环境浓度抗生素引起斑马鱼焦虑_抑郁样行为与“肠-脑”途径关联的研究进展.pdf

生态毒理学报Asian Journal of Ecotoxicology第 18 卷 第 5 期 2023 年 10 月Vol.18,No.5 Oct.2023 基金项目:学科交叉创新团队建设项目(董武2023 年度);科研创新平台能力建设支持计划(薛江东2023 年度);内蒙古自治区直属高校基本科研业务费项目(GXKY22093,GXKY22001);内蒙古民族大学博士科研启动基金(BS562);内蒙古民族大学创新创业项目(202208035)第一作者:马阳光(1999),男,硕士研究生,研究方向为基础兽医学,E-mail: *通信作者(Corresponding author),E-mail:DOI:10.7524/AJE.1673-5897.20221219002马阳光,康威,赵可欣,等.环境浓度抗生素引起斑马鱼焦虑/抑郁样行为与“肠-脑”途径关联的研究进展J.生态毒理学报,2023,18(5):36-55Ma Y G,Kang W,Zhao K X,et al.Research progress on association between anxiety/depression-like behavior and“gut-brain”axis in zebrafish inducedby environmental concentrations of antibiotics J.Asian Journal of Ecotoxicology,2023,18(5):36-55(in Chinese)环境浓度抗生素引起斑马鱼焦虑/抑郁样行为与“肠-脑”途径关联的研究进展马阳光1,2,康威1,2,赵可欣1,2,马璐瑶1,2,董武1,2,于建华1,2,*1.内蒙古民族大学动物科技学院,通辽 0280002.内蒙古自治区毒物监控及毒理学重点实验室,通辽 028000收稿日期:2022-12-19 录用日期:2023-01-29摘要:抗生素在环境中广泛被检出,对动物和人类造成潜在不良影响。抗生素能够改变斑马鱼肠道菌群组成和丰度,进而引起斑马鱼焦虑/抑郁样行为。本文对有关抗生素残留的报道进行了总结,概括分析了抗生素对斑马鱼焦虑/抑郁样行为与斑马鱼肠道菌群的关联。主要从高级神经系统途径、神经内分泌途径、免疫途径、肠道菌群代谢途径和氧化应激途径探讨了抗生素引起斑马鱼焦虑/抑郁样行为变化与“肠-脑”途径作用的关联机制。本文为抗生素和斑马鱼神经行为变化机制研究提供一定的参考。关键词:抗生素;斑马鱼;焦虑/抑郁样行为;“肠-脑”途径文章编号:1673-5897(2023)5-036-20 中图分类号:X171.5 文献标识码:AResearch Progress on Association between Anxiety/Depression-like Behav-ior and“Gut-Brain”Axis in Zebrafish Induced by Environmental Con-centrations of AntibioticsMa Yangguang1,2,Kang Wei1,2,Zhao Kexin1,2,Ma Luyao1,2,Dong Wu1,2,Yu Jianhua1,2,*1.School of Animal Science and Technology,Inner Mongolia MinZu University,Tongliao 028000,China2.Key Laboratory of Toxics Monitoring and Toxicology of Inner Mongolia Autonomous Region,Tongliao 028000,ChinaReceived 19 December 2022 accepted 29 January 2023Abstract:Antibiotics are widely detected in the environment,causing potential adverse effects on animals and hu-mans.Antibiotics can change the composition and abundance of intestinal microflora in zebrafish,thereby causinganxiety/depression-like behavior.In this paper,reports on antibiotic residues were summarized,and the associationbetween antibiotics on anxiety/depression-like behavior and intestinal microflora in zebrafish was summarized andanalyzed.This paper mainly discusses