动物营养学报 >

2023 , Vol. 35 >Issue 4: 2661 - 2667

DOI: https://doi.org/10.12418/CJAN2023.248

研究论文

产肠毒素大肠杆菌K88对BALB/c小鼠肝脏炎症反应、程序性坏死和焦亡信号通路关键基因表达的影响

  • 连欣 ,
  • 王东方 ,
  • 杨阳 ,
  • 刘玉兰 ,
  • 胡进 , *
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  • 武汉轻工大学,动物营养与饲料科学湖北省重点实验室,武汉 430023
*胡 进,副教授,硕士生导师,E-mail:

连 欣(1998—),女,河南信阳人,硕士研究生,研究方向为动物肠道微生态与肠道健康。E-mail:

Copy editor: 田艳明

收稿日期: 2022-09-15

  网络出版日期: 2023-04-12

基金资助

武汉市科技局知识创新专项基础研究项目(2022020801010391)

武汉轻工大学引进(培养)人才科研启动资金资助(2021RZ087)

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Effects of Enterotoxigenic Escherichia coli K88 on Expression of Key Genes in Liver Inflammatory Response, Necroptosis and Pyroptosis Signaling Pathways in Liver of BALB/c Mice

  • LIAN Xin ,
  • WANG Dongfang ,
  • YANG Yang ,
  • LIU Yulan ,
  • HU Jin , *
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  • Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
*associate professor, E-mail:

Received date: 2022-09-15

  Online published: 2023-04-12

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摘要

本试验旨在研究产肠毒素大肠杆菌(ETEC)K88对BALB/c小鼠肝脏炎症反应、程序性坏死和焦亡信号通路关键基因表达的影响。试验选取25只9周龄、体重(17±1) g的雌性BALB/c小鼠,随机分为5个组,每组5只,每只小鼠腹腔注射1×107 CFU/mL ETEC K88菌液0.2 mL;分别于注射ETEC K88 0、12、24、36和48 h时屠宰小鼠,取肝脏组织测定炎性因子、程序性坏死和焦亡信号通路关键基因mRNA的表达。结果表明:1)与0 h相比,小鼠肝脏中炎性因子肿瘤坏死因子-α(TNF-α)的mRNA相对表达量在24、36和48 h时显著升高(P<0.05),白细胞介素-1β(IL-1β)的mRNA相对表达量在12和36 h时显著升高(P<0.05),白细胞介素-6(IL-6)的mRNA相对表达量在36和48 h时显著升高(P<0.05);2)与0 h相比,小鼠肝脏中受体相互作用蛋白激酶1(RIPK1)的mRNA相对表达量在12 h时显著升高(P<0.05),受体相互作用蛋白激酶3(RIPK3)的mRNA相对表达量在36 h时显著升高(P<0.05),混合谱系激酶结构域样假激酶(MLKL)的mRNA相对表达量在12、36和48 h时显著升高(P<0.05);3)与0 h相比,小鼠肝脏中核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)的mRNA相对表达量在36 h时显著升高(P<0.05),凋亡相关斑点样蛋白(ASC)的mRNA相对表达量在12、36和48 h时显著升高(P<0.05),半胱氨酸天冬氨酸蛋白酶-1(Caspase-1)的mRNA相对表达量在24和36 h时显著升高(P<0.05),消皮素D(GSDMD)的mRNA相对表达量在12、24和36 h时显著升高(P<0.05),白细胞介素-18(IL-18)的mRNA相对表达量在24 h时显著升高(P<0.05)。综上所述,ETEC K88感染引起小鼠肝脏炎症反应,激活了小鼠肝脏程序性坏死和焦亡信号通路。

关键词： 产肠毒素大肠杆菌; 肝脏; 炎症; 程序性坏死; 焦亡

本文引用格式

连欣 , 王东方 , 杨阳 , 刘玉兰 , 胡进 . 产肠毒素大肠杆菌K88对BALB/c小鼠肝脏炎症反应、程序性坏死和焦亡信号通路关键基因表达的影响[J]. 动物营养学报, 2023 , 35(4) : 2661 -2667 . DOI: 10.12418/CJAN2023.248

