目的 采用16S rDNA測(cè)序技術(shù)分析對(duì)乙酰氨基酚（APAP）所致藥物性肝損傷（DILI）小鼠腸道菌群的變化，并探討小鼠DILI的可能機(jī)制。方法 20只雄性C57BL/6N小鼠隨機(jī)分為對(duì)照組和APAP組，APAP組ig APAP（600 mg·kg^-1）復(fù)制DILI小鼠模型，對(duì)照組ig 0.5%羧甲基纖維素鈉（CMC-Na）溶液。連續(xù)14 d后，試劑盒法檢測(cè)血清中丙氨酸氨基轉(zhuǎn)移酶（ALT）、天冬氨酸氨基轉(zhuǎn)移酶（AST）、脂多糖（LPS）、腫瘤壞死因子-α（TNF-α）、白細(xì)胞介素-6（IL-6）的含量或活性；HE染色法觀察肝臟和腸道病理變化；16S rDNA測(cè)序法分析糞便腸道菌群組成結(jié)構(gòu)。結(jié)果 與對(duì)照組相比，APAP組小鼠血清中ALT、AST、LPS、TNF-α、IL-6的含量或活性顯著升高（P＜0.01），肝細(xì)胞內(nèi)可見(jiàn)大量的嗜酸性變和明顯的炎性細(xì)胞浸潤(rùn)，回腸和結(jié)腸黏膜層腺體皺縮。腸道菌群結(jié)構(gòu)紊亂，變形菌門(mén)（Proteobacteria）、放線菌門(mén)（Actinobacteria）、不動(dòng)桿菌屬（Acinetobacter）相對(duì)豐度顯著升高（P＜0.01），疣微菌門(mén)（Verrucomicrobia）、艾克曼菌屬（Akkermansia）相對(duì)豐度、Shannon指數(shù)顯著下降（P＜0.05）。結(jié)論 APAP致小鼠DILI時(shí)腸道菌群的結(jié)構(gòu)和組成均發(fā)生變化，APAP可能通過(guò)破壞腸道微生物穩(wěn)態(tài)和腸道屏障，增加腸道通透性致內(nèi)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

重慶市教委科學(xué)技術(shù)研究項(xiàng)目（KJZD-K202202701）；重慶三峽醫(yī)藥高等專(zhuān)科學(xué)校苗圃項(xiàng)目（XJ2022002505）