Probiotics for the Management of Oral Mucositis: An Interpretive Review of Current Evidence

Abstract

Introduction Anti-carcinoma therapies have various side effects, including mucositis; mucositis may be developed in up to 80% of cancer patients.1,2 In this regard, the diversity and population of oral microflora, as well as subjects' diets play a crucial role.3 Mucositis could appear as painful oral ulcers with potential gastrointestinal complications, such as diarrhea and nausea.3 Almost all cancer patients who undergo bone marrow transplant or myeloablative therapy are at risk for oral mucositis.4 As an unwanted complication of anticancer therapy, mucositis may lead to exacerbation of symptoms, especially in young patients with depression, infection, and pain.5 Several factors at the level of submucosa and epithelium contribute to the formation of oral mucositis.6 Although there is no specific treatment for oral mucositis, a number of pharmacological and non-pharmacological strategies are available to suppress its development.7 Low energy laser is one of these strategies.8 Recent evidence demonstrates the promising effect of natural agents, including probiotics in healing oral mucositis lesions.9,10 Probiotics are known to enhance the functions of gastrointestinal tract and immune system. Among probiotics, Lactobacillus and Bifidobacterium axe the most common bacteria,11 and Saccharomyces boulardii is the best-known yeast.12 Beneficial roles of probiotics have been reported in a number of disorders, including various types of diarrhea, H. pylori inflammation, inflammatory bowel disease, inflammatory bowel syndrome, gluten intolerance, gastrointestinal cancer, and mucositis.13 Furthermore, probiotics may have psychological protective effects, reducing the risk for the development of depression, perceived stress, and anxiety14 Benefits of probiotics in a rat model of chemotherapy-induced mucositis, and intestinal injuries have been reported.15 Lactobacillus reuteri is known to be a beneficial probiotic for peri-implant mucositis and Lactobacillus brevis CD2 is an effective species of probiotics for inhibiting chemotherapy-induced oral mucositis.3 Probiotics may lead to healing of oral mucositis by improving the immune system function.16 Also, they may increase the hosts defence mechanisms to overcome Streptococcus mutans by increasing the synthesis of immunoglobulins.17 Even though there has been a lot of attention to probiotics as adjuvant therapy for oral mucositis, the current evidence is not convincing.3 In this review, we have critically evaluated current literature on the benefits of probiotics in the management of oral mucositis along with their potential mechanisms of action. Limited studies have reported benefits of steroids against mTOR-induced oral ulcers.23 Animal studies also reported that induction of mucositis was associated with changes in inflammatory pathways and nitric oxide metabolism.24 Available literature suggests that the transcription factor NF-kB plays a crucial role in the formation of mucositis.25 This may result in increasing cyclooxygenase-2 activity, leading to accumulation of submucosal fibroblasts and increased prostaglandin production. Management of oral mucositis Despite advances in medical therapy, our knowledge in the area of prevention and treatment of drug-induced mucositis is very limited.26 Washing the oral cavity with saline associated with the use of soda bicarbonate, benzydamine, and low-degree laser are commonly recommended for the prevention of radiation-induced oral mucositis.27 Benzydamine hydrochloride (BZD) has multiple biological functions that can interfere with the processes of oral mucositis formation.2 It has been reported that BZD consumption could cause an increment in epithelial cell proliferation and a decrement in the secretion of inflammatory cytokines, like IL-1B and TNF-a.28 Low-level laser therapy (LLLT) may prevent the development of mucositis or reduce its severity, especially in younger patients.8 Co-administration of photochemotherapy and LLLT may result in synergic beneficial effects on oral mucositis status.29 Photodynamic therapy could be recommended for the treatment of mucositis in children and younger patients.30 Another method of treatment is using 0.5% methylene blue for washing the oral cavity.