the correlation mechanism between anxiety/depression-like behavior changesand the“gut-brain”axis of zebrafish induced by antibiotics from the aspects of higher nervous system pathway,第 5 期马阳光等:环境浓度抗生素引起斑马鱼焦虑/抑郁样行为与“肠-脑”途径关联的研究进展37 neuroendocrine pathway,immune pathway,intestinal flora metabolic pathway and oxidative stress pathway.This re-view provides some references for the study of antibiotics and the mechanism of neurobehavioral changes in ze-brafish.Keywords:antibiotics;zebrafish;anxiety/depression-like behavior;“gut-brain”axis 抗生素的发现给医疗带来划时代的飞跃,在临床上被广泛使用。世界上,每年抗生素的使用量已经超过了 10 万 t1。然而抗生素的大量生产及滥用,导致地表水和土壤抗生素的大量残留(表 1)。在韩国仁川农田土壤表层检测到四环素高达17.74 mg kg-1 2,我国珠江三角洲和珠江口流域的 8 个监测点均检测到大环内酯类、氟喹诺酮类和磺酰胺类抗生素,残留浓度为 0.7 127 ngL-1 3。在我国江苏某畜禽养殖场周围地表水中共检测出了 9 种抗生素,其中最多的是磺胺二甲嘧啶,检测的最大浓度为211 g L-1 4。另外,Sim 等5在牲畜废水处理厂进水口则检测到了浓度高达 3 005 gL-1的林可霉素,在制药污水处理厂的出水口残留的林可霉素浓度甚至达到了 43 909 g L-1。正常情况下,废水处理厂的能力有限,大多数具有一定浓度的抗生素被持续和大量的输入水体中,并且有些抗生素的半衰期较长,水体的流动性较差,导致抗生素残留浓度极高。同时也导致了环境中残留的抗生素浓度跨度极大5-6。环境中残留的抗生素可通过食物链进入人体,造成潜在的危害,尤其是对孕妇和婴幼儿造成不利影响。斑马鱼(Danio rerio)的行为变化与环境联系密?切,环境抗生素可引起斑马鱼的焦虑/抑郁样行为。斑马鱼产生焦虑/抑郁样行为时,其行为表现与啮齿类动物相似,如斑马鱼对刺激较为敏感,在水中会更趋向于水底和黑暗环境、游泳速度不稳定,有突然转弯或者静止不动的行为7-10。由于斑马鱼具有产卵数量多、孵化快、价格低廉、对药物和污染物敏感等诸多的优点11。并且斑马鱼的基因和人类具有87%的同源性,所以实验结果对人类疾病研究有一定的参考意义12-14。此外,斑马鱼神经系统具有神经递质,例如多巴胺、五羟色胺、乙酰胆碱等,是进行神经系统研究的良好模型15。斑马鱼肠道结构也与人类较为相似,分为上皮层、黏膜层、肌肉层和浆膜层,具有生物屏障、黏液屏障和上皮屏障。研究表明,斑 马 鱼 焦 虑/抑 郁 行 为 与 肠-脑 途 径 密 切 相关16-17。抗生素可通过影响斑马鱼肠道微生物及其代谢产物组成,后经由多种途径联系大脑,传递信息,最终诱发焦虑/抑郁,引起斑马鱼行为的改变。本文对抗生素引起不同年龄阶段斑马鱼焦虑/抑郁样行为进行了总结,并从”肠-脑”途径机制方面进行分析。以期为抗生素和斑马鱼神经行为机制方面研究提供一定的参考。1抗生素对斑马鱼焦虑/抑郁样行为的影 响(Effect of antibiotics on anxiety/depression behav-ior of zebrafish)1.1 抗生素对幼鱼/青年斑马鱼(0 5 月龄)焦虑/抑郁样行为影响(Effects of antibiotics on anxiety/de-pression-like behavior in juvenile/young zebrafish(0 5 months of age)高浓度抗生素可造成斑马鱼焦虑/抑郁样行为(表 2)。研究表明,抗生素单一和联合暴露均会降低幼龄斑马鱼的平均游泳速度,增加移动距离。Gonalves 等18将斑马鱼暴露于浓度为 100 mgL-1的阿莫西林溶液中 7 d 后,通过分析新型水槽试验结果发现阿莫西林暴露显著抑制斑马鱼平均游泳速度,延长其静止不动的时间。Cheng 等19将 6 hpf(hour post fertilization,hpf)的斑马鱼卵暴露在不同浓度林可霉素溶液(15、30、60 gmL-1)中,暴露至 6dpf(day post fertilization,dpf),发现随着林可霉素浓度的增加,斑马鱼的移动距离和平均速度减小。Han 等20将 5 dpf 的斑马鱼暴露于新霉素 125 mol L-11 h 后,新霉素组在黑暗中游泳的总距离显著下降,平均速度降低。