CN115044518B - 一种护肝益生菌及其应用 - Google Patents
一种护肝益生菌及其应用 Download PDFInfo
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- CN115044518B CN115044518B CN202210953041.7A CN202210953041A CN115044518B CN 115044518 B CN115044518 B CN 115044518B CN 202210953041 A CN202210953041 A CN 202210953041A CN 115044518 B CN115044518 B CN 115044518B
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Abstract
本发明公开了一种护肝益生菌及其应用,为保藏编号为CGMCC No.15028的长双歧杆菌W68,其对肝损伤具有很好的修复效果,从降脂护肝、修复肝细胞损伤、减少肝脏氧化应激反应、提高肝脏免疫力、清除肝脏内毒素等多种方式同步进行,具有明显的养护肝作用。
Description
技术领域
本发明涉及益生菌技术领域,尤其涉及一种护肝益生菌及其应用。
背景技术
肝脏是人体最大的腺体,由多种类型细胞构成,包括上皮细胞(肝细胞和胆管细胞)、Kupffer细胞、单核细胞、肝星状细胞、窦状内皮细胞、自然杀伤细胞和肝树突状细胞等,担负着人体代谢、解毒、分泌、排泄、生物转化等许多重要的功能。具体来说,肝脏可生成胆汁,参与糖、蛋白质、脂类和维生素等多种物质代谢,调控人体解毒、吞噬、防御以及造血等生理过程。
近年来,随着人们生活压力的增加,各类肝脏疾病的发病率呈逐年上升趋势。肝脏疾病是全球最普遍的疾病之一,主要包括乙型肝炎(Hepatitis B,HB)、丙型肝炎(Hepatitis C,HC)、非酒精性脂肪性肝病(Non-alcoholic Fatty Liver Disease,NAFLD)、酒精性肝病(Alcoholic Liver Disease,ALD)、自身免疫性肝病、药物性肝损伤、肝硬化、肝衰竭和肝癌等。虽然肝脏在体内具有较强的再生能力,但当其受到过度或持续损伤干扰(如:慢性病毒感染、脂肪性肝炎、长期药物肝损伤等)时,它的再生修复能力也会遭到破坏,因此在日常中对于肝损伤的减少,对于肝脏的保护就显得格外重要。
市面上的护肝类产品主要是有中药类、西药类,它们的药性偏强,短期服用虽能起到一定效果,但是长期服用后,会强化药物的偏性以及毒素在肝脏中的累积,容易对肝脏产生二次损伤。同时,这些产品对肝脏的修复是短期的、不持续的。因此,积极寻找护肝效果显著、毒副作用少、可持续护肝的产品至关重要。
益生菌作为新兴的生物疗法,具有效果显著、无毒素、安全健康、可持续等特点。因此,寻找一种有护肝效果的益生菌具有积极效果。
发明内容
为了克服现有技术的不足,本发明的目的之一在于提供一种护肝益生菌,疗效显著,健康安全。
本发明的目的之二在于提供所述护肝益生菌的应用。
本发明的目的之一采用如下技术方案实现:
一种护肝益生菌,所述益生菌为保藏编号为CGMCC No.15028的长双歧杆菌W68。
作为本发明的一个优选方案,所述长双歧杆菌W68发挥护肝效果,包括:增强肝脏代谢脂质的能力,降脂护肝、提高肝脏免疫力、清除肝脏内毒素,提高肠道酶活性,调控糖脂代谢,修复肝损伤,增强肝脏的抗氧化应激能力。
本发明的目的之二采用如下技术方案实现:
本发明还提供了一种益生菌在制备护肝产品中的应用,所述益生菌为保藏编号为CGMCC No.15028的长双歧杆菌W68。
作为本发明的一个优选方案,所述护肝产品包括护肝食品、护肝保健品、护肝药品和护肝营养补充剂。
作为本发明的一个优选方案,所述护肝产品包括益生菌发酵物、活菌型益生菌固体饮料、灭活型益生菌固体饮料和益生菌缓释片。
作为本发明的一个优选方案,所述护肝产品的活性成分包括长双歧杆菌W68的活菌体和/或灭活型菌体。益生菌可通过体外发酵产生护肝后生元,亦可定殖于肠道中生长繁殖进行体内发酵,增加优势菌群的种类和数量,调节肠道微生态,减少人体内毒素的积累,减轻肝脏负担;分泌护肝益生因子,干预脂肪肝的形成,使肝细胞的形态趋于正常,降低肝脏病理学评分,病变明显减轻,肝功指标明显降低;促进营养物质的吸收。此外,灭活型的益生菌也有护肝的效果,灭活菌的菌体细胞壁组分中的肽聚糖、脂多糖、脂磷壁酸和DNA等成分能赋活肝脏细胞,强化肝脏免疫屏障。
作为本发明的一个优选方案,所述长双歧杆菌W68在所述护肝产品中的添加量为106-1011CFU/g或106-1011CFU/ml。
作为本发明的一个优选方案,所述护肝产品为口服制剂,所述口服制剂的剂型包括口服液、滴剂、片剂、粉剂、胶囊剂或颗粒剂。
作为本发明的一个优选方案,本发明还提供了一种护肝益生菌固体饮料,所述护肝益生菌固体饮料包括按照重量份数计的以下原料:长双歧杆菌W68菌粉1-5份,益生元5-99份;所述长双歧杆菌W68菌粉为活菌粉和/或灭活型菌粉;所述益生元包括低聚果糖、菊粉、低聚木糖、低聚半乳糖、低聚麦芽糖、低聚异麦芽糖、抗性糊精、大豆低聚糖、水苏糖、壳聚糖和棉子糖中的一种或任意组合。
作为本发明的一个优选方案,一种护肝益生菌固体饮料,包括按照重量份数计的以下原料:活菌型长双歧杆菌W68菌粉1-5份,低聚果糖5-99份。