Abstract

This experiment was conducted to investigate the effects of enterotoxigenic Escherichia coli (ETEC) K88 on the expression of key genes in inflammatory response, necroptosis and pyroptosis signaling pathways in liver of BALB/c mice. Twenty-five nine-week-old female BALB/c mice weighing (17±1) g were randomly divided into 5 groups with 5 mice in each group. Each mouse was intraperitoneally injected with 0.2 mL 1×107 CFU/mL ETEC K88 bacterial solution. Mice were slaughtered at 0, 12, 24, 36 and 48 h after ETEC K88 injection, and liver tissues were taken to determine the mRNA expressions of key genes in inflammatory factors, necroptosis and pyroptosis signaling pathways. The results showed as follows: 1) compared with 0 h, the inflammatory factor tumor necrosis factor-α (TNF-α) mRNA relative expression level in liver of mice was significantly increased at 24, 36 and 48 h (P<0.05), the interleukin-1β (IL-1β) mRNA relative expression level was significantly increased at 12 and 36 h (P<0.05), and the interleukin-6 (IL-6) mRNA relative expression level was significantly increased at 36 and 48 h (P<0.05). 2) Compared with 0 h, the receptor-interacting protein kinase 1 (RIPK1) mRNA relative expression level in liver of mice was significantly increased at 12 h (P<0.05), the receptor-interacting protein kinase 3 (RIPK3) mRNA relative expression level was significantly increased at 36 h (P<0.05), and the mixed lineage kinase domain like pseudokinase (MLKL) mRNA relative expression level was significantly increased at 12, 36 and 48 h (P<0.05). 3) Compared with 0 h, the nucleotide binding oligomeric domain-like receptor protein 3 (NLRP3) mRNA relative expression level of in liver of mice was significantly increased at 36 h (P<0.05), the apoptosis-associated speck-like protein (ASC) mRNA relative expression level was significantly increased at 12, 36 and 48 h (P<0.05), the cysteine-aspartic protease-1 (Caspase-1) mRNA relative expression level was significantly increased at 24 and 36 h (P<0.05), the gasdermin D (GSDMD) mRNA relative expression level was significantly increased at 12, 24 and 36 h (P<0.05), and the interleukin-18 (IL-18) mRNA relative expression level was significantly increased at 24 h (P<0.05). In conclusion, ETEC K88 infection can cause liver inflammation in mice, and activate the signaling pathways of necroptosis and pyroptosis in liver of mice.

Key words： enterotoxigenic Escherichia coli; liver; inflammation; necroptosis; pyroptosis

产肠毒素大肠杆菌(enterotoxigenic Escherichia coli,ETEC)是引起幼畜腹泻的主要致病菌之一[1],其致病作用主要与黏附性菌毛有关,其中K88、K99、987P和F41等都是动物ETEC重要的黏附性毒力因子[2],且ETEC K88是引起动物腹泻的重要病原菌[3]。肝脏是机体重要的免疫器官,内含大量枯否细胞,在正常情况下,由门静脉进入肝脏的微生物、内毒素等大分子物质可被肝脏中的枯否细胞清除,从而抵抗感染[4]。当ETEC感染机体时,携带病菌的血液由肠道进入肝脏,激活细胞因子,产生炎症从而造成肝脏损伤[5-6];此外,还可生成大量氧自由基,使脂质过氧化物在体内堆积,抗氧化物酶活性降低,进一步加快细菌在体内的传播,引起肝功能衰退[6-7]。但ETEC K88引起肝脏炎症反应的机制尚未阐明。
陈茉等[8]给小鼠灌胃ETEC后,小鼠肝脏以及肠道肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-1β和IL-6的mRNA相对表达量显著提高。研究表明,ETEC可诱导凋亡信号通路,从而引起肝脏损伤。Gong等[9]使用ETEC感染小鼠,结果表明肝脏中B细胞淋巴瘤/白血病2(Bcl-2)、Bcl-2相关X蛋白(Bax)mRNA相对表达量显著降低。程序性坏死同样在肝脏炎症和损伤中起着重要作用。Lim等[10]研究发现,丙型肝炎病毒(hepatitis C virus,HCV)可引起肝细胞死亡,同时诱发凋亡和程序性坏死。研究表明,细胞焦亡与肝脏的多种疾病密切相关,HCV被肝细胞识别后,肝细胞中半胱氨酸天冬氨酸蛋白酶(Caspase)-1和Caspase-3表达显著上调,诱导炎性小体核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)的组装,引起肝细胞焦亡[11]。以往多数的研究用乙醇、四氯化碳等构建肝脏损伤模型[12],关于ETEC与肝脏损伤的关系研究鲜有报道,且程序性坏死与焦亡是否介导ETEC诱导的小鼠肝脏损伤并不清楚。鉴于此,本试验拟采用腹腔注射ETEC K88菌液感染小鼠,旨在探究ETEC K88引起小鼠肝脏炎症反应的机制,为有效治疗和营养调控ETEC K88导致的肝脏损伤提供科学依据和理论基础。