Zhang 等21将氟喹诺酮类和四环素类抗生素联合暴露于新生斑马鱼胚胎至 96hpf 后,最终 18.75 mg L-1联合暴露组平均速度显著低于对照组,而 4.69 mgL-1和 9.38 mgL-1处理组平均速度高于对照组。在低浓度的红霉素(1 gL-1和 10 g L-1)染毒中也发现斑马鱼幼鱼的移动距离较多的现象22。低浓度抗生素造成斑马鱼(3 5 月龄)焦虑样行为(表 2)。在 3 个月的持续暴露实验中,Wang 等23将 6 hpf 的斑马鱼卵暴露在-二酮抗生素(氧氟沙星、环丙沙星、恩诺沙星、强力霉素、金霉素和土霉素等浓度等体积和等质量混合物)中,发现低浓度的-二酮抗生素(6.25 mg L-1)会导致斑马鱼在上部停留38 生态毒理学报第 18 卷表 1 抗生素在环境中残留的浓度同斑马鱼实验浓度联系Table 1 The concentration of antibiotic residues in the environment is related to the experimental concentration of zebrafish抗生素种类Types ofantibiotics残留最大浓度Maximum residualconcentration残留载体Residual carrier地点Place参考文献References斑马鱼实验所暴露的浓度范围The concentration range exposedin the zebrafish experiment斑马鱼的症状The symptomsof zebrafish斑马鱼参考文献Zebrafishreferences恩诺沙星Enrofloxacin678.4 ng L-1桂林水产养殖区地表水Surface water in Guilinaquiculture area中国China1300.10 0.40 mg L-1恩诺沙星拮抗多菌灵诱发的 48 hpf孵化率的降低和 96 hpf 畸形和致死率的增加Enrofloxacin antagonizes carbendazim inducedreduction of 48hpf hatchability and increase of 96 hpfmalformation and mortality131磺胺甲恶唑Sulfamethoxazole308.98 ng L-1桂林水产养殖区地表水Surface water in Guilinaquiculture area中国China1300.1 100?g L-1磺胺甲恶唑延缓了胚胎的孵化,缩短了体长,上调了几种关键促炎细胞因子及其相应蛋白的基因表达Sulfamethoxazole delayed embryo incubation,shortened body length,and upregulated geneexpression of several key pro-inflammatorycytokines and their corresponding proteins132磺胺甲恶唑Sulfamethoxazole56 ng L-1天津水产养殖池水Tianjin aquaculture pool water中国China133磺胺甲恶唑Sulfamethoxazole0.94?g L-1白洋淀地表水Surface water of Baiyangdian Lake中国China134头孢拉定Cefradine1 328 mg L-1大型制药厂生产废水Large pharmaceutical factoriesproduce waste water中国China135磺胺嘧啶Sulfadiazine18?g kg-1大棚土壤植物Greenhouse soil plants中国China136土霉素Oxytetracycline1 692.50 g L-1天津市静海区海河流域下游养猪场污水Sewage from pig farms in thelower reaches of Haihe RiverBasin,Jinghai District,Tianjin中国China13710 100 mg L-1斑马鱼行为改变,产生类似焦虑样的行为Zebrafish behavior changes,producing anxiety-like behaviors25金霉素Chlortetracycline222 g kg-1河北施用动物粪便菜场的土壤Soil from vegetable farms usinganimal manure in Hebei Province中国China138第 5 期马阳光等:环境浓度抗生素引起斑马鱼焦虑/抑郁样行为与“肠-脑”途径关联的研究进展39 续表1抗生素种类Types ofantibiotics残留最大浓度Maximum residualconcentration残留载体Residual carrier地点Place参考文献References斑马鱼实验所暴露的浓度范围The concentration