作为本发明的一个优选方案,一种护肝益生菌固体饮料,包括按照重量份数计的以下原料:灭活型长双歧杆菌W68菌粉1-5份,低聚果糖5-99份。
作为本发明的一个优选方案,所述长双歧杆菌W68发挥护肝效果,包括:增强肝脏代谢脂质的能力,降脂护肝,提高肝脏免疫力,清除肝脏内毒素,提高肠道酶活性,调控糖脂代谢,修复肝细胞损伤,增强肝脏的抗氧化应激能力。
本发明还提供了一种护肝益生菌中药发酵物,由益生菌对中药提取液进行发酵而成,所述益生菌为保藏编号为CGMCC No.15028的长双歧杆菌W68;所述中药提取液由中药组合物经过提取而成,所述中药组合物由按照重量份数计的以下原料组成:旱芹10-15份、罗布麻1-5份、蒺藜5-10份、珍珠母1-5份、赛山蓝5-10份、紫贝1-5份、蜜环菌5-10份、绞股蓝5-10份、白芍1-5份、枸杞子15-25份、女贞子1-5份、杜仲1-5份、续断1-5份、韭子1-5份、决明子10-15份、姜黄10-15份。
旱芹具有平肝清热的功效,主治面红目赤、排尿赤热、眼睛肿痛、痤疮等病症;罗布麻具有清热平肝的功效,主治眩晕、神经衰弱等病症;蒺藜具有平肝解郁、活血祛风的功效,主治头痛眩晕、目赤翳障等病症;珍珠母具有平肝、潜阳的功效,主治头眩、耳鸣、癫狂等病症;赛山蓝具有清肝火、解郁结的功效,主治肝病、肾脏病、目赤肿痛等病症;紫贝具有平肝的功效,主治头晕目眩、热毒目翳等病症;蜜环菌具有息风平肝的功效,主治头晕头痛、腰腿疼痛等病症;绞股蓝具有清热解毒的功效,主治传染性肝炎、胃肠炎等病症;白芍具有养血柔肝的功效,主治自汗盗汗等病症;枸杞子具有养肝、滋肾的功效,主治肝肾亏虚、腰膝酸软等病症;女贞子具有滋补肝肾的功效,主治眩晕耳鸣、腰膝酸软等病症;杜仲具有补益肝肾的功效,主治腰膝酸痛、足膝痿弱、中风偏瘫等病症;续断具有补肝肾、止崩漏的功效,主治腰膝酸软、崩漏等病症;韭子具有温补肝肾的功效,主治阳痿遗精、腰膝酸痛等病症;决明子具有清肝明目的功效,主治风热赤眼、肝炎、肝硬化腹水等病症;姜黄具有消炎、破血行气的功效,主治肝纤维化、肝损伤等病症。
本发明所提供的护肝益生菌中药发酵物以清法为主、补法为辅为治疗原则,结合“君、臣、佐、使”的用药原则,从根源处减轻肝脏毒素积累,修复肝脏损伤,强化肝脏功能。“清”有两种含义, 一则为清除、驱除,二则为凉、冷,而“补”这个字则有“滋补、扶助、帮助”的意思,主要着眼于“补益”的作用,温中补虚,以资气血生化之源,正气充盛,则邪气自退,能够辅助阴阳之所从缺,使阴阳达到平衡,恢复正气,强化正气。所述护肝益生菌中药发酵物遵循的“清法为主,补法为辅”的治疗原则,就是指以清除、躯除邪毒为主,从根源处减少肝脏内毒素,清肝泻火,并且辅以扶助正气的方法,通过多途径、多靶点减少肝脏氧化应激,降低并修复肝细胞损伤,疏肝理气,养肝护肝。即“清法为主,补法为辅”能消灭致病源,促使症状缓解,使身体机能对病原菌的抵抗力增强,人体的免疫力提高,通过加强人体自我修复能力,进而达到恢复人体正常机能的方法。此外,两法搭配可协同益生菌抑制有害菌的生长繁殖,减少肝脏毒素累计,增加有益菌的种类和数量,调节肠道菌群正向平衡,稳固养肝护肝效果。
君药为“枸杞子、决明子、姜黄、旱芹”,能养肝清肝、平肝利水,有利于助肝气、解肝毒。臣药为“赛山蓝、蒺藜、蜜环菌、绞股蓝”,可协助君药治疗肝阴虚或肾阴虚而导致的肝阳上亢。佐药为“白芍、女贞子、杜仲、断续、韭子、罗布麻”,可作为正佐药从补益方向修复肝损伤,辅助疏肝理气,防止肝气郁结。使药为“珍珠母、紫贝”,平肝潜阳,活血通经,有利于减少肝损伤,作为调和药调和方中诸药,强化组方养肝护肝的功效。
本发明所提供的中药组合物方从中药配方(不包括益生菌)上来说,已经非常具有创新性,其虽作为中药配方,但药效温和,可以由内而外实现养肝护肝的效果。
作为本发明的一个优选方案,在制备所述护肝益生菌中药发酵物时,所述长双歧杆菌W68对所述中药提取液进行发酵,所述长双歧杆菌W68的添加量为所述中药提取液体积的4-8%,优选地为6-7%,更加优选地为6%。
作为本发明的一个优选方案,本发明提供了一种护肝益生菌中药发酵物的制备方法,包括以下步骤:
1、破壁:将配方量的旱芹、赛山蓝、蜜环菌、绞股蓝、枸杞子加35-45倍量软水破壁,得基料A;
2、粉碎:将配方量的罗布麻、蒺藜、杜仲、女贞子、韭子、续断、白芍、决明子、姜黄用中药粉碎机粉碎至150-250目粉末,再用8-12倍量软水浸泡15-25 min,得基料B;
3、一次熬煮:将基料A、基料B、配方量的珍珠母、配方量的紫贝加入煎煮锅中,水开后煎煮40-60min,冷却后用150-250目滤布过滤,得基料C;
4、二次熬煮:在步骤3的滤渣加20-30倍量软水,水开后重复煎煮20-40min,冷却后用150-250目滤布过滤,得基料D;
5、三次熬煮:在步骤4的滤渣加8-12倍量软水,水开后重复煎煮15-25min,冷却后用150-250目滤布过滤,得基料E;
6、浓缩:将基料C、基料D和基料E合并滤液,于25-35℃进行低温浓缩得基料F;
7、调配:向基料F中加入12-18%的葡萄糖,0.02-0.08%尿素,用小苏打调pH至6.5~7.0,得基料G;
8、灭菌:将基料G于130-140℃、0.50-0.85MPa下灭菌2-6s,冷却至30-35℃,得基料H;
