CN110079485B - 缓解抑郁的乳酸片球菌ccfm6432、其发酵食品及其应用 - Google Patents
缓解抑郁的乳酸片球菌ccfm6432、其发酵食品及其应用 Download PDFInfo
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Abstract
本发明涉及缓解抑郁的乳酸片球菌CCFM6432、其发酵食品及其应用。本发明所述的乳酸片球菌CCFM6432能够用于制备具有抗抑郁、抗炎症、抗炎症性肠病、抗肥胖和抗I型糖尿病等的功能的食品、保健品和药品,本发明还提供发酵食品,所述发酵食品使用乳酸片球菌CCFM6432发酵生产制得,所述发酵食品包括固态食品、液态食品、半固态食品,具有非常广泛的应用前景。
Description
技术领域
本发明属于微生物技术领域,具体涉及缓解抑郁的乳酸片球菌 CCFM6432、其发酵食品及其应用。
背景技术
抑郁症以显著而持久的情绪低落为主要临床特征。目前全球有超过3.5亿人患有抑郁症,且近年来发病率持续上升。目前被广泛应用于临床治疗的抗抑郁药物,如选择性五羟色胺重摄取抑制剂(Selective Serotonin Reuptake Inhibitor,SSRI)普遍存在起效缓慢、治疗效果不一致、副作用大等缺点,使得抑郁症的治疗存在严重的局限性。
人体肠道内含有超过1000多种微生物,总数约为1014~1015个,其质量可达1~1.5千克。这些肠道微生物编码基因的总数超过330万,约为人类自身编码基因总数的100倍,因此肠道微生物又被认为是人体的第二基因组。肠道微生物基因组与人体基因组一起,通过与环境因素的相互作用,影响宿主的多种重要的生理功能。肠道菌群及其代谢产物与宿主之间的正常交流,对于维持宿主的健康是必要的。肠道微生态的紊乱与许多疾病相关,包括糖尿病、肥胖症、炎性肠病、神经退行性疾病和肿瘤等。
许多临床研究显示,抑郁症患者的肠道菌群与健康对照组相比存在显著差异,包括多样性降低、有益菌类群丰度减少等。此外,抑郁症常伴随有便秘、腹泻等胃肠道的功能异常,这可能于肠道菌群的紊乱、抗抑郁药物的副作用相关。神经功能异常的动物和健康对照动物的肠道菌群之间也存在显著差异,并被多种抑郁模型所证实,包括嗅球切除模型、母婴分离模型、社会应激模型、慢性不可预知性应激模型等。这些研究均说明,肠道菌群在抑郁症的发生发展中发挥着至关重要的作用。
益生菌作为膳食补充剂,已被消费者广泛接受。目前,大部分关于益生菌功能的研究都集中在改善胃肠道功能、调节营养代谢和免疫等方面。大量的科学研究和临床实验已经证明,益生菌对便秘、肠炎、乳糖不耐、抗感染、炎症、过敏、糖脂代谢紊乱均具有显著改善作用。随着“脑肠轴”理论的逐渐成熟,通过益生菌来调节肠道菌群进而改善神经功能,成为治疗抑郁症的一种新的手段。某些双歧杆菌和乳杆菌对神经功能的调节作用也已被动物研究和临床研究所证实,例如Lactobacillus helveticus R0052、Bifidobacterium longumR0175等。
发明内容
本部分的目的在于概述本发明的实施例的一些方面以及简要介绍一些较佳实施例。在本部分以及本申请的说明书摘要和发明名称中可能会做些简化或省略以避免使本部分、说明书摘要和发明名称的目的模糊,而这种简化或省略不能用于限制本发明的范围。
鉴于上述的技术缺陷,提出了本发明。