1 材料与方法

1.1 试验材料

ETEC K88(血清型为O149:K91:K88ac)购于中国兽医药品监察所;BALB/c小鼠购于北京维通利华实验动物技术有限公司;RNA提取、反转录、实时荧光定量PCR试剂盒购于TaKaRa公司。

1.2 细菌培养

细菌培养方法参照杨阳等[13]。

1.3 饲养管理

将小鼠饲养在标准无特异性病原体(SPF)的鼠房中,饲养条件为:环境温度(20±3) ℃,每天光照12 h。小鼠适应性饲养3 d,期间自由饮水和采食。

1.4 试验设计

选取25只9周龄、体重(17±1) g的雌性BALB/c小鼠,随机分为5个组,每组5只,每只小鼠腹腔注射1×107 CFU/mL ETEC K88菌液0.2 mL。5组小鼠分别于注射ETEC K88 0、12、24、36和48 h时屠宰,取肝脏组织测定mRNA的相对表达量。

1.5 检测指标与方法

肝脏炎症基因,包括TNF-α、IL-6和IL-1β;程序性坏死关键基因,包括受体相互作用蛋白激酶1(RIPK1)、受体相互作用蛋白激酶3(RIPK3)、混合谱系激酶结构域样假激酶(MLKL);焦亡关键基因,包括NLRP3、凋亡相关斑点样蛋白(ASC)、Caspase-1、消皮素D(GSDMD)和IL-18。以上基因的mRNA相对表达量采用实时荧光定量PCR法测定,测定方法参照黄洋等[14],以磷酸甘油醛脱氢酶(GAPDH)为内参,使用2-ΔΔCt法计算目的基因mRNA的相对表达量[15],引物序列见表1。
表1 引物序列

Table 1 Primer sequences

基因
Genes		 引物序列
Primer sequences
(5'—3')		 扩增长度
Amplification
length/bp		 参考序列
Reference
sequences
肿瘤坏死因子-α
TNF-α		 F:AGTCCGGGCAGGTCTACTTT
R:CAGGTCACTGTCCCAGCATC		 123 NM_013693.3
白细胞介素-1β
IL-1β		 F:GGCTGGACTGTTTCTAATGC
R:ATGGTTTCTTGTGACCCTGA		 166 NM_008361.4
白细胞介素-6
IL-6		 F:TAAGCTGGAGTCACAGAAGGAG;
R:GCACTAGGTTTGCCGAGTAGAT		 137 NM_001314054.1
受体相互作用蛋白激酶1
RIPK1		 F:CTGACTGATGAACACCTGAACC
R:TCTGGCTGGCACGAATCAA		 268 XM_030247206.2
基因
Genes		 引物序列
Primer sequences
(5'—3')		 扩增长度
Amplification
length/bp		 参考序列
Reference
sequences
受体相互作用蛋白激酶3
RIPK3		 F:GGCTCTCGTCTTCAACAA
R:ACTGTGCTTGGTCATACTT		 110 NM_001164108.1
混合谱系激酶结构域样假激酶
MLKL		 F:GCTGTTGCTGCTGCTTCA
R:CCACGGAGGTCCAAGATGT		 256 XM_006531443.5
核苷酸结合寡聚化结构域样受体蛋白3
NLRP3		 F:AGACCTCCAAGACCACTAC
R:ACATAGCAGCGAAGAACTC		 297 NM_145827.4
凋亡相关斑点样蛋白
ASC		 F:TGCCTCTCATCTACTTCCT
R:CACCATTCTTCTCCTCTACA		 147 NM_009201.2
半胱氨酸天冬氨酸蛋白酶-1
Caspase-1		 F:GACATCCTTCATCCTCAGAA
R:CTCCAGCAGCAACTTCAT		 260 NM_009807.2
消皮素D
GSDMD		 F:TTAATTGAGGCGGCAGAC
R:CCAGCAGGTAGAAGATAGG		 289 XM_006521343.5
白细胞介素-18
IL-18		 F:ACTCTTGCGTCAACTTCA
R:GTCCTCTTACTTCACTGTCT		 261 NM_008360.2
磷酸甘油醛脱氢酶
GAPDH		 F:ATGGTGAAGGTCGGTGTGAA
R:TGGAAGATGGTGATGGGCTT		 254 NM_001289726.1

1.6 数据统计分析

采用SPSS 18.0软件对数据进行独立样本t检验,12、24、36和48 h分别与0 h比较,结果采用“平均值±标准误”表示,以P<0.05表示差异显著,0.05≤P<0.10表示差异有显著趋势。