Headnote

Article info

Article History:

Received: August 15, 2021 Revised: November 3, 2021 Accepted: January 5, 2022 epublished: January 5, 2022

Keywords:

Cancer, Chemotherapy, Mucositis, Oral mucositis, Probiotic, Radiotherapy

Abstract

Mucositis is one of the major side effects of anti-cancer therapies. Mucositis may lead to other abnormalities such as depression, infection, and pain, especially in young patients. Although there is no specific treatment for mucositis, several pharmacological and non-pharmacological options are available to prevent its complications. Probiotics have been recently considered as a preferable protocol to lessen the complications of chemotherapy, including mucositis. Probiotics could affect mucositis by anti-inflammatory and anti-bacterial mechanisms as well as augmenting the overall immune system function. These effects may be mediated through anti microbiota activities, regulating cytokine productions, phagocytosis, stimulating IgA releasement, protection of the epithelial shield, and regulation of immune responses. We have reviewed available literature pertaining to the effects of probiotics on oral mucositis in animal and human studies. While animal studies have reported protective effects of probiotics on oral mucositis, the evidence from human studies is not convincing.

Introduction

Anti-carcinoma therapies have various side effects, including mucositis; mucositis may be developed in up to 80% of cancer patients.1,2 In this regard, the diversity and population of oral microflora, as well as subjects' diets play a crucial role.3 Mucositis could appear as painful oral ulcers with potential gastrointestinal complications, such as diarrhea and nausea.3 Almost all cancer patients who undergo bone marrow transplant or myeloablative therapy are at risk for oral mucositis.4 As an unwanted complication of anticancer therapy, mucositis may lead to exacerbation of symptoms, especially in young patients with depression, infection, and pain.5 Several factors at the level of submucosa and epithelium contribute to the formation of oral mucositis.6 Although there is no specific treatment for oral mucositis, a number of pharmacological and non-pharmacological strategies are available to suppress its development.7 Low energy laser is one of these strategies.8 Recent evidence demonstrates the promising effect of natural agents, including probiotics in healing oral mucositis lesions.9,10 Probiotics are known to enhance the functions of gastrointestinal tract and immune system. Among probiotics, Lactobacillus and Bifidobacterium axe the most common bacteria,11 and Saccharomyces boulardii is the best-known yeast.12 Beneficial roles of probiotics have been reported in a number of disorders, including various types of diarrhea, H. pylori inflammation, inflammatory bowel disease, inflammatory bowel syndrome, gluten intolerance, gastrointestinal cancer, and mucositis.13 Furthermore, probiotics may have psychological protective effects, reducing the risk for the development of depression, perceived stress, and anxiety14 Benefits of probiotics in a rat model of chemotherapy-induced mucositis, and intestinal injuries have been reported.15 Lactobacillus reuteri is known to be a beneficial probiotic for peri-implant mucositis and Lactobacillus brevis CD2 is an effective species of probiotics for inhibiting chemotherapy-induced oral mucositis.3 Probiotics may lead to healing of oral mucositis by improving the immune system function.16 Also, they may increase the hosts defence mechanisms to overcome Streptococcus mutans by increasing the synthesis of immunoglobulins.17 Even though there has been a lot of attention to probiotics as adjuvant therapy for oral mucositis, the current evidence is not convincing.3 In this review, we have critically evaluated current literature on the benefits of probiotics in the management of oral mucositis along with their potential mechanisms of action.

Pathogenesis of oral mucositis

As a multifactorial disorder, mucositis is categorized into the oral and gastrointestinal types, based on the tissue it has damaged.18 The actual pathogenesis of oral mucositis is still under discussion. Damages to several types of cells, and tissues of the oral mucosa have been reported in oral mucositis.19 The functions of oral microorganisms in the treatment or prevention of this disorder are still unknown.20 One of the possible reasons that radiotherapy results in oral mucositis is its destructive effects on DNA molecules.21 As shown in a previous study, the thickness of the oral mucosa epithelium was minimized significantly after chemotherapy.22 The authors of this study suggested that oral mucositis lesions could be a toxic side effect of mammalian target of rapamycin (mTOR) inhibitors, like everolimus. Limited studies have reported benefits of steroids against mTOR-induced oral ulcers.23 Animal studies also reported that induction of mucositis was associated with changes in inflammatory pathways and nitric oxide metabolism.24 Available literature suggests that the transcription factor NF-kB plays a crucial role in the formation of mucositis.25 This may result in increasing cyclooxygenase-2 activity, leading to accumulation of submucosal fibroblasts and increased prostaglandin production. In cancer patients, an alteration in oral or intestinal bacterial microflora typically happens through the usage of antibiotics, xerostomia, and neutropenia. Also, after transplantation of hematopoietic cells, some microbiota (mostly from streptococci species) have been detected in the oral cavity. Other biofactors like TNF, IL-1B, MMP-3 and other inflammatory markers as well as epidermal growth factor may also play a role in the development of oral mucositis.