因此,作为本发明其中一个方面,本发明克服现有技术中存在的不足,提供一种乳酸片球菌(Pediococcus acidilactici)CCFM6432,于2019年4月26 日保藏于广东省微生物菌种保藏中心,保藏地址为广州市先烈中路100号大院 59号楼5楼广东省微生物研究所,保藏编号为GDMCC No.60638。
作为本发明另一个方面,本发明克服现有技术中存在的不足,提供一种发酵食品。
为解决上述技术问题,本发明提供如下技术方案,其中:所述发酵食品为使用乳酸片球菌CCFM6432发酵生产制得,所述发酵食品包括固态食品、液态食品、半固态食品。
作为本发明所述发酵食品的一种优选方法,其中:所述发酵食品包括乳制品、豆制品、果蔬制品,所述乳制品包括牛奶、酸奶油、干酪;所述果蔬制品包括黄瓜、胡萝卜、甜菜、芹菜、圆白菜制品。
作为本发明另一个方面,本发明克服现有技术中存在的不足,提供乳酸片球菌CCFM6432在制备体内定植益生菌中的应用。
作为本发明另一个方面,本发明克服现有技术中存在的不足,提供乳酸片球菌CCFM6432在制备抗抑郁、抗炎症性肠病、抗肥胖和抗II型糖尿病的功能性食品、药物和保健品中的应用。
作为本发明所述乳酸片球菌CCFM6432在制备体内定植益生菌中的应用的一种优选方案,其中:所述乳酸片球菌CCFM6432能够减轻抑郁小鼠的抑郁样行为、提高脑中神经递质5-羟色胺含量、促进外周组织神经递质前体5- 羟色氨酸的生物合成;所述乳酸片球菌CCFM6432能够抑制下丘脑促肾上腺皮质激素释放因子的过度分泌,降低血清中皮质酮的水平,从而缓解“下丘脑- 垂体-肾上腺轴”功能亢进;所述乳酸片球菌CCFM6432能够调节宿主的免疫力,提高脾脏调节性T细胞比例,降低血清中促炎因子IL-1β、IL-6和TNF-α的浓度;所述乳酸片球菌CCFM6432还能够善肠道菌群多样性,恢复应激造成的肠道菌群紊乱,提高芽孢杆菌属、粪球菌属的丰度、提高肠道丁酸的含量、减少炎症性肠病、肥胖和II型糖尿病发生的风险。
作为本发明另一个方面,本发明克服现有技术中存在的不足,提供所述的发酵食品在制备抗抑郁、抗炎症、抗炎症性肠病、抗肥胖和抗I型糖尿病等的功能性食品中的应用。
作为本发明所述发酵食品在制备抗抑郁功能性食品中的应用的一种优选方案,其中:所述乳酸片球菌CCFM6432能够减轻抑郁小鼠的抑郁样行为、提高脑中神经递质5-羟色胺含量、促进外周组织神经递质前体5-羟色氨酸的生物合成;所述乳酸片球菌CCFM6432能够抑制下丘脑促肾上腺皮质激素释放因子的过度分泌,降低血清中皮质酮的水平,从而缓解“下丘脑-垂体-肾上腺轴”功能亢进;所述乳酸片球菌CCFM6432能够调节宿主的免疫力,提高脾脏调节性T细胞比例,降低血清中促炎因子IL-1β、IL-6和TNF-α的浓度;所述乳酸片球菌CCFM6432还能够善肠道菌群多样性,恢复应激造成的肠道菌群紊乱,提高芽孢杆菌属、粪球菌属的丰度、提高肠道丁酸的含量、减少炎症性肠病、肥胖和II型糖尿病发生的风险。
为解决上述技术问题,本发明提供了如下技术方案:
本发明的有益效果:在抑郁模型小鼠实验中,服用本发明的乳酸片球菌 CCFM6432能够减轻应激造成的小鼠的抑郁样行为、提高抑郁小鼠脑组织神经递质(5-HT)含量、增加外周组织神经递质前体(5-HTP)的生物合成、抑制下丘脑促肾上腺皮质激素释放因子(CRF)的过度分泌、降低血清中的皮质酮水平;所述发酵食品还能调节宿主的免疫力、提高脾脏调节性T细胞比例、降低血清中促炎因子IL-1β、IL-6和TNF-α的浓度;此外,所述发酵食品能够改善肠道菌群多样性、恢复应激造成的肠道菌群紊乱、提高有益菌的丰度(芽孢杆菌属、粪球菌属)、提高肠道丁酸的含量、减少炎症性肠病、肥胖和II型糖尿病发生的风险。
