four studies comprising 141 patients in the biotics group and 104 individuals in the control group assessed the role of biotics in xerostomia. Xerostomia is the medical term for dry mouth caused by reduced saliva production.
The meta-analysis showed a slight but insignificant decrease in xerostomia in the biotics group compared to the control group. The risk ratio was 0.92 (95% CI [0.75, 1.14]), with moderate heterogeneity (I² = 58%).
In plain language, biotics reduced the risk of xerostomia by about 8%, but this result was not statistically significant. This means the researchers could not conclude that biotics effectively reduce dry mouth in these patients.
This finding was new and had not been well addressed in previous research. The researchers noted that this low efficacy of probiotics in lowering the occurrence of xerostomia was an unaddressed finding.
Tolerability and Side Effects
Eight studies reported on the side effects and tolerability of patients receiving biotics. The results were generally reassuring.
Of the eight studies:
- Six studies reported no adverse effects in patients taking biotics.
- Two studies reported mild or moderate side effects in the probiotic group.
The reported side effects included:
- Gastrectasia reactions (stomach stretching or bloating) with an incidence of 1.72% (1 of 58 patients)
- Nausea in 12% of subjects (of 17 subjects)
- Oral pain
- Fatigue
- Diarrhea
- Mucosal inflammation
These side effects were generally mild to moderate. The overall tolerability profile suggests that biotics are safe for most patients with thyroid and head and neck cancers.
Study Quality Assessment
The researchers assessed the quality of all included studies using the Cochrane Risk-of-Bias tool for randomized trials (ROB2). This tool evaluates potential sources of bias that could affect study results.
The risk-of-bias assessment examined several domains, including the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. The results of this assessment were presented in a summary figure in the original article.
The quality assessment is important because it helps readers understand how much confidence they can place in the findings. Studies with low risk of bias provide more reliable evidence than those with high risk of bias.
How Biotics May Work
The exact way probiotics reduce the occurrence or severity of cancer therapy-induced oral mucositis is not entirely understood. However, researchers have proposed several mechanisms.
Probiotics are microorganisms that can balance the oral microecosystem and restrain the growth of harmful pathogens. Some studies suggest that specific probiotics, such as Lactobacillus, may regulate gene transcription related to inflammation and cell death. This regulation could inhibit undesirable events that lead to mucositis.
The proposed mechanisms for oral mucositis in both radiotherapy and concurrent chemoradiotherapy (CCRT) are multifactorial. They include:
- DNA damage from radiation
- Food-derived reactive oxygen species (ROS) levels
- Programmed cell death of oral epithelial cells
- Chemotherapy drugs modifying and destroying the balance of oral flora
- Disruption of epithelial wound healing through reactive oxygen species production
- Inflammatory cytokine production in epithelial cells
- Promotion of cell apoptosis (programmed cell death)
These factors trigger inflammatory innate immune pathways, particularly the nuclear factor kappa-B (NF-κB) pathway. This pathway leads to the production of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-A), along with oxidative stress responders. These substances prolong tissue inflammation. Continued inflammation causes ulceration, which leads to a localized immune response that may worsen mucosal damage.
Microbial dysbiosis and infection or colonization of the oral mucosa appear to play a role in the pathophysiology of oral mucositis. Probiotics may help by restoring a healthier balance of oral bacteria.
Lactobacilli are non-pathogenic, gram-positive, rod-shaped bacteria known for their lack of spore formation. These bacteria produce lactic acid. The Lactobacillus genus includes over 200 species and is part of normal oral flora. These bacteria are also used in producing foods such as yogurts and cheese.
For the general population, taking lactobacilli may decrease abnormal vaginal discharge, treat periodontitis, and improve mild symptoms of sadness in adults. In cancer patients, lactobacilli could lessen side effects of cancer treatments, such as diarrhea and oral mucositis.
Future implications suggest that these bacteria may be crucial in cancer treatment, its side effects, and prevention. They can modulate the immune response and directly influence cancer cells. The potential of lactobacilli alone or combined with other bacterial species (such as Bifidobacterium) is being considered for expanded clinical applications.
However, attention should be given to identifying the suitable species or strain, because different strains may produce varying therapeutic effects.
Clinical Implications for Patients
The findings of this study have several important implications for patients with thyroid and head and neck cancers who are undergoing treatment.
