CN115569154A - 防治念珠菌***炎的鼠李糖乳杆菌LRa05及其应用 - Google Patents
防治念珠菌***炎的鼠李糖乳杆菌LRa05及其应用 Download PDFInfo
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Abstract
本发明属于微生物技术领域,尤其是涉及防治念珠菌***炎的鼠李糖乳杆菌LRa05及其应用。本发明提供鼠李糖乳杆菌LRa05在制备防治念珠菌***炎药物上的应用。通过白色念珠菌***炎小鼠模型试验,鼠李糖乳杆菌LRa05可显著降低念珠菌***炎小鼠***内的白色念珠菌浓度,有效预防白色念珠菌***炎小鼠的复发。
Description
技术领域
本发明属于微生物技术领域,尤其是涉及防治念珠菌***炎的鼠李糖乳杆菌LRa05及其应用。
背景技术
健康妇***道内存在着多种微生物,它们与宿主、环境之间构成了相互制约、相互协调、动态的平衡微生态***。当这个***平衡被破坏,会出现由于***菌群失调引起的多种疾病。如细菌性***炎、真菌性***炎、滴虫性***炎等等。其中妇科临床上多见的真菌性***炎主要是由白色念珠菌感染所致。
白色念珠菌又称白假丝酵母菌,细胞呈圆形或卵圆形,很像酵母菌,直径3-6um,比葡萄球菌大5-6倍,革兰氏阳性,但着色不均一,出芽方式繁殖。白色念珠菌通常在正常***环境中存在,但数量很少,不引起疾病,当***正常环境被破坏时,该菌大量繁殖并进入细胞引起疾病。
目前临床上治疗念珠菌***炎的方法主要是抗生素疗法,通过口服咪康等抗生素类药物或***内给药抑制白色念珠菌***炎患者体内的白色念珠菌等真菌性***炎致病菌。但是,抗生素疗法有效杀死***致病菌的同时,也同样会杀死***微生态中的正常菌群,造成***菌群失调,从而导致治疗效果不佳、复发率高等问题,最终造成***炎患者久治不愈。
鉴于此问题,我们需要一种有效的药物或治疗方式,能够预防这种***炎的反复发作。有研究表明,***炎发生的核心是***微生态菌群失衡,其重要标志是乳酸菌数量的骤减;而乳酸菌是健康妇***道中最重要、数量最多的菌群,其分离率能够达到50%-80%,数量占95%以上。因此筛选能够拮抗白色念珠菌的乳酸菌,恢复患者***微生态环境对治疗真菌性***炎具有重要意义。
发明内容
本发明要解决的技术问题是提供一种鼠李糖乳杆菌LRa05及其在防治念珠菌***炎方面的应用。
本发明涉及的鼠李糖乳杆菌LRa05,其微生物保藏号为CGMCC No.24377,命名为Lactobacillus rhamnosus;保藏时间:2022年01月24日;保藏地址为北京市朝阳区北辰西路1号院3号;保藏单位:中国科学院微生物研究所。
所述鼠李糖乳杆菌LRa05从粪便样品中分离纯化而来;通过拮抗白色念珠菌的打孔法实验进行初筛,最后经过与白色念珠菌共培养实验进行精筛验证,得到一株具有较强拮抗白色念珠菌的鼠李糖乳杆菌LRa05。
实验证明,本发明提供的鼠李糖乳杆菌LRa05,对白色念珠菌具有较强的拮抗作用,其拮抗能力优于商业菌株LGG,罗伊氏乳杆菌RC-14及鼠李糖乳杆菌GR-1。
本发明提供的鼠李糖乳杆菌LRa05与白色念珠菌共培养24h后,抑制白色念珠菌浓度3个数量级,抑制率高达99.66%
本发明提供的鼠李糖乳杆菌LRa05发酵上清液具有较强的抑制白色念珠菌的能力,其抑制率高达90.05%,有利于***酸性环境的维持与改善,防止白色念珠菌***炎的复发。
本发明提供的鼠李糖乳杆菌LRa05细胞悬浮液及无细胞上清液能有效抑制白色念珠菌生物膜的形成,最终杀死白色念珠菌细胞。
本发明的另一个目的是提供鼠李糖乳杆菌LRa05在制备防治念珠菌***炎药物上的应用。通过白色念珠菌***炎小鼠模型试验,鼠李糖乳杆菌LRa05可显著降低念珠菌***炎小鼠***内的白色念珠菌浓度,经14天治疗的小鼠***炎症反应症状明显得到改善或几乎没有,白细胞明显较少,停药后观察也无反复情况发生,说明鼠李糖乳杆菌LRa05能有效防治白色念珠菌***炎小鼠的复发。
附图说明