本发明所述的乳酸片球菌CCFM6432能够用于制备具有抗抑郁、抗炎症、抗炎症性肠病、抗肥胖和抗I型糖尿病等的功能的食品、保健品和药品,具有非常广泛的应用前景。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其它的附图。其中:
图1为小鼠在高架十字迷宫中的表现。(A)进入开放臂的次数;(B) 在开放臂中的停留时间;(C)小鼠在十字迷宫中的行动轨迹;其中*P<0.05, **P<0.01。
图2为小鼠在悬尾实验和糖水偏好实验中的表现。(A)小鼠在悬尾实验中静止不动的时间;(B)小鼠对糖水的消耗比例;其中*P<0.05,**P<0.01, ***P<0.001。
图3为CCFM6432对小鼠脑组织中神经递质5-HT含量的影响。(A)前额叶皮质中5-HT的浓度;(B)脑干中5-HT的浓度;其中*P<0.05, ****P<0.0001。
图4为CCFM6432对小鼠肠道5-HT前体合成和分泌的影响。(A)肠嗜铬细胞中色氨酸羟化酶1(Tph1)mRNA的表达量;(B)肠嗜铬细胞分泌的 5-HTP的含量;其中*P<0.05,****P<0.0001。
图5为CCFM6432对抑郁小鼠HPA亢进的缓解作用。(A)下丘脑中促肾上腺皮质激素释放因子的水平;(B)血清中皮质酮的水平。其中*P<0.05, **P<0.01,***P<0.001。
图6为CCFM6432对抑郁小鼠脾脏调节性T细胞比例的影响。其中 *P<0.05,**P<0.01。
图7为CCFM6432对抑郁小鼠血清中炎症因子水平的影响。(A)血清中 IL-1β的含量;(B)血清中IL-6的含量;(C)血清中TNF-α的含量。
图8为CCFM6432对小鼠肠道菌群的影响。(A)香浓指数;(B)辛普森指数;(C)PCoA散点图;(D)放线菌门丰度;(E)变形菌门丰度;(F) 放线菌门和变形菌门比例。其中**P<0.01,***P<0.001。
图9为CCFM6432对肠道益生菌属及代谢产物的影响。(A)芽孢杆菌属 (Bacillus)丰度;(B)粪球菌属(Coprococcus)丰度;(C)粪便中丁酸含量。其中*P<0.05,**P<0.01。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂,下面结合具体实施例对本发明的具体实施方式做详细的说明。
在下面的描述中阐述了很多具体细节以便于充分理解本发明,但是本发明还可以采用其他不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本发明内涵的情况下做类似推广,因此本发明不受下面公开的具体实施例的限制。
其次,此处所称的“一个实施例”或“实施例”是指可包含于本发明至少一个实现方式中的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非均指同一个实施例,也不是单独的或选择性的与其他实施例互相排斥的实施例。
本发明的乳酸片球菌CCFM6432(Pediococcus acidilactici),于2019年4 月26日保藏于广东省微生物菌种保藏中心,保藏编号为GDMCC No.60638。
所述乳酸片球菌CCFM6432具有以下生物学特性:
(1)菌体特征:呈革兰氏染色阳性,不形成抱子,不运动的细菌。
(2)菌落特征:菌落呈乳白色,圆形,边缘整齐,微凸起,不透明,表面湿润光滑;
(3)生长特性:该菌株的最低生长温度为15℃,最高生长温度为45℃,在温度35-37℃下生长最佳,最适生长pH为6.5,培养18h后进入稳定期;