Management of oral mucositis

Despite advances in medical therapy, our knowledge in the area of prevention and treatment of drug-induced mucositis is very limited.26 Washing the oral cavity with saline associated with the use of soda bicarbonate, benzydamine, and low-degree laser are commonly recommended for the prevention of radiation-induced oral mucositis.27 Benzydamine hydrochloride (BZD) has multiple biological functions that can interfere with the processes of oral mucositis formation.2 It has been reported that BZD consumption could cause an increment in epithelial cell proliferation and a decrement in the secretion of inflammatory cytokines, like IL-1B and TNF-a.28 Low-level laser therapy (LLLT) may prevent the development of mucositis or reduce its severity, especially in younger patients.8 Co-administration of photochemotherapy and LLLT may result in synergic beneficial effects on oral mucositis status.29 Photodynamic therapy could be recommended for the treatment of mucositis in children and younger patients.30 Another method of treatment is using 0.5% methylene blue for washing the oral cavity. It could soothe the pain of oral mucositis ulcers.31 Oral cryotherapy is the other treatment for preventing and reducing the severity of chemotherapy-induced oral mucositis.32 In this method, practitioners chill the oral cavity by using ice, ice cream, or cold water to reduce blood flow and thereby reduce the local effects of the chemotherapy agents on oral mucosa.33 On the other side, Smad7 could suppress NF-kB and TGF(3, causing a decrease in apoptosis and inflammation while increasing epithelial migration. This could suggest that Smad7 could be considered as a major treatment for oral mucositis.6 Human keratinocyte growth factors, such as Palifermin could be also considered for the treatment of oral mucositis.34 Soft and liquid diets are suggested for patients with oral mucositis to ease eating and facilitate adequate nutrient intakes.35 Lately, more attention has been paid to the use of natural products, including honey, aloe vera, royal jelly, and propolis for their roles in the prevention and/or treatment of cancer-induced oral mucositis.36 Black mulberry molasses is another example of natural products used to reduce the burden of oral mucositis.37 Hydration, patient education, proper dietary intakes, and pain reduction methods are also included in the treatment protocols for oral mucositis. In addition to the above-mentioned protocols, several studies have reported the benefits of probiotics in the management of oral mucositis as discussed below.

Probiotic and oral mucositis Animal studies

Probiotic supplementation alleviated oral and intestinal infection in a rat model of chemotherapy-induced mucositis.15 Streptococcus thermophilus TH-4 was recently introduced as a probiotic that improves chemotherapy-induced mucositis via the folate production-like pathway.38 Another study suggested that probiotics (Lactobacillus and Bifidobacteria) may activate anti-viral macrophages through the secretion of nitric oxide and inflammatory agents like IL-6.39 The effects of various probiotics on animal models of oral mucositis are summarized in Table 1.

Human studies

Lactobacillus reuteri and L. brevis CD2 have been shown to produce beneficial effects against chemotherapy-induced oral mucosa injuries.3 In a double-blind trial, the effects of these probiotics on peri-implant mucositis patients have been investigated. The results of this investigation indicated synergistic effects of oral hygiene and probiotics in alleviating symptoms of mucosal injuries.45 The beneficial effects of L. rhamnosus, L. acidophilus, and B. bifidum have been noticed in candidiasis patients. The probiotic product showed a reducing effect on the colonization of Candida in denture wearers.46 It seems that probiotics are more useful than usual antifungal therapies in ameliorating the prevalence and complications of candidiasis.47 The combination of mechanical therapies with probiotics (L. reuteri) seems to be more effective than only mechanical therapy for the implant and peri-implant mucositis treatment. Similarly, the use of L. reuteri alone has minimal effects on peri-implant microbiota.48 The effects of probiotics on peri-implant mucositis may be mediated through regulating cytokines and other biomarker levels.49 In a triple-blind clinical trial, the positive effects of probiotics (L. reuteri) on mucositis have been evaluated. Reductions in implants mucositis were associated with reduced P. gingivalis population in the oral cavity.48 Another study reported L. rhamnosus and L. casei's anti-fungal function which could be helpful in candidiasis treatment.44 There wasn't any noticeable change in oral microbiota after the consumption of probiotic drinks in healthy denture wearers.50 In a triple-blind study, L. reuteri was used for peri-implant mucositis treatment, but the outcomes were comparable among all study groups.51 Another examination on oropharyngeal mucositis did not report the benefits of L. brevis CD2 in head and neck cancer patients. The benefits of probiotics on human mucositis are summarized in Table 2.

