CN111281896A - 一种调节妇科微生态平衡的复合菌剂 - Google Patents
一种调节妇科微生态平衡的复合菌剂 Download PDFInfo
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- CN111281896A CN111281896A CN202010093338.1A CN202010093338A CN111281896A CN 111281896 A CN111281896 A CN 111281896A CN 202010093338 A CN202010093338 A CN 202010093338A CN 111281896 A CN111281896 A CN 111281896A
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- lactobacillus
- sil1
- lactobacillus salivarius
- microbial inoculum
- cycloastragenol
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Abstract
本发明公开了一种用于调节妇科微生态平衡的复合菌剂,其包括:卷曲乳杆菌,唾液乳杆菌(Lactobacillus salivarius)SIL1以及其他可接受的药物赋形剂。所述卷曲乳杆菌(Lactobacillus crispatus),该菌株的保藏号为CGMCC No.6364。所述唾液乳杆菌(Lactobacillus salivarius)SIL1,该菌株的保藏号:CCTCC M2010281。所述复合菌剂可以做成口服液,也可以做成发酵食品,优选为胶囊,菌粉,奶片,发酵食品等。作为进一步优选,还包括环黄芪醇。
Description
技术领域
本发明涉及一种调节妇科微生态平衡的复合菌剂,属于微生物技术领域。
背景技术
阴道微生态失调可引起各类妇科炎症,包括阴道炎、(急、慢性)宫颈炎、宫颈疾病、子宫内膜炎、子宫体炎、附件炎等。
抗生素等传统杀菌产品,在调理女性生殖系统外源性感染杀灭有害菌的同时也杀灭了机体内的正常有益菌群,由于阴道内的菌群失衡从而导致生殖道内源性感染或机会感染,带来了致病菌耐药性、疾病复发率高、双重感染以及毒性反应等。妇科微生态平衡益生菌促菌治疗代替抗菌治疗的微生态疗法。
细菌性阴道炎(BV)是一种由阴道加特纳菌和一些厌氧菌的混合感染,导致阴道内微生态平衡失调,引起的阴道分泌物增多,白带有鱼腥臭味及外阴瘙痒灼热的综合征。可分为嗜血杆菌性阴道炎、棒状杆菌阴道炎、厌氧菌性阴道病炎、加特纳菌性阴道炎等。本病也可通过性接触传染,在性关系混乱的人群中发病率较高。分泌物涂片检查可发现大量脓球,找到致病菌。
念珠菌阴道炎即霉菌性阴道炎,属于妇科常见疾病,目前临床针对该病主要通过抗菌药物治疗,但长期应用抗菌药物易导致疾病复发。通过益生菌组合物改善复发性念珠菌阴道炎患者阴道微生态环境,有助于减少疾病复发。
本发明旨在提供一种调节妇科微生态平衡的复合菌剂。
发明内容
本发明旨在提供一种调节妇科微生态平衡的复合菌剂,其可以直接口服给药,也可以阴道内给药。
本发明的一个重要发明点在于,提高通过口服复合菌剂的效果。现有技术有人证明,即使通过食用酸奶,也能在阴道内增加乳杆菌的数量,但是其具体机制一直并不十分清楚。一般而言,通过口服能够进入阴道的乳杆菌很少,其微生态调节能力有限,很难达到治疗细菌性阴道炎,霉菌性阴道炎的效果。而很多女性心理上很抵触阴道给药,且使用并不方便。本发明旨在提供一种调节妇科微生态平衡的复合菌剂,其可以直接口服给药,也可以阴道内给药,口服时也可以达到很好的治疗阴道炎的效果,显著恢复妇科微生态平衡。
念珠菌阴道炎即霉菌性阴道炎,属于妇科常见疾病,目前临床针对该病主要通过抗菌药物治疗,但长期应用抗菌药物易导致疾病复发。通过益生菌组合物改善复发性念珠菌阴道炎患者阴道微生态环境,有助于减少疾病复发。
