CN117771278A - Prevotella copri在制备治疗老年衰弱综合征的药物中的用途 - Google Patents
Prevotella copri在制备治疗老年衰弱综合征的药物中的用途 Download PDFInfo
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Abstract
本发明涉及Prevotella copri在制备治疗老年衰弱综合征的药物中的用途，属于药物领域。本发明Prevotella copri用于治疗老年衰弱综合征，药效明确，Prevotella copri属于益生菌，临床使用安全，弥补了老年衰弱综合征肠道菌群治疗的空缺，实用性高，适用范围广。
Description
技术领域
本发明涉及Prevotella copri在制备治疗老年衰弱综合征的药物中的用途，属于药物领域。
背景技术
衰弱（Frailty）是一种常见的老年综合征，是指老年人生理储备下降导致机体易损性增加、抗应激能力减退的非特异性状态。衰弱老人经历外界较小刺激即可导致一系列临床负性事件的发生。衰弱目前应用较广泛的诊断标准为Fried等提出的，包括肌力下降、能量耗竭、步速缓慢、活动耐力下降及无目的性的体重下降，满足三条或以上则为衰弱。衰弱患病率随增龄而增加，女性高于男性，医疗机构高于社区。美国的研究显示社区老年人群中，65岁以上衰弱发生率为7%-12%，80岁以上的高龄老人可达三分之一。衰弱导致老人发生失能、功能下降，导致住院率和死亡率的增加，大大增加了老人对长期照护的需求和医疗费用。目前研究发现遗传因素、增龄、经济条件差、受教育程度低、不良的生活方式、老年综合征（跌倒、肌少症、营养不良）、未婚和独居等都是衰弱的危险因素【Woo J, Chan R, LeungJ, et al. Relative contributions of geographic, socioeconomic, and lifestylefactors to quality of life, frailty, and mortality in elderly [J]. PLoS One,2010, 5(1): e8775.】。
衰弱的发病机制目前并不十分明确，其中基因多态性可能影响衰弱的临床表型，研究发现非裔美国人衰弱比例是其他美国人的4倍，墨西哥裔美国人衰弱患病率比欧裔美国人高4.3%。其中载脂蛋白E（APOE）基因、胰岛素受体样基因-2（DAF-2）、C反应蛋白编码区（CRP1846G＞A）、肌肉细胞线粒体DNA（mt204C）、白细胞介素（IL-6）等均可能与衰弱有关【Vina J, Tarazona-Santabalbina FJ, Perez-Ros P, et al. Biology of frailty:Modulation of ageing genes and its importance to prevent age-associated lossof function [J]. Mol Aspects Med, 2016, 50(4): 88-108.】。慢性炎症引起的炎性衰老在衰弱中发挥重要作用【Chen X, Mao G, Leng SX. Frailty syndrome: an overview[J]. Clin Interv Aging, 2014, 9:433-441.】，大量研究表明老年衰弱人群会显示慢性炎症状态，表现为炎症分子如白细胞介素（IL-6）、C反应蛋白（CRP）和肿瘤坏死因子-alpha（TNF-α）的升高以及白细胞数目的增加【Leng S, Chaves P, Koening K, et al. Seruminterleukin-6 and hemoglobin as physiological correlates in the geriatricsyndrome of frailty: a pilot study [J]. J Am Geriatr Soc, 2002, 50: 1268-1271.】。而生长激素（GH）-IGF-1促生长轴异常、下丘脑-垂体-肾上腺轴和其他激素也可能参与了衰弱的病理过程【Maggio M, Cappola AR, Ceda GP, et al. The hormonalpathway to frailty in older men [J]. J Endocrinol Invest, 2005, 28:15-19.】。