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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
TIAN Guobao, E-mail: tiangb@mail.sysu.edu.cn
QIN Lina, E-mail: qinlna@mail.sysu.edu.cn
Published:20 July 2024,
Received:07 May 2024,
Accepted:13 June 2024
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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.
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。
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.
抑郁症慢性不可预测轻度应激感染肠道菌群炎症
depressionchronic unpredictable mild stressinfectionsgut microbiotainflammation
Fonkwo PN. Pricing infectious disease. the economic and health implications of infectious diseases[J]. EMBO Rep, 2008, 9 (Suppl 1): S13-S17.
Muzaheed. Helicobacter pylori oncogenicity: mechanism, prevention, and risk factors[J]. Scient World J, 2020, 2020: 3018326.
Eldin C, Mélenotte C, Mediannikov O, et al. From Q fever to coxiella burnetii infection: a paradigm change[J]. Clin Microbiol Rev, 2017, 30(1): 115-190.
Nudel R, Appadurai V, Schork AJ, et al. A large population-based investigation into the genetics of susceptibility to gastrointestinal infections and the link between gastrointestinal infections and mental illness[J]. Hum Genet, 2020, 139(5): 593-604.
Cruz-Pereira JS, Rea K, Nolan YM, et al. Depression's unholy trinity: dysregulated stress, immunity, and the microbiome[J]. Annu Rev Psychol, 2020, 71: 49-78.
Adams TB, Wharton CM, Quilter L, et al. The association between mental health and acute infectious illness among a national sample of 18- to 24-year-old college students[J]. J Am Coll Health, 2008, 56(6): 657-663.
Seminog OO, Goldacre MJ. Risk of pneumonia and pneumococcal disease in people with severe mental illness: english record linkage studies[J]. Thorax, 2013, 68(2): 171-176.
Sloan RP, Cole SW. Parasympathetic neural activity and the reciprocal regulation of innate antiviral and inflammatory genes in the human immune system[J]. Brain Behav Immun, 2021, 98: 251-256.
Cillóniz C, Pericàs JM, Rojas JR, et al. Severe infections due to respiratory viruses[J]. Semin Respir Crit Care Med, 2022, 43(1): 60-74.
Andersson NW, Goodwin RD, Okkels N, et al. Depression and the risk of severe infections: prospective analyses on a nationwide representative sample[J]. Int J Epidemiol, 2016, 45(1): 131-139.
Wang Q, Xu R, Volkow ND. Increased risk of COVID-19 infection and mortality in people with mental disorders: analysis from electronic health records in the United States[J]. World Psychiatry, 2021, 20(1): 124-130.
Lee JW, Lee H, Kang HY.. Association between depression and antibiotic use: analysis of population-based National Health Insurance claims data[J]. BMC Psychiatry, 2021, 21(1): 536.
Sanacora G, Yan Z, Popoli M. The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders[J]. Nat Rev Neurosci, 2022, 23(2):86-103.
Kaplan GB, Lakis GA, Zhoba H. Sleep-wake and arousal dysfunctions in post-traumatic stress disorder: role of orexin systems[J]. Brain Res Bull, 2022, 186: 106-122.
Willner P, Muscat R, Papp M. Chronic mild stress-induced anhedonia: a realistic animal model of depression[J]. Neurosci Biobehav Rev, 1992, 16(4): 525-534.
Xu YH, Yu M, Wei H, et al. Fibroblast growth factor 22 is a novel modulator of depression through interleukin-1β[J]. CNS Neurosci Ther, 2017, 23(11): 907-916.
Zhang J, Zhou H, Yang J, et al. Low-intensity pulsed ultrasound ameliorates depression-like behaviors in a rat model of chronic unpredictable stress[J]. CNS Neurosci Ther, 2021, 27(2): 233-243.
Burokas A, Arboleya S, Moloney RD, et al. Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice[J]. Biol Psychiatry, 2017, 82(7): 472-487.
Simpson CA, Diaz-Arteche C, Eliby D, et al. The gut microbiota in anxiety and depression-a systematic review[J]. Clin Psychol Rev, 2021, 83: 101943.
Opazo MC, Ortega-Rocha EM, Coronado-Arrázola I, et al. Intestinal microbiota influences non-intestinal related autoimmune diseases[J]. Front Microbiol, 2018, 9: 432.
Fu J, Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation[J]. Annu Rev Immunol, 2023, 41: 301-316.
Hei M, Chen P, Wang S, et al. Effects of chronic mild stress induced depression on synaptic plasticity in mouse hippocampus[J]. Behav Brain Res, 2019, 365: 26-35.