Possible mechanisms of the beneficial effects ofprobiotics on oral mucositis

Probiotics might protect the mucosa from Candida and other infectious agents through displacing different pathogens,54,55 regulating cytokine production and phagocytosis,56,57 stimulating IgA releasement, protection of the epithelial shield, and enhancing immune responses.58,59 It has been suggested that probiotics could stimulate the expression of anti-inflammatory agents like IL-1RII which binds to proinflammatory cytokines and neutralize them.60,61 The results of another study have shown that probiotics couldn't make a significant impact on ameliorating oral scars when using lozenges and topical oils.62 It has been reported that L. reuteri DSM17938 and PTA 5289 could remove mutans of streptococci from the mouth cavity. L. reuteri might make a change on host genes and leads to variations in epitopes receptors.63 In vitro studies suggest two possible pathways for antiviral effects of probiotics. Probiotics could impede the virus and prevent absorption and cell internalization of the virus. Another possible way is that probiotics can communicate with cells to create an antiviral mechanism.64 Mechanisms by which probiotics may generate beneficial effects in the management of oral mucositis are illustrated in Figure 1.

Conclusion

In this review, we have reviewed and summarized information on the benefits of probiotics in the treatment and/or prevention of mucositis. The benefits of probiotics on alleviating complications of mucositis have been reported mainly through animal studies; such effects have not been produced by human studies.

This could be because of limited number of human studies on the effects of probiotics on oral mucositis. Overall, it may be suggested that probiotics may generate beneficial effects on oral mucositis under certain conditions. However, more human studies are needed to establish the efficacy of different strains of probiotics on oral mucositis and their complications. It should be taken into account that different species of microbiota have their attributes and have specific mechanisms of action. Future studies should consider this fact and should examine the efficacy of different species of probiotics according to their specific mechanism and properties.65 Acknowledgments We thank the Research Center for Biochemistry and Nutrition in Metabolic Diseases at Kashan University of Medical Sciences for the provision of facilities needed to perform this review article. MHM's Research Program is supported by Natural Sciences and Engineering Research Council of Canada (NSERC). Competing Interests The authors do hereby declare that there are no actual or perceived conflicts of interest regarding this manuscript. Ethical Approval Not applicable.

References

References 1. Bowen JM, Wardill HR. Advances in the understanding and management of mucositis during stem cell transplantation. Curr Opin Support Palliat Care 2017;11(4):341-6. doi: 1 0.1 097/spc.000000000000031 0

2. SonisST. Oral mucositis in head and neck cancer: risk, biology and management. Am Soc Clin Oncol Educ Book 2013. doi: 1 0.1200/EdBook_AM.201 3.33.e236

3. Cereda E, Caraccia M, Caccialanza R. Probiotics and mucositis. Curr Opin Clin Nutr Metab Care 201 8;21 (5):399-404. doi: 10.1097/mco.0000000000000487

4. Silverman S Jr. Diagnosis and management of oral mucositis.) Support Oncol 2007';5(2 Suppl 1):13-21.

5. Allen C, Logan R, Revesz T, Keefe D, Cue S. The prevalence and investigation of risk factors of oral mucositis in a pediatric oncology inpatient population; a prospective study. / Pediatr Hematol Oncol 2018;40(1):15-21. doi: 10.1097/ mph.0000000000000970

6. Bian L, Han C, Zhao CW, Carl PJ, Wang XJ. The role of Smad7 in oral mucositis. Protein Cell 201 5;6(3):1 60-9. doi: 10.1007/ s1 3238-014-01 30-4

7. El BousaadaniA, Eljahd L, Abada R, RouadiS, Roubal M, Mahtar

M. [Prevention and treatment of mucositis in children with oral cancers: practical recommendations]. Cancer Radiother 201 6;20(3):226-30. doi: 1 0.1 01 6/j.canrad.201 5.11.006