近期研究发现衰老过程与肠道菌群密切相关，老年人的菌群稳定性下降【Biagi E, CandelaM, Fairweather-Tai S, et al. Ageing of the human metaorganism: the microbialcounterpart [J]. Age, 2012; 34(1): 247-67.】，老年衰弱症患者的核心肠道菌落如普氏菌、拟杆菌属多样性减少【O’Toole PW, Jeffery IB. Gut microbiota and aging [J].Science, 2015; 350(6265): 1214-5.、Jackson MA, Jeffery IB, Beaumont M, et al.Signatures of early frailty in the gut microbiota [J]. Genome Med, 2016; 8(1): 81-91.】。研究发现衰老会增强肠道菌群分解代谢蛋白质、脂肪的能力，拟杆菌和梭菌将蛋白质腐败分解成有害的氨、胺类、酚类、吲哚类，对脂肪的分解则产生内毒素、低度炎症【Lynch DB, Jeffery IB, O’Toole PW, et al. Diet-microbiota-health interactionsin older subjects: implications for healthy aging [J]. Interdiscipl TopGerontol, 2015; 40(44): 141-54.】，而对碳水化合物的消化分解能力降低，多糖类可通过肠道菌群如柔嫩梭菌群发酵产生短链脂肪酸如丁酸这一能够作为肠上皮细胞能量来源并具有抗炎活性的物质，碳水化合物能够提高肠道菌群的多态性【Wu GD, Chen J,Hoffmann C, et al. Linking long-term dietary patterns with gut microbialenterotypes [J]. Science, 2011; 334(6052): 105-8.】。
Prevotella copri（普氏菌）是普氏菌属的一类菌株。由于普氏菌的培养困难性和非致病性，目前对该菌的认识还不够充分。普氏菌属是人肠道微生物三大肠型代表菌之一,同时也是人肠道微生物的核心菌属之一。多项研究表明Prevotella属或P.copri与胰岛素抵抗、类风湿关节炎和高血压等疾病呈正相关,而与运动障碍症帕金森病和孤独症等呈负相关【Ley Ruth E,Gut microbiota in 2015: Prevotella in the gut: choosecarefully.[J] .Nat Rev Gastroenterol Hepatol, 2016, 13: 69-70.】。然而对于如此重要的肠道微生物,其基础生物学研究存在许多不足乃至空白。近来有研究发现，炎症性肠病患者的肠道菌群水平与对照组相比，普氏菌(P.copri)显著减少、普氏粪杆菌(F.prausnitzii)显著富集。多项研究表明，普氏菌属起着有益的作用【Iljazovic A, RoyU, Gálvez EJC, Lesker TR, Zhao B, Gronow A, Amend L, Will SE, Hofmann JD,Pils MC, Schmidt-Hohagen K, Neumann-Schaal M, Strowig T. Perturbation of thegut microbiome by Prevotella spp. enhances host susceptibility to mucosalinflammation. Mucosal Immunol. 2021 Jan;14(1):113-124.】。研究表明，从人类肠道中的共生细菌中分离出的普氏菌可降低HLA-DQ8小鼠中胶原诱导的关节炎的严重程度【Randis TM, Ratner AJ. Gardnerella and Prevotella: Co-conspirators in thePathogenesis of Bacterial Vaginosis. J Infect Dis. 2019;220(7):1085-1088.doi:10.1093/infdis/jiy705】。普氏菌可抑制几种促炎性细胞因子（例如IL-2，IL-17和TNF-α）的血清水平。移植普氏菌的小鼠显示出肠道中调节性T细胞增加，抗原特异性Th17反应降低。