CN116286484A - 卷曲乳杆菌及其用途 - Google Patents
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- CN116286484A CN116286484A CN202310084559.6A CN202310084559A CN116286484A CN 116286484 A CN116286484 A CN 116286484A CN 202310084559 A CN202310084559 A CN 202310084559A CN 116286484 A CN116286484 A CN 116286484A
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- lactobacillus crispatus
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- lactobacillus
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Abstract
本发明公开了卷曲乳杆菌及其用途,卷曲乳杆菌为卷曲乳杆菌chen‑01(Lactobacillus crispatus chen‑01),其保藏编号为CGMCC NO.23396。卷曲乳杆菌可用于制备药物,药物用于治疗和/预防HPV感染以及阴道感染。本发明阴道局部移植所述卷曲乳杆菌制备的药物后,可有效降低HPV病毒载量,显著提高HPV清除率,能有效改善阴道炎,明显降低阴道菌群多样性和丰度;此外,阴道局部移植卷曲乳杆菌还可显著改善阴道微生态构成,与正常健康人群接近。
Description
技术领域
本发明属于生物医药技术领域,具体涉及卷曲乳杆菌及其用途。
背景技术
宫颈癌是最严重的宫颈病变,是妇科常见的恶性肿瘤,是导致女性死亡的第二大癌症,现已经确定是由人乳头状瘤病毒(human papilloma virus,HPV)导致的实体肿瘤,而高危型HPV持续感染是宫颈癌及癌前病变的必要条件。人乳头状瘤病毒(HPV)一种小型环状双链DNA病毒,是一种具有感染表皮和粘膜鳞状上皮的病毒。根据HPV致病力大小或致癌危险性大小不同,可将HPV分为低危型、高危型两大类。高危型包括HPV16、18、31、33、35、45、51、52、56、58、61等。据报道,在侵袭性宫颈癌中,几乎所有的宫颈癌活检中都存在完整的HPV DNA在侵袭性宫颈癌中,几乎所有的宫颈癌活检中都存在完整的HPV DNA,其主要的HPV致癌蛋白(特别是E6和E7)参与宫颈癌的转化、永生化和恶性肿瘤。
关于HPV感染的治疗,目前临床上尚缺乏公认有效的治疗手段,其主要的方法有:物理治疗(主要是去除肉眼可见的瘤体和亚临床感染)包括:激光、微波、冷冻、电灼、手术切除(妇科的LEEP刀等)等;药物治疗:0.5%足叶草脂毒素酊,5%咪喹莫特,50%三氯醋酸、氟尿嘧啶软膏等;免疫疗法:其在于减少复发和加快清除病灶,药物有:干扰素、白介素、胸腺肽、转移因子、卡介苗、异维A酸、自体疫苗等;治疗性疫苗:目前还没有有效的治疗性疫苗。但以上方法均存在各种缺陷,治疗效果差强人意。因此,寻找安全有效的抗HPV的治疗方法一直是子宫颈癌前病变及宫颈癌防治的研究热点。
微生态学是一门新兴学科,随着社会的不断发展,微生态学越来越受到学者们的关注。阴道微生态系统是人体四大生态系统中较为复杂且重要的系统,它在人类繁衍和疾病的防御机制中起着重要作用。女性阴道微生态体系,由解剖结构、阴道菌群、局部免疫功能及机体的内分泌调节功能共同组成,其中阴道内正常菌群是阴道微生态系统研究的核心内容。阴道微生态作为复杂的生态系统,随宿主年龄而变化,月经周期、妊娠及不同身体条件下处于动态平衡状态,这种平衡有益于宿主的健康。
