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Effect of Depression on Bacterial Infection Based on Chronic Unpredictable Mild Stress Model
- Journal of Sun Yat-sen University(Medical Sciences) Vol. 45, Issue 4, Pages: 567-581(2024)
- 作者机构：
1.成都医学院检验医学院，四川 成都 610500
2.中山大学中山医学院，广东 广州 510080
3.中山大学热带病防治教育部重点实验室，广东 广州 510080
4.中山大学附属第五医院药学部，广东 珠海 519000
5.中山大学医学院免疫学教研室，广东 深圳 518107
6.中山大学中山医学院法医学教研室，广东 广州 510080
7.广东省法医学转化医学工程技术研究中心，广东 广州 510080
- 作者简介：
TIAN Guobao， E-mail： tiangb@mail.sysu.edu.cn
QIN Lina， E-mail： qinlna@mail.sysu.edu.cn
- 基金信息：国家自然科学基金(81830103;82061128001)
DOI：10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240617.011
CLC： R37Published：20 July 2024，
Received：07 May 2024，
Accepted：13 June 2024
- 稿件说明：
扫 描 看 全 文
徐磊,赵润平,陈洁云等.基于CUMS模型探究抑郁症对细菌感染的影响及作用[J].中山大学学报（医学科学版）,2024,45(04):567-581.
XU Lei,ZHAO Runping,CHEN Jieyun,et al.Effect of Depression on Bacterial Infection Based on Chronic Unpredictable Mild Stress Model[J].Journal of Sun Yat-sen University(Medical Sciences),2024,45(04):567-581.
徐磊,赵润平,陈洁云等.基于CUMS模型探究抑郁症对细菌感染的影响及作用[J].中山大学学报（医学科学版）,2024,45(04):567-581. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240617.011.
XU Lei,ZHAO Runping,CHEN Jieyun,et al.Effect of Depression on Bacterial Infection Based on Chronic Unpredictable Mild Stress Model[J].Journal of Sun Yat-sen University(Medical Sciences),2024,45(04):567-581. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240617.011.
摘要
目的
2
抑郁症是一种常见的精神疾病，对患者的身体健康有着深远的影响。抑郁症与较高的细菌感染风险相关；然而，这是否是一种因果关系，以及抑郁症如何影响感染仍不清楚。因此，本研究旨在通过构建慢性不可预测轻度应激（CUMS）模型，探究抑郁表型在小鼠细菌感染中的作用。
方法
2
小鼠经CUMS诱导4周，通过行为学测试评估抑郁表型。随后，小鼠腹腔注射肺炎克雷伯菌模拟细菌感染，感染后48 h收集血清和腹腔组织。苏木精-伊红染色（ HE）观察组织病理学改变，酶联免疫吸附试验（ELISA）检测炎性因子水平。此外，对感染前收集的小鼠粪便样本进行肠道菌群16S rDNA基因测序分析，并检测未感染小鼠结肠组织中
NF-κB
/
NLRP3
信号通路的表达水平。
结果
2
行为学测试结果显示，与对照组相比，CUMS小鼠体质量显著降低（
P
<
0.000 1，
t
=5.426），蔗糖偏好率显著降低（
P
<
0.001，
t
=4.937），游泳静止时间显著增加（
P
<
0.001，
t
=16.37），旷场中央区域停留时间显著减少（
P
<
0.01，
t
=3.575）。生存分析显示，与对照组小鼠相比，感染后CUMS小鼠的生存率显著降低（
P
<
0.05）。HE染色结果显示，CUMS小鼠肝脏（
P
<
0.05，
t
=4.025）、肾脏（
P
<
0.05，
t
=2.828）、肠系膜（
P
<
0.01，
t
=5.367）组织损伤程度明显加重。ELISA结果显示，炎症因子IL-6（
P
<
0.01，
t
=3.365）、IL-1β（
P
<
0.01，
t
=4.061）、TNF-α（
P
<
0.01，
t
=4.460）和LPS（
P
<
0.000 1，
t
=27.24）水平升高。16S rDNA测序结果显示，CUMS小鼠肠道菌群结构发生改变，与对照组小鼠明显不同，表现出菌群失调。与对照组相比，CUMS小鼠结肠组织中
NF-κB
（
P
<
0.01，
t
=6.825）和
NLRP3
（
P
<
0.001，
t
=9.561）的表达水平升高。
结论
2
CUMS小鼠发生更严重的细菌感染。CUMS诱导的抑郁表型可能因为破坏肠道菌群组成和激活NF-κB/NLRP3信号通路，增加了小鼠对细菌感染的易感性。
Abstract
Objective
2
Depression is a common mental illness with a profound impact on physical health. Depression has been associated with a higher risk of bacterial infection； however， whether this relationship is causal and how depression affects infection remains unclear. Therefore， we aimed to investigate the effects of depressive phenotype in infected mice by constructing a chronic unpredictable mild stress （CUMS） model.
Methods
2
Mice were induced with CUMS for 4 weeks. The depressive phenotype was evaluated using behavioral tests. Subsequently， the mice were intraperitoneally injected with
Klebsiella pneumoniae
to establish bacterial infection. Serum and abdominal tissues were collected 48 h after infection. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in the tissues， and enzyme-linked immunosorbent assay （ELISA） was used to measure the levels of inflammatory factors. In addition， the fecal samples collected before infection were analyzed for 16S rDNA gene of gut microbiota， and the expression levels of
NF-κB
/
NLRP3
signaling pathway in colon tissues of uninfected mice were detected.
Results
2
Behavioral tests showed that compared with the control mice， CUMS mice had significantly lower body weight （
P
<
0.000 1，
t
=5.426）， lower sucrose preference rate （
P
<
0.001，
t
=4.937）， increased swimming stationary time （
P
<
0.001，
t
=16.37）， and decreased time spent in the central area of the open field （
P
<
0.01，
t
=3.575）. Survival analysis showed that compared with the control mice， the survival rate of CUMS mice significantly decreased after infection （
P
<
0.05）. Additionally， histochemical staining showed that tissue damage in the liver （
P
<
0.05，
t
=4.025）， kidney （
P
<
0.05，
t
=2.828）， and mesentery （
P
<
0.01，
t
=5.367） significantly increased. Furthermore， ELISA results showed that the levels of the inflammatory cytokines IL-6 （
P
<
0.01，
t
=3.365）， IL-1β （
P
<
0.01，
t
=4.061）， TNF-α （
P
<
0.01，
t
=4.460） and LPS （
P
<
0.000 1，
t
=27.24） were elevated. The difference was statistically significant. According to 16S rDNA sequencing， CUMS-induced changes in the intestinal bacterial community structure of mice， making them significantly different from the control mice. Compared with the control mice， the expression levels of
NF-κB
（
P
<
0.01，
t
=6.825） and
NLRP3
（
P
<
0.001，
t
=9.561） were upregulated in CUMS mice.
Conclusion
2
The CUMS model was successfully constructed and CUMS mice developed more severe bacterial infection. Gut microbiota was dysregulated and the expression of NF-κB/NLRP3 signaling pathway was up-regulated in CUMS mice， which was related to the susceptibility to bacterial infection.
关键词
抑郁症慢性不可预测轻度应激感染肠道菌群炎症
Keywords
depressionchronic unpredictable mild stressinfectionsgut microbiotainflammation
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