而普氏菌分泌的酶可促进食物发酵产生短链脂肪酸，主要包括丁酸和丙酸，其中普氏栖粪杆菌是丁酸盐生产者，以其抗炎特性而闻名【Arweiler NB, Netuschil L. TheOral Microbiota. Adv Exp Med Biol. 2016;902:45-60. doi: 10.1007/978-3-319-31248-4_4. PMID: 27161350.】。短链脂肪酸不仅是肠道上皮细胞的主要营养物质，还可通过激活G蛋白偶联受体和抑制组蛋白去乙酰化酶调节免疫应答，并且可抑制部分炎症因子的表达，与炎性疾病的防治有关。还可与骨骼肌肉细胞的脂肪酸受体2和3结合，靶向肌肉线粒体，促进线粒体生物合成【Si J, You HJ, Yu J, Sung J, Ko G. Prevotella as a Hubfor Vaginal Microbiota under the Influence of Host Genetics and TheirAssociation with Obesity. Cell Host Microbe. 2017 Jan 11;21(1):97-105.】。此外，Fielding等人在间隔一个月的时间内对不同躯体功能的老年人进行了两次肠道菌群检测，发现在SPPB判定为高躯体功能的老人肠道菌群中，普氏菌科和普氏菌属存在稳定的升高【Fielding R A, Reeves A R, Jasuja R, et al. Muscle strength is increased inmice that are colonized with microbiota from high-functioning older adults[J]. Exp Gerontol, 2019, 127: 110722.】。将两组老人的肠道菌群移植给小鼠后，移植高躯体功能组粪便的小鼠肠道中普氏菌科和普氏菌属的丰度都增高，且握力显著增加6.4%【Van Tongeren S P, Slaets J P, Harmsen H J, et al. Fecal microbiotacomposition and frailty [J]. Applied and environmental microbiology, 2005, 71(10): 6438-6442.】。在衰弱老年人的粪便中也发现了普氏菌属的显著减少【Xu Y, WangY, Li H, et al. Altered Fecal Microbiota Composition in Older Adults WithFrailty [J]. Front Cell Infect Microbiol, 2021, 11: 696186.，Everard A,Lazarevic V, Derrien M, et al. Responses of gut microbiota and glucose andlipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice [J]. Diabetes, 2011, 60(11): 2775-2786.】。动物研究发现，喂食益生元可以使肥胖小鼠肠道中普氏菌科和普氏菌属丰度增加，同时肌肉质量增加或脂肪质量减少【Pisanu S, Palmas V, Madau V, et al. Impact of a Moderately HypocaloricMediterranean Diet on the Gut Microbiota Composition of Italian ObesePatients [J]. Nutrients, 2020, 12(9).】。在Pisanu等人的研究中，对肥胖和超重者进行适度的低热量地中海饮食干预，使得肠道中普氏菌的丰度增加，体脂量减少，但对肌肉质量无明显影响【Chen C, Fang S, Wei H, et al. Prevotella copri increases fataccumulation in pigs fed with formula diets. Microbiome. Aug 21 2021;9(1):175.】。此外chen等人发现肠道菌群中普氏菌的丰度与饲喂配方饲料的猪的脂肪积累以及血清中与肥胖相关的代谢物如脂多糖、支链氨基酸、芳香族氨基酸和代谢物的浓度呈正相关。他们进一步使用无菌小鼠模型发现，普氏菌定植通过 TLR4 和 mTOR 信号通路激活宿主慢性炎症反应，表明普氏菌显著上调了与脂肪生成和脂肪积累相关的基因的表达。