CN116814505B - 一种鼠李糖乳杆菌及其应用 - Google Patents
一种鼠李糖乳杆菌及其应用 Download PDFInfo
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Abstract
本发明公开了一种鼠李糖乳杆菌,其保藏于中国微生物菌种保藏管理委员会普通微生物中心(CGMCC),保藏号为CGMCC No.25804。本发明菌株可以单独形成制剂,也可作为添加剂加入其它药品、保健品或功能性食品中用于肥胖、以及焦虑或抑郁等不良情绪的改善,具有十分广泛的应用和市场前景。
Description
技术领域
本发明属于食用微生物领域,具体涉及一种鼠李糖乳杆菌极其应用。
背景技术
肥胖是一种以体脂肪累积过多和(或)体脂肪分布异常为主要表现的慢性代谢性疾病。随着人们膳食结构和生活方式的改变,近年来肥胖已成为世界范围内的流行病。除了自身的不利影响之外,肥胖还与一系列并发症相关联,如糖尿病、高血压、脂代谢紊乱、高尿酸血症等代谢性疾病,除此之外,流行病学调查显示,在超重人群中焦虑抑郁疾病的发病率也有所升高,肥胖症患者经常同时罹患抑郁症和焦虑症等精神疾病。同时大约43%患有抑郁症的成年人同时患有肥胖症,并且与精神健康的成年人相比,患有精神疾病的成年人更容易肥胖。肥胖症与抑郁焦虑不良情绪之间存在着双向的联系,即随着肥胖程度的增加,患者发生抑郁焦虑的风险也明显升高,反之,随着抑郁焦虑程度的上升,发生肥胖症的风险也相应增加。
在治疗肥胖和抑郁方面,尽管药物开发取得了可喜的成绩,但大多数接受治疗的个体并没有充分达到症状缓解和功能恢复的目的。目前多种减肥药物在带来减肥疗效的同时,也因存在的安全问题逐步退出市场。而抑郁和焦虑尤其抑郁焦虑和肥胖的共病治疗率低,治疗效果差,复发率高,造成巨大的医疗费用支出,给家庭和社会造成了沉重的负担,已成为全世界所面临的最为严峻的健康挑战。
益生菌(Probiotics)是一类对宿主发挥有益健康作用的活微生物,目前益生菌在防治肥胖以及抑郁和焦虑等不良情绪方面的作用研究引起了国内外学者的高度重视,有可能为改善肥胖和抑郁、焦虑提供新思路和新方向。比如现有报道筛选出了能改善不良情绪的鼠李糖乳杆菌,也有报道筛选出了具备减肥功效的鼠李糖乳杆菌,但目前尚未见报道兼具减肥和改善抑郁等不良情绪作用的益生菌,特别是鼠李糖乳杆菌的研究报道。
发明内容
为解决上述问题,本发明的目的在于提供一种新型菌株,该菌株可用于改善肥胖,同时缓解抑郁和焦虑等不良情绪。
本发明提供了一种鼠李糖乳杆菌,所述鼠李糖乳杆菌保藏于中国微生物菌种保藏管理委员会普通微生物中心(CGMCC),保藏号为CGMCC No.25804。
本发明还提供了一种前述鼠李糖乳杆菌在制备减肥和/或改善不良情绪的食品或药品中的用途。
进一步地,所述食品或药品具有改善空腹血糖升高的作用。
进一步地,所述食品或药品具有降低体重的作用。
进一步地,所述食品或药品具有改善抑郁样、焦虑样行为的作用。
更进一步地,所述食品或药品具有升高血清和海马中5-羟色胺、脑源性神经营养因子BDNF水平的作用。
更进一步地,所述食品或药品具有缓解应激造成的下丘脑-垂体-肾上腺(HPA)轴亢奋的作用。
更进一步地,所述食品或药品具有降低大鼠海马和血清中皮质酮CORT,和/或降低血清中肾上腺皮质激素释放激素CRH和促肾上腺皮质激素ACTH的水平的作用。
进一步地,所述食品或药品具有降低血清中炎症因子TNF-α和IL-1β水平的作用。
进一步地,所述食品或药品是以鼠李糖乳杆菌为活性成分,加上食品或药品上可接受的辅料制成的制剂;所述制剂为口服制剂;所述口服制剂中鼠李糖乳杆菌的活菌数≥2×109CFU/mL。
本发明还前权利要求1所述的鼠李糖乳杆菌。
本发明最后提供了一种减肥和/或改善不良情绪的药物,它的制备原料包括前述的鼠李糖乳杆菌。