8. He M, Zhang B, Shen N, Wu N, Sun J. A systematic review and meta-analysis of the effect of low-level laser therapy (LLLT) on chemotherapy-induced oral mucositis in pediatric and young patients. Eur) Pediatr 201 8;1 77(1 ):7-1 7. doi: 1 0.1 007/ S00431-01 7-3043-4

9. Nagi R, Patil DJ, Rakesh N, Jain S, Sahu S. Natural agents in the management of oral mucositis in cancer patients-systematic review. / Oral Biol Craniofac Res 2018;8(3):245-54. doi: 1 0.1016/j.jobcr.201 7.12.003

1 0. Coqueiro AY, de Oliveira Garcia AB, Rogero MM, Tirapegui J. Probiotic supplementation in sports and physical exercise: does it present any ergogenic effect? Nutr Health 201 7;23(4):239-49. doi: 10.1177/0260106017721000

11. Sarowska J, Choroszy-Krol I, Regulska-llow B, Frej-M^drzak M, Jama-Kmiecik A. The therapeutic effect of probiotic bacteria on gastrointestinal diseases. Adv Clin Exp Med 2013;22(5):759-66.

1 2. Szajewska H, Konarska Z, Kotodziej M. Probiotic bacterial and fungal strains: claims with evidence. Dig Dis 201 6;34(3):251 -9. doi: 10.1159/000443359

13. Korada SK, Yarla NS, Bishayee A, Aliev C, Aruna Lakshmi K, Arunasree MK, et al. Can probiotics cure inflammatory bowe diseases? Curr Pharm Des 201 6;22(7):904-1 7. doi: 10.2174/1 381612822666151209153249

14. McKean J, Naug H, Nikbakht E, Amiet B, Colson N. Probiotics and subclinical psychological symptoms in healthy participants: a systematic review and meta-analysis. / Altern Complement Med 201 7;23(4):249-58. doi: 10.1089/ acm.201 6.0023

1 5. Gerhard D, Sousa F, Andraus RAC, Pardo PE, Nai GA, Neto HB, et al. Probiotic therapy reduces inflammation and improves intestinal morphology in rats with induced oral mucositis. Braz Oral Res 2017;31:e71. doi: 1 0.1 590/1 807-31 07BOR-201 7.vol31.0071

1 6. Roy S, Trinchieri G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 201 7;1 7(5):2 71 -85. doi: 10.1038/ nrc.2017.13

1 7. Chanda W, Joseph TP, Wang W, Padhiar AA, Zhong M. The potential management of oral candidiasis using anti-biofilm therapies. Med Hypotheses 2017;106:15-8. doi: 10.1016/j. mehy.201 7.06.029

18. Cinausero M, Aprile G, Ermacora P, Basile D, Vitale MG, Fanotto V, et al. New frontiers in the pathobiology and treatment of cancer regimen-related mucosal injury. Front Pharmacol2017;8:354. doi: 1 0.3389/fphar.201 7.00354

19. Dodd M. The pathogenesis and characterization of ora mucositis associated with cancer therapy. Oncol Nurs Forum 2004;31 (4 Suppl):5-11. doi: 1 0.11 88/04.onf.s4.5-11

20. Vanhoecke B, De RyckT, Stringer A, Van de WieleT, Keefe D. Microbiota and their role in the pathogenesis of oral mucositis. Oral Dis 201 5;21 (1 ):1 7-30. doi: 1 0.1111/odi.1 2224

21. Hubenak JR, Zhang Q, Branch CD, Kronowitz SJ. Mechanisms of injury to normal tissue after radiotherapy: a review. Plast Reconstr Surg 2014;133(1 ):49e-56e. doi: 10.1097/01. prs.000044081 8.23647.0b

22. Al-Azri AR, Gibson RJ, Bowen JM, Stringer AM, Keefe DM, Logan RM. Involvement of matrix metalloproteinases (MMP-3 and MMP-9) in the pathogenesis of irinotecan-induced oral mucositis. / Oral Pathol Med 201 5;44(6):459-67. doi: 10.1111/jop.12255

23. Peterson DE, O'Shaughnessy JA, Rugo HS, Elad S, Schubert MM, Viet CT, et al. Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice. Cancer Med

