CN112121066B - 瘤胃球菌在制备治疗多囊卵巢综合征中的应用以及培养方法 - Google Patents
瘤胃球菌在制备治疗多囊卵巢综合征中的应用以及培养方法 Download PDFInfo
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- CN112121066B CN112121066B CN202011333916.0A CN202011333916A CN112121066B CN 112121066 B CN112121066 B CN 112121066B CN 202011333916 A CN202011333916 A CN 202011333916A CN 112121066 B CN112121066 B CN 112121066B
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Abstract
本发明公开了瘤胃球菌(Ruminococcus spp.)在制备治疗和/或预防多囊卵巢综合征药物或食品中的应用,以及其培养方法。本发明提供的瘤胃球菌可以显著改善PCOS小鼠模型的动情周期紊乱、胰岛素抵抗、血性激素失调以及卵巢多囊样变,可以用于制备治疗多囊卵巢综合征的药物或食品。
Description
技术领域
本发明涉及微生物学领域,具体地,本发明涉及瘤胃球菌(Ruminococcus spp.)在治疗和预防多囊卵巢综合征中的应用,也涉及包含瘤胃球菌的组合物及其应用。
背景技术
生育力下降成为严重的社会问题,全球的不孕不育率达到10% -15%,生殖内分泌紊乱是目前导致女性不孕的首位病因。多囊卵巢综合征(简称PCOS)是无排卵性不孕症的最常见原因之一。PCOS是一种内分泌代谢紊乱的综合征,以高雄激素血症、排卵异常和卵巢多囊样改变为特征,常伴发胰岛素抵抗。由于其临床表现的高度异质性,PCOS的治疗已经成为妇科和内分泌领域共同关注的热点和难点问题。
肠道微生态主要包括肠道细菌、真菌、病毒以及代谢产物,其中对肠道细菌的研究较为深入。近期研究证实,人体微生态与多囊卵巢综合征的发生发展密切相关,肠道细菌可以转化胆酸影响宿主天然免疫系统,进而调节胰岛素抵抗,影响多囊卵巢综合征的发生发展。因此,以人体微生态为研究切入点,开发对应的微生态制剂和药品,可以为多囊卵巢综合征的治疗和预防提供新的路径及更为有效的措施。
瘤胃球菌(Ruminococcus spp.),主要包括扭链瘤胃球菌(Ruminococcus torques), 活泼瘤胃球菌(Ruminococcus gnavus) ,酸奶瘤胃球菌(Ruminococcus lactaris ),已知为生存于共生的哺乳动物(包括人类)肠道中的常见的共生菌,目前没有研究发现表明口服瘤胃球菌(Ruminococcus spp.)菌体可以缓解或治疗多囊卵巢综合征。
发明内容
本发明的目的在于提供瘤胃球菌(Ruminococcus spp.)在治疗多囊卵巢综合征方面的用途。
本发明的另一目的是提供一种用于治疗多囊卵巢综合征的药品、饮料、食品组合物,或动物饲料组合物。
在本发明的第一方面,提供了一种瘤胃球菌(Ruminococcus spp.)的用途,所述菌用于制备治疗多囊卵巢综合征的组合物。
在另一优选例中,所述组合物为药物组合物、食品组合物、饮料组合物,或饲料组合物。
在本发明的第二方面,提供了一种食品组合物,所述食品组合物含有有效量的瘤胃球菌(Ruminococcus spp.)和/或其代谢产物,以及余量的食品上可接受的载体。
在另一优选例中,所述的食物组合物的剂型选自固体、乳品、溶液制品、粉末制品、或悬浮液制品。
在本发明的第三方面,提供了一种药物组合物,所述药物组合物中含有有效量的瘤胃球菌(Ruminococcus spp.)和/或其代谢产物,以及药学上可接受的载体。
在另一优选例中,所述的药物组合物剂型选自颗粒剂、胶囊、片剂、粉末剂、口服液、混悬液或乳剂。
进一步的,本发明提供了一种瘤胃球菌培养方法,其特征是厌氧条件下,瘤胃球菌接到斜面上,在10-40 ℃和斜面上的培养基中生长2-3天,挑取菌体在10-40 ℃和培养液中培养2-3天,所述的培养基是10-30 g/L碳源、6-15 g/L氮源、1-3 g/L琼脂、0.2-1 g/L 无机盐和pH 值3.0至7.0所组成,所述的培养液是10-30 g/L碳源、6-15 g/L氮源、1-3 g/L琼脂、0.2-1 g/L 无机盐和pH 值3.0至7.0所组成,所述的碳源是果糖、葡萄糖或蔗糖,所属的氮源是玉米浆、酵母膏或玉米粉。
应理解,在本发明范围内,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以相互组合,从而构成新的或优选的技术方案。