图1是鼠李糖乳杆菌LRa05 CFS对白色念珠菌抑制率。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。
下述实施例中涉及的BALB/c小鼠购自北京维通利华公司;下述实施例中涉及的白色念珠菌购自中国普通微生物菌种保藏管理中心,产品编号为:ATCC90028;下述实施例中涉及的DMEM培养基购自Gibco公司。商业菌株1购自广东微生物菌种保藏中心;商业菌株2、商业菌株3可从市购商品中分离获得。
下述实施例中涉及的培养基如下:
MRS液体培养基:葡萄糖20g/L,酵母蛋白胨10g/L,牛肉浸粉10g/L,酵母浸粉5g/L,无水乙酸钠5g/L,吐温-801g/L,柠檬酸氢二铵2g/L,磷酸氢二钾2g/L,七水硫酸镁0.58g/L,一水硫酸锰0.19g/L,水1000mL,ph6.8。
YPD液体培养基:葡萄糖10g/L,蛋白胨10g/L,酵母抽提物5g/L,水1000mL,pH7.0。
发酵培养基配方:葡萄糖2.0%、吐温-800.15%、磷酸氢二钾0.15%、乙酸钠0.3%,硫酸镁·7H2O 0.05%,硫酸锰0.003%、柠檬酸三铵0.4%,可溶性淀粉0.3%、酵母膏1.0%,pH7.0
固体培养基:添加琼脂粉15g/L。
实施例1:抑制白色念珠菌能力的初筛
所筛选菌株来源于微康益生菌菌种资源库,并已经菌种鉴定,从菌种库甘油管出发,按照1%接种量接种到MRS液体培养基中,37℃静置培养16h,得到发酵液;白色念珠菌50ul接种于50mLYPD液体培养基中30℃摇床培养16h,制备菌悬液。
打孔法:将MRS培养基冷却至55℃左右,分别与指示病原菌菌悬液按一定比例混匀,使指示菌的活菌数在105CFU/mL数量级,然后迅速倾注于预先放置牛津杯的平板中,待培养基冷却凝固后,取出牛津杯,每孔打入200ul 108CFU鼠李糖乳杆菌发酵液,37℃兼性厌氧培养24h左右,观察并记录抑菌能力强的抑菌圈情况。实验结果如下表1所示:
表1鼠李糖乳杆菌LRa05抑制白色念珠菌能力记录表
菌株编号 | 抑菌圈直径/mm |
LRa05 | 26 |
商业菌株1鼠李糖乳杆菌LGG | 14 |
商业菌株2罗伊氏菌株RC-14 | 18.5 |
商业菌株3鼠李糖乳杆菌GR-1 | 18 |
商业菌株1购自广东微生物菌种保藏中心。
商业菌株2、商业菌株3可从市购商品中分离获得。
实验结果表明,鼠李糖乳杆菌LRa05对白色念珠菌具有较强的抑制作用,明显强于商业菌株LGG,RC-14及GR-1,其抑菌圈高达26mm。
实施例2:鼠李糖乳杆菌LRa05抑制白色念珠菌生长活性检测
实验分为3组,分别为LRa05组、LGG组以及空白对照组;其中LRa05组、LGG组各取100ul菌液和100ul白色念珠菌菌液接种于装有10mLMRS液体培养基的试管中,振荡混匀,将试管在37℃培养箱培养24h,得到培养液,空白对照组(CK)为:取100uLMRS液体培养基和100uL白色念珠菌菌液接种于装有10mLMRS液体培养基的试管中。振荡混匀,将试管在37℃培养箱培养24h,得培养液。
将各组培养液用无菌生理盐水稀释后,取100ul涂布于YPD固体培养基上,于37℃培养箱倒置培养48h后进行平板计数,获得各组培养液中白色念珠菌的菌落数。
表2鼠李糖乳杆菌LRa05对白色念珠菌生长活性的影响
实验组 | CA活菌数 |
LRa05 | 7.4×10<sup>4</sup> |
LGG | 2.29×10<sup>6</sup> |
CK | 2.20×10<sup>7</sup> |
实验结果表明,鼠李糖乳杆菌LRa05经与白色念珠菌共培养后,与空白对照组(CK)相比,LRa05能够抑制白色念珠菌浓度3个数量级,抑制率高达99.66%,显著高于商业菌株LGG。
实施例3:鼠李糖乳杆菌LRa05发酵上清液(CFS)对白色念珠菌抑制率的检测
乳酸菌CFS的制备:将活化好的乳酸菌菌液吸取1ml,用0.22um的无菌滤膜过滤,即得乳酸菌CFS。实验组为100ulCFS加入96孔板,同时加入100ul白色念珠菌菌液(调整白色念珠菌菌液为106cfu/mL),每组3-6个平行。空白对照组为100ulMRS加入100ul白色念珠菌菌液,96孔板在37℃培养箱培养24h后。用酶标仪在OD630nm下测量96孔板的每孔吸光度值并计算CFS对白色念珠菌的抑菌率。计算公式如下:
抑菌率/%=[(ODcontrol-ODcfs)/ODcontrol]×100%。
实验结果如图1所示:鼠李糖乳杆菌LRa05 CFS对白色念珠菌抑制率高达90.05%,显著高于商业菌株LGG(74.38%)。说明鼠李糖乳杆菌LRa05顺利定植***后,其发酵持续产酸,能够维持或改善***酸性环境,防止白色念珠菌***炎症的复发。
实施例4:鼠李糖乳杆菌LRa05生物膜形成能力及对白色念珠菌生物膜形成抑制能力
试剂:XTT:3,3’-[1-(苯胺酰基)-3,4-四氮唑]-二(4-甲氧基-6-硝基)苯黄酸钠(XTT)(Sigma,美国);甲萘醌(Sigma公司);
1mg/ml XTT的配制:采用PBS溶液将XTT配成1mg/mL的溶液,0.22um滤膜过滤,分装后-70℃避光保存。
0.4mM甲萘醌溶液的配制:用无水乙醇配制,现配现用。
取100ul白色念珠菌菌液(107cfu/ml)接种于96孔板中,将96孔板在37℃75r/min条件下培养1.5h后,各组为:实验组:100ul乳酸菌(107cfu/mL)(或CFS)加入100ul白色念珠菌(107cfu/mL);乳酸菌组:100ulL.b+100ulMRS;CA组:100ul CA+100ulYPD。
将加好样的96孔板在37℃条件下培养48h后;用PBS缓冲液清洗96孔板3遍,将79ulPBS、20ul XTT(1mg/ml)和1ul PMS(0.4mM甲萘醌溶液)加入到96孔板中,避光培养2h后,使用酶标仪在OD492nm下测量96孔板的每个孔的吸光度值,并计算乳酸菌CFS对白色念珠菌生物膜形成的抑制率。
表3鼠李糖乳杆菌LRa05生物膜形成能力及对白色念珠菌生物膜形成抑制率
生物膜是白色念珠菌自然状态下的存在形式,故有必要研究白色念珠菌生物膜的去除,实验结果如表3所示:鼠李糖乳杆菌LRa05的OD492nm远低于白色念珠菌吸光度值,吸光度值越低表明生物膜形成能力越低,从以上数据可以看出鼠李糖乳杆菌LRa05形成生物膜能力较低,而LRa05与白色念珠菌混合液的检测结果表明鼠李糖乳杆菌LRa05(尤其是其发酵上清液)可以显著降低白色念珠菌的生物膜形成能力,从而减少或破坏白色念珠菌对***上皮细胞的粘附,最终杀死白色念珠菌细胞,同时其CFS还能维持或改善***酸性环境,防止念珠菌***炎的复发。
实施例5:鼠李糖乳杆菌LRa05对念珠菌***炎小鼠***内白色念珠菌浓度的影响
取32只雌性、8周龄、体重20-25g的BALB/c小鼠,随机分成3组,每组8只、3组分别为空白组、模型组、鼠李糖乳杆菌LRa05治疗组1(LRa05发酵悬浮液)及鼠李糖乳杆菌LRa05治疗组2(LRa05发酵上清液)
实验分为造模和治疗两部分,实验开始前3天,除空白对照组小鼠外,其余组小鼠均皮下注射100ul戊酸***,诱导小鼠发情,实验开始后,除空白对照组小鼠外,其余组小鼠仍需平均每周皮下注射1次100ul戊酸***。
造模第一天,除空白对照组小鼠外,其余组小鼠均***内接种20ul菌浓度为108CFU/mL的白色念珠菌菌液,接种后,将小鼠倒立5min,以防止菌液流出,第一次接种完毕后,每2天接种1次,共接种3次,直至造模结束。
治疗第1天,模型组小鼠***内注射20ul生理盐水,鼠李糖乳杆菌LRa05组1小鼠***内接种20ul菌浓度为108CFU/mL的鼠李糖乳杆菌LRa05细胞悬液,鼠李糖乳杆菌LRa05组2小鼠***内接种20ul菌浓度为108CFU/mL的鼠李糖乳杆菌LRa05发酵上清液,每天治疗1次,共治疗14天,空白对照组小鼠不作处理。
(1)小鼠***白色念珠菌浓度载量分析
分别在治疗的第0天、7天、14天用50ul无菌PBS缓冲液灌洗各组小鼠***3次,收集灌洗液,置于洁净无菌管中,将3次取得的灌洗液充分混匀,用0.9%的生理盐水进行梯度稀释后用移液器吸取100ul涂布于YPD固体培养基上,于37℃培养箱倒置培养48h后,进行平板计数,获得各组小鼠***内的白色念珠菌浓度(计数结果或抑制率见表4-5)。