(4)在抑郁小鼠模型中能够显著改善小鼠的行为学表现;
(5)在抑郁小鼠模型中能够提高小鼠脑中的5-HT的水平;并促进肠道中 5-HT前体——5-HTP的合成和分泌;
(6)在抑郁小鼠模型中能够显著降低下丘脑促肾上腺皮质激素释放因子的浓度,降低血清中皮质酮浓度;
(7)在抑郁小鼠模型中能够显著提高脾脏调节性T细胞(Treg)的比例;
(8)在抑郁小鼠模型中能够显著降低血清中IL-1β、IL-6和TNF-α的浓度;
(9)能够提高肠道菌群α-多样性,改善抑郁小鼠的肠道菌群紊乱;提高抑郁小鼠肠道粪球菌属(Coprococcus)和芽孢杆菌属(Bacillus)的丰度,提高肠道丁酸的含量,减少炎症性肠病、肥胖和II型糖尿病发生的风险;
所述乳酸片球菌CCFM6432的提取方法为:
(一)乳酸片球菌的分离筛选:
(l)取1g健康人的新鲜粪便。梯度稀释后涂布于mMRS固体培养基,置于厌氧环境下37℃培养72小时;
(2)观察记录菌落形态,挑取菌落划线纯化;
(3)在MRS液体培养基中,37℃培养48小时,所得菌落进行革兰氏染色,记录菌落形态。
(4)弃除菌落中的革兰氏阴性菌菌株和革兰氏阳性球菌,挑选得到革兰氏阳性杆菌。
(5)过氧化氢酶分析后,弃除过氧化氢酶阳性菌株,保留过氧化氢酶阴性菌株。
(二)乳酸片球菌的分子生物学鉴定:
(l)单菌基因组抽提:将步骤(二)所筛选得到的乳酸片球菌培养过夜,取培养过夜的菌悬液lmL于1.5mL离心管,10000rpm离心2min,弃上清得菌体;用lmL无菌水吹洗菌体后,10000rpm离心2min,弃上清得菌体;加入200μL SDS裂解液,80℃水浴30min;加入酚-氯仿溶液200μL于菌体裂解液中,其中酚-氯仿溶液的组成成分及体积比为Tris饱和酚:氯仿:异戊醇=25:24:1,颠倒混匀后,12000rpm离心5-10min,取上清200μL;加入400μL冰乙醇或冰异丙醇于200uL上清中,﹣20℃静置1h,12000rpm离心5-10min,弃上清;加入 500μL70%(体积百分数)冰乙醇重悬沉淀,12000rpm离心1-3min,弃上清; 60℃烘箱烘干,或者自然晾干;50μL ddH2O重溶沉淀以备PCR;
(2)16S rDNAPCR:
A.细菌16S rDNA 50μLPCR反应体系:
10×Taqbuffer,5μL;dNTP,5μL;27F,0.5μL;1492R,0.5μL;Taq酶, 0.5μL;模板,0.5μL;ddH2O,38μL。
B.PCR条件:
95℃5min;95℃10s;55℃30s;72℃30s;step2-430×;72℃5min;12℃ 2min;
C.制备1%琼脂糖凝胶,之后将PCR产物与10000×loading buffer混合,上样量2μL,120V跑30min,然后进行凝胶成像;
D.将得到PCR产物送专业测序公司,将得到的测序结果与使用BLAST 在GeneBank中进行搜索和相似性比对,鉴定为乳酸片球菌。
(3)全基因组测序
将提取的全基因组送专业测序公司,利用二代测序仪对菌的全基因组进行测序,将得到的序列结果使用BLAST在GeneBank中进行搜索和相似性比对,测序结果鉴定为属于乳酸片球菌的一种新发现的菌株。菌株-80℃保藏备用。
实施例1:乳酸片球菌CCFM6432能够减少小鼠的抑郁样行为
取6周龄雄性C57BL/6J小鼠32只,适应环境一周后,根据体重随机分为四组:正常对照组、抑郁模型组、药物干预组、CCFM6432干预组,每组含8 只小鼠。动物分组及处理方法见表1。
