CN118086154A - 一种改善慢性低度炎症的益生菌剂及其应用 - Google Patents
一种改善慢性低度炎症的益生菌剂及其应用 Download PDFInfo
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Abstract
本发明涉及一种改善慢性低度炎症的益生菌剂及其应用,所述改善慢性低度炎症的益生菌剂中的菌株包括动物双歧杆菌乳亚种Bifidobacterium animalis subsp.lactis BLa36菌株和乳酸片球菌Pediococcus acidilactici PA53菌株。两者存在潜在的相互作用,能够相互配合,在改善肥胖及其相关慢性低度炎症的功效上协同增效,具体表现在:显著改善机体炎症水平,通过调节免疫反应,有效降低体内炎症因子的水平,减轻慢性低度炎症状态;增强肠道屏障功能,通过提升肠道上皮细胞的紧密连接,减少炎症诱导的肠道渗透性增加,降低血清脂多糖水平,从而防止炎症的进一步加剧;调节体重和改善代谢。
Description
技术领域
本发明属于益生菌技术领域,涉及一种改善慢性低度炎症的益生菌剂及其应用。
背景技术
慢性低度炎症被认为是多种代谢性疾病的关键驱动因素,包括肥胖、2型糖尿病、心血管疾病等。这种类型的炎症通常由不健康的生活方式因素诱发,特别是高脂肪饮食和脂多糖的摄入,能够通过增强炎症反应而促进疾病的发展。因此,寻找有效的干预措施以缓解或预防慢性低度炎症是很有意义的。益生菌,作为活性微生物的一种,显示出调节宿主免疫反应的潜力,特别是在抑制慢性低度炎症方面。益生菌通过多种机制发挥作用,包括但不限于改善肠道屏障功能、调节肠道微生物组成、产生具有抗炎作用的代谢产物等。这些作用共同促进了对慢性炎症状态的改善,为治疗和预防相关疾病提供了一种潜在的策略。
发明内容
针对现有技术的不足,本发明的目的在于提供一种改善慢性低度炎症的益生菌剂及其应用,具体提供一种改善慢性低度炎症的益生菌剂及其在制备预防或治疗慢性低度炎症、糖尿病或肥胖症的产品中的应用。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供一种改善慢性低度炎症的益生菌剂,所述改善慢性低度炎症的益生菌剂中的菌株包括保藏编号为CGMCC No.24029的动物双歧杆菌乳亚种Bifidobacterium animalis subsp. lactis BLa36菌株和保藏编号为CGMCC No.18798的乳酸片球菌Pediococcus acidilactici PA53菌株。
本发明开发了一种全新的益生菌复配方式,是将动物双歧杆菌乳亚种Bifidobacterium animalis subsp. lactis BLa36菌株和乳酸片球菌Pediococcus acidilactici PA53菌株进行复配,发现两者存在潜在的相互作用,能够相互配合,在改善肥胖及其相关慢性低度炎症的功效上协同增效,具体表现在:(1)显著改善机体炎症水平,通过调节免疫反应,有效降低体内炎症因子的水平,减轻慢性低度炎症状态;(2)增强肠道屏障功能,通过提升肠道上皮细胞的紧密连接,减少炎症诱导的肠道渗透性增加,降低血清脂多糖水平,从而防止炎症的进一步加剧;(3)调节体重和改善代谢。在使用菌量一致的情况下,与单一的BLa36菌株或单一的PA53菌株相比,两种菌的复配在上述功效的发挥显著提高。因此,该益生菌剂为预防、改善或治疗慢性低度炎症提供了新的策略。由于动物双歧杆菌乳亚种和乳酸片球菌均为益生菌,因此其在用于制备相关功效产品时,安全性高,且不易产生依赖性。
优选地,所述BLa36菌株与PA53菌株的活菌数之比为1:10-10:1,例如1:10、1:9、1:8、1:7、1:6、1:5、1:4、1:3、1:2、1:1、2:1、4:1、6:1、8:1、10:1等,上述数值范围内的其他具体点值均可选择,在此便不再一一赘述。
优选地,在所述益生菌剂中,活菌总数不低于1×109 CFU/mL或1×109 CFU/g,例如1×109 CFU/mL(CFU/g)、5×109 CFU/mL(CFU/g)、1×1010 CFU/mL(CFU/g)、2×1010 CFU/mL(CFU/g)、1×1011 CFU/mL(CFU/g)、1×1012 CFU/mL(CFU/g)、1×1013 CFU/mL(CFU/g)等;该数值范围内的其他具体点值均可选择,在此便不再一一赘述。