9、菌株复活:取出在-(90-80)℃条件下甘油保藏的长双歧杆菌W68菌株,解冻至室温。在无菌操作台上进行平板划线,随后置于生化培养箱中35-37℃恒温培养8~10 h,重复操作2-5次,使其充分活化。在无菌条件下挑取单菌落,接种到MRS液体培养基中,35-37℃、180-250 r/min摇床振荡培养8~10 h后取出,获得发酵用菌悬液I;
10、发酵:将发酵用菌悬液以合适比例接种到基料H中于35-37℃恒温培养6-10h,得基料J;
11、冻干:用软水将12-17%麦芽糊精、5-6%乳糖、2-3%海藻糖、1-2%果胶溶解混匀,灭菌后冷却至室温,得溶液K。在无菌环境中,将溶液K加到基料J中混合均匀,预冻至-(40-35)℃,保持3-5h,在“温度-(35-25)℃,真空度220-250mTorr”的条件下,升华干燥85-95 h,在“温度22-27℃,真空度220-250 mTorr”的条件下,解析干燥25-35 h,得护肝益生菌中药发酵物。
本发明还提供了所述护肝益生菌中药发酵物在制备护肝产品中的应用。
本发明还提供了一种护肝益生菌缓释片,按照重量份数计,包括所述护肝益生菌中药发酵物12-17份,还包括:魔芋葡甘聚糖25-35份、海藻酸钠5-35份、乳糖6-26份、微晶纤维素5-25份、硬脂酸镁0.5-5份、十二烷基硫酸钠1-5份、交联聚维酮1-5份、交联羧甲基纤维素钠0.5-5份、碳酸氢钠5-10份。
作为本发明的一个优选方案,在本发明所提供的护肝益生菌缓释片中,所述护肝益生菌中药发酵物由所述长双歧杆菌W68对中药提取液进行发酵而成,所述中药提取液由中药组合物经过提取而成,所述中药组合物由按照重量份数计的以下原料组成:旱芹10-15份、罗布麻1-5份、蒺藜5-10份、珍珠母1-5份、赛山蓝5-10份、紫贝1-5份、蜜环菌5-10份、绞股蓝5-10份、白芍1-5份、枸杞子15-25份、女贞子1-5份、杜仲1-5份、续断1-5份、韭子1-5份、决明子10-15份、姜黄10-15份。
作为本发明的一个优选方案,本发明提供了一种护肝益生菌缓释片,按照重量份数计,包括所述护肝益生菌中药发酵物12-17份,还包括:魔芋葡甘聚糖25-35份、海藻酸钠5-35份、乳糖6-26份、微晶纤维素5-25份、硬脂酸镁0.5-10份、十二烷基硫酸钠1-5份、交联聚维酮1-10份、交联羧甲基纤维素钠0.5-10份、碳酸氢钠5-10份、活菌型长双歧杆菌W68菌粉1-5份。
作为本发明的一个优选方案,本发明提供了一种护肝益生菌缓释片的制备方法,包括以下步骤:
1、破壁:将配方量的旱芹、赛山蓝、蜜环菌、绞股蓝、枸杞子加35-45倍量软水破壁,得基料A;
2、粉碎:将配方量的罗布麻、蒺藜、杜仲、女贞子、韭子、续断、白芍、决明子、姜黄用中药粉碎机粉碎至150-250目粉末,再用8-12倍量软水浸泡15-25min,得基料B;
3、一次熬煮:将基料A、基料B、配方量的珍珠母、配方量的紫贝加入煎煮锅中,水开后煎煮40-60min,冷却后用150-250目滤布过滤,得基料C;
4、二次熬煮:在步骤3的滤渣加20-30倍量软水,水开后重复煎煮20-40min,冷却后用150-250目滤布过滤,得基料D;
5、三次熬煮:在步骤4的滤渣加8-12倍量软水,水开后重复煎煮15-25min,冷却后用150-250目滤布过滤,得基料E;
6、浓缩:将基料C、基料D和基料E合并滤液,于25-35℃进行低温浓缩得基料F;
7、调配:向基料F中加入12-18%的葡萄糖,0.02-0.08%尿素,用小苏打调pH至6.5~7.0,得基料G;
8、灭菌:将基料G于130-140℃、0.50-0.85MPa下灭菌2-6s,冷却至30-35℃,得基料H;
9、菌株复活:取出在-(90-80)℃条件下甘油保藏的长双歧杆菌W68菌株,解冻至室温。在无菌操作台上进行平板划线,随后置于生化培养箱中35-37℃恒温培养8~10 h,重复操作2-5次,使其充分活化。在无菌条件下挑取单菌落,接种到MRS液体培养基中,35-37℃、180-250 r/min摇床振荡培养8~10 h后取出,获得发酵用菌悬液I;
10、发酵:将一定比例的发酵用菌悬液I接种到基料H中于35-37℃恒温培养6-10h,得基料J;
11、冻干:用软水将12-17%麦芽糊精、5-6%乳糖、2-3%海藻糖、1-2%果胶溶解混匀,灭菌后冷却至室温,得溶液K。在无菌环境中,将溶液K加到基料J中混合均匀,预冻至-(40-35)℃,保持3-5h,在“温度-(35-25)℃,真空度220-250mTorr”的条件下,升华干燥85-95 h,在“温度22-27℃,真空度220-250mTorr”的条件下,解析干燥25-35h,得益生菌发酵制品L;
12、粉碎过筛:将益生菌发酵制品L用粉碎机粉碎至80-150目,整粒得基料M;
13、混合:将25-35份魔芋葡甘聚糖、5-35份海藻酸钠、6-26份乳糖、12-17份基料M、5-25份微晶纤维素、0.5-5份硬脂酸镁、1-5份十二烷基硫酸钠、1-5份交联聚维酮、0.5-5份交联羧甲基纤维素钠与5-10份碳酸氢钠混合15-25min,得基料N;
14、干法制粒:将基料N干压制粒,过筛,筛网10-30目,未成形颗粒的干粉经50-70目筛网筛分后,重复干压制粒,至细粉比例小于投料量20%,制成的粒为基料O;
15、混合:将1-5份长双歧杆菌W68菌粉(优选为活菌型)、基料O、干法制粒的剩余细粉、1-5份交联聚维酮、0.5-5份交联羧甲基纤维素钠,1-5份硬脂酸镁混合10min,得基料P;
16、压片:将基料P用35-45KN的压力压制片,片重差异控制在±7.5%,即得肠道定位释放的护肝益生菌缓释片。