本发明鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12,于2022年9月26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(CGMCC),保藏编号为CGMCC No.25804,分类命名为:鼠李糖乳杆菌Lactobacillus rhamnosus,保藏地址为: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中国微生物菌种保藏管理委员会普通微生物中心。
相对现有技术,本发明的有益效果为:
本发明鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12可显著降低肥胖小鼠体重,不抑制肥胖小鼠食欲,且可改善肥胖小鼠空腹血糖的升高。提高抑郁模型大鼠血清和海马5-HT和BDNF水平,缓解应激造成的下丘脑-垂体-肾上腺(HPA)轴亢奋,降低抑郁模型大鼠血清炎症因子水平,该菌株在动物实验中可改善焦虑和抑郁行为。本发明菌株可以单独形成制剂,也可作为添加剂加入其它药品、保健品或功能性食品中用于肥胖、以及焦虑或抑郁等不良情绪的改善,具有十分广泛的应用和市场前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1鼠李糖乳杆菌GM12(LacR)对ob/ob小鼠体重及体重增长的影响。(A)体重;(B)体重增长;每组10只动物。#P<0.05vs正常对照组(Normal);##P<0.01vs正常对照组(Normal);*P<0.05vs肥胖小鼠(ob/ob);**P<0.01vs肥胖小鼠(ob/ob)。
图2鼠李糖乳杆菌GM12(LacR)对ob/ob小鼠摄食量的影响。#P<0.05vs正常对照组(Normal);每组10只动物。#P<0.05vs正常对照组(Normal);##P<0.01vs正常对照组(Normal);*P<0.05vs肥胖小鼠(ob/ob);**P<0.01vs肥胖小鼠(ob/ob)。
图3鼠李糖乳杆菌GM12(LacR)对ob/ob小鼠空腹血糖的影响。#P<0.05vs正常对照组(Normal);每组10只动物。#P<0.05vs正常对照组(Normal);##P<0.01vs正常对照组(Normal);*P<0.05vs肥胖小鼠(ob/ob);**P<0.01vs肥胖小鼠(ob/ob)。
图4鼠李糖乳杆菌GM12(LacR)对CUMS大鼠行为学实验的影响。(A)高架十字迷宫试验;(B)旷场试验;(C)强迫游泳试验;(D)糖水偏好试验;每组10只动物。#P<0.05vs正常对照组(Normal);##P<0.01vs正常对照组(Normal);*P<0.05vs抑郁模型组(CUMS);**P<0.01vs抑郁模型组(CUMS)。
图5鼠李糖乳杆菌GM12(LacR)对CUMS大鼠血清5-羟色胺(5-HT)、脑源性神经营养因子(BDNF)和HPA轴相关指标水平的影响。(A)5-HT水平;(B)BDNF水平;(C)皮质酮(CORT)水平;(D)促肾上腺皮质激素释放激素(CRH)水平;(E)促肾上腺皮质激素(ACTH)水平;每组10只动物。#P<0.05vs正常对照组(Normal);##P<0.01vs正常对照组(Normal);*P<0.05vs抑郁模型组(CUMS);**P<0.01vs抑郁模型组(CUMS)。
图6鼠李糖乳杆菌GM12(LacR)对CUMS大鼠血清炎症因子水平的影响。(A)TNF-α水平;(B)IL-1β水平;每组10只动物。#P<0.05vs正常对照组(Normal);##P<0.01vs正常对照组(Normal);*P<0.05vs抑郁模型组(CUMS);**P<0.01vs抑郁模型组(CUMS)。
图7鼠李糖乳杆菌GM12(LacR)对CUMS大鼠海马5-羟色胺(5-HT)、脑源性神经营养因子(BDNF)和HPA轴相关指标水平的影响。(A)5-HT水平;(B)BDNF水平;(C)皮质酮(CORT)水平;每组10只动物。#P<0.05vs正常对照组(Normal);##P<0.01vs正常对照组(Normal);*P<0.05vs抑郁模型组(CUMS);**P<0.01vs抑郁模型组(CUMS)。
具体实施方式
实施例1鼠李糖乳杆菌的筛选及功效实验
一、方法
1.菌株筛选及菌液制备