201 6;5(8):1 897-907. doi: 1 0.1 002/cam4.761

24. Leitao RF, Ribeiro RA, Bellaguarda EA, Macedo FD, Silva LR, Oria RB, et al. Role of nitric oxide on pathogenesis of 5-fluorouracil induced experimental oral mucositis in hamster. Cancer Chemother Pharmacol 2007;59(5):603-12. doi: 1 0.1 007/s002 80-006-03 01 -y

25. Al-Dasooqi N, Sonis ST, Bowen JM, Bateman E, Blijlevens N, Gibson RJ, et al. Emerging evidence on the pathobiology of mucositis. Support Care Cancer 201 3;21 (7):2075-83. doi: 10.1007/s00520-013-1810-y

26. Nemes J, Jenei A, Marton I. [Oral mucositis as the most common complication of childhood cancer therapy. Review of the literature]. Orv Hetil 2018;159(13):495-502. doi: 10.1556/650.2018.31011

27. Khaw A, Logan R, Keefe D, Bartold M. Radiation-induced ora mucositis and periodontitis - proposal for an inter-relationship. Oral Dis 2014;20(3):e7-1 8. doi: 1 0.1111/odi.1 21 99

28. Cmelak AJ, Arneson K, Chau NG, Gilbert RW, Haddad Rl. Locally advanced head and neck cancer. Am Soc Clin Oncol Educ Book 2013:23 7-44. doi: 10.14694/EdBook_ AM.2013.33.237

29. Medeiros-Filho JB, Maia Filho EM, Ferreira MC. Laser and photochemotherapy for the treatment of ora I mucositis in young patients: randomized clinical trial. Photodiagnosis Photodyn Ther 201 7;1 8:39-45. doi: 1 0.1 01 6/j.pdpdt.201 7.01.004

30. Ribeiro da Silva VC, da Motta Silveira FM, Barbosa Monteiro MG, da Cruz MMD, Caldas Junior AF, Pina Godoy G. Photodynamic therapy for treatment of oral mucositis: pilot study with pediatric patients undergoing chemotherapy. Photodiagnosis Photodyn Ther 2018;21:115-20. doi: 10.1 01 6/j.pdpdt.201 7.11.010

31. Roldan CJ, Nouri K, Chai T, Huh B. Methylene blue for the treatment of intractable pain associated with oral mucositis. Pain Pract 201 7;1 7(8):111 5-21. doi: 1 0.1111/papr.12566

32. ChenJ, SeabrookJ, Fulford A, Rajakumar I. Icingoral mucositis: Oral cryotherapy in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant. / Oncol Pharm Pract 201 7;23(2):11 6-20. doi: 1 0.11 77/1 0781 5521 5620920

33. Sharifi H, Heydari A, Salek R, Emami Zeydi A. Ora cryotherapy for preventing chemotherapy-induced ora mucositis: an effective but yet neglected strategy./ Cancer Res Ther 201 7;1 3(2):386-7. doi: 1 0.41 03/0973-1482.1 88301

34. Spielberger R, Stiff P, Bensinger W, Rong A, Gayko U, Emmanouilides C. Palifermin (recombinant human keratinocyte growth factor) reduces severe oral mucositis in patients with haematological malignancies undergoing autologous peripheral blood progenitor cell transplantation: a combined analysis of phase 2 and 3 data. Bone Marrow Transplant 2005;35:S77.

35. Sung L, Robinson P, Treister N, BaggottT, Gibson P, Tissing W, et al. Guideline for the prevention of oral and oropharyngea mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation. BMJ Support Palliat Care 2017;7(1 ):7-16. doi: 10.1136/ bmjspcare-2014-000804

36. Izgu N. [Complementary therapies in the management of induced oral mucositis during cancer treatment]. / Educ Res Nurs 201 7;14(4):304-11. doi: 1 0.5222/head.201 7.304

3 7. Demir Dogan M, Can G, Meral R. Effectiveness of black mulberry molasses in prevention of radiotherapy-induced ora mucositis: a randomized controlled study in head and neck cancer patients. / Altern Complement Med 201 7;23(12):971 -9. doi: 1 0.1 089/acm.201 6.0425