在上述护肝益生菌缓释片的制备方法的制备方法中,步骤11的原料混合是将多种保护剂混合,以保持菌株的活性;步骤13的混合是将缓释片的骨架辅料进行混合,制粒后再到步骤15的混合,以实现片剂的缓释效果。
相比现有技术,本发明的有益效果在于:
本发明所提供的护肝益生菌长双歧杆菌W68,对肝损伤具有很好的修复效果,从降脂护肝、修复肝细胞、减少肝脏氧化应激反应、提高肝脏免疫力、清除肝脏内毒素等多种方式同步进行,具有明显的养护肝脏作用。
生物材料保藏信息:
长双歧杆菌W68,保藏编号为CGMCC No.15028,分类命名为:长双歧杆菌Bifidobacterium longum ,已于2017年12月07日保藏于中国微生物菌种保藏管理委员会普通微生物中心 (地址: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,邮政编码:100101),保藏单位的缩写为CGMCC。
具体实施方式
下面,结合具体实施方式,对本发明做进一步描述,需要说明的是,在不相冲突的前提下,以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。在下述实施例中所采用的原材料、设备等除特殊限定外均可以通过购买方式获得。
体系一:筛选益生菌
本发明实施例筛选一种护肝的益生菌,通过动物模型直接筛选出能够降脂护肝、修复肝损伤的益生菌。
一、具有改善Caco-2细胞单层屏障功能的乳酸菌菌种的体外筛选
1、实验菌株:发酵乳杆菌、动物双歧杆菌乳亚种、戊糖片球菌、嗜热链球菌,分别编号A-D。
2、实验细胞:本实验使用的人克隆结肠腺癌细胞系(Human colon carcinomacell line,Caco-2),购自美国ATCC生物生物标准品资源中心。
3、MRS培养基:
蛋白胨10.0g,酵母粉4.0g,牛肉粉8.0g,K2HPO42.0g,MgSO4 0.2g,MnSO4 0.04g,柠檬酸氢二铵2.0g,乙酸钠5.0g,葡萄糖20.0g,吐温80 1.0mL,蒸馏水定容至1000mL,pH5.7,121℃灭菌20min。固体培养基在液体培养基的基础上加入1. 6%的琼脂。
3、实验方法:
(1)菌株的培养及处理:取-80℃冻存保藏的菌株,在MRS固体平板上划线,置于37℃条件下活化培养,然后挑取单菌落接入5 ml 的MRS液体培养基中,继续37℃下二代培养18~20 h,再接入2%的菌液至2 L的MRS液体培养基中,37℃培养18~20 h,至对数期。菌悬液在4℃下,8000g,离心10 min,弃去上清液,收集菌体。菌体用超纯水洗涤,再次离心,重复两次,得到菌泥。菌泥用细胞培养液重悬,用于细胞实验。使用前用生理盐水梯度稀释,并利用倾注法对活菌数进行计数,计算菌落形成单位(Colony-forming Units,CFU)。
(2)细胞的培养及细胞单层屏障模型的建立:冻存于液氮中的Caco-2细胞,用加入1%的双抗(100 U/mL青霉素,100 µg/mL链霉素)和10%的胎牛血清(Fetal bovine serum,FBS)的DMEM培养液活化后,置于37℃,5% CO2的培养箱中培养,培养液每2天更换1次。当细胞融合达到80%左右时,用37℃预热的消化液(0.25%胰蛋白酶-EDTA)消化,以1: 4进行传代。取对数生长期的细胞,消化,计数,用细胞培养液将细胞密度调整到104~105/mL后,以100µL接种于Transwell 24孔板Insert(膜面积0.33 cm2,孔径0.4μm)中。培养在 Transwell板Insert中的Caco-2细胞,每2天更换1次培养液,一个星期后每天更换1次培养液。培养约21天左右,待Caco-2细胞在Insert底部形成类似肠上皮样的完整致密的单层时,用于试验。
(3)细胞单层屏障跨膜电阻分析:用Millicell-ERS上皮跨膜细胞电阻仪对Caco-2细胞单层跨膜电阻(Trans-epithelial Electrical Resistance,TEER)进行分析,每孔细胞的TEER值连续测量三次。Caco-2细胞在Transwell板Insert中培养21天左右后,TEER到达一个稳定值,认为Caco-2细胞已完全分化形成致密的细胞单层屏障。用含5%酒精与1%菌悬液的细胞培养液,与Caco-2细胞单层共培养24小时。测定Caco-2细胞单层跨膜电阻TEER值,结果如表1。其中,空白组为用含0%酒精与1%生理盐水的培养液,与Caco-2细胞单层共培养24小时。酒精组为用含5%酒精与1%生理盐水的培养液,与Caco-2细胞单层共培养24小时。
表1 所选菌株对酒精暴露Caco-2细胞单层跨膜电阻的影响
由表1可得,不同菌种对酒精暴露的Caco-2细胞单层跨膜电阻TEER水平的恢复具有不同的作用,恢复效果最好的是动物双歧杆菌乳亚种,其次是两歧双歧杆菌、短双歧杆菌、婴儿双歧杆菌,即恢复效果最好的菌种是双歧杆菌属,其次是乳杆菌属、链球菌属、片球菌属。
二、具有护肝作用的双歧杆菌菌株筛选
1、实验益生菌菌种:
两歧双歧杆菌、动物双歧杆菌乳亚种、长双歧杆菌、婴儿双歧杆菌、短双歧杆菌、青春双歧杆菌,分别编号A-F。其中,所述长双歧杆菌为保藏编号为CGMCC No.15028的长双歧杆菌W68。
2、实验动物:雄性5周龄SPF级小鼠,购自南京生物医药研究院。
3、MRS培养基:
蛋白胨10.0g,酵母粉4.0g,牛肉粉8.0g,K2HPO42.0g,MgSO4 0.2g,MnSO4 0.04g,柠檬酸氢二铵2.0g,乙酸钠5.0g,葡萄糖20.0g,吐温80 1.0mL,蒸馏水定容至1000mL,pH5.7,121℃灭菌20min。
4、菌株复苏
(1)量取10mL超纯水加入试管内,称取0.524g MRS培养基加入试管内,密封,灭菌。
(2)取出- 80℃条件下甘油保藏的菌株,于超净台内接种于上述试管内,封口膜封口,并标记为P1代菌株,置于37℃恒温摇床中150rpm培养24小时。
(3)取上述P1代菌株,于超净台内按照上述方法接种到新的试管内,封口膜封口,并标记为P2代菌株,置于37℃恒温摇床中150rpm培养24小时。
(4)取上述P2代菌株,于超净台内按照上述方法接种到新的试管内,封口膜封口,并标记为P3代菌株,置于37℃恒温摇床中150rpm培养24小时。
5、菌株培养
(1)量取350mL超纯水置于锥形瓶内,称取18.34g MRS培养基,盖上瓶塞,封口膜封口,报纸包裹瓶口,高温高压灭菌。
(2) 取上述P3代菌株,于超净台内按照上述方法接种到锥形瓶内,封口膜封口,置于37℃恒温摇床中150rpm培养24小时。
6、益生菌灌胃前处理
将锥形瓶内培养好的菌株分装于6个50mL离心管内,置于低温冷冻离心机内4℃、12000rpm离心10分钟,弃去上清液,再将益生菌浓度调节到1×1010 CFU/mL。
7、实验动物分组
将小鼠(5周龄,体重16±2g)置于SPF设施的单独通风笼中(每笼4只动物)。在受控的环境条件下(温度24±1℃;相对湿度55-65%),小鼠可自由获取食物和蒸馏水,并保持在12h/12h光/暗周期。在实验前使小鼠适应环境一周。将小鼠随机分成8组(每组n = 4)。具体操作如下:
(1)对照组:小鼠用正常饲料喂养12w, 给予生理盐水灌胃;
(2)模型组:小鼠用45%高脂饲料喂养12w, 给予生理盐水灌胃;
(3)干预组A:小鼠用45%高脂饲料喂养12w,给予2×1010 CFU/mL 益生菌(A)灌胃;
(4)干预组B:小鼠用45%高脂饲料喂养12w,给予2×1010 CFU/mL益生菌(B)灌胃;
(5)干预组C:小鼠用45%高脂饲料喂养12w,给予2×1010 CFU/mL益生菌(C)灌胃;
(6)干预组D:小鼠用45%高脂饲料喂养12w,给予2×1010 CFU/mL益生菌(D)灌胃;
(7)干预组E:小鼠用45%高脂饲料喂养12w,给予2×1010 CFU/mL益生菌(E)灌胃;
(8)干预组F:小鼠用45%高脂饲料喂养12w,给予2×1010 CFU/mL益生菌(F)灌胃;
8、实验动物一般指标监测
每隔3周记录每组小鼠的体重,取平均值,结果如表2。
9、小鼠肝匀浆液的制备
饲养12周后,将小鼠处死,取其肝脏,将肝脏加入适量生理盐水,充分匀浆制得10%的肝匀浆,将其用低温高速离心机以3000 r/min离心10 min,取上清液,测定肝脏组织的甘油三酯(TG)、过氧化氢酶(CAT)、丙二醛(MDA)和谷胱甘肽酶(GSH)含量,结果如表3所示。
10、相关指标测定
(1)体重情况
表2 小鼠体重变化(g)
由表2可得随着喂养时间的递增,小鼠体重均有不同程度的增加。模型组体重变化最大,说明高脂饮食产生的多余脂质不能被肝脏代谢,肝脏负担加重以及受损,小鼠体重不能得到很好的控制。经益生菌干预后,小鼠体重均能得到不同程度的控制。其中,干预组C(长双歧杆菌W68)的小鼠体重变化趋于正常,说明长双歧杆菌W68能增强肝脏代谢脂质的能力,发挥降脂护肝的功效。
(2)肝脏情况
表3 小鼠肝脏指标变化
由表3可得,经高脂饲料喂食的小鼠肝脏指标均有不同程度的波动,TG值和MDA值均显著性升高,GSH值和CAT值均显著性降低,说明高脂饮食容易导致肝脏脂质代谢异常、肝脏氧化损伤程度加重。经益生菌干预后,小鼠肝脏各指标均有明显改善。其中,干预组C(长双歧杆菌W68)的小鼠肝脏各指标变化趋于正常,说明长双歧杆菌W68定殖于肠道后能提高酶活性,调控糖脂代谢以及修复肝损伤,增强肝脏的抗氧化应激能力。再结合表2实验结论,验证了长双歧杆菌W68是一种具有良好护肝效果的益生菌。
体系二:长双歧杆菌W68发酵比例筛选
本发明实施例提供了一种护肝益生菌中药发酵物,由长双歧杆菌W68对中药提取液进行发酵而成,中药提取液由中药组合物经过提取而成,中药组合物由以下原料组成:旱芹12份、罗布麻3份、蒺藜8份、珍珠母3份、赛山蓝8份、紫贝3份、蜜环菌7份、绞股蓝8份、白芍4份、枸杞子20份、女贞子3份、杜仲3份、续断2份、韭子3份、决明子12份、姜黄13份。该护肝益生菌中药发酵物按照以下方法制备而成:
1、破壁:将旱芹、赛山蓝、蜜环菌、绞股蓝、枸杞子加40倍量软水破壁,得基料A;
2、粉碎:将罗布麻、蒺藜、杜仲、女贞子、韭子、续断、白芍、决明子、姜黄用中药粉碎机粉碎至200目粉末,再用10倍量冷的软水浸泡20 min,得基料B;
3、一次熬煮:将基料A、基料B、珍珠母、紫贝加入煎煮锅中,水开后煎煮50min,冷却后用200目滤布过滤,得基料C;
4、二次熬煮:在步骤3的滤渣加25倍量软水,水开后重复煎煮30min,冷却后用200目滤布过滤,得基料D;
5、三次熬煮:在步骤4的滤渣加10倍量软水,水开后重复煎煮20min,冷却后用200目滤布过滤,得基料E;
6、浓缩:将基料C、基料D和基料E合并滤液,于30℃进行低温浓缩得基料F;