从高原奶制品、高原盐湖、四川特色发酵食品(泡菜、豆瓣等)来源筛选获得的多类植物乳杆菌、鼠李糖乳杆菌、乳酸乳球菌等,经过理化分析、类别鉴定及部分安全指标检测,将前期检测符合基本要求的菌株筛选出鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12。使用鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12制备菌液,菌液中活菌数≥2×109CFU/mL。
2、鉴定和保藏
经鉴定,GM12菌株为鼠李糖乳杆菌(Lactobacillus rhamnosus),并于2022年9月26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;保藏地址为:北京市朝阳区北辰西路1号院,中国科学院微生物研究所;保藏编号为:CGMCC No.25804。
其具体的鉴定特征如下:
(1)形态特征
革兰氏阳性菌,不产芽孢,在电子显微镜下,通常为细长杆状,无鞭毛,不运动。在MRS固体培养基上,形成的菌落较小,圆形或类圆形、湿润、边缘整齐,中央隆起的白色或乳白色菌落,不透明、有光泽、质地软,菌落背面为微黄色。
(2)生理生化特性
果糖、半乳糖、葡萄糖、阿拉伯糖、纤维二糖、乳糖、麦芽糖、鼠李糖、核糖、甘露醇等均能被发酵,棉子糖不能被发酵;不产吲哚和H2S;接触酶、硝酸盐还原和明胶液化结果均为阴性。
(3)16S rDNA的序列分析
序列如下(SEQ ID NO.1):
CTTTAGATGCAAGTCGAACGAACTCTGGTATTGATTGGTGCTTGCATCATGATTTACATTTGAGTGAGTGGCGAACTGGTGAGTAACACGTGGGAAACCTGCCCAGAAGCGGGGGATAACACCTGGAAACAGATGCTAATACCGCATAACAACTTGGACCGCATGGTCCGAGCTTGAAAGATGGCTTCGGCTATCACTTTTGGATGGTCCCGCGGCGTATTAGCTAGATGGTGGGGTAACGGCTCACCATGGCAATGATACGTAGCCGACCTGAGAGGGTAATCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCACAATGGACGAAAGTCTGATGGAGCAACGCCGCGTGAGTGAAGAAGGGTTTCGGCTCGTAAAACTCTGTTGTTAAAGAAGAACATATCTGAGAGTAACTGTTCAGGTATTGACGGTATTTAACCAGAAAGCCACGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTGTCCGGATTTATTGGGCGTAAAGCGAGCGCAGGCGGTTTTTTAAGTCTGATGTGAAAGCCTTCGGCTCAACCGAAGAAGTGCATCGGAAACTGGGAAACTTGAGTGCAGAAGAGGACAGTGGAACTCCATGTGTAGCGGTGAAATGCGTAGATATATGGAAGAACACCAGTGGCGAAGGCGGCTGTCTGGTCTGTAACTGACGCTGAGGCTCGAAAGTATGGGTAGCAAACAGGATTAGATACCCTGGTAGTCCATACCGTAAACGATGAATGCTAAGTGTTGGAGGGTTTCCGCCCTTCAGTGCTGCAGCTAACGCATTAAGCATTCCGCCTGGGGAGTACGGCCGCAAGGCTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCTACGCGAAGAACCTTACCAGGTCTTGACATACTATGCAAATCTAAGAGATTAGACGTTCCCTTCGGGGACATGGATACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATTATCAGTTGCCAGCATTAAGTTGGGCACTCTGGTGAGACTGCCGGTGACAAACCGGAGGAAGGTGGGGATGACGTCAAATCATCATGCCCCTTATGACCTGGGCTACACACGTGCTACAATGGATGGTACAACGAGTTGCGAACTCGCGAGAGTAAGCTAATCTCTTAAAGCCATTCTCAGTTCGGATTGTAGGCTGCAACTCGCCTACATGAAGTCGGAATCGCTAGTAATCGCGGATCAGCATGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGTTTGTAACACCCAAAGTCGGTGGGGTAACCTTTTAGGAACCAGCCGCCTAAG
在NCBI网站上使用BLAST工具在基因库中对该序列进行同源性比对,结果显示GM12的16S rDNA与鼠李糖乳杆菌(Lactobacillus rhamnosus)的16S rDNA序列相似性达99%以上,结合形态学和生理生化特征,鉴定菌株GM12为一株新的鼠李糖乳杆菌(Lactobacillus rhamnosus)。
3.益生菌对肥胖以及焦虑和抑郁的改善作用研究
(1)肥胖模型动物实验
1)实验动物分组及干预
将实验动物分为正常对照组(Normal)、肥胖模型组(ob/ob)、肥胖模型+鼠李糖乳杆菌GM12干预组(LacR)。正常对照组采用6-8周龄雄性ob/ob野生型小鼠进行实验,肥胖模型组和鼠李糖乳杆菌GM12干预组采用6-8周龄ob/ob基因突变肥胖小鼠进行实验。正常对照组每天自由饮水不灌胃,肥胖模型组和鼠李糖乳杆菌GM12干预组每天固定时间灌胃等量生理盐水和益生菌菌液进行干预,干预周期8周。
2)体重和摄食量测定
每周固定时间测定各组小鼠体重。每周固定时间测定各组动物的给食量和剩食量,计算摄食量。
3)空腹血糖测定
实验动物禁食12h后,小鼠尾静脉消毒采血,采用三诺血糖仪测定空腹血糖。
(2)抑郁焦虑模型动物实验
1)动物模型构建
慢性不可预知温和刺激(Chronic Unpredictable Mild Stress,CUMS)包含以下11种刺激:①禁食24h;②禁水+空瓶刺激24h;③夹尾3min;④潮湿垫料24h;⑤制动束缚3h;⑥45℃倾斜笼盒24h;⑦强迫游泳10min;⑧孤养24h;⑨持续光照24h;⑩无垫料;拥挤刺激。为避免生物节律,每天随机施加其中1~2种(每周随机刺激6天),每种刺激在整个试验期间不连续使用3天。
2)实验动物分组及干预
雄性SD大鼠,180g-220g,将大鼠分为正常对照组(Normal)和抑郁模型组(CUMS),抑郁模型组大鼠采用慢性不可预知温和应激刺激3周。造模3周后,再将抑郁模型组分为模型组(CUMS)、鼠李糖乳杆菌GM12组(LacR)。干预期间仍然持续给予慢性刺激。益生菌干预给药3周后开始进行行为学测定,行为学测定期间仍每天灌胃益生菌菌液。抑郁模型组灌胃等量生理盐水。
3)行为学指标检测
①高架十字迷宫:将大鼠从中央格面向开放臂放入迷宫,立刻开始计时和录像,记录5分钟内的活动情况。测定开放臂停留时间。
②旷场实验:将动物放入旷场中心后,立刻开始计时和录像,观测10min后停止录像。计算大鼠在旷场中心区域停留的时间。
③强迫游泳:实验桶内装约30cm高清水,水温24±1℃,在正式实验前24小时,每只大鼠均进行10分钟的适应性游泳训练。正式实验时,观察6min并记录每只大鼠在后4min内的累计不动时间。
④糖水偏好试验:实验开始前对实验鼠进行24h的糖水适应,结束后禁水禁食24h。正式实验时,同时给予每只大鼠预先定量的2瓶水:1瓶1%蔗糖水,1瓶自来水,于1h后结束实验,计算每只大鼠的蔗糖水消耗量和纯水消耗量。按公式计算糖水偏好指数%=糖水消耗量/(糖水消耗量+纯水消耗量)×100%。
4)血生化指标测定
取全血静置,离心收集上层血清。采用酶联免疫吸附法(Enzyme-linked immune-sorbent assay,ELISA)测定皮质酮(CORT)、5-羟色氨(5-HT)、脑源性神经营养因子(BDNF)、肾上腺皮质激素释放激素(CRH)、促肾上腺皮质激素(ACTH)、炎症因子TNF-α、IL-1β。具体实验步骤依照试剂盒说明书进行。