表1动物实验分组及处理方法
慢性不可预知应激抑郁小鼠模型:每天随机采用1-2种刺激,每天刺激的时间随机决定,避免昼夜节律。每种方法不超过三次,为期五周。刺激因素包括:(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1~2h;(6)45°倾斜笼盒24h;(7)持续光照24h;(8) 无垫料24h;(9)强迫游泳15分钟;(10)孤养24h。
乳酸菌灌胃剂:取活化2代的乳酸片球菌CCFM6432并于37℃下培养至 24h,于4℃、8000r/min离心3min收集菌体,弃去上清并用5%灭菌脱脂乳液重悬菌体,使乳酸菌浓度达到5×109CFU/mL。灌胃体积为0.2mL/只/天。
第五周开始,停止每日的慢性不可预知应激以及药物和益生菌的干预,同时对所有小鼠进行行为学测试。包括高架十字迷宫实验、悬尾实验和糖水偏好实验。具体实施方法和结果如下:
(1)高架十字迷宫实验
实验开始时将小鼠从中央格面向闭合臂放入迷宫,记录10分钟内的活动情况。观察指标包括:开放臂进入次数(必须有两只前瓜进入臂内),开放臂停留时间,闭合臂进入次数,闭合臂停留时间。计算开放臂停留时间比例,开放臂进入次数比例,高架十字迷宫中总进入次数。实验完成后将小鼠取出,将两臂清理干净,喷洒酒精除去气味,进行下一只实验。结果如图1所示,抑郁小鼠进入开放臂的次数和停留时间均显著降低,服用CCFM6432能够显著改善这一症状,氟西汀对小鼠在十字迷宫中的抑郁样行为无改善作用。
(2)悬尾实验
悬尾实验与强迫游泳实验类似,也是一种行为绝望模型。将小鼠尾部后1/3 处用胶带固定,悬挂于支架上,头部距离台面30cm,进行摄像,摄像背景与小鼠毛色呈明显反差。计时6min后停止,利用小动物行为学分析软件对小鼠后四分钟(3-6min)的不动时间进行统计。其中,不动状态是指动物放弃主动挣扎,处于完全不动的状态。实验结果如图2A所示,抑郁小鼠在悬尾实验中静止不动的时间显著增加,而服用CCFM6432能够降低其不动时间,缓解其抑郁状态,且CCFM6432的效果优于抗抑郁药物氟西汀。
(3)糖水偏好实验
糖水偏好测试是检测抑郁症快感缺失的模型。在开始测试之前,笼内放置两个相同的饮水瓶,使小鼠适应性饮水至少3天。适应结束后,将其中一瓶水替换为含有1%蔗糖的水溶液。通过称量瓶子重量来检测水和蔗糖溶液的摄入量。每天更换两个瓶子的位置,以减少因水量不同引起的饮水偏好。蔗糖偏好计算公式为:蔗糖偏好=V(蔗糖溶液)/[V(蔗糖溶液)+V(水)]×100%,总共测试3天,取平均值。实验结果如图2B所示,抑郁小鼠的糖水偏好程度显著下降,服用CCFM6432后,小鼠恢复至正常的糖水偏好程度,表明 CCFM6432能缓解抑郁导致的快感缺失。
实施例2:CCFM6432能显著提高抑郁小鼠脑中神经递质(5-HT)水平
实施例2中的小鼠于第六周末安乐处死,取小鼠脑组织,并于冰上分离脑干和前额叶皮质。分别取一定质量的新鲜脑干和前额叶皮质组织(重量不低于 50mg),加入9倍体积的无菌PBS缓冲液(相当于1g组织加9mL的匀浆液),用组织匀浆器进行匀浆,组织液经过3000g、20min离心后取上清,加入等体积的5%高氯酸沉淀蛋白,10000g离心10min,吸取上清液经0.22μm水系滤膜过滤后,采用ELISA试剂盒检测5-HT的含量。实验结果如图3所示,结果表明,服用CCFM6432能够显著逆转慢性应激造成的脑干和前额叶皮质中5-HT 水平的降低。其中,CCFM6432对脑干和前额叶皮质中5-HT的改善程度优于氟西汀。研究报道表明,作为选择性5-HT重摄取抑制剂,氟西汀在不同个体内发挥作用的能力具有不一致性,且存在2-4周的起效延迟期。本实验结果表明,服用乳酸片球菌CCFM6432五周后,即可显著提高脑内5-HT的含量,不存在起效延迟的现象,显示出良好的抗抑郁治疗潜力。
