CN114848683B - 一种长双歧杆菌在制备预防或治疗多囊卵巢所致不孕症药物中的应用 - Google Patents
一种长双歧杆菌在制备预防或治疗多囊卵巢所致不孕症药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种长双歧杆菌在制备预防或治疗多囊卵巢所致不孕症药物中的应用，长双歧杆菌CECT7894可以保养卵巢，调理内分泌失调，有效抑制卵巢囊肿产生。
Description
技术领域
本发明属于药物领域，特别涉及一种长双歧杆菌在制备预防或治疗多囊卵巢所致不孕症药物中的应用。
背景技术
不孕症被列为21世纪影响人类健康的主要疾病，排卵功能障碍约占30％。女性罹患不孕症，严重降低患者的生活质量，给家庭和社会带来巨大精神和经济负担。随着生活方式和环境因素变化,我国不孕症患病率呈增长趋势。目前确切病因尚仍不清楚，缺乏病因学治疗手段，但学者普遍认为不孕症可能是遗传基因与环境相互作用的结果。由于病因不清、发病率高及疗效不佳等特点，阐明不孕症发病机制，寻求精准治疗靶点，对于这种复杂的异质性疾病的有效防治具有重要意义。
多囊卵巢是一种育龄期女性常见内分泌紊乱疾病，以高雄激素血症，月经稀发或者不排卵，B超见卵巢一侧或双侧多囊样改变为主要特征，临床症状有月经紊乱和不孕等，伴发症状可为胰岛素抵抗等。多囊卵巢人群总发病率6％-15％，中国发病率高达16％，育龄期妇女不孕症发病率为50％-70％。多囊卵巢不仅影响育龄期妇女生育能力，而且长期未干预会增加患者子宫内膜癌等罹患风险。目前多囊卵巢的西医治疗主要为药物治疗和手术治疗，主要是诱发排卵，氯米芬、促性腺激素类药物和辅助生殖技术进行治疗，但该类药品或技术治疗费用较高，副作用较多，可造成卵巢增大、囊肿形成，过度刺激卵巢。因此寻找一个针对多囊卵巢所致不孕症无副作用的治疗方法刻不容缓。
益生菌是对人体健康发挥有益作用的活性有益微生物的总称，具有一定的疾病治疗作用。通过调节宿主粘膜与系统免疫功能或调节肠道内菌群平衡，促进营养吸收，保持肠道健康的作用，从而产生有利于健康作用的单微生物或组成明确的混合微生物。但据我们检索目前还没有专门预防和治疗多囊卵巢所致不孕症的长双歧杆菌。
环境内分泌干扰物邻苯二甲酸二(2-乙基己基)酯[Di(2-ethylhexyl)phthalate，DEHP]作为常见塑化剂，具有持久性有机污染物的属性。流行病学调查结果显示，DEHP体内暴露可影响卵巢正常功能，增加不孕症的患病风险。动物毒理实验也发现，DEHP通过干扰卵巢生殖内分泌功能，进而诱发不孕症。DEHP对雌性生殖系统的内分泌干扰作用，为使用DEHP建立不孕症大鼠在体模型提供了理论依据。
发明内容
本发明所要解决的技术问题是提供一种长双歧杆菌在制备预防或治疗多囊卵巢引起的不孕症药物中的应用。
本发明提供一种长双歧杆菌在制备预防或治疗多囊卵巢引起的不孕症药物中的应用。
本发明提供一种长双歧杆菌在制备调节肠道菌群药物中的应用。
所述药物有效抑制卵巢囊肿产生。
所述长双歧杆菌为长双歧杆菌CECT7894。
所述药物的制剂剂型包括口服液、胶囊剂、片剂或注射剂。
所述药物包括食品、健康食品或营养补充剂。
所述药物包括单方制剂或复方制剂。
有益效果
本发明中长双歧杆菌CECT7894能够显著缓解多囊卵巢引起的不孕症症状，对卵巢功能具有一定的修复作用。不孕症大鼠经灌胃给予长双歧杆菌CECT7894干预，结果显示，长双歧杆菌CECT7894可以保养卵巢，调理内分泌失调，有效抑制卵巢囊肿产生。
附图说明
图1为CECT7894对不孕症的干预机制示意图；
图2为各组大鼠表型特征比较研究；(A)体重变化比较；(B)卵巢的一般形态；(C)卵巢卵泡形态的HE染色结果(50μm)；(D)卵巢间质细胞的HE染色结果(50μm)；(E)小肠组织的HE染色结果(100μm)；
图3为各组卵泡发育情况比较；(A)卵泡和黄体(1mm)*卵泡，#黄体；(B)卵泡和黄体计数；(C)卵巢组织卵泡发育相关基因表达情况；(D)小肠组织关键基因表达情况，**P≤0.01，****P≤0.0001；