38. Wang H, Brook CL, Whittaker AL, Lawrence A, Yazbeck R, Howarth GS. Effects of Streptococcus thermophilus TH-4 in a rat model of doxorubicin-induced mucositis. Scand ) Gastroenterol 2013;48(8):959-68. doi:

1 0.31 09/00365521.201 3.81 21 42

39. Ivec M, Botic T, Koren S, Jakobsen M, Weingartl H, Cencic A. Interactions of macrophages with probiotic bacteria lead to increased antiviral response against vesicular stomatitis virus. Antiviral Res 2007;75(3):266-74. doi: 10.1016/j. antiviral.2 007.03.01 3

40. Trindade LM, Martins VD, Rodrigues NM, Souza ELS, Martins FS, Costa CMF, et al. Oral administration of Simbioflora(r) (synbiotic) attenuates intestinal damage in a mouse mode of 5-fluorouracil-induced mucositis. Benef Microbes 201 8;9(3):477-86. doi: 1 0.3920/bm201 7.0082

41. Mauger CA, Butler RN, Ceier MS, Tooley KL, Howarth CS. Probiotic effects on 5-fluorouracil-induced mucositis assessed by the sucrose breath test in rats. Dig Dis Sci 2007;52(3):612-9. doi: 1 0.1 007/s1 0620-006-9464-y

42. Huang L, Chiang Chiau JS, Cheng ML, Chan WT, Jiang CB, Chang SW, et al. SCID/NOD mice model for 5-FU induced intestinal mucositis: safety and effects of probiotics as therapy. Pediatr Neonatol 201 9;60(3):252-60. doi: 1 0.1 01 6/j. pedneo.201 8.07.007

43. Yeung CY, Chan WT, Jiang CB, Cheng ML, Liu CY, Chang SW, et al. Amelioration of chemotherapy-induced intestina mucositis by orally administered probiotics in a mouse model. PLoS One 2015;1 0(9):e0138746. doi: 1 0.1 371/journal. pone.01 38746

44. Song YC, Lee SH. Inhibitory effects of Lactobacillus rhamnosus and Lactobacillus casei on Candida biofilm of denture surface. Arch Oral Biol 201 7;76:1 -6. doi: 1 0.1 01 6/j. archoralbio.2016.12.014

45. Hallstrom H, Lindgren S, Widen C, Renvert S, Twetman S. Probiotic supplements and debridement of peri-implant mucositis: a randomized controlled trial. Acta Odontol Scand 201 6;74(1):60-6. doi: 1 0.31 09/0001 6357.201 5.1 040065

46. Ishikawa KH, Mayer MP, Miyazima TY, Matsubara VH, Silva EC, Paula CR, et al. A multispecies probiotic reduces ora Candida colonization in denture wearers. / Prosthodont 201 5;24(3):1 94-9. doi: 10.1111/jopr.12198

47. Li D, Li Q, Liu C, Lin M, Li X, Xiao X, et al. Efficacy and safety of probiotics in the treatment of Cand/cfa-associated stomatitis. Mycoses 201 4;57(3):141 -6. doi: 1 0.1111/myc.1 211 6

48. Calofre M, Palao D, Vicario M, Nart J, Violant D. Clinical and microbiological evaluation of the effect of Lactobacillus reuteri in the treatment of mucositis and peri-implantitis: a triple-blind randomized clinical trial. / Periodontal Res 201 8;53(3):3 78-90. doi: 10.1111/jre.12523

49. Flichy-Fernandez AJ, Ata-Ali J, Alegre-Domingo T, Candel-Martf E, Ata-Ali F, Palacio JR, et al. The effect of orally administered probiotic Lactobacillus reuteri-containing tablets in peri-implant mucositis: a double-blind randomized controlled trial. / Periodontal Res 2015;50(6):775-85. doi: 1 0.1111/j re. 12264

50. Sutula J, Coulthwaite L, Thomas L, Verran J. The effect of a commercial probiotic drink on oral microbiota in healthy complete denture wearers. Microb Ecol Health Dis 2012;23. doi: 1 0.3402/mehd.v23i0.1 8404