7、调配:向基料F中加入15%的葡萄糖,0.05%尿素,用小苏打调pH至6.5~7.0,得基料G;
8、灭菌:将基料G于135℃、0.75MPa下灭菌4s,冷却至35℃,得基料H;
9、菌株复活:取出在 - 80 ℃条件下甘油保藏的长双歧杆菌W68菌株,解冻至室温。在无菌操作台上进行平板划线,随后置于生化培养箱中37 ℃恒温培养8~10 h,重复操作3次,使其充分活化。在无菌条件下挑取单菌落,接种到MRS液体培养基中,37 ℃、200 r/min摇床振荡培养8~10 h后取出,获得发酵用菌悬液I;
10、发酵:将发酵用菌悬液I按表4的比例接种到基料H中于37℃恒温培养8h,得基料J;
11、冻干:用软水将15%麦芽糊精、6%乳糖、3%海藻糖、1%果胶溶解混匀,灭菌后冷却至室温,得溶液K。在无菌环境中,将溶液K加到基料J中混合均匀,预冻至- 40℃,保持4h,在“温度- 29℃,真空度 250 mTorr”的条件下,升华干燥90 h,在“温度25℃,真空度250mTorr”的条件下,解析干燥30 h,得护肝益生菌中药发酵物(益生菌发酵制品)。
表4 长双歧杆菌W68发酵中药组合物的添加量/%
采用黄酮含量测定方法对益生菌制品的黄酮进行含量检测,结果如表5。黄酮是一种很强的抗氧化剂,能够有效地清除体内自由基,降低肝组织中MDA、NO、TNF-α 和IL-6含量,以及血清中ALT、AST、ALP和TBIL水平,同时增强SOD、GSH-PX活性,减少肝脏中过氧化脂质反应,缓解酒精对肝脏的损伤,起到保护肝脏的作用。
采用绿原酸含量测定方法对益生菌制品的绿原酸进行含量检测,结果如表6。绿原酸具有肝保护生物活性,可以通过抑制Toll样受体(Toll-like Receptor 4, TLR4),TNF-ɑ和NFκB等炎症因子在肝脏的蛋白表达,缓解肝损伤。还可酸通过激活肝脏星状细胞,抑制血管内皮生长因子(Vascular Endothelial Growth Factor, VEGF)和转化生长因子(Transforming Growth Factor, TGF-1)mRNA 的表达,抑制ɑ-平滑肌肌动蛋白(Alpha-smooth Muscle Actin, ɑ-SMA)和糖调节蛋白78和94(Glucose-regulated Proteins 78and 94, GRP 78 and 94)蛋白表达,从而抑制肝纤维化,发挥肝脏保护作用。
黄酮含量测定
实验方法:用芦丁作为标准品,分别加入1 mL 10%硝酸铝溶液,1 mL 5%硝酸钠溶液,用80%乙醇定容到10mL,静置1h,用分光光度计在510 nm处测定吸光值。芦丁标准曲线:y=0.6514x - 0.0054(R2 = 0.9991)。称取1 g益生菌发酵制品捣碎成粉,用80%乙醇超声提取,重复两次,过滤,合并滤液,定容至 100 mL。移取1 mL样品提取液,按照以上进行测定,根据上述曲线计算黄酮含量。
表5 益生菌发酵制品总黄酮含量/%
由表5可得,通过添加益生菌对中药提取液进行发酵,可以使益生菌发酵制品的黄酮总量显著增加,益生菌的添加量在6-7%时总黄酮含量稳定,且在7%时含量最高,表明黄酮产生量趋于饱和,添加量>7%时,黄酮量减少,因此,初步选择益生菌的添加量为6-7%。
绿原酸含量测定
1)色谱条件:色谱柱:C18(Alltech Hypersil ODS柱(250mm×4.6mm,5μm);流动相:乙腈-0.4%磷酸溶液(1:9);流速:1.0mL·min-1;进样量:10μL;检测波长:327nm;柱温:室温。在此色谱条件下样品中绿原酸与其他成分得到较好分离,分离度值大于1.5,理论塔板数为3000以上。
2)对照溶液制备:精密称取绿原酸对照品17.10mg,置100mL棕色量瓶中,加30%甲醇至刻度,摇匀,即得。
3)标准曲线的制作:精密取对照品溶液适量分别加30%甲醇,稀释成6.8,13.6,20.4,27.2,34.0,68.0,171.0mg·L-1。分别吸取10μL注入液相色谱仪中,按上述色谱条件测定峰面积,将对照品量与峰面积进行回归处理,得回归方程为Y=22.0106X-0.2635,R2=0.9998(n=7),表明绿原酸对照品在0.068~1.71μg范围内呈良好的线性关系。
4)样品溶液制备:取益生菌发酵制品适量,研细,精密称取约0.4g,置具塞三角瓶中,各组分别选择30%甲醇30mL为提取溶剂,超声处理30min(功率(250±70)W,频率(33±2)kHz),蒸除溶剂,残渣用30%甲醇溶解并转移至100mL量瓶中,加30%甲醇稀释至刻度,摇匀,滤过,取续滤液用微孔滤膜(0.45μm)滤过,测定含量。
表6 益生菌发酵制品绿原酸含量/%
由表6可得,通过添加益生菌对中药提取液进行发酵,可以使益生菌发酵制品的绿原酸总量显著增加,益生菌的添加量的添加量在7%时,绿原酸含量显著性降低,且随着添加量的增加,绿原酸的含量在逐步降低。益生菌添加量为6%时,绿原酸含量最大,再结合表5实验结论,选择益生菌添加量为6%作为益生菌发酵中药组合物的菌粉最佳添加量。
体系三:肠道定位释放的护肝益生菌缓释片组方筛选
一种护肝益生菌缓释片,包括护肝益生菌中药发酵物12-17份(基料M),还包括:魔芋葡甘聚糖25-35份、海藻酸钠5-35份、乳糖6-26份、微晶纤维素5-25份、硬脂酸镁0.5-5份、十二烷基硫酸钠1-5份、交联聚维酮1-5份、交联羧甲基纤维素钠0.5-5份、碳酸氢钠5-10份、活菌型长双歧杆菌W68菌粉1-5份。