细菌性阴道病(BV)是育龄妇女最常见的生殖器感染性疾病,其特征是栖居在阴道内的菌群平衡失调,乳酸杆菌特别是产过氧化氢(H2O2)的菌株减少,而其他菌群如阴道加德纳菌、动弯杆菌、拟杆菌、消化链球菌、人型支原体等的大量繁殖而引起的一种无阴道黏膜炎症表现的综合证。BV治愈时间长且易复发,与许多严重的妇产科并发症有直接关系,能导致BV患者的早产率增加,婴儿体质量低下,组织性绒毛炎,羊水感染,字宫内膜炎等危险因素。此外BV还与输卵管炎、盆腔炎、不孕症、宫外孕、泌尿系感染、术后感染及妇科肿瘤等疾病有关。已经证实BV能增加人类免疫缺陷病毒感染的危险因素。由于BV的发病率高易复发,许多研究表明采用微生物及免疫治疗,通过生态制剂调整疗法是治疗此类疾病的必然选择。益生菌是一种活的微生物,因此用口服或阴道内植入乳酸杆菌来恢复其自然对外来菌侵袭的抵抗力,促进阴道本身的自净作用,对治愈和预防BV的复发都有良好的作用。
中国专利2013100043553公开过一株卷曲乳杆菌,该菌株为卷曲乳杆菌(Lactobacillus crispatus)的菌株,其特征在于,该菌株的保藏号为CGMCC No.6364。在该专利披露的内容中,卷曲乳杆菌CGMCC No.6364可实现对多种致病菌的拮抗作用,还具有更高的对阴道上皮细胞的粘附能力以及更高的产乳酸能力,因而本发明的菌株能够较好地满足实际的临床应用需求。本发明用到的卷曲乳杆菌CGMCC No.6364由赠送获得。
中国专利CN102061272A公开了一株唾液乳杆菌菌株,保藏名称为:唾液乳杆菌(Lactobacillus salivarius)SIL1,保藏单位:中国典型培养物保藏中心,地址:武汉市武昌区珞珈山武汉大学,保藏日期:2010年10月26日,保藏号:CCTCC M2010281。该菌株的已知功能为用于调节动物肠道菌群,促进动物生长。本发明用到的唾液乳杆菌(Lactobacillussalivarius)SIL1为赠送获得。
本申请人研发团队发现,唾液乳杆菌(Lactobacillus salivarius)SIL1可以显著促进卷曲乳杆菌口服时对阴道微生态的调节作用。
环黄芪醇(cycloastragenol,CAG)是从中药黄芪提取的主要皂苷成分,属于三萜皂苷类化合物,是黄芪甲苷的苷元。CAG具有免疫调节、抗炎、抗氧化、抗缺血性脑损伤、抗衰老等作用,例如:CAG通过抑制NLRP3炎性小体抑制炎症,预防小鼠心肌细胞纤维化;或通过抑制NF-κB活性作为炎症诱导的前列腺癌化学治疗的辅助治疗等。同时,CAG是中药提取化合物中现今唯一发现的端粒酶激活剂,能够有效激活神经元细胞的端粒酶活性,可以作为抑郁症的辅助治疗;或者通过影响端粒酶活性和klotho基因的表达延缓人胚胎肺成纤维细胞衰老,从而被认为具有抗衰老的作用。本发明所用环黄芪醇(HPLC≥98%)购自成都曼思特生物公司。
本申请人研发团队通过大量研究进一步发现,环黄芪醇也可以显著促进卷曲乳杆菌口服时对阴道微生态的调节作用,并且环黄芪醇和唾液乳杆菌SIL1合用时具有协同促进乳杆菌定植的效果。推测可能的机制是唾液乳杆菌和环黄芪醇是通过对肠道的影响达到上述作用的。
本发明所需要解决的技术问题可以通过以下技术方案来实现。
一种用于调节妇科微生态平衡的复合菌剂,其包括:
卷曲乳杆菌,唾液乳杆菌(Lactobacillus salivarius)SIL1以及其他可接受的药物赋形剂。
所述卷曲乳杆菌(Lactobacillus crispatus),该菌株的保藏号为CGMCCNo.6364。
所述唾液乳杆菌(Lactobacillus salivarius)SIL1,该菌株的保藏号:CCTCCM2010281。
所述复合菌剂可以做成口服液,也可以做成发酵食品,优选为胶囊,菌粉,奶片,发酵食品等。
作为进一步优选,还包括环黄芪醇。
本发明的细菌性阴道炎造模方法:每天给予小鼠阴道注射由大肠杆菌、金葡菌、铜绿假单胞菌按1∶1∶1配制成的混合菌悬液0.3mL(三种菌的浓度均为0.5*107cfu/ml),连续处理7天后可见小鼠阴道口有明显红肿和脓状物流出,建模成功。
本发明的优点:
(1)成分安全,均为允许加入食品的益生菌。