CN201810669508.9，发明名称：阿克曼粘细菌或普氏菌在制备用于增强抗肿瘤免疫功能的药物中的应用，提供了阿克曼粘细菌或普氏菌在制备用于增强CD4+T细胞和/或CD8+T细胞抗肿瘤免疫功能和/或增强肿瘤微环境中CD8+T细胞的抗肿瘤免疫功能的药物中的应用。阿克曼粘细菌或普氏菌可以显著抑制***性CD4+T细胞和/或CD8+T细胞表达PD-1，也可以促进肿瘤微环境中CD8+T细胞的浸润和/或积累，抑制PD-1分子表达，显著抑制肿瘤的生长。CN201480043869.2，发明名称：通过使用来自普雷沃氏菌属的至少一种细菌菌株治疗肥胖、代谢综合征、2型糖尿病、心血管疾病、痴呆、阿尔茨海默病和炎性肠病，涉及一种用于治疗肥胖、代谢综合征、2型糖尿病、心血管疾病、痴呆、阿尔茨海默病和炎性肠病的产品，其包含来自物种普雷沃氏菌科的至少一种分离的细菌菌株，其中所述菌株选自肠道普雷沃氏菌，Prevotella stercorea，Prevotella histicola，栖瘤胃普雷沃氏菌，布氏普雷沃氏菌25A和狄氏普雷沃氏菌。
目前尚无普氏菌和衰弱综合征的研究。
发明内容
本发明提供了Prevotella copri的新用途，具体地，在制备治疗老年衰弱综合征的药物中的用途
本发明提供了Prevotella copri在制备治疗老年衰弱综合征的药物中的用途。
其中，所述的Prevotella copri是以活菌存在。
其中，所述的药物是以Prevotella copri为活性成分，加入药学上可接受的辅料或辅助性成分制备而成的制剂。
其中，所述的制剂是口服制剂。
其中，所述的口服制剂是片剂、胶囊剂、丸剂、颗粒剂。
所述的口服制剂中每单位制剂含Prevotella copri的活菌数不低于1.0*108 CFU。所述的每单位制剂是指每片、每粒胶囊、每袋丸剂、每袋颗粒剂。
本发明的有益效果是：
本发明Prevotella copri用于治疗老年衰弱综合征，药效明确，Prevotellacopri属于益生菌，临床使用安全，弥补了老年衰弱综合征肠道菌群治疗的空缺，实用性高，适用范围广。
附图说明
图1 动物行为学基线检测结果图（其中，a图为体重，b图为铁丝悬挂时间，c图为转棒圈数，d图为转棒速度，e图为转棒时间，f图为笼顶悬挂时间，g图为前肢抓力，h图为后肢抓力；CON是对照组，LPC是活菌组，DPC是死菌组，BCAA是支链氨基酸组）；
图2 普氏菌DNA相对表达量和各组小鼠血液支链氨基酸含量在不同分组的干预后比较图（其中，图2a指的是各组小鼠干预之后粪便里面普氏菌DNA相对含量的值，单位是拷贝数/ul的10的对数；图2b指的是各组小鼠干预之后小鼠血液支链氨基酸的水平，单位是umol/L；各组间的比较使用Wilcoxon秩和检验（*, p<0.05））；
图3 小鼠菌群干预后行为学检测结果图（其中，图3a图为体重，b图为铁丝悬挂时间，c图为转棒圈数，d图为转棒速度，e图为转棒时间，f图为笼顶悬挂时间，g图为前肢抓力，h图为后肢抓力）；
图4 各组小鼠菌群干预后肌肉组织蛋白合成和降解通路的关键蛋白mRNA相对表达量图（其中，a图为肌酸激酶（MCK）在各组之间肌肉组织中的mRNA相对表达量的比较图，b图为：MHC-1（肌球蛋白重链1）在各组之间肌肉组织中的mRNA相对表达量的比较图，c图为：MHC-2B（肌球蛋白重链2B）在各组之间肌肉组织中的mRNA相对表达量的比较图，d图为Myogenin(肌形成蛋白) 在各组之间肌肉组织中的mRNA相对表达量的比较图，e图为MuRF（肌肉特定环指蛋白）在各组之间肌肉组织中的mRNA相对表达量的比较图，f图为Atrogin-1（肌萎缩因子）在各组之间肌肉组织中的mRNA相对表达量的比较图，CON是对照组，LPC是活菌组，DPC是死菌组，BCAA是支链氨基酸组）。
具体实施方式
实施例1 本发明Prevotella copri治疗老年衰弱综合征动物实验
1普氏菌的培养和制备
普氏菌（Prevotella copri） 购自 DSM(18205)，细菌复苏后常规划线培养于血琼脂TSB培养皿上，于厌氧箱（80%N2，10%H2，10%CO2，37℃）中培养。然后在严格厌氧条件下，挑出培养在血板上的已生长3天的成熟单菌落，在含氯化血红素和维生素 K1 的厌氧灭菌PYG 液体培养基中培养过夜。然后取出厌氧箱，将其置于 37°C 的振荡器上约 24 小时。根据OD600吸光度计算细菌密度，1 OD的细菌密度约为1×109CFU/ml。
2小鼠的饲养和分组