其中,原料“护肝益生菌中药发酵物”由长双歧杆菌W68对中药提取液进行发酵而成,中药提取液由中药组合物经过提取而成,中药组合物由以下原料组成:旱芹12份、罗布麻3份、蒺藜8份、珍珠母3份、赛山蓝8份、紫贝3份、蜜环菌7份、绞股蓝8份、白芍4份、枸杞子20份、女贞子3份、杜仲3份、续断2份、韭子3份、决明子12份、姜黄13份。
本发明实施例所提供的护肝益生菌缓释片按照以下方法制备而成:
1、破壁:将旱芹、赛山蓝、蜜环菌、绞股蓝、枸杞子加40倍量软水破壁,得基料A;
2、粉碎:将罗布麻、蒺藜、杜仲、女贞子、韭子、续断、白芍、决明子、姜黄用中药粉碎机粉碎至200目粉末,再用10倍量冷的软水浸泡20 min,得基料B;
3、一次熬煮:将基料A、基料B、珍珠母、紫贝加入煎煮锅中,水开后煎煮50min,冷却后用200目滤布过滤,得基料C;
4、二次熬煮:在步骤3的滤渣加25倍量软水,水开后重复煎煮30min,冷却后用200目滤布过滤,得基料D;
5、三次熬煮:在步骤4的滤渣加10倍量软水,水开后重复煎煮20min,冷却后用200目滤布过滤,得基料E;
6、浓缩:将基料C、基料D和基料E合并滤液,于30℃进行低温浓缩得基料F;
7、调配:向基料F中加入15%的葡萄糖,0.05%尿素,用小苏打调pH至6.5~7.0,得基料G;
8、灭菌:将基料G于135℃、0.75MPa下灭菌4s,冷却至35℃,得基料H;
9、菌株复活:取出在 - 80 ℃条件下甘油保藏的长双歧杆菌W68菌株,解冻至室温。在无菌操作台上进行平板划线,随后置于生化培养箱中37 ℃恒温培养8~10 h,重复操作3次,使其充分活化。在无菌条件下挑取单菌落,接种到MRS液体培养基中,37 ℃、200 r/min摇床振荡培养8~10 h后取出,获得发酵用菌悬液I;
10、发酵:将6%的发酵用菌悬液I接种到基料H中于37℃恒温培养8h,得基料J;
11、冻干:用软水将15%麦芽糊精、6%乳糖、3%海藻糖、1%果胶溶解混匀,灭菌后冷却至室温,得溶液K。在无菌环境中,将溶液K加到基料J中混合均匀,预冻至- 40℃,保持4h,在“温度 - 29℃,真空度 250 mTorr”的条件下,升华干燥90 h,在“温度25℃,真空度 250mTorr”的条件下,解析干燥30 h,得益生菌发酵制品L;
12、粉碎过筛:将益生菌发酵制品L用粉碎机粉碎至100目,整粒得基料M;
13、混合:将魔芋葡甘聚糖、海藻酸钠、乳糖、基料M、微晶纤维素、硬脂酸镁、十二烷基硫酸钠、交联聚维酮、交联羧甲基纤维素钠与碳酸氢钠按表7重量份数称量,混合20min,得基料N;
14、干法制粒:将基料N干压制粒,过筛,筛网20目,未成形颗粒的干粉经65目筛网筛分后,重复干压制粒,至细粉比例小于投料量20%,制成的粒为基料O;
15、混合:将3份长双歧杆菌W68菌粉、基料O、干法制粒的剩余细粉、1份交联聚维酮、1份交联羧甲基纤维素钠,1份硬脂酸镁,2份头孢呋辛酯混合10min,得基料P;其中,头孢呋辛酯作为溶出度的标记物,不作为护肝片的原料;
16、压片:将基料P用40KN的压力压制片,片重差异控制在± 7.5%,即得肠道定位释放的护肝益生菌缓释片。
表7 缓释片辅料配方
采用溶出度测定法对肠道定位释放的护肝益生菌缓释片的释放情况进行测定,结果如表8。
溶出度测定法
1)溶出介质:
人工胃液(0.1mol/L盐酸溶液):量取9mL HCL,加水稀释至1000mL。
人工肠液(pH6.8含氯化钠磷酸盐缓冲液):取磷酸二氢钾:1.0g、磷酸氢二钾:2.0g、氯化钠:8.5g,溶于水900mL,调整pH值至6.8,加水至1000mL。
2)试验方法:设定溶出介质温度37±0.5℃,桨速50rpm,将制剂投入含人工胃液的溶出杯中,开始计时,于60min后取溶出液5mL,经0.45μm微孔滤膜快速滤过,得胃液溶出样品。倾出人工胃液,加入人工肠液并调整pH为6.8,于15min、30min、45min、60min后取溶出液,经0.45μm微孔滤膜快速滤过得小肠液溶出样品。取胃液、小肠液溶出样品,按头孢呋辛酯含量测定方法以头孢呋辛酯含量为指标,考察制剂的体外释放度。
表8 头孢呋辛酯溶出率/%
由表8可得,组合3、组合4、组合5、组合6的缓释片均能耐受胃液,不发生崩解。其中组合4的缓释效果最佳,能够实现均匀释放,且溶出率高,缓释片在小肠中随着小肠蠕动能够均匀释放,最终基本崩解完全。因此选择组合4作为缓释片的最佳辅料配方。
体系四:人群功效验证
1. 样品制备:
(1)活菌型益生菌粉:取长双歧杆菌W68菌粉3份,低聚果糖97份,混匀后分装成2g/袋,即得益生菌粉;
(2)灭活型益生菌粉:取热灭活的长双歧杆菌W68菌粉3份,低聚果糖97份,混匀后分装成2g/袋,即得灭活型益生菌粉;
(3)肠道定位释放的护肝益生菌缓释片A:采用本发明最佳组合制成(体系三中的组合4),2g/片。
(4)肠道定位释放的护肝益生菌缓释片B:其与护肝益生菌缓释片A的不同之处在于,在发酵时,将“长双歧杆菌W68”替换成“短双歧杆菌”,同时在制片时,将“长双歧杆菌W68”替换成“短双歧杆菌”,其他操作同缓释片A,2g/片。
(5)肠道定位释放的护肝益生菌缓释片C:其与护肝益生菌缓释片A的不同之处在于,中药组合物不同,将君药的“决明子”、臣药的“蜜环菌”、佐药的“白芍”、使药的“珍珠母”4种成分去除,其他操作同缓释片A,2g/片。