正常情况下,女性阴道内可分离出几十种微生物,包括白假丝酵母菌、加德纳菌、大肠埃希菌、肠球菌、消化链球菌、表皮葡萄球菌等条件致病菌,同时也可以分离出双歧杆菌、乳杆菌等益生菌,致病菌与益生菌二者处于动态平衡状态。阴道内最常见的乳酸杆菌是卷曲乳酸杆菌,惰性乳酸杆菌,詹氏乳酸杆菌、格氏乳酸杆菌等。阴道乳杆菌为其优势菌,栖息于阴道粘膜表面,通过代谢糖原产酸,使阴道处于酸性环境,与阴道内的粘液形成生物膜,产生细菌素、类细菌素和生物表面活性剂,阻止有害菌群在阴道内定植,还能激活多种免疫细胞进一步促进宿主体液免疫和细胞免疫的形成,有利于维持阴道微生态的平衡。当平衡被打破,除了导致各种阴道炎症,甚至可能促进癌变发生。
近年来,阴道微生态的改变在生殖道HPV感染中的作用引起了越来越多学者的关注。研究者对HPV阴性的正常女性的阴道分泌物与HPV阳性的阴道分泌物通过高通量测序,发现两者在阴道微生态存在明显的差别,HPV阳性者主要表现为高度多样化的阴道微生物,并且乳酸杆菌的减少和阴道加德纳菌的增加。此外,大量文献证明,细菌性阴道病(bacterial vaginosis,BV)与HPV感染的发病率、患病率和持久性呈正相关。BV实际为一种阴道菌群失调,主要表型为阴道内分泌H2O2的乳杆菌减少,而加德纳菌以及厌氧菌大量繁殖所致。正常情况,乳杆菌通过维持低pH和细菌素等产生,防止细菌阴道病相关细菌物种的定植,这对于维持抑制HPV进入基底角质形成细胞的宫颈上皮屏障功能很重要。当BV相关的严格厌氧菌能够定植时,它们会产生酶和代谢物,这可能会损害这种屏障,为HPV的感染和侵入提供了良好的环境。HPV的进入,特别是高危型HPV片段和宿主基因整合并最终进行肿瘤转化。因此,HPV感染与阴道局部微生态环境紊乱,尤其是乳杆菌的减少是密不可分的。
益生菌目前被定义为“当以足够数量施用时,可使宿主获得健康益处的活微生物”。益生菌包括活细菌(如双歧杆菌、乳杆菌和链球菌),它们可以调节微生物群的组成,以改善微量营养素的健康、免疫系统、炎症状态和生物利用度。
目前,益生菌已经普遍应用于胃肠疾病(如腹泻便秘,肠道易激综合征,各种肠道炎性疾病,幽门螺杆菌的根治等),以及婴幼儿乳糖不耐受,新生儿坏死性肠炎等。它可以降低患糖尿病的风险,并改善血脂异常治疗心血管疾病、过敏性疾病和某些癌症,在预防口腔感染及龋齿,甚至自闭症中也有报道。在女性生殖道,益生菌已经被证实可用于治疗细菌性阴道病,念珠菌性阴道炎等炎性疾病,是一种安全有效的方法。
目前,临床上益生菌应用于治疗宫颈阴道HPV感染的文献报道比较少,因此本研究拟探讨HPV感染者阴道微生态的变化,以及益生菌对宫颈阴道HPV感染患者的治疗作用,以期提高HPV感染的清除率,为预防及治疗宫颈上皮内瘤变及宫颈癌提供新的方法。
发明内容
针对现有技术中的不足与难题,本发明旨在提供一种卷曲乳杆菌及其用途,阴道局部移植卷曲乳杆菌后HPV感染者阴道微生态发生变化,对宫颈阴道HPV感染患者具有治疗作用,提高了HPV感染的清除率,为预防及治疗宫颈上皮内瘤变及宫颈癌提供新的方法。
本发明通过以下技术方案予以实现:
本发明一方面提供一种卷曲乳杆菌,该卷曲乳杆菌已于2021年09月13日保藏于在中国微生物菌种保藏管理委员会普通微生物中心(简称CGMCC),保藏单位地址为:北京市朝阳区北辰西路1号院3号,中国科学院微生物研究所,保藏登记号为CGMCC NO.23396,该菌株的分类命名为卷曲乳杆菌(Lactobacillus crispatus chen-01)。
本发明另一方面提供上述卷曲乳杆菌在制备药物中的用途,所述药物用于治疗和/预防HPV感染。
进一步地,所述药物具有降低HPV病毒载量和提高HPV清除率的功能。