51. Peha M, Barallat L, Vilarrasa J, Vicario M, Violant D, Nart J. Evaluation of the effect of probiotics in the treatment of peri-implant mucositis: a triple-blind randomized clinical trial. Clin Oral Investig 201 9;23(4):1 673-83. doi: 1 0.1 007/s00784-01 8-2578-8

52. Jiang C, Wang H, Xia C, Dong Q, Chen E, Qiu Y, et al.

A randomized, double-blind, placebo-controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngea carcinoma. Cancer 2019;125(7):1081-90. doi: 10.1002/ cncr.31907

53. De Sanctis V, Belgioia L, Cante D, La Porta MR, Caspiani O, Cuarnaccia R, et al. Lactobacillus brevis CD2 for prevention of oral mucositis in patients with head and neck tumors: a multicentric randomized study. Anticancer Res 201 9;39(4):1 935-42. doi: 1 0.21 873/anticanres.1 3303

54. Collado MC, Crzeskowiak L, Salminen S. Probiotic strains and their combination inhibit in vitro adhesion of pathogens to pig intestinal mucosa. Curr Microbiol 2007;55(3):260-5. doi: 1 0.1 007/s002 84-007-01 44-8

55. Wang H, Yan Y, Wang J, Zhang H, Qi W. Production and characterization of antifungal compounds produced by Lactobacillus plantarum IMAU10014. PLoS One 2012;7(1):e29452. doi: 1 0.1 371/journal.pone.0029452

56. Chermesh I, Eliakim R. Probiotics and the gastrointestinal tract: where are we in 2005? World) Gastroenterol 2006;1 2(6):853-7. doi: 10.3748/wjg.v12.i6.853

57. Rodes L, Khan A, Paul A, Coussa-Charley M, Marinescu D, Tomaro-Duchesneau C, et al. Effect of probiotics Lactobacillus and Bifidobacterium on gut-derived lipopolysaccharides and inflammatory cytokines: an in vitro study using a human colonic microbiota model. / Microbiol Biotechnol 201 3;23(4):51 8-26. doi: 1 0.4014/jmb. 1205.0501 8

58. Wagner RD, Pierson C, Warner T, Dohnalek M, Farmer J, Roberts L, et al. Biotherapeutic effects of probiotic bacteria on candidiasis in immunodeficient mice. Infect Immun 1997;65(10):41 65-72. doi: 1 0.1128/iai.65.1 0.41 65-4172.1997

59. Jafarzadeh A, Sadeghi M, Asadi Karam C, Vazirinejad R. Salivary IgA and IgE levels in healthy subjects: relation to age and gender. Braz Oral Res 201 0;24(1 ):21 -7. doi: 10.1590/ s1 806-8324201 00001 00004

60. Jensen LE. Targeting the IL-1 family members in skin inflammation. Curr Opin Investig Drugs 201 0;11 (11):1211-20.

61. Sim TC, Grant JA, Hilsmeier KA, Fukuda Y, Alam R. Proinflammatory cytokines in nasal secretions of allergic subjects after antigen challenge. Am ) Respir Crit Care Med 1994;149(2 Pt1 ):339-44. doi: 1 0.11 64/ajrccm. 149.2.8306027

62. Twetman S, Keller MK, Lee L, Yucel-Lindberg T, Pedersen AML. Effect of probiotic lozenges containing Lactobacillus reuteri on oral wound healing: a pilot study. Benef Microbes 201 8;9(5):691 -6. doi: 1 0.3920/bm201 8.0003

63. Romani Vestman N, Chen T, Lif Holgerson P, Ohman C, Johansson I. Oral microbiota shift after 12-week supplementation with Lactobacillus reuteri DSM 17938 and PTA 5289; a randomized control trial. PLoS One 201 5;1 0(5):e01 25812. doi: 1 0.1 371/journal.pone.01 2581 2

64. Botic T, Klingberg TD, Weingartl H, Cencic A. A nove eukaryotic cell culture model to study antiviral activity of potential probiotic bacteria. Int ) Food Microbiol 2007;11 5(2):227-34. doi: 1 0.1 01 6/j.ijfoodmicro.2006.1 0.044

65. Pico-Monllor JA, Mingot-Ascencao JM. Search and selection of probiotics that improve mucositis symptoms in oncologic patients. A systematic review. Nutrients 201 9;11 (1 0):2322. doi: 10.3390/nu111 02322