优选地,所述益生菌剂的剂型包括冻干粉剂、胶囊剂、片剂或颗粒剂。
本发明所涉及的益生菌剂的剂型不受限制,包括最常用的冻干粉剂,或进一步制得的胶囊剂、片剂或颗粒剂。其中冻干粉剂示例性地可以采用如下方法制得:
将BLa36菌株与PA53菌株分别接种于培养基中进行培养,得到培养液;培养液离心,得到菌体;菌体用冻干保护剂重悬,得到重悬液;重悬液冻干,即得,然后按比例将二者复配。
或者,将BLa36菌株与PA53菌株分别接种于培养基中进行培养,得到培养液;培养液离心,得到菌体;将两种菌体按照比例混合后用冻干保护剂重悬,得到重悬液;重悬液冻干,即得。
优选地,所述冻干采用真空冷冻法。
优选地,所述益生菌剂还包括冻干保护剂和/或辅助添加剂。
优选地,所述冻干保护剂包括脱脂乳、蔗糖、乳糖、海藻糖、右旋糖酐、明胶、糊精、阿拉伯胶、藻胶钠、聚乙烯吡咯烷酮、山梨醇或木糖醇中的任意一种或至少两种的组合。
优选地,所述辅助添加剂包括菊粉、低聚果糖、低聚木糖、低聚半乳糖、低聚异麦芽糖、大豆低聚糖、螺旋藻、节旋藻、云芝多糖、水苏糖、聚葡萄糖、α-乳清蛋白或乳铁蛋白中的任意一种或至少两种的组合。
第二方面,本发明提供根据第一方面所述的改善慢性低度炎症的益生菌剂在制备预防或治疗慢性低度炎症的产品中的应用。
第三方面,本发明提供根据第一方面所述的改善慢性低度炎症的益生菌剂在制备预防或治疗糖尿病的产品中的应用。
第四方面,本发明提供根据第一方面所述的改善慢性低度炎症的益生菌剂在制备预防或治疗肥胖症的产品中的应用。
相对于现有技术,本发明具有以下有益效果:
本发明开发了一种全新的益生菌复配方式,是将动物双歧杆菌乳亚种Bifidobacterium animalis subsp. lactis BLa36菌株和乳酸片球菌Pediococcus acidilactici PA53菌株进行复配,发现两者存在潜在的相互作用,能够相互配合,在改善肥胖及其相关慢性低度炎症的功效上协同增效,具体表现在:(1)显著改善机体炎症水平,通过调节免疫反应,有效降低体内炎症因子的水平,减轻慢性低度炎症状态;(2)增强肠道屏障功能,通过提升肠道上皮细胞的紧密连接,减少炎症诱导的肠道渗透性增加,降低血清脂多糖水平,从而防止炎症的进一步加剧;(3)调节体重和改善代谢。在使用菌量一致的情况下,与单一的BLa36菌株或单一的PA53菌株相比,两种菌的复配在上述功效的发挥显著提高。因此,该益生菌剂为预防、改善或治疗慢性低度炎症提供了新的策略。由于动物双歧杆菌乳亚种和乳酸片球菌均为益生菌,因此其在用于制备相关功效产品时,安全性高,且不易产生依赖性。
本发明所涉及的动物双歧杆菌乳亚种BLa36菌株的分类命名为动物双歧杆菌乳亚种Bifidobacterium animalis subsp. lactis,保藏单位为中国微生物菌种保藏管理委员会普通微生物中心,保藏时间为2021年12月02日,保藏编号为CGMCC No.24029,地址为:北京市朝阳区北辰西路1号院3号。
本发明所涉及的乳酸片球菌PA53菌株的分类命名为乳酸片球菌Pediococcus acidilactici,保藏单位为中国微生物菌种保藏管理委员会普通微生物中心,保藏时间为2019年11月04日,保藏编号为CGMCC No.18798,地址为:北京市朝阳区北辰西路1号院3号。
附图说明
图1是各组小鼠的体重变化情况统计结果图;
图2是各组小鼠的空腹血糖水平的统计结果图;
图3是各组小鼠的空腹胰岛素水平的统计结果图;
图4是各组小鼠的血清LPS水平的统计结果图;
图5是各组小鼠的血清IL-10水平的统计结果图;
图6是各组小鼠的血清IL-6水平的统计结果图;
图7是各组小鼠的血清TNF-α水平的统计结果图;
图8是各组小鼠的血清IL-1β水平的统计结果图;
图9是各组小鼠的血清屏障紧密连接蛋白-1水平的统计结果图;
图10是各组小鼠的血清闭锁蛋白Occludin水平的统计结果图;
图11是各组小鼠的血清封闭蛋白-1水平的统计结果图;