First, biotics appear to be effective and safe for reducing the severity of oral mucositis. While they did not significantly reduce how often oral mucositis occurred, they did significantly reduce how severe it became. This is clinically meaningful because severe oral mucositis can lead to treatment interruptions, feeding tube placement, and poorer cancer control.
Second, the type of biotic matters. Products containing Bifidobacterium were more effective than other blends in reducing the severity of oral mucositis. Lactobacillus-containing products also showed benefit. Streptococcus-containing products did not show significant benefit in this analysis.
Third, biotics did not effectively reduce xerostomia (dry mouth). Patients should not expect biotics to solve this problem based on current evidence.
Fourth, biotics were generally well tolerated. Most studies reported no adverse effects, and the side effects that did occur were mild to moderate.
The researchers noted that their results are similar to previous meta-analyses by Lin et al., Feng et al., and Liu et al. These earlier studies also showed a marked decrease in the rate and severity of oral mucositis in probiotics-receiving cancer patients.
However, the current study also uncovered a new finding regarding the low efficacy of probiotics in lowering the occurrence of xerostomia. This had not been well addressed in previous research.
One study by Jiang et al. elaborated on how probiotics can reduce oral mucositis by improving immune defense mechanisms. The data showed that subjects in concurrent chemoradiotherapy plus probiotics had a lower incidence of grade 3 oral mucositis than those in the CCRT alone group (15.52% versus 45.71%). This is consistent with a protective effect of the probiotic combination against oral mucositis.
Another study by De Sanctis et al. compared oral mucositis in individuals receiving sodium bicarbonate mouthwashes with those who received Lactobacillus brevis CD2 lozenges. The outcome was that Lactobacillus brevis CD2 had no effect on the risk of severe oral mucositis. The rates in intervention and control arms were 40.6% versus 41.6%, respectively. However, the trial was statistically limited because of suboptimal availability of the probiotic product. No apparent improvements in quality of life and acute toxicities (weight loss, discomfort, dysphagia) were observed in the experiment group.
In contrast, Sharma et al. reported positive results showing reduced grade 3 or 4 oral mucositis incidences by 14% in patients treated with Lactobacillus brevis CD2 compared to placebo (52% versus 77%; p-value < 0.001). The current study could not confirm these beneficial effects.
The researchers noted that the results of their study challenge the previously reported beneficial effects of Lactobacillus brevis CD2. Those effects were on lowering grade 3-4 radiation therapy-induced oral mucositis in patients with head and neck cancer. This is especially important considering that the De Sanctis trial had under-recruitment followed by premature study closure, which further weakened its statistical strength.
Limitations of the Research
The researchers acknowledged several limitations of their meta-analysis.
The primary limitation was the relatively small number of patients included in the analysis. With only 885 participants across 12 studies, the statistical power to detect small effects was limited.
Another limitation was the different probiotic mixture formulations used across studies. This diversity may explain the significant heterogeneity observed in some analyses. The variation might be due to different cancer types in the studies analyzed, ethical division of subjects, and other drugs used for chemotherapy or radiation doses.
Additionally, the duration of treatment and the dosage at which probiotics were taken limit the researchers' ability to make specific recommendations. Different studies used different doses and treatment durations, making it difficult to determine the optimal regimen.
Only one study assessing the effect of synbiotics was included, and no study assessing the efficacy of prebiotics met the inclusion criteria. This means the researchers could not draw conclusions about these types of biotics.
Despite these constraints, the researchers emphasized that their results stress the importance of using probiotics as an adjuvant therapy (additional treatment) for treating oral mucositis.
The researchers also noted that more investigation in this field is required. They expressed hope that their results will inspire additional research.
Recommendations
Based on the findings of this systematic review and meta-analysis, the following recommendations can be made:
- Consider probiotics as an adjunctive therapy. The evidence supports using probiotics alongside standard cancer treatment to help reduce the severity of oral mucositis.
- Discuss biotic products with your oncology team. Before starting any probiotic, prebiotic, or synbiotic supplement, talk with your cancer care team about whether it is appropriate for your situation.
- Look for products containing Bifidobacterium. The analysis found that Bifidobacterium-containing products were more effective than other blends in reducing the severity of oral mucositis.