图4为各组大鼠血清激素和免疫因子分泌水平；(A)性激素分泌水平；(B)免疫因子分泌水平；其中*P≤0.1，**P≤0.01，***P≤0.001；
图5为卵巢组织的免疫组化染色结果(20μm)；(A)AR；(B)ER；(C)FSHR；(D)LHCGR；(E)PR；
图6为粪便肠道菌群组成；(A)Class水平差异菌群；(B)Family水平差异菌群；(C-D)genus水平差异菌群；(E-F)phylum水平差异菌群；
图7为粪便菌群代谢产物差异性；(A)Prostaglandin C1；(B)Arachidonate；(C)Norethindrone；(D)富集气泡图。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
长双歧杆菌CECT7894：迪辅乐安双歧益生菌。
实施例1
选择用1月龄wistar大鼠，模型组：采用500mg/kg/d DEHP灌胃4周，每周六天。治疗组：采用1×108CFU/g/d CECT7894，灌胃时间与模型组相同；对照组：采用玉米油灌胃，灌胃时间同上。
使用DEHP建立不孕症大鼠在体模型，经CECT7894干预，CECT7894对不孕症的治疗作用。
长双歧杆菌CECT7894可以改变肠道菌群组成，通过调控卵巢WNT/β-catenin信号通路缓解不孕症症状(如图1所示)。
如图2A所示，对各组雌性大鼠体重进行统计分析，结果显示，染毒第1周时，各组大鼠体重无明显差异(P＞0.05)；染毒第2周和第3周时，与对照组比较，模型组体重明显下降，经CECT7894干预后，体重明显上调，差异具有统计学意义(P＜0.05)；染毒第4周时，与对照组相比，模型组体重明显下降，经CECT7894干预，尽管体重没有显著增加，但具有一定的上升趋势(P＜0.05)。
处死大鼠后剖腹，迅速取出双侧卵巢，肉眼可见，对照组卵巢形状规则，红白色，外表面光滑、圆润，附有致密的结缔组织被膜；模型组卵巢充血、肿胀，部分卵巢组织内可见大量黄色脓性液体；治疗组卵巢充血肿胀现象有所缓解，黄色脓性液体明显减少，见图2B。镜下观察见图2C，对照组卵泡颗粒细胞结构完整，排列紧密成层，呈椭圆形，细胞核大小均一，胞膜和核膜完整。模型组大鼠卵泡内颗粒细胞存在不同程度的损伤现象，可见颗粒细胞结构疏松、轮廓模糊、塌陷明显，胞核大小不均；部分颗粒细胞出现核碎裂等病理改变。治疗组卵泡颗粒细胞结构完整，排列紧密成层，颗粒细胞损伤现象明显减少。图2D可见，间质细胞外形呈回形或椭圆形，胞质丰富，着色淡。模型组卵泡间质出现异常，间质细胞黄素化，有些间质细胞呈印戒样改变。治疗组间质细胞未见上述病理现象。如图2E所示，小肠组织镜下观察结果显示，对照组肠道组织结构完整，无明显炎症变化。模型组绒毛上皮细胞排列不整齐或脱落，大量的炎症细胞渗透如淋巴细胞和嗜酸性粒细胞被观察到。治疗组绒毛上皮细胞排列整齐，炎症细胞浸润现象明显减少。
如图3A所示，对照组大鼠卵巢组织结构完整，可见处于不同发育阶段的卵泡数目和形态未见异常，黄体、白体及卵巢间质组织正常。模型组大鼠卵巢组织结构不完整，卵泡数目明显减少，未见成熟卵泡。与模型组比较，治疗组卵巢组织结构相对完整，可见不同发育阶段的卵泡。卵泡计数结果也显示，与对照组比较，模型组大鼠卵巢处于不同发育阶段的卵泡数目显著减少，经CECT7894干预后，卵泡数目明显增加，见图3B。QPCR法检测卵巢关键基因表达结果显示，与对照组比较，模型组卵泡发育调节相关基因WNT2、WNT4和β-catenin表达明显上调，经CECT7894干预后，上述基因表达水平明显下降(P＜0.05)，见图3C。小肠基因检测分析发现，不孕症大鼠GATA3表达水平明显升高，而CECT7894能够明显抑制GATA3的过度表达(P＜0.05)。尽管模型组IL-22表达未见显著变化，但具有一定的上升趋势，经CECT7894干预后，IL-22表达水平明显下调(P＜0.05)，见图3D。