20个月大的雌性 C57BL/6 小鼠（购自北京维通利华公司）以每笼 5 只为一组饲养（过滤顶笼），在严格的 12 小时光照循环下自由进食和饮水。在给它们喂食标准食物之前使它们适应新环境，然后分成四组，分别用无菌 PBS、BCAA、活普氏菌和热灭活普氏菌灌胃，剂量为 5 × 108CFUs/100 μl PBS 每周 3 次，持续 6 周。在灌胃之前和实验结束时测量体重、抓力、转棒时间等。在灌胃前和实验结束时收集粪便样本，并在进一步分析前立即储存在-80°C。本研究未采用随机化，将适应环境的小鼠根据体重分组，以确保起点相同。所有程序均经四川大学华西医院动物护理委员会批准。
3小鼠悬挂实验
在第一次进行测试之前需先训练小鼠。为此，让动物进行三次试验，每次试验 30秒，试验之间让小鼠休息 30 分钟。在开始测试之前，将小鼠放在网格上，让它牢牢抓住，然后快速将网格向上翻转。网格可以放置在一个固定装置上，也可以用手将其固定在距地板固定距离（80 厘米）的地方，下面有一个软垫，以避免小鼠跌倒后受伤。反转网格时启动计时器以记录小鼠掉落的延迟时间（以秒为单位）。重复3次，直到每只小鼠都完成了 3 次测试，选择最大值为最终结果。
4小鼠握力检测实验
从笼子里取出一只老鼠，用拇指和食指夹住小鼠尾巴的底部。将抓力仪（JiangsuCyons Biotechnology, SA417）置于水平平台，悬提小鼠尾部，将小鼠前爪放置在抓力仪的感应横杆上，待小鼠前爪抓紧横杆后，水平向后拖拽小鼠尾部，至其前肢松开，抓力仪自动记录最大抓力，重复测量3次，取最大值记为小鼠前肢绝对抓力。1 分钟间隔，重复 3 次并选择最大值。
5小鼠转棒测试实验
我们的研究中使用了转棒疲劳测试仪（江苏赛昂生物技术公司，SA102）。在4r.p.m.开始旋转，并快速将每只鼠标放在旋转棒的单独通道中。一旦所有的老鼠都放置好并背对着研究者，在300秒内将旋转杆加速到 40r.p.m。记录小鼠掉落时的延迟时间及速度，重复三次实验并选择最大值。
6 小鼠组织收集
在研究结束时，配制浓度为1%的戊巴比妥溶液，按照50mg/kg的用量对小鼠进行腹腔注射，使小鼠充分麻醉后，将小鼠仰卧位固定，皮肤消毒后，逐层剪开肋骨、胸腔，打开心包，右手持注射器，从左心室心尖处进针，采血2ml。将血样在 3,000 rpm、4 °C 下离心 15分钟。分离血浆并储存在-80°C，用于随后的生化测试。而后将灌注针***心脏，缓慢匀速灌注冰冻肝素生理盐水，同时剪开右心耳，释放静脉血，待流出的液体清亮后，在冰上迅速分离小鼠两侧完整的腓肠肌，分析天平称重记录，一半用锡纸包裹后置于-80℃保存用于后续的western-blot实验，一半浸泡于4%多聚甲醛溶液，24小时后进行石蜡包埋切片。
7 小鼠血液 BCAA 检测
检测支链氨基酸BCAA的目的是寻找prevotella copri参与改善衰弱综合征的机制，推测可能是通过prevotella copri的某种成分或者酶促进食物的代谢，并且促进支链氨基酸的吸收，而提高了血液里的支链氨基酸水平。
在灌胃前和实验结束时抽取血液用于 BCAA 测量。将血液收集在冰上的 EDTA 涂层试管中，并在 4°C 下以 1,000g 离心 10 分钟，然后在 -80°C 下储存直至进一步分析。BCAA 的测定遵循支链氨基酸检测试剂盒 (ab83374)。
8小鼠肌肉组织相关蛋白的mRNA含量测定
使用 TRIzol 试剂从肌肉组织中提取总 RNA。对于基于 SYBR Green 的定量逆转录 PCR (qRT-PCR)，使用 Superscript II 和随机引物 (Invitrogen) 对分离的 RNA 进行逆转录。 qRT-PCR 分析一式三份进行，数据标准化为 Rpl27 和 Rpl13，并使用 qBase软件进行分析。
9 小鼠粪便中普氏菌的 DNA 提取和定量分析
使用 QIAamp 快速 DNA 提取试剂盒 (Qiagen) 将每只小鼠的粪便样本用于宏基因组 DNA 提取。具体步骤如下：
（1）称取粪便样本 0.1-0.5g，在液氮中充分研磨成细粉末，加入 450ul 溶液 A震荡混匀。
（2）加入 50ul 溶液 B 充分颠倒混匀( 不要剧烈震荡)，65℃水浴 6min，每 2min充分颠倒混匀一次。
（3）加入 100ul 溶液 C 充分颠倒混匀( 不要剧烈震荡)，12000 rpm 离心 10min 。
（4）将上清转移到新的离心管，12000rpm 离心 2min 。
（5）在吸附柱中加入 200ul 溶液 D ，将离心后的上清加入到带有溶液 D 的吸附柱中，用移液器吹吸几次混匀，12000 rpm 离心 1min。
