## 4 Discussion
### Probiotics in Oral Wound Healing and Oral Mucositis Related with Cancer Therapy  
Wound healing in the oral mucosa involves several inflammatory mediators/molecules and is impacted by several factors such as age, dietary habits, and the oral microbiome [109; 110]. Cancer therapy affects salivary quality and reduce salivary glycoproteins that cover and protect oral mucosa against microorganism's adherence and irritation. In addition, it induces oral mucositis that may favor the emergence of opportunistic infections, fever, anorexia, hemorrhage, severe pain, dysphagia and dysguesia [111]. Oral glutamine has been recommended to mitigate radiotherapy-induced oral mucositis in head and neck cancer patients but other effective interventions are needed [112]. As mentioned previously, probiotics may participate indirectly in re-epithelialization and tissue regeneration due to their potential to: (1) influence immune-regulating factors (e.g., kB nuclear factor, toll-like receptors in dendritic cells), (2) modulate inflammatory mediator levels (e.g., cytokines such as IL-1\(\beta\), TNF-\(\alpha\), IL-6 and IL-15 and chemokineses such as IL-8); and (3) induce the production of proteolytic enzymes involved in tissue remodeling (MMPs). A few clinical trials have investigated the role of topical administration of probiotics in oral wound healing and in the treatment of oral mucositis in patients undergoing chemo-radiotherapy (Table S10). In a study by [PERSON] et al. [113], the application of _L. reuteri_ in adults with healthy mucosa one week before standardized biopsy of the oral mucosa and one week later showed no improvement in healing. However, patients in the probiotic group had lower pain, less erythema/edema and the fibrin more rapidly covered the wound. There was no change in the levels of MMP1-3 and IFN-\(\alpha\)2, IFN-\(\beta\) and IFN-\(\gamma\) in the wound exudate during the first healing week [114]. [PERSON] et al. [115] evaluated the effects of _L. reuteri_ supplements administered 3 times a day for 2 weeks on the healing of wounds after surgical extraction of lower third molars. Probiotic had no effect on the healing process as determined by extra-oral swelling, level of salivary oxytocin, and presence of bacteria. However, in patients on probiotic the subjective perception of pain, discomfort and swelling was significantly reduced and leading to improved quality of life during the healing process. [PERSON] et al. [116] assessed the safety and tolerability of a 1, 3 or 6 mouthwash/day containing _Lactococcus lactis_ (AG013, a strain that produces human trefoil factor 1) in patients newly diagnosed with advanced squamous cell head and neck cancer who were to start chemotherapy. The mean number of days with oral mucositis was reduced by 35% in the probiotic group, and there were fewer emergency visits (36% vs. 60%). The placebo patients had at least 2 days with oral mucositis while 29% of those taking AG013 had oral mucositis for 0 or 1 day. _Lactococcus lactis_ AG013 was detected in mucosa and saliva shortly after the mouthwash, and up to 14 days after the mouthwash in equivalent number in the test groups. The probiotic was safe as there was no infection in neutropic patients. In a study by [PERSON] et al. [117], a significant improvement in oral mucositis was observed in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy taking a probiotic combination of _Bifidobacterium longum_, _Lactobacillus lactis_, and _Enterococcus faecium_. Finally, [PERSON] et al. [118] evaluated the effect of _L. brevis_ CD2 taken in lozenges in patients with squamous cell carcinoma of head and neck submitted to chemo-radiotherapy. The incidence and severity of oral mucositis was reduced in the probiotic group. In the probiotic group, more patients completed the cancer treatment, and fewer patients needed adjuvant medications to control the pain associated with mucositis.