Radiotherapy (RT) is an important treatment for head and neck malignant tumors and can be used alone or in combination with chemotherapy as radical or adjuvant therapy. Despite improvements in RT equipment and techniques, there are still a variety of acute oral complications, including oral mucositis (OM), xerostomia, taste dysfunction, and oral infection. OM is one of the most common acute radiation-related toxicity in head and neck malignant tumor patients receiving RT, and approximately 50\~70% of patients experience severe oral mucositis (SOM). The painful inflammation and ulceration associated with OM not only profoundly affect patients' ability to eat, swallow, and speak but also decrease patients' tolerance to anti-cancer treatment, seriously impairing patients' quality of life (QoL) and causing interruptions and cancellations of cancer treatment. Standard treatment for OM focuses on pain control, rehydration, and good oral hygiene. For patients with hematopoietic stem cell transplantation, palifermin (keratinocyte growth factor-1) is recommended. Although some clinical strategies for OM such as non-steroidal anti-inflammatory drugs, mucosal protective agents, growth factors and cytokines, antibacterial, and pain relief drugs have been recommended by the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO), the therapeutic benefit is limited6. Thus, it is crucial to develop effective drugs or treatment strategies to decrease radiation-induced mucosal toxicity.

The resident microbiota plays an important role in the pathogenesis and development of radiation-induced OM. Microbiota can release pathogen-associated molecular patterns (PAMPs) that bind to pathogen recognition receptors (PRR) and activate the initial innate immune response, a known pathogenic pathway. Recent studies have suggested that dysbiosis of oral microbial contributes to the occurrence and severity of radiation-induced OM and manipulation of the patient microbial community may be key to preventing and treating effectively OM. Probiotics are defined as live microorganisms which when administered in adequate amounts can improve the microecological balance and confer a health benefit on the host. Conventional probiotics typically belong to the genera Lactobacillus or Bifidobacterium and Lactobacillus brevis CD2 is the most widely studied probiotic for preventing cancer therapy-induced OM, but its effectiveness is still debated.

Lactobacillus Reuteri is the body's natural flora and can be found in the gastrointestinal tract, skin, breast milk, etc. And they do not trigger infections in healthy individuals15. Among them, Lactobacillus Reuteri DSM 17938 and ATCC PTA 5289 can be isolated from healthy mammals as well as poultry, and are common Lactobacillus strains used in the market for making oral probiotics16. Lactobacillus Reuteri DSM 17938 has been reported to alleviate chronic inflammatory conditions such as infantile colic and irritable bowel-syndrome17.In oral inflammatory diseases, Lactobacillus Reuteri DSM 17938 and ATCC PTA 5289 have been found to reduce gingival and periodontal inflammation, which is mainly achieved through mechanisms such as modulation of the host inflammatory response and displacement of pathogenic bacteria. The development of oral mucositis caused by radiotherapy or chemoradiotherapy is associated with DNA damage and high production of various inflammatory factors such as interleukin-1(IL-1), interleukin-6 (IL-6) and tumor necrosis factor-a(TNF-a). Recently, the results of the study by Nitasha et al. showed that Lactobacillus Reuteri DSM 17938 and ATCC PTA 5289 can reduce oxidative stress and Inflammation in a preclinical rodent model. All of the above imply Lactobacillus reuteri's potential use in the prevention of OM.

The purpose of this placebo-controlled randomized trial was to investigate the prevention effects of Lactobacillus Reuteri versus placebo in patients with head and neck malignant tumors receiving RT.