（6）将收集管中的滤出液混匀后重新吸入吸附柱( 必须)，12000 rpm 离心 1min。
（7）倒掉收集管中的废液，在吸附柱中加入漂洗液 500ul，12000 rpm 离心 1min。
（8）倒掉收集管中的废液，重复步骤 7 两次(共漂洗三次)。
（9）倒掉收集管中的废液，将吸附柱放回收集管，12000 rpm 离心 2min 。
（10）拿出吸附柱在室温干燥数分钟( 因季节及气候等因素不等)，或 50℃干燥1min。
（11）将吸附柱放入一个新的离心管中，加入 50-100ul 洗脱液(65 ℃预热)，12000 rpm 离心 1min。
（12）将离心管中的液体重新加入到吸附柱中，12000 rpm 离心 1min。离心管中即为粪便微生物 DNA 溶液。
使用 NanoDrop 2000 分光光度计（Thermo Scientific）测量 DNA 浓度。使用MJOPTICON 2定量PCR仪（Bio-Rad，USA）及MJ OPTICON MONITOR分析软件（version 3.1）分析小鼠粪便中普氏菌的DNA相对含量。
10 数据的统计分析
所有数据均以平均数±标准差( x ±S)表示，采用 SPSS 13.0 统计软件建立数据库，并用graphpad prism 8.0.1对实验结果进行统计处理。
11研究结果
11.1各组小鼠基线行为学检测结果
我们对各组小鼠的基线行为学进行监测，包括体重、抓力、转棒时间和悬挂时间，经分析发现小鼠的基线行为学检测各组之间无明显差异，如图1。
11.2各组小鼠粪便普氏菌DNA含量和血液支链氨基酸水平的比较
我们给不同分组的小鼠分别灌胃生理盐水（对照组），活菌（普氏菌），死菌（普氏菌），支链氨基酸（BCAA）后，通过采集基线小鼠的粪便和干预6周后的小鼠粪便，进行普氏菌的DNA定量分析，发现活菌组的普氏菌DNA含量显著高于对照组，且活菌组的普氏菌DNA含量在干预后显著高于干预前的DNA含量，说明普氏菌灌胃后在小鼠肠道定植成功，如图2a。在干预后的活菌组和BCAA组小鼠的血液支链氨基酸浓度均显著高于对照组，提高BCAA的量可以提高免疫力，可解决衰弱综合征带来的免疫功能下降等问题，也可以促进肌肉的合成，而死菌组的血液支链氨基酸浓度与对照组无明显差异，如图2b。
11.3各组小鼠菌群干预后行为学检测结果
我们通过检测各组小鼠干预后的行为学指标，包括体重、抓力、悬挂时间和转棒时间，经统计分析发现，活菌组小鼠在干预后的体重显著高于对照组，而死菌组和BCAA组的体重与对照组无显著差异，活菌组小鼠在干预后的抓力也是显著高于对照组，而死菌组和BCAA组的抓力与对照组相比无显著差异，活菌组的转棒时间在干预后显著高于对照组，而死菌组和BCAA组与对照组相比无显著差异，悬挂时间各组之间均无显著差异，如图3。
普氏菌活菌灌胃小鼠后可改善老年小鼠的衰弱综合征的情况包括铁丝悬挂时间、转棒时间、转棒速度、前肢和四肢的抓力。
11.4各组小鼠菌群干预后肌肉组织的蛋白相关RT-PCR检测
对小鼠的肌肉组织（腓肠肌）进行相关蛋白的mRNA相对定量分析，包括肌肉合成相关蛋白MCK（肌酸激酶）、MHC-1（肌球蛋白重链1）、MHC-2B（肌球蛋白重链2B）、Myogenin(肌形成蛋白)，以及肌肉分解通路中的关键蛋白MuRF（肌肉特定环指蛋白）和Atrogin-1（肌萎缩因子），通过分析发现，活菌组的肌肉分解通路的关键蛋白MuRF和Atrogin-1的mRNA相对含量显著低于对照组，提示活菌组的肌肉分解较对照组减少。而Myogenin的mRNA相对含量仅死菌组较对照组显著降低，提示死菌组的肌肉合成较对照组下降，如图4。
综上，通过给小鼠额外补充活普氏菌（prevotella copri）可通过增加小鼠的运动能力包括延长铁丝悬挂时间、转棒时间，增大前肢和四肢的抓力，提高小鼠的血液支链氨基酸水平，增强小鼠的免疫能力，从而改善衰弱综合征。
Claims (5)
1.Prevotella copri在制备治疗老年衰弱综合征的药物中的用途。
2.根据权利要求1所述的用途，其特征在于：所述的Prevotella copri是以活菌存在。
3.根据权利要求1或2所述的用途，其特征在于：所述的药物是以Prevotella copri为活性成分，加入药学上可接受的辅料或辅助性成分制备而成的制剂。
4.根据权利要求3所述的用途，其特征在于：所述的制剂是口服制剂。
5.根据权利要求4所述的用途，其特征在于：所述的口服制剂是片剂、胶囊剂、丸剂、颗粒剂。
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