2 结果

2.1 ETEC K88感染对小鼠肝脏炎症反应关键基因mRNA相对表达量的影响

如表2所示,ETEC K88感染后,与0 h相比,小鼠肝脏中炎性因子TNF-α的mRNA相对表达量在12 h时有上升趋势(P=0.063),在24、36和48 h时显著升高(P<0.05);IL-1β的mRNA相对表达量在12和36 h时显著升高(P<0.05),在24 h时有上升趋势(P=0.054);IL-6的mRNA相对表达量在12 h时有上升趋势(P=0.093),在24 h时无显著变化(P>0.05),在36和48 h时显著升高(P<0.05)。
表2 ETEC K88感染对小鼠肝脏炎症反应关键基因mRNA相对表达量的影响

Table 2 Effects of ETEC K88 infection on mRNA relative expression levels of key genes in inflammatory response in liver of mice

项目
Items		 0 h 12 h 24 h 36 h 48 h P值P-value
0 h vs.
12 h		 0 h vs.
24 h		 0 h vs.
36 h		 0 h vs.
48 h
肿瘤坏死因子-α
TNF-α		 1.00±0.08 33.24±10.62 8.49±0.67 32.27±8.15 24.67±2.30 0.063 0.007 0.019 0.009
白细胞介素-1β
IL-1β		 1.00±0.04 25.02±8.56 6.56±2.06 21.04±0.42 11.97±4.99 0.049 0.054 <0.001 0.159
白细胞介素-6 IL-6 1.00±0.21 10.52±3.71 5.10±2.68 5.24±0.53 2.31±0.08 0.093 0.265 0.002 0.004

2.2 ETEC K88感染对小鼠肝脏程序性坏死信号通路关键基因mRNA相对表达量的影响

如表3所示,ETECK88感染后,与0h相比,小鼠肝脏中RIPK1的mRNA相对表达量在12 h时显著升高(P<0.05),但在24~48 h时无显著变化(P>0.05);RIPK3的mRNA相对表达量在24 h时有上升趋势(P=0.085),在36 h时显著升高(P<0.05),在48 h时有上升趋势(P=0.063);MLKL的mRNA相对表达量在12、36和48 h时显著升高(P<0.05)。
表3 ETEC K88感染对小鼠肝脏程序性坏死信号通路关键基因mRNA相对表达量的影响

Table 3 Effects of ETEC K88 infection on mRNA relative expression levels of key genes in necroptosis signaling pathway in liver of mice

项目
Items		 0 h 12 h 24 h 36 h 48 h P值P-value
0 h vs.
12 h		 0 h vs.
24 h		 0 h vs.
36 h		 0 h vs.
48 h
受体相互作用
蛋白激酶1
RIPK1		 1.00±0.07 1.30±0.05 1.24±0.20 1.24±0.10 1.48±0.32 0.026 0.318 0.116 0.274
受体相互作用
蛋白激酶3
RIPK3		 1.00±0.06 3.89±1.36 2.47±0.64 4.70±0.00 3.89±0.77 0.167 0.085 <0.001 0.063
混合谱系激酶结构
域样假激酶
MLKL		 1.00±0.02 6.38±1.85 3.69±1.30 3.67±0.36 2.00±0.11 0.044 0.175 0.002 0.001

2.3 ETEC K88感染对小鼠肝脏焦亡信号通路关键基因mRNA相对表达量的影响

如表4所示,ETEC K88感染后,与0 h相比,小鼠肝脏中NLRP3的mRNA相对表达量在12、24和48 h时无显著变化(P>0.05),但在36 h时显著升高(P<0.05);ASC的mRNA相对表达量在12、36和48 h时显著升高(P<0.05),在24 h时有上升趋势(P=0.067);Caspase-1的mRNA相对表达量在24和36 h时显著升高(P<0.05);GSDMD的mRNA相对表达量在12、24和36 h时显著升高(P<0.05),在48 h时有上升趋势(P=0.058);IL-18的mRNA相对表达量在24 h时显著升高(P<0.05),在48 h时有上升趋势(P=0.053)。
表4 ETEC K88感染对小鼠肝脏焦亡信号通路关键基因mRNA相对表达量的影响

Table 4 Effects of ETEC K88 infection on mRNA relative expression levels of key genes in pyroptosis signaling pathway in liver of mice

