Table_2_A Phase II Randomized Clinical Trial and Mechanistic Studies Using Improved Probiotics to Prevent Oral Mucositis Induced by Concurrent Radiotherapy and Chemotherapy in Nasopharyngeal Carcinoma.docx

Earlier evidence has proven that probiotic supplements can reduce concurrent chemoradiotherapy (CCRT)-induced oral mucositis (OM) in nasopharyngeal cancer (NPC). The incidence of severe OM (grade 3 or higher) was the primary endpoint in this study. We first enrolled 85 patients with locally advanced NPC who were undergoing CCRT. Of them, 77 patients were finally selected and randomized (1:1) to receive either a probiotic cocktail or placebo. To investigate the protective effects and the mechanism of probiotic cocktail treatment on OM induced by radiotherapy and chemotherapy, we randomly divided the rats into the control (C) group, the model (M) group, and the probiotic (P) group. After treatment, samples from the tongue, blood, and fecal and proximal colon tissues on various days (7th, 14th, and 21st days) were collected and tested for the inflammatory response, cell apoptosis, intestinal permeability, and intestinal microbial changes. We found that patients taking the probiotic cocktail showed significantly lower OM. The values of the incidence of 0, 1, 2, 3, and 4 grades of OM in the placebo group and in the probiotic cocktail group were reported to be 0, 14.7, 38.2, 32.4, and 14.7% and 13.9, 36.1, 25, 22.2, and 2.8%, respectively. Furthermore, patients in the probiotic cocktail group showed a decrease in the reduction rate of CD3+ T cells (75.5% vs. 81%, p < 0.01), CD4+ T cells (64.53% vs. 79.53%, p < 0.01), and CD8+ T cells (75.59 vs. 62.36%, p < 0.01) compared to the placebo group. In the rat model, the probiotic cocktail could ameliorate the severity of OM, decrease the inflammatory response, cause cell apoptosis and intestinal permeability, and restore the structure of gut microbiota to normalcy. In conclusion, the modified probiotic cocktail significantly reduces the severity of OM by enhancing the immune response of patients with NPC and modifying the structure of gut microbiota.
Clinical Trial Registration: The Clinical Trial Registration should be the NCT03112837.

既往研究证实，益生菌补充剂可减轻鼻咽癌（nasopharyngeal cancer, NPC）患者同步放化疗（concurrent chemoradiotherapy, CCRT）诱导的口腔黏膜炎（oral mucositis, OM）。本研究以重度口腔黏膜炎（≥3级）的发生率为主要终点。我们最初纳入85例接受同步放化疗的局部晚期鼻咽癌患者，最终筛选出77例，按1:1随机分为益生菌合剂组与安慰剂组。为探究益生菌合剂对放化疗诱导口腔黏膜炎的保护作用及其机制，我们将大鼠随机分为对照组（C组）、模型组（M组）与益生菌组（P组）。于给药后第7、14、21天采集舌组织、血液、粪便及近端结肠组织样本，检测炎症反应、细胞凋亡、肠道通透性及肠道菌群变化。本研究发现，服用益生菌合剂的患者口腔黏膜炎程度显著降低。安慰剂组与益生菌合剂组的0、1、2、3、4级口腔黏膜炎发生率分别为0、14.7%、38.2%、32.4%、14.7%与13.9%、36.1%、25%、22.2%、2.8%。此外，与安慰剂组相比，益生菌合剂组患者的CD3+ T细胞（75.5% vs. 81%，p<0.01）、CD4+ T细胞（64.53% vs. 79.53%，p<0.01）及CD8+ T细胞（75.59 vs. 62.36%，p<0.01）的降低幅度显著降低。在大鼠模型中，益生菌合剂可减轻口腔黏膜炎严重程度、抑制炎症反应、调节细胞凋亡与肠道通透性，并使肠道菌群结构恢复至正常稳态。综上，改良型益生菌合剂可通过增强鼻咽癌患者的免疫应答、调节肠道菌群结构，显著减轻口腔黏膜炎的严重程度。临床试验注册：临床试验注册号为NCT03112837。