表4各实验组每次取样白色念珠菌平均浓度
表5LRa05上清液治疗组对白色念珠菌的抑制率
由表4-5可知,造模结束后,空白对照组小鼠***内不含白色念珠菌,其余组别小鼠***内白色念珠菌浓度约为108CFU/mL;治疗结束后,鼠李糖乳杆菌LRa05细胞悬液治疗组小鼠***内白色念珠菌浓度普遍降低了近3个数量级。表明***内接种鼠李糖乳杆菌LRa05可显著降低念珠菌***炎小鼠***内的白色念珠菌浓度。经14天治疗后,与模型组(前1周,由于自身免疫***作用白色念珠菌浓度有降低趋势,但第14天时,白色念珠菌浓度增高)相比,LRa05发酵上清液治疗组的LRa05发酵上清液对小鼠***内白色念珠菌的抑制率高达87.76%。
(2)治疗后外阴观察及停止治疗后第7天小鼠外阴观察
观察并记录各组小鼠外阴红肿、***分泌物多少的情况,并取各组小鼠做灌洗液涂片,染色。
表6治疗后小鼠外阴红肿及分泌物等炎症情况
表6实验结果表明白色念珠菌在小鼠***引起的炎症反应情况,模型组小鼠外阴出现严重红肿,分泌物多且成块状等典型念珠菌症状,表明造模成功;经鼠李糖乳杆菌LRa05发酵液或上清液治疗后,各症状均有明显减轻,尤其是LRa05发酵液组有些小鼠红肿,外阴充血等症状几乎没有,分泌物也较少。
同时,***灌洗液染色结果显示空白组小鼠白细胞数目较少,模型组小鼠白细胞数目较多,说明小鼠***黏膜被严重破坏,经LRa05发酵液治疗后的小鼠白细胞数目明显较少,上皮细胞占比较多;LRa05发酵上清液治疗组的小鼠白细胞数目也有一定程度的减少。
停药后第7天观察结果表明,模型组炎症反应情况变得越来越严重,而治疗组小鼠炎症反应症状与给药后观察结果相比,无反复情况发生。
实施例6鼠李糖乳杆菌LRa05在生态妇科外用药物洗剂及凝胶剂中的应用
将活化好的鼠李糖乳杆菌LRa05接种于发酵培养基中,接种量1.0%。37℃发酵24h,再将温度降至32℃继续培养,经检测还原糖耗尽,结束发酵,将发酵液离心,收集离心液,得到所说的益生菌发酵培养物。
(1)鼠李糖乳杆菌LRa05生态妇科外用药物组合物洗剂的制备:将鼠李糖乳杆菌LRa05发酵完成后加入苯扎溴铵,使苯扎溴铵的浓度为0.05ml/100ml,搅拌均匀,同时,使得最终洗剂活菌含量为50亿CFU/mL。即得到本洗剂。
(2)鼠李糖乳杆菌LRa05生态妇科外用凝胶剂的制备:根据比例,将羟丙甲纤维素15g加热至90℃,继续搅拌并加热至微沸,保持微沸15min,不断搅拌,温度降至55℃时,加入鼠李糖乳杆菌LRa05发酵培养物800ml,同时,加入苯扎溴铵溶液,使终浓度为0.05vol%,取薄荷脑0.8g,研细,加入甘油100mL,研匀溶解,并加入到LRa05发酵培养物中,不断搅拌,温度降至30℃以下时,结束搅拌,即得LRa05生态妇科外用凝胶剂。
Claims (5)
1.鼠李糖乳杆菌LRa05在制备防治念珠菌***炎药物上的应用,鼠李糖乳杆菌LRa05,其微生物保藏号为CGMCC No.24377,命名为Lactobacillus rhamnosus;保藏时间:2022年01月24日;保藏单位:中国科学院微生物研究所。
2.根据权利要求1所述的应用,其特征在于,所述药物为洗剂。
3.根据权利要求2所述的应用,其特征在于,将权利要求1所述的鼠李糖LRa05发酵完成后加入苯扎溴铵,使苯扎溴铵的浓度为0.05ml/100ml,搅拌均匀,同时,使得最终洗剂活菌含量为50亿CFU/mL,即得到洗剂。
4.根据权利要求1所述的应用,其特征在于,所述药物为凝胶剂。
5.根据权利要求4所述的应用,其特征在于,根据比例,将羟丙甲纤维素15g加热至90℃,继续搅拌并加热至微沸,保持微沸15min,不断搅拌,温度降至55℃时,加入鼠李糖乳杆菌LRa05发酵培养物800ml,同时,加入苯扎溴铵溶液,使终浓度为0.05vol%,取薄荷脑0.8g,研细,加入甘油100mL,研匀溶解,并加入到LRa05发酵培养物中,不断搅拌,温度降至30℃以下时,结束搅拌,即得LRa05生态妇科外用凝胶剂。
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