P2X7受体抑制剂对青春期创伤后应激障碍大鼠行为及肠道菌群的影响

doi:10.6040/j.issn.1671-7554.0.2024.1315

摘要/Abstract

摘要： 目的探讨嘌呤能离子通道型7(purinergic ligand-gated ion channel 7, P2X7)受体抑制剂对青春期创伤后应激障碍(post-traumatic stress disorder, PTSD)大鼠行为及肠道菌群的影响。方法 3周龄雄性Wistar大鼠按随机数字表法分为对照组、模型组和抑制剂组。通过单一延长应激和情景恐惧条件反射方法构建PTSD动物模型,并在应激后早期腹腔注射P2X7受体抑制剂亮蓝G进行干预。采用行为学实验评估大鼠行为表现,通过宏基因组绝对定量测序检测粪便菌群变化。结果与模型组相比,P2X7受体抑制剂显著缩短大鼠僵住时间(P=0.049 9),增加开放臂停留时间百分比(P=0.004),提升中央区域运动距离和停留时间百分比(P=0.001,P=0.003),以及自发交替正确率(P=0.008)。宏基因组绝对定量测序分析显示,P2X7受体抑制剂显著增加肠道菌群的总丰度(P=0.003),尤其是厚壁菌门(P=0.002)、毛螺菌科(P=0.006)和颤螺菌科(P=0.003)的绝对丰度,并影响脂质代谢、异种生物降解和代谢、辅酶因子和维生素代谢等功能。此外,Spearman相关性分析显示,差异菌群的绝对丰度与PTSD样行为显著相关。结论应激后早期给予P2X7受体抑制剂干预能够显著改善青春期大鼠的PTSD样行为,其作用可能与调节肠道菌群的总丰度、组成及代谢功能有关。

关键词: 嘌呤能离子通道型7受体抑制剂, 创伤后应激障碍, 青春期, 肠道菌群, 宏基因组绝对定量测序

Abstract: Objective To investigate the effects of the purinergic ligand-gated ion channel 7(P2X7)receptor inhibitor on behaviour and gut microbiota in adolescent rats with post-traumatic stress disorder(PTSD). Methods Three-week-old male Wistar rats were randomly assigned to three groups: control group, model group, and inhibitor group. An animal model of PTSD was established using single prolonged stress and contextual fear conditioning. Following stress induction, early intervention was administered via intraperitoneal injection of the P2X7 receptor inhibitor Brilliant Blue G. Behavioural tests were conducted to assess the rats’ behaviour and metagenomic absolute quantification sequencing was employed to analyse alterations in the fecal microbiota. Results Compared to the model group, the P2X7 receptor inhibitor significantly reduced freezing time(P=0.049 9), increased the percentage of time spent in the open arms(P=0.004), increased both movement distance and time spent in the central area(P=0.001, P=0.003), and improved the accuracy of spontaneous alternation(P=0.008). Analysis of metagenomic absolute quantification sequencing revealed that the P2X7 receptor inhibitor increased the overall abundance of the gut microbiota(P=0.003), particularly the absolute abundances of Bacillota(P=0.002), Lachnospiraceae(P=0.006)and Oscillospiraceae(P=0.003). In addition, metabolic functions including lipid metabolism, biodegradation and metabolism of xenobiotics, and metabolism of cofactors and vitamins were affected. Furthermore, Spearman correlation analysis revealed a significant association between the absolute abundances of the different microbiota and PTSD-like behaviour. Conclusion Early intervention with the P2X7 receptor inhibitor after stress exposure can significantly alleviate PTSD-like behaviour in adolescent rats. These effects may be related to modulation of the overall abundance, composition, and metabolic functions of the gut microbiota.

Key words: Purinergic ligand-gated ion channel 7 receptor inhibitor, Post-traumatic stress disorder, Adolescent, Gut microbiota, Metagenomic absolute quantification sequencing

中图分类号:

R395

徐晶晶,王新起,张洋,许旺旺,高进. P2X7受体抑制剂对青春期创伤后应激障碍大鼠行为及肠道菌群的影响[J]. 山东大学学报 (医学版), 2025, 63(4): 1-9.

XU Jingjing, WANG Xinqi, ZHANG Yang, XU Wangwang, GAO Jin. Effects of P2X7 receptor inhibitors on behaviour and gut microbiota in adolescent rats with post-traumatic stress disorder[J]. Journal of Shandong University (Health Sciences), 2025, 63(4): 1-9.