- Do not expect biotics to prevent dry mouth. The evidence does not support using biotics specifically to reduce xerostomia.
- Report any side effects. While biotics were generally well tolerated, some patients experienced bloating, nausea, oral pain, fatigue, diarrhea, or mucosal inflammation. Report these to your healthcare provider.
- Recognize that more research is needed. The optimal doses and specific bacterial strains for preventing and treating oral mucositis and xerostomia have not yet been determined.
The researchers concluded that probiotics remain a promising option for treating cancer therapy-induced oral mucositis. They demonstrated a 10% reduction in the risk of developing oral mucositis and a 38% reduction in severe oral mucositis during cancer treatment. The combination of Lactobacillus and Bifidobacterium may be the most effective in mitigating the severity of oral mucositis.
However, these products did not effectively reduce the incidence of xerostomia. Further trials are needed to determine the optimal doses of each bacterial strain or species for the most effective prevention and treatment of oral mucositis and xerostomia following cancer therapy.
Frequently Asked Questions
Can probiotics help with mouth sores from thyroid or head and neck cancer treatment?
In a review of 12 randomized trials with 885 patients, probiotics did not significantly reduce how often oral mucositis occurred. However, they did significantly reduce how severe it became, cutting the risk of severe mucositis by 38%. Products containing Bifidobacterium worked better than other blends in this analysis.
Do probiotics prevent dry mouth (xerostomia) during cancer treatment?
No. In four studies with 245 patients, probiotics reduced the risk of xerostomia by only about 8%, which was not statistically significant. The researchers could not conclude that biotics effectively reduce dry mouth. Patients should not expect probiotics to solve this problem based on current evidence.
Which type of probiotic is more effective for severe oral mucositis?
In this analysis, Bifidobacterium-containing products reduced severe oral mucositis risk more than Lactobacillus-containing products. The risk ratio for Bifidobacterium was 0.37 versus 0.57 for Lactobacillus. Streptococcus-containing products did not show a significant benefit. However, none of the three types significantly prevented mucositis from occurring.
What does a 38% reduction in severe oral mucositis mean for patients?
It means that in the studies analyzed, patients taking biotics had a 38% lower risk of developing severe (grade 3 or 4) oral mucositis compared to those not taking them. This is statistically significant. Severe mucositis can lead to treatment interruptions, feeding tube placement, and poorer cancer control, so reducing its severity is clinically meaningful.
Can probiotics help with oral thrush (candidiasis) during cancer treatment?
Only one study met the criteria for oral candidiasis. It found that a blend of Lactobacillus, Bifidobacterium, and Saccharomyces significantly decreased colony counts of several Candida species, both alone and with antifungal therapy. Because only one study was included, the researchers could not perform a meta-analysis and more research is needed.
Should I take probiotics, prebiotics, or synbiotics during my cancer treatment?
Discuss it with your oncology team first. The evidence supports probiotics as an additional therapy to reduce the severity of oral mucositis, but not to prevent it or to treat dry mouth. The optimal doses and specific strains are not yet determined. Report any side effects such as bloating, nausea, or diarrhea to your healthcare provider.
If I have thyroid or head and neck cancer treatment and my mouth sores are getting severe, when should I get a second opinion?
Severe oral mucositis is the point where a second opinion can matter most. Biotics reduced the risk of severe mucositis by 38%, and Bifidobacterium-containing products worked better than other blends, while Lactobacillus products also helped. Biotics did not significantly reduce how often mucositis occurred, and they did not significantly reduce dry mouth. Because doses and strains are not established, an independent review can help weigh whether adding biotics alongside standard treatment is appropriate for your situation. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Efficacy and tolerability of probiotics, prebiotics, and symbiotics consumption on oral complications of patients with thyroid and head and neck cancers: a systematic review and meta-analysis.
Authors: Mohammadreza Shafiei, Shayan Mardi, Soodeh Ghadimi, Helia Poorshahbazi, Roozbeh Pourabbas, Mohammadamin Keykhah, and Hosein Rafiemanesh
Publication: BMC Oral Health (2025) 25:677
DOI: https://doi.org/10.1186/s12903-025-05876-9
Article type: Systematic Review (Open Access)
This patient-friendly article is based on peer-reviewed research. The original study was published in BMC Oral Health and is available as an open-access article under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