5)海马5-HT、BDNF水平测定
海马样本称重,加入海马组织重量9倍体积的预冷的PBS缓冲液,制备成匀浆上清,离心取上清液进行下一步的测定。采用ELISA法检测海马5-HT、BDNF、CORT。具体实验步骤依照试剂盒说明书进行。
二、结果
(1)鼠李糖乳杆菌GM12对ob/ob小鼠肥胖的改善作用
与肥胖模型组相比,鼠李糖乳杆菌GM12可显著降低ob/ob肥胖小鼠体重(图1A)和体重增长(图1B),对ob/ob肥胖小鼠摄食量无显著影响(图2)。同时鼠李糖乳杆菌GM12可显著改善肥胖小鼠空腹血糖的升高(图3)。
(2)鼠李糖乳杆菌GM12对CUMS大鼠行为学的改善作用
与CUMS模型组相比,鼠李糖乳杆菌GM12可显著增加高架十字迷宫实验中,大鼠在开放臂的活动时间(图4A);增加旷场实验中大鼠在中心区域的活动时间(图4B)。同时还可显著降低强迫游泳实验中,大鼠后4分钟的不动时间(图4C),显著增加大鼠在糖水消耗实验中糖水消耗比例(图4D)。如结果所示,鼠李糖乳杆菌GM12可以显著改善CUMS模型大鼠的抑郁样、焦虑样行为。
(3)鼠李糖乳杆菌GM12对CUMS大鼠血清生化指标的影响
与CUMS模型组相比,鼠李糖乳杆菌GM12可显著升高抑郁模型大鼠血清5-羟色胺(5-HT)水平(图5A)。鼠李糖乳杆菌GM12可显著升高血清脑源性神经营养因子(BDNF)水平(图5B)。同时还可降低大鼠血清中皮质酮(CORT)(图5C)、肾上腺皮质激素释放激素(CRH)(图5D)、和促肾上腺皮质激素(ACTH)(图5E)的水平。如结果所示,鼠李糖乳杆菌GM12可缓解应激造成的下丘脑-垂体-肾上腺(HPA)轴亢奋。
(4)鼠李糖乳杆菌GM12对CUMS大鼠血清炎症因子水平的影响
与CUMS模型组相比,鼠李糖乳杆菌GM12可显著降低抑郁模型大鼠血清炎症因子TNF-α(图6A)和IL-1β(图6B)水平。
(5)鼠李糖乳杆菌GM12对CUMS大鼠海马生化指标的影响
与CUMS模型组相比,鼠李糖乳杆菌GM12可显著升高抑郁模型大鼠海马5-羟色胺(5-HT)水平(图7A)。与模型组相比,鼠李糖乳杆菌GM12具有升高脑源性神经营养因子(BDNF)水平的趋势(图7B)。同时与模型组相比,鼠李糖乳杆菌GM12还可显著降低大鼠海马皮质酮(CORT)水平(图7C)。
综上,本发明鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12可显著降低肥胖小鼠体重,不抑制肥胖小鼠食欲,且可改善肥胖小鼠空腹血糖的升高。提高抑郁模型大鼠血清和海马5-HT和BDNF水平,缓解应激造成的下丘脑-垂体-肾上腺(HPA)轴亢奋,降低抑郁模型大鼠血清炎症因子水平,该菌株在动物实验中可改善焦虑和抑郁行为。
Claims (4)
1.一种具有减肥和改善不良情绪作用的鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12,其特征在于:所述鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12保藏于中国微生物菌种保藏管理委员会普通微生物中心(CGMCC),保藏号为CGMCC No. 25804。
2.权利要求1所述鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12在制备减肥和/或改善不良情绪的药品中的用途;所述不良情绪是抑郁。
3.如权利要求2所述的用途,其特征在于:所述药品是以鼠李糖乳杆菌为活性成分,加上药品上可接受的辅料制成的制剂;所述制剂为口服制剂;所述口服制剂中鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12的活菌数≥2×109CFU/mL。
4.一种减肥和/或改善不良情绪的药物,其特征在于:它的制备原料包括权利要求1所述的鼠李糖乳杆菌(Lactobacillus rhamnosus)GM12。
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