参考文献

[1] McLaughlin KA, Koenen KC, Hill ED, et al. Trauma exposure and posttraumatic stress disorder in a national sample of adolescents[J]. J Am Acad Child Adolesc Psychiatry, 2013, 52(8): 815-830.
[2] Nooner KB, Oriana Linares L, Batinjane J, et al. Factors related to posttraumatic stress disorder in adolescence[J]. Trauma Violence Abuse, 2012, 13(3): 153-166.
[3] An YY, Huang JL, Chen YR, et al. Longitudinal cross-lagged relationships between posttraumatic stress disorder and depression in adolescents following the Yancheng tornado in China[J]. Psychol Trauma, 2019, 11(7): 760-766.
[4] Bandelow B, Allgulander C, Baldwin DS, et al. World Federation of Societies of Biological Psychiatry(WFSBP)guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part II: OCD and PTSD[J]. World J Biol Psychiatry, 2023, 24(2): 118-134.
[5] Ke S, Hartmann J, Ressler KJ, et al. The emerging role of the gut microbiome in posttraumatic stress disorder[J]. Brain Behav Immun, 2023, 114: 360-370. doi:10.1016/j.bbi.2023.09.005
[6] Tanelian A, Nankova B, Cheriyan A, et al. Differences in gut microbiota associated with stress resilience and susceptibility to single prolonged stress in female rodents[J]. Neurobiol Stress, 2023, 24: 100533. doi:10.1016/j.ynstr.2023.100533
[7] Bajaj JS, Sikaroodi M, Fagan A, et al. Posttraumatic stress disorder is associated with altered gut microbiota that modulates cognitive performance in veterans with cirrhosis[J]. Am J Physiol Gastrointest Liver Physiol, 2019, 317(5): 661-669.
[8] Lynch CMK, Cowan CSM, Bastiaanssen TFS, et al. Critical windows of early-life microbiota disruption on behaviour, neuroimmune function, and neurodevelopment[J]. Brain Behav Immun, 2023, 108: 309-327. doi: 10.1016/j.bbi.2022.12.008
[9] Bartlett R, Stokes L, Sluyter R. The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease[J]. Pharmacol Rev, 2014, 66(3): 638-675.
[10] Perruzza L, Gargari G, Proietti M, et al. T follicular helper cells promote a beneficial gut ecosystem for host metabolic homeostasis by sensing microbiota-derived extracellular ATP[J]. Cell Rep, 2017, 18(11): 2566-2575.
[11] Su QQ, Tian YY, Liu ZN, et al. Purinergic P2X7 receptor blockade mitigates alcohol-induced steatohepatitis and intestinal injury by regulating MEK1/2-ERK1/2 signaling and egr-1 activity[J]. Int Immunopharmacol, 2019, 66: 52-61. doi:10.1016/j.intimp.2018.11.012
[12] Torres-Rodríguez O, Rivera-Escobales Y, Castillo-Ocampo Y, et al. Purinergic P2X7 receptor-mediated inflammation precedes PTSD-related behaviors in rats[J]. Brain Behav Immun, 2023, 110: 107-118. doi:10.1016/j.bbi.2023.02.015
[13] Vandeputte D, Kathagen G, Dhoe K, et al. Quantitative microbiome profiling links gut community variation to microbial load[J]. Nature, 2017, 551(7681): 507-511.
[14] Zhao HY, Li Y, Luo T, et al. Preventing Post-Traumatic Stress Disorder(PTSD)in rats with pulsed 810 nm laser transcranial phototherapy[J]. Transl Psychiatry, 2023, 13(1): 281. doi:10.1038/s41398-023-02583-3
[15] Ye TX, Zhou YP, Yang JX, et al. P2X7 receptor inhibition prevents atrial fibrillation in rodent models of depression[J]. Europace, 2024, 26(2): euae022. doi:10.1093/europace/euae022
[16] Pang F, Yang YH, Huang SQ, et al. Electroacupuncture alleviates depressive-like behavior by modulating the expression of P2X7/NLRP3/IL-1β of prefrontal cortex and liver in rats exposed to chronic unpredictable mild stress[J]. Brain Sci, 2023, 13(3): 436. doi:10.3390/brainsci13030436
[17] Thapa S, Sheu JC, Venkatachalam A, et al. Gut microbiome in adolescent depression[J]. J Affect Disord, 2021, 292: 500-507. doi:10.1016/j.jad.2021.05.107
[18] Liang JJ, Zhao YM, Xi Y, et al. Association between depression, anxiety symptoms and gut microbiota in Chinese elderly with functional constipation[J]. Nutrients, 2022, 14(23): 5013. doi:10.3390/nu14235013
[19] Zhang L, Zhang SW, Jiang MZ, et al. Limosilactobacillus reuteri alleviates anxiety-like behavior and intestinal symptoms in two stressed mouse models[J]. Nutrients, 2024, 16(18): 3209. doi:10.3390/nu16183209
[20] Vicentini FA, Szamosi JC, Rossi L, et al. Colitis-associated microbiota drives changes in behaviour in male mice in the absence of inflammation[J]. Brain Behav Immun, 2022, 102: 266-278. doi:10.1016/j.bbi.2022.03.001
[21] Zheng SJ, Zhu YB, Wu WD, et al. A correlation study of intestinal microflora and first-episode depression in Chinese patients and healthy volunteers[J]. Brain Behav, 2021, 11(8): e02036. doi:10.1002/brb3.2036
[22] Teichman EM, ORiordan KJ, Gahan CGM, et al. When rhythms meet the blues: circadian interactions with the microbiota-gut-brain axis[J]. Cell Metab, 2020, 31(3): 448-471.
[23] Ahmed H, Leyrolle Q, Koistinen V, et al. Microbiota-derived metabolites as drivers of gut-brain communication[J]. Gut Microbes, 2022, 14(1): 2102878. doi:10.1080/19490976.2022.2102878
[24] Mellon SH, Bersani FS, Lindqvist D, et al. Metabolomic analysis of male combat veterans with post traumatic stress disorder[J]. PLoS One, 2019, 14(3): e0213839. doi:10.1371/journal.pone.0213839
[25] Wang J, Fan L, Teng T, et al. Adolescent male rats show altered gut microbiota composition associated with depressive-like behavior after chronic unpredictable mild stress: Differences from adult rats[J]. J Psychiatr Res, 2024, 173: 183-191. doi:10.1016/j.jpsychires.2024.03.026
[26] Jiang ZF, Wu W, Hu HB, et al. P2X7 receptor as the regulator of T-cell function in intestinal barrier disruption[J]. World J Gastroenterol, 2022, 28(36): 5265-5279.
[27] Liu J, Wang HW, Lin L, et al. Intestinal barrier damage involved in intestinal microflora changes in fluoride-induced mice[J]. Chemosphere, 2019, 234: 409-418. doi:10.1016/j.chemosphere.2019.06.080

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