(6)肠道定位释放的护肝益生菌缓释片D:其与护肝益生菌缓释片A的不同之处在于,在发酵时,将“长双歧杆菌W68”的添加量修改为5%,其他操作同缓释片A,2g/片。
(7)护肝益生菌发酵粉:取护肝益生菌中药发酵物(本发明实施例体系二中制备的护肝益生菌中药发酵物,且在发酵时,益生菌添的加量为6%)3份,低聚果糖97份,混匀后分装成2g/袋,即得护肝益生菌发酵粉。
2. 样品服用方法:
(1)活菌型益生菌粉:饭后半小时食用,每日2次,每次1袋,加入150ml、37℃温水调匀饮用。
(2)灭活型益生菌粉:饭后半小时食用,每日2次,每次1袋,加入150ml、37℃温水调匀饮用。
(3)肠道定位释放的护肝益生菌缓释片A、B、C和D:饭后半小时食用,每日2次,每次1片,用150ml、37℃温水送服。
(4)护肝益生菌发酵粉:饭后半小时食用,每日2次,每次1袋,加入150ml、37℃温水调匀饮用。
3. 人群招募:招募56名志愿者,志愿者的谷丙转氨酶(GPT),谷草转氨酶(GOT)均均偏高(均为29U/L以上),年龄范围22~60岁。
4. 测试周期:30天。
5. 试验方法:将志愿者随机分成7组,每组8人,记为A、B、C、D、E、F、G组,安排志愿者分别服用上述样品,即A组志愿者服用活菌型益生菌粉,B组志愿者服用灭活型益生菌粉,C组志愿者服用肠道定位释放的护肝益生菌缓释片A,D组志愿者服用肠道定位释放的护肝益生菌缓释片B,E组志愿者服用肠道定位释放的护肝益生菌缓释片C,F组志愿者服用肠道定位释放的护肝益生菌缓释片D,G组志愿者服用护肝益生菌发酵粉;记录志愿者的谷丙转氨酶(GPT),谷草转氨酶(GOT)前后变化,结果如表9。
表9 志愿者的GPT、GOT水平变化(U/L)
由表9可得,A组、B组、C组志愿者服用本发明实施例所提供的益生菌产品后,GPT、GOT水平均有发生显著性降低,且志愿者均反馈非常好。服用长双歧杆菌W68发酵制品制成的益生菌产品(护肝益生菌缓释片A)护肝效果最佳,其次是活菌型益生菌粉,灭活型的益生菌粉的护肝效果虽然效果没有A组和C组好,但是也有一定的护肝效果。D组、E组、F组和G组的结果表明,更换菌粉或是变动中药组分或是修改菌种发酵添加量或是仅添加益生菌发酵粉制成的益生菌产品其护肝效果均有明显减弱,且更换菌粉后,护肝效果减弱程度最为明显。本发明的益生菌对肝损伤具有很好的修复效果,从降脂护肝、修复肝细胞、减少肝脏氧化应激反应、提高肝脏免疫力、清楚肝脏内毒素等多种方式同步进行,具有明显的养护肝脏作用。
上述实施方式仅为本发明的优选实施方式,不能以此来限定本发明保护的范围,本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。
Claims (10)
1.一种益生菌在制备护肝产品中的应用,其特征在于,所述益生菌为保藏编号为CGMCCNo.15028的长双歧杆菌W68;所述护肝产品的活性成分包括长双歧杆菌W68的活菌体和/或灭活型菌体。
2.如权利要求1所述的应用,其特征在于,所述护肝产品包括护肝食品、护肝保健品、护肝药品和护肝营养补充剂。
3.如权利要求1所述的应用,其特征在于,所述护肝产品为护肝益生菌固体饮料,所述护肝益生菌固体饮料包括按照重量份数计的以下原料:长双歧杆菌W68菌粉1-5份,益生元5-90份;所述长双歧杆菌W68菌粉为活菌粉和/或灭活型菌粉;所述益生元包括低聚果糖、菊粉、低聚木糖、低聚半乳糖、低聚麦芽糖、低聚异麦芽糖、抗性糊精、大豆低聚糖、水苏糖、壳聚糖和棉子糖中的一种或任意组合。
4.如权利要求1所述的应用,其特征在于,所述长双歧杆菌W68发挥护肝效果,包括:增强肝脏代谢脂质的能力,增强肝脏的抗氧化应激能力。
5.如权利要求4所述的应用,其特征在于,所述长双歧杆菌W68具有护肝效果,可以降低肝脏组织的甘油三酯和丙二醛含量,提高肝脏组织的过氧化氢酶和谷胱甘肽酶含量。
6.一种护肝益生菌中药发酵物,其特征在于,由益生菌对中药提取液进行发酵而成,所述益生菌为保藏编号为CGMCC No.15028的长双歧杆菌W68;所述中药提取液由中药组合物经过提取而成,所述中药组合物由按照重量份数计的以下原料组成:旱芹10-15份、罗布麻1-5份、蒺藜5-10份、珍珠母1-5份、赛山蓝5-10份、紫贝1-5份、蜜环菌5-10份、绞股蓝5-10份、白芍1-5份、枸杞子15-25份、女贞子1-5份、杜仲1-5份、续断1-5份、韭子1-5份、决明子10-15份、姜黄10-15份。
7.如权利要求6所述的护肝益生菌中药发酵物,其特征在于,所述长双歧杆菌W68对所述中药提取液进行发酵时,所述长双歧杆菌W68的添加量为所述中药提取液体积的4-8%。
8.如权利要求6所述的护肝益生菌中药发酵物,其特征在于,所述长双歧杆菌W68对所述中药提取液进行发酵时,所述长双歧杆菌W68的添加量为所述中药提取液体积的6-7%。
9.权利要求6-8任一项所述的护肝益生菌中药发酵物在制备护肝产品中的应用。
10.一种护肝益生菌缓释片,其特征在于,按照重量份数计,包括权利要求6-8任一项所述的护肝益生菌中药发酵物12-17份,还包括:魔芋葡甘聚糖25-35份、海藻酸钠5-35份、乳糖6-26份、微晶纤维素5-25份、硬脂酸镁0.5-5份、十二烷基硫酸钠1-5份、交联聚维酮1-5份、交联羧甲基纤维素钠0.5-5份、碳酸氢钠5-10份。
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