Probiotics Applications in Treating Oral Mucositis

Oral mucositis is a common side effect of cancer treatment, leading to nutritional challenges for the body and resulting in weight loss and a decreased quality of life. The lack of effective treatments and preventive guidelines for oral mucositis makes predicting the patient’s disease progression difficult. After 60 years, researchers discovered the complex mechanisms underlying the pathophysiology of oral mucositis, and in 2007, they coined the term “oral mucositis” to describe injuries caused by the cytotoxic effects of chemicals and/or radiation therapy [1].

Impact of Oral Mucositis on Patients

Oral mucositis affects the entire digestive tract and oral cavity, causing pain, difficulty in eating, weight loss, and localized infections. Moreover, patients with severe oral mucositis may need to reduce their chemotherapy regimen, leading to delayed cancer treatment and a worse prognosis. Approximately 30–40% of cancer patients undergoing chemotherapy experience oral mucositis, and this rate increases to 60–85% for patients receiving hematopoietic stem cell transplantation and nearly 90% for patients with head and neck cancer undergoing chemotherapy, radiation therapy, and combined treatments [2].

Oral mucositis symptoms include diarrhea, abdominal pain, bleeding, fatigue, malnutrition, electrolyte imbalance, and infection, leading to life-threatening complications [3]. Figure 1 shows some images of patients suffering from oral mucositis, a side effect of cancer treatment [1].

Figure 1: Some images of oral mucositis in cancer patients undergoing treatment.

Preclinical and clinical trials have demonstrated the efficacy of probiotics in reducing oral mucositis.

The chemotherapy drug 5-Fluorouracil (5-FU) is one of the most widely used in clinical cancer treatment [4]. However, over 50% of patients receiving 5-FU experience oral mucositis or gastrointestinal tract complications. As inflammation progresses, ulcers may develop, leading to immune responses and exacerbating mucosal damage [5]. Nonetheless, researchers believe that bacterial dysbiosis, invasion, and colonization of the oral mucosa play a role in the development of oral mucositis, contributing to the pathophysiology of the condition [6].

Patients undergoing radiation therapy have experienced a significant reduction in severe oral mucositis rates when using probiotics. Additionally, the use of probiotics containing Lactobacilli strains has been associated with a decreased incidence of severe oral mucositis after cancer treatment. Additionally, preclinical evidence suggests that probiotics help preserve the intestinal mucosal structure, prevent damage, and reduce symptoms of oral mucositis in general [7].

Certain live bacteria have shown preliminary signs of effectiveness in treating chemotherapy-induced intestinal mucositis and alleviating oral mucositis symptoms. A study assessed the impact of supernatants (sN) derived from Escherichia coli and Lactobacillus fermentum on reducing 5-Fluorouracil (5-FU)-induced mucosal injuries in mice [7,8]. A positive trial aimed to examine the role of Lactobacillus in preventing symptoms of oral mucositis induced by irinotecan [9]. Irinotecan is a drug primarily used in colorectal cancer treatment but has the side effect of causing oral mucositis, particularly diarrhea [10]. This study initially indicated that Lactobacillus probiotics could alleviate irinotecan-induced diarrhea in colorectal cancer patients.

Moreover, Lactobacillus reuteri has demonstrated protective effects against oral mucosal injuries caused by 5-FU in mice [11]. Another animal study reported that Streptococci salivarius prevents oral mucositis induced by radiation therapy in mice by regulating the oral microbiota and improving bacterial dysbiosis, associated with the development and progression of oral mucositis post-radiation therapy [12].

In summary, the use of probiotics may prevent or minimize oral mucositis by reducing inflammatory or oxidative reactions, regulating and improving oral microbiota disorders, and enhancing mucosal cell protection. However, the underlying mechanisms of different bacterial species or strains in preventing and minimizing oral mucositis may vary [6], and all mentioned studies are based on animal models. Therefore, it is important to exercise caution in explaining these mechanisms, and researchers should make sure to conduct additional studies that focus on humans.

The systematic review, which assessed the safety of probiotics in cancer patients, did not attribute any cases of death to their use [13]. In a study published in 2016, the use of Lactobacillus brevis CD2 reduced the incidence of oral mucositis in patients with hematological disorders undergoing high-dose chemotherapy and hematopoietic stem cell transplantation [14]. Trials involving over 350 cancer patients using probiotics reported no serious adverse effects, such as bloodstream infections or deaths directly related to their use. In general, the use of probiotics seems safe, with a low rate of adverse effects over time. However, patients with specific clinical conditions, such as immunosuppression, should exercise caution, as probiotic use may pose risks. This requires careful consideration of the balance between benefits and harms.