range exposedin the zebrafish experiment斑马鱼的症状The symptomsof zebrafish斑马鱼参考文献Zebrafishreferences金霉素Chlortetracycline27 718.06 ng g-1宁波市张溪流域猪粪Pig manure in ZhangxiValley of Ningbo City中国China139金霉素Chlortetracycline57.95 mg kg-1浙江省饲养场猪粪Pig manure from a farm inZhejiang Province中国China140阿奇霉素Azithromycin984 ng L-1广州秋季污水处理厂Guangzhou Autumn SewageTreatment Plant中国China141甲氧苄胺嘧啶Trimethoprim12 440 ng L-1莱州湾小清河Laizhou Bay Xiaoqing River中国China142环丙沙星Ciprofloxacin25.68 g kg-1北部湾沉积物Beibu Gulf sediment中国China1430.7 100 g kg-11 100 3 000 g kg-1谷胱甘肽 S-转移酶活性增加Glutathione S-transferase activity increased鱼的谷胱甘肽还原酶活性显著降低;谷胱甘肽过氧化物酶活性也显著降低The glutathione reductase activity of fish wassignificantly decreased;glutathione peroxidaseactivity was also significantly decreased144环丙沙星Ciprofloxacin104.4?g kg-1山东省蔬菜种植区土壤Soil of vegetable growingarea in Shandong Province中国China145环丙沙星Ciprofloxacin6 310?g kg-1白洋淀植物Plants of Baiyangdian Lake中国China134环丙沙星Ciprofloxacin195.11 ng L-1华东地区饮用水水源地East China drinking water source中国China146差向四环素Epi-tetracycline9.615?g kg-1北京郊区养猪场废水Wastewater from pig farms onthe outskirts of Beijing中国China14720 g L-1斑马鱼幼鱼在 96 hpf 时观察到卵黄囊吸收延迟和鱼鳔缺乏Delayed yolk sac absorption and swimbladder deficiency were observedin juvenile zebrafish at 96 hpf14840 生态毒理学报第 18 卷续表1抗生素种类Types ofantibiotics残留最大浓度Maximum residualconcentration残留载体Residual carrier地点Place参考文献References斑马鱼实验所暴露的浓度范围The concentration range exposedin the zebrafish experiment斑马鱼的症状The symptomsof zebrafish斑马鱼参考文献Zebrafishreferences头孢唑林Cefazolin50 ng L-1松花江流域哈尔滨段Songhua River basin,Harbin section中国China149多西环素Doxycycline695.2 ng g-1城市集水区Urban catchment area中国宁波市Ningbo,China1500 100 g L-1导致斑马鱼肠道菌群多样性降低The results showed that the intestinal floradiversity of zebrafish decreased37多西环素Doxycycline112.41 g L-1天津市某农场废水Waste water from afarm in Tianjin中国China151多西环素Doxycycline70.8 ng g-1江汉平原养殖区Jianghan Plain breeding area中国China152克拉霉素Clarithromycin6 524 ng L-1某县污水处理厂A county sewage treatment plant中国China153罗红霉素Roxithromycin1 076?g kg-1白洋淀动物Baiyangdian animals中国China134诺氟沙星Norfloxacin658.3?g kg-1山东省蔬菜种植区蔬菜Vegetables in vegetable growingareas of Shandong Province中国China145600 