本发明另一方面提供上述卷曲乳杆菌在制备药物中的用途,其特征在于:所述药物用于治疗和/预防阴道感染。
进一步地,所述药物用于显著改善阴道微生态和降低阴道菌群多样性和丰度。
本发明还提供一种药物产品,其含有前述的卷曲乳杆菌以及任选的一种或多种药学上可接受的药物载体和/或药用辅料。
与现有技术相比,本发明卷曲乳杆菌(Lactobacillus crispatus chen-01)是一株全新的分离株,阴道局部移植该卷曲乳杆菌后,可有效降低HPV病毒载量,显著提高HPV清除率,能有效改善阴道炎,明显降低阴道菌群多样性和丰度;此外,阴道局部移植卷曲乳杆菌还可显著改善阴道微生态构成,与正常健康人群接近。
附图说明
图1为L.crispatus chen-01阴道内移植对阴道菌群多样性和丰度的影响;其中图(A)为比较H-b、H-f、H-Bb组的Chaol、Observed species、Shannon、Simpson和Good′scoverage;图(B)为益生菌处理前后的PCoA分析;图(C)为益生菌处理前(H-b)与处理后(H-Bb)的物种组成热图。
图2为L.crispatus chen-01阴道内移植对阴道微生态组成的影响;其中图(A)为C.H-b、H-f和H-Bb组阴道门水平微生态组成的比较;图(B)为C、H-b、H-f和H-Bb组阴道微生态组成属水平的比较;图(C)-图(E)分别为C、H-b、H-f和H-Bb组厚壁菌门(Firmicutes)、拟杆菌门(Bcateroidetes)和放线菌门(Actinobacteria)门组成比较;图(F)-图(H)分别为C、H-b、H-f、H-Bb组乳酸菌属、普雷沃氏菌属、加德纳菌属组成比较。
具体实施方式
下面结合附图,对本发明作进一步地说明。实施例的实验中所用到的试剂,如无特殊说明,均可通过市售获得。
实施例1卷曲乳杆菌(Lactobacillus crispatus chen-01)的筛选及体外性质评价
1、卷曲乳杆菌(Lactobacillus crispatus chen-01)的筛选
运用培养组学的技术,将临床收集的健康妇女阴道分泌物倍比稀释,平板涂布分离筛选,提取分离菌落的DNA送公司测序,鉴定菌株,分离筛选出阴道卷曲乳酸杆菌,并于2021年09月13日将该卷曲乳杆菌保藏于在中国微生物菌种保藏管理委员会普通微生物中心(简称CGMCC),保藏单位地址为:北京市朝阳区北辰西路1号院3号,中国科学院微生物研究所,保藏登记号为CGMCC NO.23396,该菌株的分类命名为卷曲乳杆菌chen-01(Lactobacillus crispatus chen 01)。
筛菌鉴定测序序列(SEQ ID NO.1):
2、卷曲乳酸杆菌(Lactobacillus crispatus chen-01)体外性质评价
1.耐酸试验
将卷曲乳酸杆菌菌株(Lactobacillus crispatus chen-01)用MRS培养基在37℃摇床培养24h;24h后取出100μL菌液分别加入pH=2、4、5、6、7的PBS缓冲液中,厌氧培养4h后,进行点板计数。
结果表明卷曲乳酸杆菌(Lactobacillus crispatus chen-01)对高浓度酸具有良好的耐受性。
2.抗氧化性试验
(1)DPPH自由基清除能力的测定:
将卷曲乳酸杆菌菌株(Lactobacillus crispatus chen-01)用MRS培养基在37℃摇床培养24h;24h后将菌液于8000rpm离心3min取上清液。
取1mL菌液上清液与1mL配制好的DPPH自由基的甲醇溶液混合,震荡均匀后避光条件下室温反应30min,517nm波长处测其OD值(去离子水作为空白对照)。
DPPH自由基清除率:[1-A517(样品)/A517(空白)]×100%
(2)清除羟自由基的能力测定:
将卷曲乳酸杆菌菌株(Lactobacillus crispatus chen-01)用MRS培养基在37℃摇床培养24h;24h后将菌液于8000rpm离心3min取上清液。
取1mL上清液加入玻璃试管中(样品管),空白管中加入1mLddH2O,另分别加入1mL3mmol/L的水杨酸,1mL 1mmol/L的FeSO4,1mL 3mmol/L的H2O2,混合均匀后37℃水浴锅中反应15min,用分光光度计在510nm波长处测定吸光度。
羟自由基清除率(%)=[1-A510(样品)/A510(空白)]×100%
结果表明卷曲乳酸杆菌菌株(Lactobacillus crispatus chen-01)表现出良好的抗氧化能力,DPPH、O2-和OH-还原能力。
3.抑菌实验
将卷曲乳酸杆菌菌株(Lactobacillus crispatus chen-01)用MRS培养基在37℃摇床培养24h;24h后将菌液于8000rpm离心3min取上清液。
将白色念珠菌、金黄色葡萄球菌、大肠杆菌O157、乙型溶血性链球菌、粪肠球菌、加德纳菌涂布LB固体培养基中。将牛津杯轻轻放于平板上,吸取益生菌培养上清250μL于牛津杯中(每组做两个重复),37℃恒温培养,每隔2h观察抑菌圈大小,8h后测量抑菌圈直径。
结果表明卷曲乳酸杆菌菌株(Lactobacillus crispatus chen-01)表现出对白色念珠菌、金黄色葡萄球菌、大肠杆菌O157、乙型溶血性链球菌、粪肠球菌、加德纳菌良好的抑制效果。
实施例2阴道局部移植卷曲乳杆菌对高危型HPV感染妇女的影响
1、研究对象说明
研究对象为2021年7月1日至2022年6月30日在南昌市第一医院和景德镇市妇幼保健院妇科门诊或住院部招募的宫颈HR-HPV感染女性患者,通过询问病史及查看既往病例资料,选取宫颈HR-HPV感染的女性161例纳入研究。所有研究对象均接受阴道镜检查,必要时宫颈活检。研究对象的年龄、孕产史、吸烟、避孕方式、初始性行为年龄、性伴侣个数等情况被收集(表1)。所有患者获得知情同意。本项目已通过医院医学伦理会批准,并在中国临床实验注册中心官网注册(注册号ChiCTR2100046239)。
入选标准:①患者签订知情同意书;②年龄在18-65岁,有性生活史;③未使用任何药物;④检查前3天无性生活,无阴道冲洗及上药;⑤无异常阴道出血;⑥无合并全身系统性疾病:糖尿病、需用激素类药物治疗疾病(急慢性肾炎)等。
排除标准:①宫颈高级别上皮内瘤变或宫颈癌患者或生殖道肿瘤者;②不同意参与实验的妇女;③受检者在检查前3天有阴道灌洗、放药史或性生活史;④受检者在检查前3天服用避孕药、抗生素、免疫抑制剂等药物;⑤子宫全切或次全切除术后患者;⑥有严重内科合并症,如糖尿病、自身免疫性疾病、免疫缺陷病等;⑦对益生菌过敏者。
分组及处理:根据纳入和排除标准,最后符合条件有100人。采用随机数表法,将研100名研究对象按1∶1随机分配到安慰剂组(H-f)和益生菌组(H-Bb)。本实施例H-Bb组使用的益生菌制剂为卷曲乳杆菌(L.crispatus chen-01,编号CGMCC 23396)与甘薯粉的混合物,每胶囊活菌菌落形成单位(CFU)为1×109CFU(以下简称益生菌)。益生菌组患者采用阴道局部给予益生菌胶囊,具体用药方法:清洁外阴后,戴上指套,将本品放入阴道深部,晚上睡前上药每次一粒,每日一次。第1-3月每晚连用10天。第4-5月开始每三天使用一次,共5次。避开月期间,用药期间不可冲洗阴道。安慰剂组患者使用仅装有配料的胶囊,用法同益生菌组。
试验开始时有161名女性参与,根据纳入和排除标准评估符合条件的100人,最后随机分为益生菌组(H-Bb组)和安慰剂组(H-f组),每组各50例。
表1患者基本特征(均值±标准差)