(2)环黄芪醇(cycloastragenol,CAG)不仅能够促进乳杆菌的定植,而且还具有免疫调节、抗炎、抗氧化、抗缺血性脑损伤、抗衰老等作用。
(3)本产品可以阴道用,也可以直接口服,使用方便。
具体实施方式
下面详细描述本发明的实施例,所述实施例仅用于解释本发明,而不能理解为对本发明的限制。
本发明的具体实施例如以下说明。
实施例1
1、活化菌种:
卷曲乳杆菌CGMCC No.6364:取卷曲乳杆菌CGMCC No.6364到MRS固体培养基中划线,37℃厌氧培养24h。挑取平板中长势较好的单菌落接种至MRS液体培养基中活化,厌氧培养成0.5*108cfu/ml卷曲乳杆菌CGMCC No.6364种子液。
唾液乳杆菌SIL1:活化菌种方法同上。最后配置成0.5*108cfu/ml唾液乳杆菌卷曲种子液。
2、配置液体
环黄芪醇溶液,浓度为2mg/ml,2-8℃,避光密封、低温下保存。
3、KM小鼠造模
小鼠细菌性阴道炎造模:小鼠阴道注射3种杂菌产生阴道炎性疾病。本次试验使用的为大肠杆菌、金葡菌、铜绿假单胞菌按1∶1∶1配制成的混合菌悬液0.3mL(三种菌的浓度均为0.5*107cfu/ml),连续处理7天后可见小鼠阴道口有明显红肿和脓状物流出,建模成功。
取45只体重20-25g的雌性KM小鼠,饲养于SPF级动物房,21±2℃,自由饮水取食,12h昼夜交替。将45只KM小鼠分为9组,各组小鼠之间无统计学差异。9组分别为空白对照组(正常小鼠)、阳性对照组(左氧氟沙星组)、阴性对照组、卷曲乳杆菌CGMCC No.6364处理组、唾液乳杆菌SIL1处理组、卷曲+唾液乳杆菌处理组、卷曲+本环黄芪醇处理组、唾液+本环黄芪醇处理组、卷曲+唾液乳杆菌+本环黄芪醇处理组。每组小鼠5只。其中,正常小鼠组作为空白对照,阳性对照组、阴性对照组、处理组均使用细菌性阴道炎造模成功小鼠。
处理组活化乳杆菌,并配置好三种不同活菌悬液,浓度均为0.5*108cfu/ml,不同组别给与相应细菌灌胃处理。具体给药方式如下:
空白对照组和阴性对照组:不给药;
阳性对照组:左氧氟沙星的混悬液进行灌胃,根据药品用药指导转换成小鼠用药量,内含有左氧氟沙星溶液0.01g/kg。
卷曲乳杆菌CGMCC No.6364处理组:每只小鼠500μL/d卷曲乳杆菌;
唾液乳杆菌SIL1处理组:每只小鼠500μL/d唾液乳杆菌SIL1;
卷曲+唾液乳杆菌处理组:每只小鼠250μL/d卷曲乳杆菌+250μL/d唾液乳杆菌SIL1;
卷曲+本环黄芪醇处理组:每只小鼠500μL/d卷曲乳杆菌+250μL/d本环黄芪醇溶液;
唾液+本环黄芪醇处理组:每只小鼠500μL/d唾液乳杆菌+250μL/d本环黄芪醇溶液;
卷曲+唾液乳杆菌+本环黄芪醇处理组:每只小鼠250μL/d卷曲乳杆菌+250μL/d唾液乳杆菌SIL1+250μL/d本环黄芪醇溶液;
所有组别均连续处理7天,第8天收集小鼠血清炎性因子及阴道分泌物数据。
4、炎症因子
处理的第8天对小鼠眼眶静脉取血,EP管静置2h离心取上层血清,Elisa法检验小鼠血清中的降钙素原(PCT)、C反应蛋白(CRP)、白介素6(IL-6)。试验结果如表1所示。
5、统计学处理
使用SPSS16.0,进行统计学分析,计量资料的结果表示为均值±标准差,采用组间t检验。
表1不同组别小鼠治疗后的炎症因子检测
注:t检验,l:P<0.05(与空白组比较);2:P<0.05(和阳性对照组比较);3:P<0.05(和阴性对照组比较)
经过相应处理后,将对阳性对照组、阴性对照组、处理组的小鼠血清炎症因子检测进行分析。结果显示:卷曲+唾液乳杆菌处理组和卷曲+唾液乳杆菌+本环黄芪醇处理组小鼠的降钙素原(PCT)、C反应蛋白(CRP)、白介素6(IL-6)含量相对于阴性对照组具有显著性差异(<0.05),而其他处理组相对于阴性对照组不具有显著性差异;卷曲+唾液乳杆菌+本环黄芪醇处理组3种炎性物质含量最少,说明本环黄芪醇和唾液乳杆菌SIL1(CCTCC M2010281)分别对微生态起作用,并且环黄芪醇和唾液乳杆菌SIL1合用时具有协同促进卷曲乳杆菌CGMCC No.6364定植的效果。单独乳杆菌治疗组与阴性对照组相比,没有明显差异(P>0.05);说明卷曲+唾液乳杆菌+本环黄芪醇治疗具有协同消除体内炎症因子的作用,作用接近于抗生素治疗。