实施例3:乳酸片球菌CCFM6432能够刺激肠嗜铬细胞分泌5-HTP
细胞上清中5-HTP的测定:RIN14B细胞以4×105/mL的密度种在24孔板,孵育72h。弃去培养基,用含有0.1%牛血清白蛋白(BSA)和2μM氟西汀的 HBSS(1mL)清洗细胞,加入1mL含有CCFM6432的HBSS悬液(对照组为不含菌体的HBSS),37℃孵育20min,收集上清,6000g离心5min去除沉淀,取上清液冷冻于-80℃待测。HPLC-FLD检测细胞上清中的5-HTP(参考实施例3)。
色氨酸羟化酶1(TPH1)的mRNA测定:上述步骤中的贴壁细胞用HBSS洗涤三次,加入1mL Trizol,置于冰上孵育5-10min,吹打使细胞脱落,将裂解液转移至无酶EP管。采用常规方法提取细胞总RNA,根据反转录试剂盒的说明进行 cDNA的合成(Prime Script RTreagent Kit gDNA Eraser,Takara)。合成的cDNA 样品经过超微量分光光度计(NanoDrop2000C)检测其浓度和纯度(A260/A280), -80℃保存待用。用荧光染料SYBR Green supermix(Qiagen,Germany)混合样本,PCR体系为5μLmix、1μL cDNA、1μL正向和反向引物,用dd水补至总体积为10μL。在实时荧光定量基因扩增仪器CFX96TMReal-Time System(Bio-Rad,USA)上进行检测,每个样本设立3个平行孔,并以管家基因β-Actin为内参,所得结果用2-ΔΔCq的方法进行分析;所用的引物序列见表2。
表2qPCR引物序列
结果表明(图4),CCFM6432刺激RIN14B细胞后,细胞内Tph1的mRNA水平显著提高。相应地,细胞分泌5-HTP的量也显著提高。肠嗜铬细胞分泌的5-HTP 能够进入血液循环,并通过血脑屏障,为脑中5-HT的合成提供前体物质。因此 CCFM6432能够特异性地通过刺激肠嗜铬细胞分泌5-HTP从而促进大脑中5-HT 的合成,实现抗抑郁功能。
实施例4:乳酸片球菌CCFM6432能够缓解抑郁小鼠HPA功能亢进
实施例2中的小鼠于第六周末安乐处死,收集小鼠血液,1000g离心15min 获得血清。取小鼠脑组织,并于冰上分离下丘脑,制备组织匀浆液(参考实施例2)。用ELISA试剂盒检测血清中皮质酮的含量和下丘脑中促肾上腺皮质激素释放因子(corticotropinreleasing factor,CRF)的含量。实验结果表明(图5),抑郁小鼠由于持续的慢性应激,出现下丘脑-垂体-肾上腺轴(HPA)功能亢进,下丘脑释放的CRF显著增多,并导致血清中皮质酮浓度显著上升,服用 CCFM6432能显著抑制CRF的释放,降低血清皮质酮水平,从而缓解HPA亢进,显示出良好的抗抑郁功效。
实施例5:乳酸片球菌对抑郁小鼠的免疫调节作用
