CN115869330A - 特女贞苷在制备肠道菌群调节剂中的应用 - Google Patents
特女贞苷在制备肠道菌群调节剂中的应用 Download PDFInfo
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Abstract
本发明公开了特女贞苷在制备肠道菌群调节剂中的应用。本发明首次发现，与正常小鼠相比，D‑半乳糖诱导衰老小鼠肠道菌群中Butyrivibrio、Ruminiclostridium和Lactobacillus的丰度发生异常变化，而特女贞苷能够显著改变D‑半乳糖诱导衰老小鼠肠道菌群中Butyrivibrio、Ruminiclostridium和Lactobacillus的丰度使其恢复到正常水平，使肠道菌群恢复平衡，为肠道菌群的调节提供了新思路、新途径。
Description
技术领域
本发明属于生物医药技术领域，特别涉及特女贞苷在制备肠道菌群调节剂中的应用。
背景技术
肠道菌群是人体内最复杂、菌群种类数量最多的微生态系统，所含菌种种类繁多，超过1000种，数量约为人体细胞总数的10倍。这些肠道微生物参与机体的物质代谢、营养物质的吸收合成等生理活动，维持人机体正常的免疫、代谢等生理活动，与机体建立了互惠互利的共生关系。
研究表明肠道菌群可能通过调节体重、胆汁酸代谢、促炎活性、胰岛素敏感性和肠道激素的释放等来影响宿主机体的健康状态。而饮食结构的改变、疾病的发生发展及药物的不正当使用等因素都会造成肠道菌群的失衡，进而给人体健康造成威胁。因此，如何有目的地调节肠道菌群使其恢复或保持平衡是当前的热门话题。
目前的肠道菌群调节剂主要以益生菌为主，如乳酸菌、乳杆菌、粪球菌以及双歧杆菌等。也有一些天然提取物具备肠道菌群调节的功能，如公开号为CN1285704A的中国发明专利申请公开了一种黑皮鸡枞菌多糖ORP-1可以促进双歧杆菌BB和嗜酸乳杆菌LA的增殖及在D-gal诱导的Caco-2细胞上黏附与定植，抑制肠道条件性病原菌大肠杆菌EC的增殖及在在D-gal诱导的Caco-2细胞上黏附与定植。
特女贞苷是从女贞子果实中提取出来的天然产物，目前尚未见到关于特女贞苷调控肠道菌群方面的报道，未见到特女贞苷调控胆汁酸代谢方面的报道。
发明内容
本发明的发明目的是提供特女贞苷在制备肠道菌群调节剂中的应用，为肠道菌群的调节提供了新思路、新途径。
为实现上述发明目的，本发明的技术方案如下：
特女贞苷在制备肠道菌群调节剂中的应用。
本发明首次发现，与正常小鼠相比，D-半乳糖诱导衰老小鼠肠道菌群中丁酸弧菌(Butyrivibrio)、瘤胃梭菌(Ruminiclostridium)和乳杆菌(Lactobacillus)的丰度发生异常变化，而特女贞苷能够显著改变D-半乳糖诱导衰老小鼠肠道菌群中丁酸弧菌(Butyrivibrio)、瘤胃梭菌(Ruminiclostridium)和乳杆菌(Lactobacillus)的丰度使其恢复到正常水平，使肠道菌群恢复平衡。
基于此，本发明还提供了一种肠道菌群调节剂，该肠道菌群调节剂中至少含有特女贞苷。
具体地，上述的肠道菌群调节剂能够用于降低肠道菌群中丁酸弧菌(Butyrivibrio)和瘤胃梭菌(Ruminiclostridium)中至少一种的丰度；以及用于提高肠道菌群中乳杆菌(Lactobacillus)的丰度。
由于Butyrivibrio、Ruminiclostridium和Lactobacillus都是影响胆汁酸代谢的重要肠道菌类型，本发明发现，特女贞苷在发挥对上述肠道菌群的调节作用时，也能够调节胆汁酸代谢紊乱，促进胆汁酸代谢平衡、肝脏代谢平衡，可用于防治由胆汁酸代谢异常相关的疾病。
基于此，本发明还提供了特女贞苷在制备胆汁酸代谢调节剂中的应用。
同时，还提供了一种胆汁酸代谢调节剂，该胆汁酸代谢调节剂中至少含有特女贞苷。
具体地，上述的胆汁酸代谢调节剂能够用于下调α-鼠胆酸(α-MCA)、β-鼠胆酸(β-MCA)、石胆酸(LCA)和脱氧胆酸(DCA)中至少一种初级胆汁酸的水平；以及用于上调熊脱氧胆酸(UDCA)和鹅去氧胆酸(CDCA)中至少一种次级胆汁酸的水平。
与现有技术相比，本发明的技术方案具有以下技术效果：
(1)本发明首次发现，与正常小鼠相比，D-半乳糖诱导衰老小鼠肠道菌群中Butyrivibrio、Ruminiclostridium和Lactobacillus的丰度发生异常变化，而特女贞苷能够显著改变D-半乳糖诱导衰老小鼠肠道菌群中Butyrivibrio、Ruminiclostridium和Lactobacillus的丰度使其恢复到正常水平，使肠道菌群恢复平衡，为肠道菌群的调节提供了新思路、新途径。