1 200 mg L-1诺氟沙星诱导斑马鱼胚胎大脑出现明显的细胞凋亡Norfloxacin induced apoptosisof zebrafish embryo brain154诺氟沙星Norfloxacin1 140?g kg-1白洋淀沉淀物Baiyangdian sediment中国China134氧氟沙星Ofloxacin51.6 ng L-1杭州钱塘江地表水Qiantang River surfacewater in Hangzhou中国China155氧氟沙星Ofloxacin1 405 ng L-1杭州污水处理厂流入段Hangzhou sewage treatmentplant inflow section中国China155第 5 期马阳光等:环境浓度抗生素引起斑马鱼焦虑/抑郁样行为与“肠-脑”途径关联的研究进展41 表 2 抗生素对斑马鱼行为的影响Table 2 Summary of the effects of antibiotics on zebrafish behavior抗生素Antibiotics鱼龄Age of fish暴露时间Exposure duration浓度Concentration行为的变化Change in behavior参考文献References20 余种抗生素More than 20 kindsof antibiotics4 6 mth10 d100 g L-1运用 3D 运动测试的方法,发现红霉素、庆大霉素、磺胺嘧啶、四环素同对照组相比,能够显著增加斑马鱼在顶部的时间,氧氟沙星、磺胺甲恶唑和磺胺吡啶则会缩短其在顶部的时间,显著增加在底部区域的时间Using the 3D exercise test method,it was found that erythromycin,gentamicin,sulfadiazine and tetracycline could significantly increase the time at the top ofzebrafish compared with the control group,while ofloxacin,sulfamethoxazoleand sulfapyridine could shorten the time at the top and significantly increase thetime at the bottom30多拉菌素、伊维菌素Doramectin,ivermectin新产出的斑马鱼卵Newly producedzebrafish eggs24 h0.1 1 mg L-1随着浓度的升高,运动频率下降As the concentration increases,the frequency of motion decreases156土霉素Oxytetracycline120 dpf1 mth5 000 ng L-1在震动反应实验和光暗刺激实验中,斑马鱼的总游泳距离是增加的The total swimming distance of zebrafish increased in the shock response experi-ment and the light and dark stimulation experiment24土霉素Oxytetracycline7 8 mth96 h10、20、100 mg L-1新缸实验中在顶部停留的时间均少于对照组The time of staying at the top of the new cylinder experiment was less than thatof the control group25土霉素Oxytetracycline4 mth2 mth0、0.1、10、10 000 mg L-1斑马鱼在底部的时间随浓度升高同对照组相比有略微上升的趋势,在浓度为0.1 mg L-1和10 000 mg L-1时,斑马鱼游动的距离同对照组相比增加了35.1%和 30.4%;光暗移动实验中,无论光或暗,暴露于土霉素的组别移动距离同对照组相比均有提升The time of zebrafish at the bottom showed a slightly upward trend with the in-crease of concentration compared with the pair group;when the concentrationwas 0.1 mg L-1and 10 000 mgL-1,the swimming distance of zebrafish in-creased by 35.1%and 30.4%compared with the control group;in the light-darkmobility experiment,the oxytetracycline exposure group moved significantlymore than the control