In conclusion, oral mucositis remains an understudied and widely unassessed side effect of cancer treatment. Researchers need to conduct further in-depth studies to develop treatments for oral mucositis in cancer patients. Previous studies have proven that probiotic strains contribute to reducing oral mucositis symptoms without causing any harm [15]. The potential for treating oral mucositis-reducing symptoms such as diarrhea, pain, weight loss, and overall mucosal inflammation with probiotic strains is substantial, with promising avenues for future research and development.

References:

1. Pulito, Claudio, Antonio Cristaudo, Caterina La Porta, Stefano Zapperi, Giovanni Blandino, Aldo Morrone, and Sabrina Strano. “Oral mucositis: the hidden side of cancer therapy.” Journal of experimental & clinical cancer research39 (2020): 1-15.
2. Chansky, Kari, Jacqueline Benedetti, and John S. Macdonald. “Differences in toxicity between men and women treated with 5‐fluorouracil therapy for colorectal carcinoma.” Cancer: Interdisciplinary International Journal of the American Cancer Society103, no. 6 (2005): 1165-1171.
3. Sonis, Stephen T. “The pathobiology of mucositis.” Nature Reviews Cancer4, no. 4 (2004): 277-284.
4. Fata, Farid, Ilan G. Ron, Nancy Kemeny, Eileen O’Reilly, David Klimstra, and David P. Kelsen. “5‐Fluorouracil‐induced small bowel toxicity in patients with colorectal carcinoma.” Cancer: Interdisciplinary International Journal of the American Cancer Society86, no. 7 (1999): 1129-1134.
5. Villa, A., and S. T. Sonis. “Mucositis: pathobiology and management. 159–164.” (2015).
6. Sonis, Stephen T. “The chicken or the egg? Changes in oral microbiota as cause or consequence of mucositis during radiation therapy.” EBioMedicine18 (2017): 7-8.
7. Prisciandaro, Luca D., Mark S. Geier, Ross N. Butler, Adrian G. Cummins, and Gordon S. Howarth. “Probiotic factors partially improve parameters of 5-fluorouracil-induced intestinal mucositis in rats.” Cancer Biology & Therapy11, no. 7 (2011): 671-677.
8. Mauger, Chad A., Ross N. Butler, Mark S. Geier, Katie L. Tooley, and Gordon S. Howarth. “Probiotic effects on 5-fluorouracil-induced mucositis assessed by the sucrose breath test in rats.” Digestive diseases and sciences52 (2007): 612-619.
9. Mego, Michal, Jozef Chovanec, Iveta Vochyanova-Andrezalova, Peter Konkolovsky, Milada Mikulova, Maria Reckova, Vera Miskovska et al. “Prevention of irinotecan induced diarrhea by probiotics: a randomized double blind, placebo-controlled pilot study.” Complementary therapies in medicine23, no. 3 (2015): 356-362.
10. Michael, Michael, MaryAnne Brittain, Jane Nagai, Ronald Feld, David Hedley, Amit Oza, Lillian Siu, and Malcolm J. Moore. “Phase II study of activated charcoal to prevent irinotecan-induced diarrhea.” Journal of Clinical Oncology22, no. 21 (2004): 4410-4417.
11. Gupta, Nitasha, Joao Ferreira, Catherine Hsu Ling Hong, and Kai Soo Tan. “Lactobacillus reuteri DSM 17938 and ATCC PTA 5289 ameliorates chemotherapy-induced oral mucositis.” Scientific Reports10, no. 1 (2020): 1-11.
12. Wang, Yan, Jiatong Li, Haonan Zhang, Xin Zheng, Jiantao Wang, Xiaoyue Jia, Xian Peng et al. “Probiotic Streptococcus salivarius K12 alleviates radiation-induced oral mucositis in mice.” Frontiers in Immunology12 (2021): 684824.
13. Hassan, Hadeel, Menie Rompola, A. W. Glaser, Sally E. Kinsey, and R. S. Phillips. “Systematic review and meta-analysis investigating the efficacy and safety of probiotics in people with cancer.” Supportive care in cancer26 (2018): 2503-2509.
14. Sharma, Atul, T. V. S. V. G. K. Tilak, Sameer Bakhshi, Vinod Raina, Lalit Kumar, SurendraPal Chaudhary, RanjitKumar Sahoo, Ritu Gupta, and Sanjay Thulkar. “Lactobacillus brevis CD2 lozenges prevent oral mucositis in patients undergoing high dose chemotherapy followed by haematopoietic stem cell transplantation.” Esmo Open1, no. 6 (2016): e000138.
15. Batista, Viviane Lima, Tales Fernando Da Silva, Luís Cláudio Lima de Jesus, Nina Dias Coelho-Rocha, Fernanda Alvarenga Lima Barroso, Laisa Macedo Tavares, Vasco Azevedo, Pamela Mancha-Agresti, and Mariana Martins Drumond. “Probiotics, prebiotics, synbiotics, and paraprobiotics as a therapeutic alternative for intestinal mucositis.” Frontiers in Microbiology11 (2020): 544490.