实施例2中的小鼠于第六周末安乐处死,取新鲜小鼠脾脏(~50mg),加入 5mL预冷的PBS缓冲液,剪碎、研磨、用200目尼龙晒过滤得到组织细胞悬液。加入2mL红细胞裂解液裂解4min,室温下离心去除裂解液(300×g,5min),所得细胞沉淀用预冷的PBS洗两遍,用一定量的PBS重悬,得到淋巴细胞悬浮液。调节性T细胞(Regulatory cells,Tregs)的抗体标记按照eBioscience Mouse Regulatory T Cell Staining Kit(Invitrogen Corporation,Carlsbad,CA,USA)的说明书进行操作。采用流式细胞仪对Tregs(CD4+CD25+Foxp3+)进行检测。血清中 IL-1β、IL-6和TNF-α的含量采用ELISA试剂盒进行检测。实验结果如图5所示,慢性应激可导致小鼠脾脏的Tregs比例显著减少,是小鼠免疫能力受损;与此同时,小鼠血清中促炎因子IL-1β、IL-6和TNF-α的含量显著上升(图6),说明抑郁小鼠伴随着系统性炎症。氟西汀和CCFM6432均能显著改善抑郁小鼠的免疫状态,降低炎症程度。特别地,相比与氟西汀,服用CCFM6432能够显著降低血清中TNF-α的含量,具有更好的抗炎效果。
实施例6:乳酸片球菌CCFM6432对抑郁小鼠肠道菌群及代谢物的调节作用
取实施例2中小鼠第六周末的新鲜粪便,采用MP的粪便试剂盒提取小鼠粪便样品中总DNA。具体操作步骤如下主要参照试剂盒说明书进行。以小鼠粪便基因组为模板,以上游引物520F(5′-AYTGGGYDTAAAGNG-3′)、下游引物802R(5′-TACNVGGGTATCTAATCC-3′)为引物扩增16S rDNA的V3-V4区片段,目的片段长度为247bp左右。PCR反应结束,将观察到目的条带的所有PCR样品再次进行电泳,配制2.0%琼脂糖凝胶,于120V条件下电泳40min,跑胶结束后,在紫外灯下快速进行目的条带的切割。按照QIAquick Gel Extraction Kit胶回收试剂盒说明书进行目的条带胶回收。根据Qubit DNA3.0试剂盒检测样品DNA浓度,随后根据TurSeq DNA LT Sample Preparation Kit及其说明构建文库,最后根据 MiSeq RegentKit及其说明经过Illumina Miseq测序仪上机测定。测序完成后,剔除掉序列长度<200bp、引物序列、不能拼接的单序列,按照重叠碱基>10bp且无错配的标准拼接序列。将相似度大于97%序列定义为一个分类单元 (Operational Taxonomic Unit,OTU),通过RibosomalDatabase Project(RDP) Bayesclassifier来确定物种。计算样品的α-多样性、β-多样性,用来评估样品的菌群多样性。其中α-多样性用香浓指数(shanno index)和辛普森指数 (simpson index)来表征,结果显示(图8A、B),抑郁小鼠的肠道菌群,α-多样性降低,表明抑郁伴随着一定程度的肠道菌群紊乱。服用CCFM6432能显著上调肠道菌群的α-多样性,改善肠道菌群的物种丰度和均匀程度。在门水平上,抑郁小鼠肠道菌群结构与正常小鼠存在显著差异,尤其是变形菌门和放线菌门的丰度。抑郁小鼠放线菌门丰度增加,放线菌门和变形菌门比例显著升高,而服用CCFM6432能够显著逆转这一现象,使肠道菌群结构恢复正常(图8D、E、F);β-多样性用主坐标分析(principal co-ordinates analysis,PCoA)进行评估(图8C),从结果也可以看出,氟西汀和CCFM6432干预均能使小鼠肠道菌群结构趋于正常化。此外,服用CCFM6432能够显著提高芽孢杆菌属(Bacillus)的丰度(图8A)。芽孢杆菌属是宿主体内一类重要的乳酸产生菌,对维持肠道正常蠕动、缓解便秘具有十分重要的作用。