ELISA法检测血清激素和免疫因子分泌水平。如图4A所示，对各组大鼠血清孕酮(PROG)、卵泡刺激素(FSH)、黄体生成素(LH)、雄烯二酮(ASD)、孕激素(P)、雌二醇(E2)和雄激素(T)分泌水平进行分析，结果显示，模型组大鼠血清PROG、FSH、LH和E2激素水平显著高于对照组，经CECT7894干预后，激素水平明显下调(P＜0.05)。各组大鼠ASD和T激素水平差异无统计学意义(P＞0.05)。
如图4B所示，对各组大鼠血清IL-4、IL-6、IFN-γ和TGF-β免疫因子水平及IFN-/IL-4比值进行分析。结果显示，与对照组比较，模型组大鼠血清IL-4水平显著增高，IFN-γ/IL-4比值明显下调(P＜0.05)，经CECT7894干预，尽管上述免疫因子水平没有显著变化，但在一定程度上得到了缓解。除此之外，各组大鼠IL-6、IFN-γ和TGF-β水平差异无统计学意义(P＞0.05)；
采用免疫组织化学法观察各组大鼠雄激素受体(AR)、雌激素受体(ER)、卵泡刺激素受体(FSHR)、绒毛膜促性腺激素受体(LHCGR)和孕激素受体(PR)的表达情况。通过医学图像分析系统Image-Pro Plus 6.0对各组卵巢、子宫组织的MOD进行半定量分析，结果显示，与对照组比较，模型组大鼠卵巢ER和LHCGR表达水平有下降趋势，但差异无统计学意义，经CECT7894干预后，表达水平明显增高(P＜0.05)。其他激素受体在各组大鼠卵巢组织中表达水平差异无统计学意义(P＞0.05)，见图5。
宏基因高通量测序技术分析粪便肠道菌群组成。如图6A-F所示，从不同的分类水平对肠道菌群进行了分析。模型组与对照组比较，有害菌梭杆菌纲(Fusobacteriia)的丰度明显增加(P＜0.05)，治疗组有下降趋势，但不显著，见图6A。模型组与对照组比较，有害菌紫单胞菌科(Porphyromonadaceae)的丰度明显增加，经CECT7894干预，明显下降(P＜0.05)，见图6B。模型组与对照组比较，有害菌奇异菌属(Atopobium)和甲基杆菌属(Methylobacterium)的丰度被富集，而在治疗组被明显抑制(P＜0.05)，见图6C-D。有害菌脱硫菌门(Desulfobacterota)丰度在模型组明显增加，经CECT7894干预，有害菌Desulfobacterota_G丰度明显被抑制(P＜0.05)，见图6E-F。
采用液质联用LC-MS的非靶向代谢组学技术检测粪便菌群代谢产物差异性。如图7A所示，与对照组比较，模型组粪便菌群代谢产物中卵泡营养物质前列腺素(Prostaglandin)C1的含量均有所下降，经CECT7894干预，含量明显增加。花生四烯酸(Arachidonate)和炔诺酮(Norethindrone)两种物质均与排卵抑制有关，模型组花生四烯酸含量明显增高，而CECT7894明显促使其含量降低，尽管模型组炔诺酮未见显著变化，但CECT7894能够明显降低其产生，见图7B-C。KEGG分析结果显示，花生四烯酸代谢(Arachidonic acid metabolism)是差异最显著的代谢通路，揭示Arachidonic acid可能是CECT7894防治不孕症的干预靶点，见图7D。
本发明中长双歧杆菌CECT7894能够显著缓解多囊卵巢引起的不孕症症状，对卵巢功能具有一定的修复作用。不孕症大鼠经灌胃给予长双歧杆菌CECT7894干预，结果显示，长双歧杆菌CECT7894可以保养卵巢，调理内分泌失调，有效抑制卵巢囊肿产生。
Claims (4)
1.一种长双歧杆菌（Bifidobacterium longum）CECT7894在制备预防或治疗多囊卵巢所致不孕症药物中的应用。
2.根据权利要求1所述应用，其特征在于，所述药物有效抑制卵巢囊肿产生。
3.根据权利要求1所述应用，其特征在于，所述药物的制剂剂型包括口服液、胶囊剂、油滴剂、粉剂、片剂或注射剂。
4.根据权利要求1所述应用，其特征在于，所述药物包括单方制剂或复方制剂。
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