项目
Items		 0 h 12 h 24 h 36 h 48 h P值P-value
0 h vs.
12 h		 0 h vs.
24 h		 0 h vs.
36 h		 0 h vs.
48 h
核苷酸结合寡聚化
结构域样受体蛋白3
NLRP3		 1.00±0.13 2.28±0.68 1.65±0.31 2.83±0.26 1.98±0.53 0.196 0.126 0.003 0.148
凋亡相关斑
点样蛋白
ASC		 1.00±0.22 3.51±0.27 1.68±0.16 3.20±0.26 2.55±0.20 0.002 0.067 0.003 0.007
半胱氨酸天冬氨
酸蛋白酶-1
Caspase-1		 1.00±0.08 3.94±1.11 2.13±0.28 4.62±0.85 2.08±0.83 0.118 0.017 0.013 0.321
消皮素D GSDMD 1.00±0.09 3.24±0.67 1.97±0.98 2.14±0.31 1.99±0.36 0.029 0.002 0.023 0.058
白细胞介素-18
IL-18		 1.00±0.06 1.21±0.25 0.58±0.13 0.98±0.16 0.59±0.14 0.455 0.047 0.915 0.053

3 讨论

大肠杆菌感染不仅会表现出肠道的症状,还可引起机体多种器官并发症的发生,如肝脾损伤、心包炎及腹膜炎等[16]。肝脏炎症反应会伴随着促炎因子的释放,因此检测促炎因子(TNF-α、IL-1β和IL-6)的水平可用来评估小鼠肝脏炎症。胡乐玉等[17]研究发现,ETEC感染小鼠24 h后,小鼠血清中IL-1β的含量显著升高;滴鼻感染ETEC 24~72 h后小鼠肝脏TNF-α、IL-1β和IL-6的含量均升高[18]。本试验与上述研究结果一致,在小鼠受到ETEC K88感染后,肝脏中炎性细胞因子TNF-α、IL-1β和IL-6 mRNA相对表达量出现显著升高,提示腹腔注射ETEC K88引起小鼠肝脏炎症反应。
此外,炎症能够诱导细胞程序性坏死[19]。TNF-α可与死亡受体(DR)结合诱发程序性坏死[20]。当细胞受到细菌、病毒等感染后,炎性因子TNF-α与DR结合,促进RIPK1-RIPK3-MLKL坏死复合物的形成,引起程序性坏死的发生。研究证明,程序性坏死参与多种疾病导致的肝脏损伤,如酒精性肝病导致的肝损伤中RIPK3蛋白表达上调[21],RIPK3抑制Caspase-8通路,使肝脏募集单核细胞和巨噬细胞,进一步促进肝损伤、炎症和肝纤维化[22-23]。本试验结果显示,在感染ETEC K88 36 h时小鼠肝脏中RIPK3 mRNA相对表达量显著上调,MLKL的mRNA相对表达量在36和48 h时显著上调,结合上述炎性因子的结果,表明ETEC K88感染后可能诱导肝脏组织发生程序性坏死,进一步促进肝脏炎症反应。
焦亡是一类是由炎性小体启动的细胞死亡模式,主要受NLRP3、ASC和GSDMD等因子调控[24]。焦亡会导致细胞膜肿胀破裂释放出大量的炎性因子,当细胞受到细菌、病毒等感染时,核苷酸结合NOD样受体与未活化的ASC形成炎性复合体,激活ASC蛋白,活化后的ASC进一步激活Caspase-1,Caspase-1剪切GSDMD形成GSDMD-N端结构域,促进IL-1β和IL-18的释放,从而引起细胞的焦亡[24-25]。Bai等[26]在小鼠肝脏损伤模型中发现,NLRP3炎性小体激活引起了细胞焦亡,进一步诱导肝脏炎症;茶金龙等[27]研究发现,猪致病性大肠杆菌HPI可激活焦亡信号通路,上调Caspase-1、IL-1β和IL-18 mRNA表达水平。本试验分析了焦亡和炎症相关指标,发现在感染ETEC K88 36 h时小鼠肝脏中NLRP3、ASC、Caspase-1和GSDMD mRNA相对表达量出现显著升高,同时炎性因子TNF-α、IL-1β和IL-6 mRNA相对表达量显著升高,提示ETEC感染后可能使肝脏组织焦亡信号通路被激活以及产生炎症。

4 结论

综上所述,ETEC K88感染下小鼠肝脏炎性因子、程序性坏死和焦亡信号通路关键基因mRNA相对表达量在不同时间点出现显著升高,表明ETEC K88感染引起肝脏组织炎症反应,激活程序性坏死和焦亡信号通路。

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