group in both light and dark28新霉素Neomycin5 hpf1 h125 mol L-1同对照组相比新霉素组在黑暗中游动的总距离显著下降,平均速度降低Compared with the control group,the total swimming distance and averagespeed of neomycin group in the dark were significantly decreased2042 生态毒理学报第 18 卷续表2抗生素Antibiotics鱼龄Age of fish暴露时间Exposure duration浓度Concentration行为的变化Change in behavior参考文献References红霉素Erythrocin2 96 hpf24 h0.001、0.01、0.1、1、10 g L-11 g L-1和 10 g L-1红霉素中幼鱼同对照组相比,移动距离更多Juveniles in 1 g L-1and 10 g L-1erythromycin moved more than those inthe control group22金霉素、环丙沙星和头孢他啶Aureomycin,ciprofloxacinand ceftazidime6 9 mth96 h6.25、12.5、25 mg L-125 mg L-1环丙沙星、12.5 mg L-1和 25 mg L-1头孢他啶,12.5 mg L-1金霉素组同对照组相比显著增加游动距离The 25 mg L-1ciprofloxacin,12.5 mgL-1and 25 mgL-1ceftazidime,12.5mg L-1aureomycin groups significantly increased the swimming distance com-pared with the control group18氟喹诺酮Fluoroquinolone6 hpf114 h50 mg L-1平均速度同对照组相比差异显著The mean speed was significantly different from that of the control group21氟喹诺酮类+四环素类Fluoroquinolones+Tetracyclines6 hpf114 h18.75、9.38、4.69 mg L-118.75 mg L-1时,平均速度显著低于对照组;4.69 mg L-1和 9.38 mg L-1处理时平均速度高于对照组At 18.75 mgL-1,the average speed was significantly lower than that of thecontrol group;the average speed of 4.69 mgL-1and 9.38 mgL-1treatmentswas higher than that of the control group21-二酮抗生素-diketone antibiotic6 hpf3 mth6.25、25 mg L-1低浓度的-二酮抗生素(氧氟沙星、环丙沙星、恩诺沙星、强力霉素、金霉素和土霉素等浓度等体积和等质量混合物)(6.25 mg L-1)会导致运动距离同对照组相比增加 15%,新缸实验中在上部所花费的时间高于对照组 40%,高浓度(25 mg L-1)会导致斑马鱼在上部所花费的时间低于对照组 29%Low concentrations of-dione antibiotics(a mixture of ofloxacin,ciprofloxacin,enrofloxacin,doxycycline,chlortetracycline and oxytetracycline with concentra-tions of equal volume and equal mass)(6.25 mgL-1)resulted in a 15%in-crease in the distance traveled compared to the control group and a 40%in-crease in the time spent on the upper part of the new tank compared to the con-trol group;high concentrations(25 mg L-1)caused zebrafish to spend 29%lesstime on the upper part than the control group23第 5 期马阳光等:环境浓度抗生素引起斑马鱼焦虑/抑郁样行为与“肠-脑”途径关联的研究进展43 的时间高于对照组 40%,运动距离也增加 15%(新型水槽试验),而高浓度的-二酮抗生素(25 mg L-1)会导致斑马鱼在上部停留的时间同对照组相比减少29%,产生焦虑样行为。