Verharen JPH, De Jong JW, Zhu Y, et al. A computational analysis of mouse behavior in the sucrose preference test[J]. Nat Commun, 2023, 14(1): 2419.
Khan MI, Nikoui V, Naveed A, et al. Antidepressant-like effect of ethanol in mice forced swimming test is mediated via inhibition of NMDA/nitric oxide/cGMP signaling pathway[J]. Alcohol, 2021, 92: 53-63.
Antiorio AT, Alemán-Laporte J, Zanatto DA, et al. Mouse behavior in the open-field test after meloxicam administration[J]. J Am Assoc Lab Anim Sci, 2022, 61(3): 270-274.
Wick MR. The hematoxylin and eosin stain in anatomic pathology-An often-neglected focus of quality assurance in the laboratory[J]. Semin Diagn Pathol, 2019, 36(5): 303-311.
Li N, Wang Q, Wang Y, et al. Fecal microbiota transplantation from chronic unpredictable mild stress mice donors affects anxiety-like and depression-like behavior in recipient mice via the gut microbiota-inflammation-brain axis[J]. Stress, 2019, 22(5): 592-602.
王叶欣, 庞芳, 唐成林. 针药结合对抑郁症大鼠脑-肠轴功能的影响[J]. 重庆医科大学学报, 2022, 47(12): 1465-1471.
Wang YX, Pang F, Tang CL. Effect of acupuncture plus medication on the brain-gut axis function in depressed rats[J]. J Chongqing Med Univ, 2022, 47(12): 1465-1471.
Smith K. Mental health: a world of depression[J]. Nature, 2014, 515(7526): 181.
Irwin MR, Levin MJ, Carrillo C, et al. Major depressive disorder and immunity to varicella-zoster virus in the elderly[J]. Brain Behav Immun, 2011, 25(4): 759-766.
Esin RG, Esin OR, Khakimova AR. Stress-induced disorders[J]. Zh Nevrol Psikhiatr Im S S Korsakova, 2020, 120(5): 131-137.
Takajo T, Tomita K, Tsuchihashi H, et al. Depression promotes the onset of irritable bowel syndrome through unique dysbiosis in rats[J]. Gut Liver, 2019, 13(3): 325-332.
Eribo OA, Du Plessis N, Chegou NN. The intestinal commensal, bacteroides fragilis, modulates host responses to viral infection and therapy: lessons for exploration during mycobacterium tuberculosis infection[J]. Infect Immun, 2022, 90(1): e0032121.
Federici S, Kredo-Russo S, Valdés-Mas R, et al. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation[J]. Cell, 2022, 185(16):2879-2898.
Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, et al. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial[J]. Nutrition, 2016, 32(3): 315-320.
Cai T, Zheng SP, Shi X, et al. Therapeutic effect of fecal microbiota transplantation on chronic unpredictable mild stress-induced depression[J]. Front Cell Infect Microbiol, 2022, 12: 900652.
Chen Y, Xu J, Chen Y. Regulation of neurotransmitters by the gut microbiota and effects on cognition in neurological disorders[J]. Nutrients, 2021, 13(6):2099.
Leighton SP, Nerurkar L, Krishnadas R, et al. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis[J]. Mol Psychiatry, 2018, 23(1): 48-58.
Beurel E, Toups M, Nemeroff CB. The bidirectional relationship of depression and inflammation: double trouble[J]. Neuron, 2020, 107(2): 234-256.
Cao YG, Bae S, Villarreal J, et al. Faecalibaculum rodentium remodels retinoic acid signaling to govern eosinophil-dependent intestinal epithelial homeostasis[J]. Cell Host Microbe, 2022, 30(9):1295-1310.
Aizawa E, Tsuji H, Asahara T, et al. Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder[J]. J Affect Disord, 2016, 202: 254-257.
Pellegrini C, Antonioli L, Calderone V, et al. Microbiota-gut-brain axis in health and disease: Is NLRP3 inflammasome at the crossroads of microbiota-gut-brain communications?[J]. Prog Neurobiol, 2020, 191: 101806.
Lee J, Zhang L. The hierarchy quorum sensing network in Pseudomonas aeruginosa[J]. Protein Cell, 2015, 6(1): 26-41.
王甲河, 邹淑娟, 谢静, 等. NLRP3炎性小体与骨及关节疾病发生的研究进展[J]. 四川大学学报(医学版), 2023, 54(3): 679-684.
Wang JH, Zou SJ, Xie J, et al. Latest findings on NOD-like receptor family pyrin domain containing protein 3 inflammasome and bone and articular diseases[J]. J Sichuan Univ (Med Sci ), 2023, 54(3): 679-684.
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