具体实施方式
发明人经过广泛而深入的研究和实验,发现瘤胃球菌(Ruminococcus spp.)具有预防和治疗多囊卵巢综合征的作用,将含有瘤胃球菌(Ruminococcus spp.)的活性组合物饲喂实验对象,发现该组合物能够改善多囊卵巢综合征小鼠模型的胰岛素抵抗、动情周期紊乱、激素分泌紊乱以及卵巢多囊样变。在此基础上完成本发明。
如本文所用,术语“含有”表示各种成分可一起应用于本发明的混合物或组合物中。因此,术语“主要由…组成”和“由…组成”包含在术语“含有”中。
本发明提供了瘤胃球菌(Ruminococcus spp.)在治疗和预防多囊卵巢综合征方面的用途。小鼠给予高雄激素刺激,造成多囊卵巢综合征模型,扭链瘤胃球菌(Ruminococcus torques,缩写为MT), 活泼瘤胃球菌(Ruminococcus gnavus,缩写为MG),酸奶瘤胃球菌(Ruminococcus lactaris,缩写为ML)具有改善模型动物胰岛素抵抗、动情周期紊乱以及多囊卵巢样变的能力。根据本发明的一个优选例,经菌株MT, MG, ML来治疗DHT及DHEA诱导的PCOS模型小鼠,与未受治疗的对照组相比,可保持动情周期、性激素以及卵巢形态正常。因此,所述菌株能够用以预防和治疗多囊卵巢综合征。
本发明药物组合物可以以药物片剂,针剂或胶囊的任一种形式给药,所述药物制剂包括赋形剂、药物允许的媒介和载体,这些物质可根据给药途径进行选择。本发明中的药物制剂可进一步包含辅助的活性组分。
乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮(PVP)、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁或矿物油等都可用作本发明中药物组合物的载体、赋形剂或稀释剂等。
此外,本发明的药物组合物可进一步包括润滑剂、润湿剂、乳化剂、悬乳液稳定剂、防腐剂、甜味剂和香料等。本发明的药物组合物可通过多种公知的方法以肠衣制剂生产,以便于药物组合物的活性成分即微生物能顺利通过胃而不被胃酸所破坏。
本发明的药物组合物可制成肠衣片供口服使用。本申请中的术语-“肠衣”包括所有常规药物允许使用的包衣,这些包衣不被胃酸降解,但在小肠中能充分分解并快速释放出本发明的微生物。本发明的肠衣能在合成胃酸如pH=1的HCl溶液中36-38℃维持2小时以上,并优选在合成肠液如pH=7.0的缓冲液中在1.0小时内分解。
本发明的肠衣以每片约16-30mg进行包衣,较佳地16-25mg,更佳地16-20mg进行包衣。本发明中肠衣厚度为5-100μm,理想的厚度为20-80μm.肠衣成分自己公开知晓的常规聚合物。
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
下述实施例中所用的菌株,均购自美国模式培养物集存库(ATCC),分别为扭链瘤胃球菌(Ruminococcus torques),保藏号为ATCC 35915,活泼瘤胃球菌(Ruminococcusgnavus),保藏号为ATCC 29149,或酸奶瘤胃球菌(Ruminococcus lactaris), 保藏号为ATCC 29176。
实施例1、瘤胃球菌(Ruminococcus spp.)对DHEA诱导的PCOS小鼠模型的改善作用
材料:
被测菌株为扭链瘤胃球菌(Ruminococcus torques,缩写为MT),保藏号为ATCC35915,活泼瘤胃球菌(Ruminococcus gnavu, 缩写为MG),保藏号为ATCC 29149,或酸奶瘤胃球菌(Ruminococcus lactaris, 缩写为ML), 保藏号为ATCC 29176,灌胃菌量定为0.15mL/10g体重,菌浓为1×107 cfu/mL,浓缩后浓度为1×109 cfu/mL,频率为每日一次。菌液需提前培养,每周活化保证新鲜,并分别测定浓度。
C57小鼠购自北京维通利华实验动物技术有限公司,温度20-24摄氏度,恒湿50-60%,光照12小时(8:00-20:00),隔音,自由摄食、饮水,适应环境一周后进行实验。血糖试纸(罗氏公司)、血糖仪(罗氏公司)、脱氢表雄酮(Sigma),性激素检测试剂盒。
方法:雌性C57小鼠3-4周,体重16-18 g,40只,随机分为(1)正常对照组,(2)模型对照组,(3)MT1×109 cfu/mL,(4)MG 1×109 cfu/mL,(5) ML 1×109 cfu/mL,每组8只,第(2)-(5)组给予DHEA皮下注射。模型对照组给予等量的厌氧PBS。各组小鼠分别灌胃给与0.15 mL/10g体重的菌液,连续4周,对照组和模型组给予等量的生理盐水。DHEA注射10天后每日检测动情周期,模型组小鼠动情周期发生明显紊乱,证明模型建立成功;末次给药前检测口服葡萄糖耐量及胰岛素耐量;末次给药后,取血,4摄氏度3000rpm离心,测定血清性激素水平,卵巢切片观察病理变化。