(2)特女贞苷在发挥对上述肠道菌群的调节作用时，也能够调节胆汁酸代谢紊乱，促进胆汁酸代谢平衡、肝脏代谢平衡，可用于防治由胆汁酸代谢异常相关的疾病。
附图说明
图1为基于OUT丰度的PCoA分析图；
其中，CON表示空白对照组，MOD表示模型组，SPN表示特女贞苷处理组；下同；
图2为不同处理下小鼠中肠道菌Butyrivibrio的相对丰度；
其中，Relative Abundance表示相对丰度；下同；
图3为不同处理下小鼠中肠道菌Ruminiclostridium的相对丰度；
图4为不同处理下小鼠中肠道菌Lactobacillus的相对丰度；
图5为不同处理下小鼠血清胆汁酸水平的变化；
其中，BAs contents(μM/g protein)表示胆汁酸内容物含量(微摩尔每克蛋白)，CA：胆酸，TCA：牛黄胆酸，GCA：甘氨胆酸，TCDCA：牛磺鹅脱氧胆酸，GCDCA：牛磺鹅去氧胆酸，TUDCA：牛磺熊去氧胆酸，GUDCA：甘氨熊脱氧胆酸，β-MCA：β-鼠胆酸，α-MCA：α-鼠胆酸，UDCA：熊脱氧胆酸，CDCA：鹅去氧胆酸，UCA：熊胆酸，LCA：石胆酸，DCA：脱氧胆酸，ACA：别胆酸，DHCA：去氢胆酸，TDCA：牛磺脱氧胆酸，GDCA：甘油脱氧胆酸，TLCA：牛磺石胆酸，GLCA：甘石胆酸；Primary Bas表示初级胆汁酸，Secondary BAs表示次级胆汁酸，SPN-L表示特女贞苷低剂量组，SPN-H表示特女贞苷高剂量组。
具体实施方式
下面结合附图和具体实施方式对本发明的技术方案做进一步详细说明。
实施例1特女贞苷对肠道菌群的调控作用分析
(1)小鼠分组
取C57雄性小鼠，20±2g，将小鼠分为四组：
①空白对照组：灌胃给予生理盐水，并皮下注射生理盐水；
②模型组：按100mg/kg/d，每天皮下注射D-半乳糖(用生理盐水溶解D-半乳糖)，并灌胃给予生理盐水，连续12周；
③特女贞苷低剂量组(5mg/kg/d)和高剂量组(10mg/kg/d)：造模方式同模型组，造模后灌胃给予特女贞苷溶液(用生理盐水溶解特女贞苷)，连续12周。
(2)基于OUT丰度的PCoA分析
分别采集各组的粪便样品，对粪便样品进行基因组DNA抽提后，以获得的基因组DNA为模版，采用待barcode的特异引物进行PCR扩增；通过Pooling和切胶纯化后，对构建的扩增子文库进行测序；对16S测序数据进行处理，给出OUT丰度表；基于OUT丰度表，使用R软件的vegan软件包配合bray_curtis距离算法进行PCoA分析，分析结果如图1所示。
由图1的分析结果发现，空白组(CON)、模型组(MOD)和特女贞苷高剂量组(SPN)具有显著区别；说明特女贞苷能改变D-半乳糖诱导衰老小鼠的整体肠道菌群水平。
(3)肠道菌群组成的差异性
对肠道菌群中不同门的菌丰度进行分析，分析结果见图2、图3和图4。
由图2、图3和图4可见，与空白组(CON)相比，模型组(MOD)的Butyrivibrio(P<0.05)和Ruminiclostridium(P<0.05)的丰度显著升高，而Lactobacillus的丰度则显著降低(P<0.05)。
而与模型组(MOD)相比，特女贞苷高剂量组(SPN)中Butyrivibrio(P<0.05)和Ruminiclostridium(P<0.05)的丰度显著降低，Lactobacillus的丰度显著升高(P<0.05)。
以上结果表明，特女贞苷能够促使D-半乳糖诱导衰老小鼠肠道菌群中异常菌的丰度恢复至正常水平，促使肠道菌群恢复平衡、正常，为肠道菌群的调节提供了新思路、新途径。
实施例2特女贞苷对血清胆汁酸代谢的调控作用
(1)样本处理
取各组小鼠的血清样本，加预冷的乙腈：甲醇(v:v＝4:1)溶液，涡旋15s，4℃下12000rpm离心10min，取上清液，冷冻干燥；再用200μL乙腈：甲醇：水(v:v:v＝＝7:2:1)混合液复溶，同前涡旋离心，取上清，用于进行UPLC-MS/MS分析。
(2)检测条件
进行UPLC-MS/MS分析的色谱条件如下：
色谱柱：Waters ACQUITY UPLC BEH C 18色谱柱(2.1mm×100mm,1.7μm)；
柱温：30℃；
流速：0.3mL·min-1；
进样量：3μL；
流动相：0.1％甲酸水(A)-乙腈(B)；