此外,Qiu 等24将 120 dpf斑马鱼暴露于环境浓度(5 gL-1)土霉素(oxytetra-cycline,OTC)中 1 个月后,在黑白箱测试实验中发现斑马鱼的总游泳距离增加。1.2 抗生素对成年斑马鱼(5 月龄以上)焦虑/抑郁样行为影响(Effects of antibiotics on anxiety/depres-sion related behaviors of adult zebrafish(5 months andolder)抗生素可引起斑马鱼(5 月龄以上)产生焦虑样相关行为(表 2)。土霉素会引起成年斑马鱼的焦虑样行为,暴露于在 OTC 浓度为10、20 和100 mg L-1时,新型水槽试验中斑马鱼在顶部停留的时间均少于对照组,说明斑马鱼有焦虑倾向25-26。与此相似,氧氟沙星、磺胺甲恶唑(sulfamethoxazole,SMX)会缩短其在顶部停留的时间,显著增加在底部区域的时间27。Almeida 等28将斑马鱼成鱼暴露于0、0.1、10、10 000 mg L-1的 OTC 中2 个月后,在新型水槽试验中发现暴露于 OTC 组别的斑马鱼在底部的停留时间随 OTC 浓度升高有上升的趋势,而 0.1 mg L-1和10 000 mg L-1的 OTC 还增加了斑马鱼游动的距离(增加了 35.1%和 30.4%)。Petersen 等29发现 25 mg L-1环丙沙星、12.5 mgL-1和 25 mgL-1头孢他啶和 12.5 mgL-1金霉素组暴露也增加了成年斑马鱼的游泳距离(暴露 96 h)。Suryanto 等30将成年斑马鱼分别暴露在100 g L-1的20 种抗生素溶液中,通过 3D 运动测试的方法,发现红霉素、庆大霉素、磺胺嘧啶、四环素显著增加斑马鱼在水缸顶部的时间,并表现出抗焦虑行为。2 抗生素通过肠-脑有关途径影响斑马鱼的焦虑/抑郁样行为(Antibiotics affect anxiety/depression-like behavior in zebrafish through gut-brain path-ways)抗生素引起斑马鱼肠道菌群的失衡,肠道菌群的变化通过肠-脑有关途径引发斑马鱼的焦虑/抑郁样行为。2.1 抗生素能够引起斑马鱼肠道菌群及其代谢物质组成和水平的改变(Antibiotics can cause changesin the intestinal flora of zebrafish)研究表明,环境浓度抗生素导致斑马鱼的肠道菌群失调(表 3)。肠道菌群在调节肠上皮细胞分化、增殖、代谢功能和免疫反应、血管生成和宿主生长方面起到重要的作用31-32。此外,肠道菌群可以合成并释放-氨基丁酸、组胺、胆碱和乙酰胆碱等多种神经递质和神经肽,同时分泌细菌素和支链氨基酸或短链脂肪酸等物质,介导生理效应33-35。当肠道菌群紊乱时,通过肠-脑有关途径引起机体行为改变。抗生素能引起肠道菌群物种多样性的降低和改变菌体代谢物的水平和种类36。Qian 等37将 6 月龄斑马鱼暴露在多西环素(doxycycline,DOX)、OTC和氟苯尼考(florfenicol,FF)(浓度为 0、10、30、100 g L-1)中 21 d,研究表明,同对照组相比,抗生素暴露组肠道菌群的数量和-多样性指数均有所下降。在门水平上,100 gL-1FF 组和 OTC 组中变形杆菌(Proteus)和拟杆菌(Bacteroidaceae)的相对丰度显?著增加,其他的类群显著减少。抗生素暴露组的梭杆菌门(Fusobacteria)的相对丰度均低于对照组。Zhou 等38将体质量为 0.1 g 的斑马鱼分别暴露在260 ng L-1SMX 和420 ng L-1OTC 中6 周,结果表明,同对照组相比,抗生素暴露组的 Ace 和 Chao1指数显著降低,菌群丰富度降低。此外,较低的环境抗生素浓度也会改变斑马鱼的肠道菌群组成,Kaya-ni 等39用 1 000 ng L-1和 5 000 ngL-1来代表环境中残留的 SMZ 和 OTC 的抗生素浓度,将2 hpf 的鱼卵暴露至 120 dpf,其中,抗生素暴露组中斑马鱼肠道黄杆菌(Flavobacterium)高度富集,影响了肠道内?黄杆菌的水平。2.2 肠道菌群的改变引起斑马鱼焦虑/抑郁样行为可能作用机制(Mechanisms for changes in intestinalflora that cause anxiety/depression-like behavior in ze-brafish)抗生素通过肠道菌群改变引起斑马鱼的焦虑/抑郁样行为(机制见图 1)。文献表明抗生素所引起肠道菌群的改变可能通过 5 种途径影响大脑,第 1种是神经系统途径40。第 2 种是神经内分泌系统途径。第 3 种是免疫系统途径。第 4 种为肠道菌群的代谢途径。第 5 种是氧化应激途径。2.2.1 神经系统途径肠道菌群调控肠神经系统和中枢神经系统41,还可通过迷走神经联系大脑传递信息16。抗生素能改变肠道菌群组成和丰度,对中枢神经系统和肠神经系统产生影响42。研究表明,肠道微生物群与焦虑/抑郁关系密切43。因此,