实施例2
实施例1的各组小鼠于处理第8天检测治疗后的阴道菌群:
小鼠阴道菌群检测:无菌条件取阴道冲洗液100ul,使用生理盐水混均,再依次进行10倍系列稀释,从原液开始选择103、104、105、106稀释度,分别滴种在MRS、EMB、SP、LB培养基上。
大肠杆菌、金葡菌和铜绿假单胞菌经37℃需氧培养,乳杆菌经厌氧培养48小时后,通过对菌落计数,计算出每毫升阴道分泌物的活菌数(cfu/ml),取对数后进行统计处理。
使用SPSS16.0,进行统计学分析,计量资料的结果表示为均值±标准差,采用组间t检验。结果如表2所示。
表2不同组别小鼠治疗后的阴道菌群检测
注:t检验,l:P<0.05(与空白组比较);2:P<0.05(和阳性对照组比较);3:P<0.05(和阴性对照组比较)
结果显示:
1、正常小鼠阴道内环境是乳杆菌相对占优势,多种杂菌共存。实验中,卷曲+唾液乳杆菌+本环黄芪醇处理组的小鼠阴道内乳杆菌定植数量最多,而大肠杆菌、金葡菌的定植数量最少,相对于空白组、阳性对照组和阴性对照组均具有显著性差异(<0.05),考虑和乳杆菌的短时间补充后,肠道爬行定植有关。
2、卷曲+唾液乳杆菌处理组、卷曲+本环黄芪醇处理组、卷曲+唾液乳杆菌+本环黄芪醇处理组卷曲的大肠杆菌、金葡菌的数量相对于阴性对照组有统计学差异(<0.05),可以说明卷曲乳杆菌治疗具有去除大肠杆菌、金葡菌在小鼠阴道内定植的作用;本环黄芪醇和唾液乳杆菌SIL1(CCTCC M2010281)对微生态起作用,并且环黄芪醇和唾液乳杆菌SIL1合用时具有协同促进卷曲乳杆菌爬行后定植拮抗杂菌的效果。
3、各组之间铜绿假单胞菌无显著差异(P>0.05),考虑该细菌对左氧氟沙星欠敏感。从数值来看,卷曲+唾液乳杆菌+本环黄芪醇处理组卷曲的铜绿假单胞菌数量最少,可能是环黄芪醇和唾液乳杆菌SIL1合用时具有协同促进卷曲乳杆菌CGMCC No.6364爬行定植,具有一定的粘附拮抗铜绿假单胞菌的作用。
综上所述,本发明团队在研究和实践过程中,发现本环黄芪醇和唾液乳杆菌SIL1(CCTCC M2010281)分别对微生态起作用,并且环黄芪醇和唾液乳杆菌SIL1合用时具有协同促进卷曲乳杆菌CGMCC No.6364定植并且拮抗杂菌的效果。目前尚不清楚该本环黄芪醇和唾液乳杆菌SIL1(CCTCC M2010281)如何增强卷曲乳杆菌的口服效果,推测是通过对肠道一系列生理生化的影响来起到协同作用的。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
尽管已经示出和描述了本发明的实施例,本领域的普通技术人员可以理解:在不脱离本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由权利要求及其等同物限定。
Claims (7)
1.一种用于调节妇科微生态平衡的复合菌剂,其包括:
卷曲乳杆菌,唾液乳杆菌(Lactobacillus salivarius)SIL1以及其他可接受的药物赋形剂。
2.权利要求1所述的用于调节妇科微生态平衡的复合菌剂,其特征在于:
所述卷曲乳杆菌(Lactobacillus crispatus),该菌株的保藏号为CGMCC No.6364。
3.权利要求2所述的用于调节妇科微生态平衡的复合菌剂,其特征在于:
所述唾液乳杆菌(Lactobacillus salivarius)SIL1,该菌株的保藏号:CCTCCM2010281。
4.权利要求1-3任一项所述的用于调节妇科微生态平衡的复合菌剂,其特征在于:
所述复合菌剂可以做成口服液和发酵食品。
5.权利要求4所述的用于调节妇科微生态平衡的复合菌剂,其特征在于:
复合菌剂可以做成胶囊,菌粉。
6.权利要求1-5任一项所述的用于调节妇科微生态平衡的复合菌剂,还包括环黄芪醇。
7.权利要求1-6任一项所述的用于调节妇科微生态平衡的复合菌剂在食品上的应用。
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