目的 采用16S rDNA测序技术分析对乙酰氨基酚（APAP）所致药物性肝损伤（DILI）小鼠肠道菌群的变化，并探讨小鼠DILI的可能机制。方法 20只雄性C57BL/6N小鼠随机分为对照组和APAP组，APAP组ig APAP（600 mg·kg^-1）复制DILI小鼠模型，对照组ig 0.5%羧甲基纤维素钠（CMC-Na）溶液。连续14 d后，试剂盒法检测血清中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、脂多糖（LPS）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）的含量或活性；HE染色法观察肝脏和肠道病理变化；16S rDNA测序法分析粪便肠道菌群组成结构。结果 与对照组相比，APAP组小鼠血清中ALT、AST、LPS、TNF-α、IL-6的含量或活性显著升高（P＜0.01），肝细胞内可见大量的嗜酸性变和明显的炎性细胞浸润，回肠和结肠黏膜层腺体皱缩。肠道菌群结构紊乱，变形菌门（Proteobacteria）、放线菌门（Actinobacteria）、不动杆菌属（Acinetobacter）相对丰度显著升高（P＜0.01），疣微菌门（Verrucomicrobia）、艾克曼菌属（Akkermansia）相对丰度、Shannon指数显著下降（P＜0.05）。结论 APAP致小鼠DILI时肠道菌群的结构和组成均发生变化，APAP可能通过破坏肠道微生物稳态和肠道屏障，增加肠道通透性致内毒素外漏，加重DILI的程度。

Objective To analyze the changes of gut microbiota during drug-induced liver injury (DILI) in mice induced by acetaminophen (APAP) using 16S rDNA sequencing technology, and to explore the possible mechanism of DILI in mice. Method 20 male C57BL/6N mice were randomly divided into control group and APAP group. The APAP group was ig with APAP (600 mg·kg^-1) to bulid the DILI mouse model, while the control group was ig with an equal amount of 0.5% carboxymethyl cellulose sodium (CMC-Na) solution. After 14 consecutive days, the contents or activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in serum were determined under anesthesia. HE staining to observe the pathological changes of the liver and intestines. 16S rDNA sequencing to analyze the composition and structure of fecal gut microbiota. Results Compared with the control group, the contents or activities of ALT, AST, LPS, TNF-α and IL-6 in serum of APAP group were significantly increased (P＜0.01), a large number of eosinophilic changes and obvious inflammatory infiltration cell were observed in liver cells. Glands in the ileum and colon mucosa were shrunk. The structure of intestinal microbiota was disordered, the relative abundance of Proteobacteria, Actinobacteria, and Acinetobacter were significantly increased (P＜0.01), the relative abundance of Verrucomicrobia, Akkermansia and Shannon index were decreased significantly (P＜0.01, 0.05). Conclusion The structure and composition of intestinal microbiota in mice with DILI induced by APAP have undergone changes. APAP may increase intestinal permeability and lead to endotoxin leakage by disrupting intestinal microbiota homeostasis and intestinal barrier, exacerbating DILI.

R965

重庆市教委科学技术研究项目（KJZD-K202202701）；重庆三峡医药高等专科学校苗圃项目（XJ2022002505）