在研究过程中,H-Bb组1例退出,2例失访,H-f组2例退出,2例失访,最后益生菌组(H-Bb)45例完成试验期,安慰剂组(H-f组)46例完成试验期。
2、标本的采集
用阴道扩张器暴露宫颈,用无菌棉球擦拭其分泌物,然后用专用刷子顺时针旋转3次。将刷子取出,放入专用的保存液中。样本一部分用于HPV DNA检测,另一部分用于TCT检测细胞学分类。混合捕获II(HC II)检测HR-HPV型别:16、18、31、33、35、39、45、51、52、56、58、59、68,以HPV-DNA≥1pg/mL为阳性标准。采用实时荧光定量PCR检测HPV型别。治愈定义为所有HPV亚型转为阴性。有效定义为一种或多种HPV亚型转为阴性。无效定义为HPV亚型增加或无HPV亚型转为阴性。HPV清除率(%)=治愈率(%)+有效率(%)。TCT检测时,将样品漂洗得到细胞,通过自动细胞检测仪进行分散和过滤,然后进行显微检测和分析。
3、DNA提取和高通量测序
入组后的第6个月,于月经干净3~7天采集阴道分泌物标本。取膀胱截石位,由妇科专业医师用一次性阴道窥器(扩阴器上不涂碘伏等消毒液,以免镜下与白细胞难以鉴别)暴露宫颈,用无菌的干棉签取患者阴道后穹窿及阴道侧壁上1/3的适量阴道分泌物,放入已灭菌的EP管中密闭,做好标记,置于-80℃冰箱备用,用于16S rDNA高通量测序。
4、阴道局部移植L.crispatus chen-01可有效降低HPV病毒载量
如表2所示,益生菌组(H-Bb)和安慰剂组(H-f)患者初始HPV病毒载量分别为267.70±27.68和245.10±26.43,两组相比无显著性差异(p=0.56>0.05)。益生菌治疗后,患者病毒载量为113.10±21.69,与治疗前相比显著降低(p<0.01),与对照组患者在随访后的病毒载量相比亦有显著性差异(p=0.01<0.05)。而安慰剂组患者在随访后的病毒载量跟入组时相比未见显著性差异(p=0.27>0.05)。
表2两组治疗前后HPV病毒载量(均值±标准差)
5、L.crispatus chen-01阴道移植可显著提高HPV清除率
如表3所示,6个月后随访,益生菌组21例转阴,5例有效,19例阳性,总有效率为57.78%。安慰剂组(H-f组)转阴性17例,有效4例,阳性25例,总有效率为45.65%。益生菌组总有效率高于对照组,但两者之间无显著性差异(p=0.25>0.05)。
表3两组治疗前后的HPV清除率(均值±标准差)
6、乳杆菌L.crispatus chen-01阴道移植能有效改善阴道炎
如表4所示,宫颈液基细胞学分析显示,与入组时相比,H-f组比入组时的细胞学异常的改善率为34.62%,炎症改善率为27.27%。H-Bb组与入组时的细胞学异常改善率为82.14%,阴道炎改善率为77.78%,均高于H-f组(p<0.05)。此外,本研究期间未发生不良事件。
表4两组治疗前后的细胞学和炎症学变化(平均值±SD)
7、阴道局部移植L.crispatus chen-01后阴道菌群多样性和丰度明显降低
使用16S RNA测序分析局部移植L.crispatus chen-01对阴道菌群多样性和丰度的影响。为了能较为全面的评估微生物群落的alpha多样,本流程以Chao1和Observedspecies指数表征丰富度,以Shannon和Simpson指数表征多样性,以Good’s coverage指数表征覆盖度,结果如图1所示,H-b:入组前HR-HPV患者;H-f:使用安慰剂组HR-HPV患者;H-Bb:益生菌治疗后的HR-HPV患者。如图1A所示,接受益生菌治疗的患者,与治疗前相比,Chao1、Observed species、Shannon和Simpson等指数显著降低(p<0.05),而Goodscoverage指数显著升高(p<0.05)。Beta多样性分析采用PCoA。如图1B所示,益生菌组患者治疗后相比,显示出明显的聚集。为了进一步比较样本间的物种组成差异,实现对各样本的物种丰度分布趋势的展示,使用热图进行物种组成分析。如图1C所示,与治疗前相比,益生菌治疗后,乳杆菌(Lactobacillus)显著增加。