结果:与模型组比较,MT, MG, ML菌株都可以显著改善胰岛素抵抗相关指标,恢复正常动情周期,改善小鼠卵巢状态及性激素水平,MT效果最为显著,结果见表1-5。
表1瘤胃球菌(Ruminococcus spp.)对DHEA小鼠动情周期的影响
表2瘤胃球菌(Ruminococcus spp.)对DHEA小鼠OGTT的影响
表3 瘤胃球菌(Ruminococcus spp.)对DHEA小鼠ITT的影响
表4 瘤胃球菌(Ruminococcus spp.)对DHEA小鼠血性激素的影响
表5 瘤胃球菌(Ruminococcus spp.)对DHEA小鼠卵巢多囊样变的影响
实施例2、瘤胃球菌(Ruminococcus spp.)对DHT诱导的PCOS小鼠模型的改善作用
材料:
被测菌株为扭链瘤胃球菌(Ruminococcus torques,缩写为MT),保藏号为ATCC35915,活泼瘤胃球菌(Ruminococcus gnavu, 缩写为MG),保藏号为ATCC 29149,或酸奶瘤胃球菌(Ruminococcus lactaris, 缩写为ML), 保藏号为ATCC 29176,灌胃菌量定为0.15mL/10g体重,菌浓为1×107 cfu/mL,浓缩后浓度为1×109 cfu/mL,频率为每日一次。菌液需提前培养,每周活化保证新鲜,并分别测定浓度。
C57小鼠购自北京维通利华实验动物技术有限公司,温度20-24摄氏度,恒湿50-60%,光照12小时(8:00-20:00),隔音,自由摄食、饮水,适应环境一周后进行实验。血糖试纸(罗氏公司)、血糖仪(罗氏公司)、二氢睾酮(DHT, Sigma),性激素检测试剂盒。
DHT诱导的PCOS小鼠模型构建:选择6-8周SPF级C57小鼠,雄鼠12只,雌鼠24只,雌雄小鼠以2:1合笼过夜,次日清晨检栓,观察到阴道栓时作为孕期第一天。孕期16-18天时,20只孕鼠皮下注射双清睾酮(250 μg/只/天),4只孕鼠皮下注射其溶剂(1 μL DMSO及玉米油),溶剂组母鼠的雌性子代作为对照组(1组),双清睾酮组母鼠产下的雌性子代小鼠随机分为模型组(2组)及给药组 [(3组)MT1×109 cfu/mL,(4组)MG 1×109 cfu/mL,(5组) ML 1×109 cfu/mL]。小鼠8周后,模型及对照组均给予等量的厌氧PBS,各组小鼠分别灌胃给与0.15 mL/10g体重的菌液,连续4周,对照组和模型组给予等量的生理盐水。8周后每日检测动情周期;末次给药前检测口服葡萄糖耐量及胰岛素耐量;末次给药后,取血,4摄氏度3000rpm离心,测定血清性激素水平,卵巢切片观察病理变化。
结果:与模型组比较,MT, MG, ML菌株都可以显著改善胰岛素抵抗相关指标,恢复正常动情周期,改善小鼠卵巢状态及性激素水平,其中菌株MT效果最为显著,结果见表6-10。
表6瘤胃球菌(Ruminococcus spp.)对DHT小鼠动情周期的影响
表7 瘤胃球菌(Ruminococcus spp.)对DHT小鼠OGTT的影响
表8 瘤胃球菌(Ruminococcus spp.)对DHT小鼠ITT的影响
表9 瘤胃球菌(Ruminococcus spp.)对DHT小鼠血性激素的影响
表10 瘤胃球菌(Ruminococcus spp.)对DHT小鼠卵巢多囊样变的影响
Claims (2)
1.一种瘤胃球菌(Ruminococcus spp.)在制备治疗多囊卵巢综合征药物中的用途,其特征在于,所述的瘤胃球菌选自扭链瘤胃球菌(Ruminococcus torques),保藏号为ATCC35915,活泼瘤胃球菌(Ruminococcus gnavus),保藏号为ATCC 29149,或酸奶瘤胃球菌(Ruminococcus lactaris), 保藏号为ATCC 29176。
2. 如权利要求1所述的用途,其特征在于,所述瘤胃球菌的培养方法为:厌氧条件下,将所述瘤胃球菌接到斜面培养基上,在10-40 ℃下生长2-3天,挑取菌体接种到培养液中,在10-40 ℃下培养2-3天,所述斜面培养基由10-30 g/L碳源、6-15 g/L氮源、1-3 g/L琼脂、0.2-1 g/L 无机盐组成,pH 值为3.0至7.0;所述培养液由10-30 g/L碳源、6-15 g/L氮源、1-3 g/L琼脂、0.2-1 g/L 无机盐组成,pH 值为3.0至7.0;所述斜面培养基或培养液的碳源选自果糖、葡萄糖或蔗糖,所述斜面培养基或培养液的氮源选自玉米浆、酵母膏或玉米粉。
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