此外,芽孢杆菌属中部分种(如凝结芽孢杆菌、枯草芽孢杆菌)能够分泌细菌素,抑制肠道致病菌的生长,预防对炎症性肠病 (Inflammatorybowel disease,IBD)的发生。服用CCFM6432还能够显著提高抑郁小鼠肠道粪球菌属(Coprococcus)的丰度(图8B),粪球菌属是肠道中重要的丁酸产生菌,丁酸能够不仅能够为肠上皮细胞氧化供能,改善肠道屏障功能,维持肠粘膜免疫稳态,而且还能通过G蛋白偶联受体(G protein-coupled receptors,GPCRs)激活途径和组蛋白去乙酰基化酶(histone deacetylases, HDACs)抑制途径两条信号通路,诱导下游糖脂代谢调节因子的表达,如胰高血糖素样多肽-1(GLP-1)、酪酪肽(PYY),对II型糖尿病、肥胖均具有显著的改善作用。
为了验证肠道菌群变化对肠道丁酸含量的影响,取对应的小鼠粪便样本,加入500uL饱和NaCl,震荡均匀;加入40uL 10%的硫酸,震荡均匀;加入1mL 乙醚,震荡均匀;18000g,4℃离心15min,取上清至2mL EP管,加入0.25g无水硫酸钠。18000g,4℃离心15min。取500uL上清液至气相小瓶,通过GC-MS以选择离子扫面的方式检测短链脂肪酸的含量(乙酸、丁酸、异丁酸、丁酸等)。结果如图8C所示,服用乳酸片球菌CCFM6432能够改善抑郁导致的丁酸水平降低,进一步证明了CCFM6432不仅能够缓解抑郁,还可以通过调节肠道丁酸含量,发挥缓解和预防II型糖尿病、肥胖等疾病的作用。
实施例7:利用本发明乳酸片球菌CCFM6432制造含该菌的发酵食品
选用新鲜蔬菜洗净后榨汁,接着进行高温瞬间灭菌,在温度140℃下高温热杀菌2秒后,立即降温至37℃,再接入本发明制备的乳酸片球菌CCFM6432菌剂发酵剂,使其浓度达到108CFU/mL以上,在温度4℃下冷藏保存,得到含有本发明乳酸片球菌CCFM6432活菌的果蔬饮料。
利用本发明能够使用长乳酸片球菌CCFM6432发酵生产制备其他发酵食品,所述发酵食品包括固态食品、液态食品、半固态食品。所述发酵食品包括乳制品、豆制品、果蔬制品,所述乳制品包括牛奶、酸奶油、干酪;所述果蔬制品包括黄瓜、胡萝卜、甜菜、芹菜、圆白菜制品。
所述发酵食品能够减轻应激造成的小鼠的抑郁样行为、提高抑郁小鼠脑组织神经递质(5-HT)含量,增加外周组织神经递质前体(5-HTP)的生物合成,抑制下丘脑促肾上腺皮质激素释放因子(CRF)的过度分泌,降低血清中的皮质酮水平;所述发酵食品还能调节宿主的免疫力,提高脾脏调节性T细胞比例,降低血清中促炎因子IL-1β、IL-6和TNF-α的浓度;此外,所述发酵食品能够改善肠道菌群多样性,恢复应激造成的肠道菌群紊乱,提高有益菌的丰度(芽孢杆菌属、粪球菌属),提高肠道丁酸的含量,减少炎症性肠病、肥胖和II 型糖尿病等发生的风险。
应说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (3)
1.一株乳酸片球菌(Pediococcus acidilactici)CCFM6432,其特征在于:所述乳酸片球菌CCFM6432于2019年4月26日保藏于广东省微生物菌种保藏中心,保藏编号为GDMCC No:60638。
2.权利要求1所述的乳酸片球菌CCFM6432在制备体内定植益生菌中的应用。
3.权利要求1所述的乳酸片球菌CCFM6432在制备抗抑郁、抗炎症、抗炎症性肠病、抗肥胖和抗II型糖尿病的功能性食品中的应用。
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