8、阴道局部移植卷曲乳杆菌显著改善阴道微生态构成
分别从门和属分析各组患者阴道微生态构成,L.crispatus chen-01阴道内移植对阴道微生态组成的影响如图2所示,图中C:无HPV感染的健康人;H-b:入组前HR-HPV患者;H-f:安慰剂治疗的HR-HPV患者;H-Bb:益生菌治疗后的HR-HPV患者。*p<0.05;**p<0.01。
在门水平(如图2A所示),正常健康人群中(C组)中阴道菌群以厚壁菌门为主(Firmicutes)占95.13%,其余菌只占不到5%,而HR-HPV治疗前Firmicutes占(60.1%),其余主要菌有Bacteroidetes(21.20%),Fusobacteria(11.93%),Actinobacteria(3.6%)。两者比较,HR-HPV组呈现明显的菌群多样性(p=0.0058)。而对于HR-HPV组中益生菌治疗后,阴道菌群又接近正常人群,呈现以厚壁菌门为优势菌(Firmicutes)占94.96%,与治疗前相比,菌群多样性有明显差异(p=0.0009),而对照组无统计学意义(p=0.0789)。
在属水平进一步分析(如图2B所示),正常健康人群中(C组)中以乳杆菌(Lactobacillus)为阴道优势菌群占94.74%,同时也包含Prevotella,Sneathia,Gardnerella,但含量极少。而HR-HPV治疗前Lactobacillus占56.45%,其余主要菌有Prevotella(13.51%),Sneathia(6.42%),Gardnerella(3.17%)丰度显著增加。与健康人群相比阴道微生态呈现明显的菌群多样性,但益生菌治疗后,阴道菌群多样性也随之下降,与正常健康人群接近(Lactobacillus占90.75%)。
图2C-2H具体展示了厚壁菌门(Firmicutes)、拟杆菌门(Bcateroidetes)、放线菌门(Actinobacteria);乳酸菌(Lactobacillus)、普雷沃氏菌(Prevotella)和加德纳菌(Gardnerlla)在两组患者中的占比分布情况。
以上所述仅表达了本发明的优选实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形、改进及替代,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (8)
1.卷曲乳杆菌,其特征在于:所述卷曲乳杆菌为卷曲乳杆菌chen-01(Lactobacilluscrispatus chen-01),其保藏编号为CGMCC NO.23396。
2.权利要求1所述的卷曲乳杆菌在制备药物中的用途,其特征在于:所述药物用于治疗和/预防HPV感染。
3.根据权利要求2所述的用途,其特征在于:所述药物具有降低HPV病毒载量的功能。
4.根据权利要求2所述的用途,其特征在于:所述药物具有提高HPV清除率的功能。
5.权利要求1所述的卷曲乳杆菌在制备药物中的用途,其特征在于:所述药物用于治疗和/预防阴道感染。
6.根据权利要求5所述的用途,其特征在于:所述药物用于显著改善阴道微生态。
7.根据权利要求5所述的用途,其特征在于:所述药物用于降低阴道菌群多样性和丰度。
8.一种药物产品,其包括权利要求1所述的卷曲乳杆菌以及任选的一种或多种药学上可接受的药物载体和/或药用辅料。
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