图12是各组小鼠的血清肠碱性磷酸酶水平的统计结果图。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
下述实施例中涉及的培养基配方如下:
MRS培养基(g/L):蛋白胨10g/L、牛肉膏10g/L、葡萄糖20g/L、乙酸钠2g/L、酵母粉5g/L、柠檬酸氢二铵2g/L、K2PO4·3H2O 2.6g/L、MgSO4·7H2O 0.1g/L、MnSO4 0.05g/L、吐温80 1mL/L、半胱氨酸盐酸盐0.5g/L。
下述实施例所涉及的动物双歧杆菌乳亚种BLa36菌株的分类命名为动物双歧杆菌乳亚种Bifidobacterium animalis subsp. lactis,保藏编号为CGMCC No.24029。
本发明所涉及的乳酸片球菌PA53菌株的分类命名为乳酸片球菌Pediococcus acidilactici,保藏编号为CGMCC No.18798。
下述涉及的菌悬液制备方法:将所需菌株接种于MRS液体培养基中,37℃下培养18h进行活化,连续活化2次,得到活化液;将活化液按2%(v/v)的接种量接种于MRS液体培养基中,37℃下培养24 h,得到菌液;将菌液在4℃下5000rpm下离心5 min,过滤,得到菌体,使用PBS溶液重悬菌体,即得。
试验结果数据使用R语言的ggplot2进行统计分析,与CTL组相比,###代表p<0.001;与MC组相比,***代表p<0.001,**代表p<0.01,*代表p<0.05,NS.代表无显著差异。
实施例
本实施例探究益生菌剂对慢性低度炎症小鼠的症状改善能力:
(1)试验动物:4周龄昆明雌性SPF小鼠56只,由上海市实验动物研究中心提供,将小鼠饲养于笼内,环境清洁安静,温度20-24℃,湿度50-60%,遵循12h光/暗循环。所有实验程序均符合上海实验动物护理与动物实验中心规定的动物护理和使用伦理指南。
(2)动物分组:按上述小鼠适应性喂养2周后,将小鼠随机分为7组(每组8只):对照组(CTL组)、模型组(MC组)、经BLa36菌株干预的小鼠组(BLa36组,记为S1组)、经PA53菌株干预的小鼠组(PA53组,记为S2组)、经市售动物双歧杆菌乳亚种ATCC27536干预的小鼠组(记为S3组)、经BLa36菌株和PA53菌株联合干预的大鼠组(两株菌的活菌数比例2:1,记为S4组)、经市售动物双歧杆菌乳亚种ATCC27536和PA53联合干预的大鼠组(两株菌的活菌数比例2:1,记为S5组)。
(3)动物建模及干预方法:
普通饲料:大小鼠维持配合饲料(购于斯莱康);高脂饲料:60%基础饲料+20%猪油+10%蔗糖+10%蛋黄(购于斯莱康SLACOM);脂多糖:规格10mg/瓶;脂多糖溶液的配制:取脂多糖粉末24.5mg溶于78.4mL生理盐水稀释,用于低剂量脂多糖造模。
CTL组小鼠自实验开始至结束均用普通饲料+无菌水喂养,其余组小鼠全部用高脂饲料喂养,同时益生菌干预组小鼠使用含有菌液的纯化水喂养2个月(干预量为1×109 CFU/只/天)。在取材前一天(24小时内)在除了对照组外的其余组小鼠后腿肌肉按0.25mg/kg的剂量注射脂多糖。
(4)样本采集:
试验期间,每周测量小鼠体重。实验结束前3天,对小鼠进行禁食不禁水12h,尾静脉取血,全自动血糖仪测空腹血糖,使用酶联免疫吸附测定空腹血清胰岛素水平。
血液采样是在实验结束时进行的,采集时间为上午10-11点。血液离心1200×g 10min后,提取血清,存放在-80℃中。使用酶联免疫吸附测定试剂盒(武汉纯度生物技术有限公司),按照制造商的指导进行量化测定脂多糖(LPS)水平、抗炎细胞因子白细胞介素-10(IL-10)水平、促炎因子白细胞介素-6(IL-6)水平、白细胞介素-1β(IL-1β)水平、肿瘤坏死因子-α(TNF-α)水平;血清肠道屏障紧密连接蛋白-1(ZO-1)、闭锁蛋白Occludin、封闭蛋白-1(Claudin-1)、肠碱性磷酸酶(IAP)浓度进行分析。
(5)指标分析:
(5.1)小鼠体重变化和胰岛素敏感性测试结果:
结果如图1、图2、图3所示,与对照组相比,模型组小鼠的体重增长异常,空腹血糖水平和空腹胰岛素水平异常升高,这些结果一致指向高脂饮食诱导的代谢异常和胰岛素抵抗状态。但益生菌干预后,小鼠体重增长趋向正常,空腹血糖和空腹胰岛素水平也趋于正常,这表明益生菌可能通过调节肠道微生物群落、改善肠道屏障功能和减少系统性炎症来促进代谢健康,且两菌联合的S4组的效果更优。