梯度洗脱：0～2min，35％ B；2～10min，35％～90％B；10～13min，90％B；13～13.1min，90％～35％B；13.1～15min，35％B；
质谱条件如下：
电喷雾离子源(ESI)负离子模式，MRM扫描方式；
离子源温度：350℃；
脱气流速：650L·h1；
锥体流速：50L·h-1；
毛细管电压：3.4kV。
(3)目标检测物
检测的胆汁酸包括：胆酸(cholic acid,CA)、牛黄胆酸(taurocholic acid,TCA)、甘氨胆酸(glycocholic acid,GCA)、牛磺鹅脱氧胆酸(taurochenodexycholic acid,TCDCA)、牛磺鹅去氧胆酸(glycochenodexycholic acid,GCDCA)、牛磺熊去氧胆酸(tauroursodeoxycholic acid,TUDCA)、甘氨熊脱氧胆酸(glycoursodeoxycholic acid,GUDCA)、β-鼠胆酸(β-muricholic acid,β-MCA)、α-鼠胆酸(α-muricholic acid,α-MCA)、熊脱氧胆酸(ursodeoxycholic acid,UDCA)、鹅去氧胆酸(chenodeoxycholic acid,CDCA)、熊胆酸(Ursocholic acid,UCA)、石胆酸(lithocholic acid,LCA)、脱氧胆酸(deoxycholicacid,DCA)、别胆酸(allocholic acid,ACA)、去氢胆酸(dehydrocholic acid,DHCA)、牛磺脱氧胆酸(taurodeoxycholic acid,TDCA)、甘油脱氧胆酸(glycodeoxycholic acid,GDCA)、牛磺石胆酸(taurolithocholic acid,TLCA)、甘石胆酸(glycolithocholic acid,GLCA)。
(4)检测结果
检测结果如图5所示。
由图5可见，和空白组(CON)相比，模型组(MOD)的5个初级胆汁酸和3个次级胆汁酸有显著改变，其中TCA(P<0.05)、UDCA(P<0.01)、CDCA(P<0.01)、UCA(P<0.01)显著降低，β-MCA(P<0.01)、α-MCA(P<0.01)、LCA(P<0.01)、DCA(P<0.01)显著升高。与模型组相比，特女贞苷低剂量给药组(SPN-L)的3个初级胆汁酸和1个次级胆汁酸有显著改变，其中β-MCA(P<0.01)、α-MCA(P<0.01)、LCA(P<0.01)显著降低，CDCA(P<0.01)显著升高。与模型组相比，特女贞苷高剂量给药组(SPN-H)的4个初级胆汁酸和2个次级胆汁酸有显著改变，其中β-MCA(P<0.01)、α-MCA(P<0.01)、LCA(P<0.01)、DCA(P<0.01)显著降低，UDCA(P<0.01)、CDCA(P<0.01)显著升高。
综上，D-半乳糖诱导衰老小鼠由于肠道菌群紊乱，尤其是影响胆汁酸代谢的肠道菌Butyrivibri、Ruminiclostridium和Lactobacillus丰度显著改变，进而造成血清中的5种初级胆汁酸和3种次级胆汁酸水平发生显著改变；而在经过特女贞苷处理后，肠道菌Butyrivibri、Ruminiclostridium和Lactobacillus的丰度均恢复至正常水平，肠道菌群恢复平衡；而且，血清中的4种初级胆汁酸和2种次级胆汁酸水平也恢复至正常水平；表明特女贞苷能够用于调控肠道菌群，进而调控胆汁酸代谢。
Claims (8)
1.特女贞苷在制备肠道菌群调节剂中的应用。
2.一种肠道菌群调节剂，其特征在于，至少含有特女贞苷。
3.如权利要求2所述的肠道菌群调节剂，其特征在于，用于降低肠道菌群中丁酸弧菌（Butyrivibrio）和瘤胃梭菌（Ruminiclostridium）中至少一种的丰度。
4.如权利要求2所述的肠道菌群调节剂，其特征在于，用于提高肠道菌群中乳杆菌（Lactobacillus）的丰度。
5.特女贞苷在制备胆汁酸代谢调节剂中的应用。
6.一种胆汁酸代谢调节剂，其特征在于，至少含有特女贞苷。
7.如权利要求5所述的胆汁酸代谢调节剂，其特征在于，用于下调α-鼠胆酸、β-鼠胆酸、石胆酸和脱氧胆酸中至少一种初级胆汁酸的水平。
8.如权利要求5所述的胆汁酸代谢调节剂，其特征在于，用于上调熊脱氧胆酸和鹅去氧胆酸中至少一种次级胆汁酸的水平。
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