目的 研究枳实总黄酮对5-氟尿嘧啶（5-fluorouracil，5-FU）诱导的肠黏膜炎和肠道菌群的影响及作用机制。方法 雄性昆明小鼠随机分为对照组、模型组及枳实总黄酮低、中、高剂量（50、100、200 mg/kg）组和洛哌丁胺（0.3 mg/kg组），ip 5-FU（50 mg/kg）5 d诱导肠黏膜炎模型，第6天开始，各给药组ig相应药物，1次/d，连续7 d，观察小鼠体质量、饮食量、饮水量、腹泻评分、胸腺指数、脾脏指数、结肠形态、隐窝深度；采用苏木素-伊红（HE）染色考察小鼠结肠组织病理变化；采用ELISA法检测小鼠结肠组织中白细胞介素-6（interleukin-6，IL-6）、IL-1β和肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）水平；检测小鼠结肠组织中超氧化物歧化酶（superoxide dismutase，SOD）、谷胱甘肽过氧化物酶（glutathione peroxidase，GSH-Px）活性和丙二醛（maleic dialdehyde，MDA）水平；采用细菌16S rRNA基因V3～4区高通量测序技术分析小鼠肠道菌群变化。结果 与模型组相比，枳实总黄酮组小鼠体质量和饮食量增加，饮水量减少，腹泻评分降低，胸腺指数和脾脏指数显著增加（P<0.05、0.01），结肠组织损伤减轻，结肠长度和隐窝深度显著增加（P<0.05、0.01），结肠组织中促炎细胞因子IL-6、IL-1β和TNF-α水平显著降低（P<0.05、0.01），SOD和GSH-Px活性显著升高（P<0.05、0.01），MDA水平显著降低（P<0.01）。16S rRNA基因测序结果显示，模型组小鼠肠道菌群多样性和丰度降低，枳实总黄酮组小鼠肠道菌群多样性和丰度增加。门水平主要表现为厚壁菌门相对丰度升高；属水平上拟杆菌属Bacteroidetes、unidentified_Clostridiales、拟普雷沃菌属Alloprevotella、unidentified_Ruminococcaceae和乳酸杆菌属Lactobacillus 5个菌属相对丰度升高。结论 枳实总黄酮能够有效改善5-FU所致的小鼠肠黏膜炎，其机制可能与抗氧化、抗炎、调节肠道菌群有关。

Objective To study the effect and mechanism of total flavonoids from Zhishi (Aurantii Frutus Immaturus, AFIF) on mice with intestinal mucositis induced by 5-fluorouracil (5-FU). Methods Male Kunming mice were randomly divided into control group, model group, low-, medium-and high-dose AFIF (50, 100, 200 mg/kg) groups and loperamide (0.3 mg/kg) group. 5-FU (50 mg/kg) was injected intraperitoneally for 5 d to induce intestinal mucositis model. Beginning on day 6, rats in each administration group were ig corresponding drugs, once a day for 7 consecutive days. The body weight, diet intake, water intake, diarrhea score, thymus index, spleen index, colon morphology and crypt depth were observed. Hematoxylin-eosin (HE) staining was used to investigate the pathological changes of colon. Levels of interlerkin-6 (IL-6), IL-1β and tumor necrosis factor-α (TNF-α) in colon tissues were determined by ELISA; Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, and malondialdehyde (MDA) level were detected; 16S rRNA gene V3—4 regions for high throughput sequencing technology was used to analysis the changes of intestinal flora. Results Compared with model group, body weight and food intake of mice in AFIF groups were increased, water intake and diarrhea score were decreased, thymus and spleen index were significantly increased (P<0.05, 0.01), colon tissue damage was reduced, colon length and crypt depth were significantly increased (P<0.05, 0.01); Levels of pro-inflammatory cytokines IL-6, IL-1β and TNF-α in colon tissue were significantly reduced (P<0.05, 0.01); Activities of SOD and GSH-Px were significantly increased (P<0.05, 0.01), and MDA level was significantly decreased (P<0.01). 16S rRNA gene sequencing results showed that diversity and abundance of intestinal flora of mice in model group was reduced, diversity and abundance of intestinal flora of mice in AFIF groups were increased. At phylum level, the relative abundance of Firmicutes was increased in AFIF groups. At genus level, the relative abundance of Bacteroidetes, unidentified_Clostridiales, Alloprevotella, unidentified_Ruminococcaceae and Lactobacillus were increased. Conclusion AFIF can effectively improve 5-FU induced intestinal mucositis in mice, and its mechanism may be related to the anti-oxidation, anti-inflammatory and regulation of intestinal flora.

R285.5

重庆科委社会事业与民生保障科技创新专项（cstc2017shmsA10004）