(5.2)对炎症因子的影响:
结果图4-图8所示,与对照组相比,模型组小鼠血清的脂多糖(LPS),促炎因子白细胞介素-6(IL-6),白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)显著升高,白细胞介素-10(IL-10)水平显著降低,这些指标的变化直接反映了肥胖状态下免疫系统的慢性低度炎症反应,揭示了肥胖及其并发症与炎症之间的密切联系。然而益生菌干预后,细胞炎症因子出现逆转,血清脂多糖(LPS),促炎因子白细胞介素-6(IL-6),白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)水平显著降低,白细胞介素-10(IL-10)水平显著升高,这一结果不仅证明了益生菌干预在调节免疫反应、降低炎症水平以及增强机体抗炎能力方面的有效性,也强调了其在治疗肥胖及其相关慢性炎症状态中的应用潜力,且两菌联合的S4组的效果更优。
(5.3)肠道屏障水平的测定:
结果如图9-图12所示,与对照组相比,模型组小鼠的屏障紧密连接蛋白-1(ZO-1)、闭锁蛋白Occludin、封闭蛋白-1(Claudin-1)、肠碱性磷酸酶(IAP)的水平显著下降,这些变化直观地反映了肠道屏障功能受损,暗示着肠道通透性增加,这是许多慢性炎症状态和代谢性疾病的关键病理生理机制。但益生菌干预后屏障紧密连接蛋白-1(ZO-1)、闭锁蛋白Occludin、封闭蛋白-1(Claudin-1)、肠碱性磷酸酶(IAP)水平显著升高,益生菌干预具有加强肠道屏障功能、降低肠道通透性以及维护肠道微环境稳定的显著能力,尤其是S4组的效果最为显著。通过显著改善肠道屏障蛋白的表达,益生菌干预不仅为肠道健康提供了强有力的保护,也为防治肠道屏障功能障碍相关的慢性疾病提供了新的治疗策略。
申请人声明,本发明通过上述实施例来说明本发明的技术方案,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
Claims (10)
1.一种改善慢性低度炎症的益生菌剂,其特征在于,所述改善慢性低度炎症的益生菌剂中的菌株包括保藏编号为CGMCC No.24029的动物双歧杆菌乳亚种Bifidobacterium animalis subsp. lactis BLa36菌株和保藏编号为CGMCC No.18798的乳酸片球菌Pediococcus acidilactici PA53菌株。
2.根据权利要求1所述的改善慢性低度炎症的益生菌剂,其特征在于,所述BLa36菌株与PA53菌株的活菌数之比为1:10-10:1。
3.根据权利要求1所述的改善慢性低度炎症的益生菌剂,其特征在于,在所述益生菌剂中,活菌总数不低于1×109 CFU/mL或1×109 CFU/g。
4.根据权利要求1所述的改善慢性低度炎症的益生菌剂,其特征在于,所述益生菌剂的剂型包括冻干粉剂、胶囊剂、片剂或颗粒剂。
5.根据权利要求1所述的改善慢性低度炎症的益生菌剂,其特征在于,所述益生菌剂还包括冻干保护剂和/或辅助添加剂。
6.根据权利要求5所述的改善慢性低度炎症的益生菌剂,其特征在于,所述冻干保护剂包括脱脂乳、蔗糖、乳糖、海藻糖、右旋糖酐、明胶、糊精、阿拉伯胶、藻胶钠、聚乙烯吡咯烷酮、山梨醇或木糖醇中的任意一种或至少两种的组合。
7.根据权利要求5所述的改善慢性低度炎症的益生菌剂,其特征在于,所述辅助添加剂包括菊粉、低聚果糖、低聚木糖、低聚半乳糖、低聚异麦芽糖、大豆低聚糖、螺旋藻、节旋藻、云芝多糖、水苏糖、聚葡萄糖、α-乳清蛋白或乳铁蛋白中的任意一种或至少两种的组合。
8.根据权利要求1-7中任一项所述的改善慢性低度炎症的益生菌剂在制备预防或治疗慢性低度炎症的产品中的应用。
9.根据权利要求1-7中任一项所述的改善慢性低度炎症的益生菌剂在制备预防或治疗糖尿病的产品中的应用。
10.根据权利要求1-7中任一项所述的改善慢性低度炎症的益生菌剂在制备预防或治疗肥胖症的产品中的应用。
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