CN114917255A - 一种可缓解自闭症并调节情绪的益生菌粉及其应用 - Google Patents
一种可缓解自闭症并调节情绪的益生菌粉及其应用 Download PDFInfo
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Abstract
本发明公开了一种可缓解自闭症并调节情绪的益生菌粉及其应用，属于微生物技术领域以及医药技术领域。本发明的益生菌粉由两歧双歧杆菌BGN4、长双歧杆菌BORI、乳双歧杆菌AD011、益生元和多种营养素组成，能够调节平衡脑肠轴微生物系统，具体体现在：这一益生菌粉可改善脑肠道微生物环境、能够很好地缓解自闭症，调节腹泻、便秘、挑食、过敏等自闭症合并的胃肠道不适问题，可有效缓解情绪、改善睡眠状态及自我认知。因此含有两歧双歧杆菌BGN4、长双歧杆菌BORI和乳双歧杆菌AD011的益生菌粉在调节平衡儿童脑肠轴微生物系统上具有很大的应用前景。
Description
技术领域
本发明涉及一种可缓解自闭症并调节情绪的益生菌粉及其应用，属于微生物技术领域和医药技术领域。
背景技术
肠道微生物是人体的“第二大脑”，肠道和大脑之间存在由大脑中枢神经系统和肠道共同构成的可以双向作用的系统—脑肠轴。它可以通过直接或间接途径来支持肠道细菌与中枢神经系统之间的双向相互作用。
脑肠轴是人体中大脑中枢神经系统和肠道共同构成的可以双向作用的系统。这个是非常复杂的过程，最主要涉及到的有迷走神经途径、免疫途径和神经内分泌途径。通过研究表明，脑肠轴中关键的神经递质是5-HT，大约95％的5-HT储存自肠道。双歧杆菌会增加分解色氨酸的Tph1的表达，并透过肠道上皮肠嗜铬细胞分泌5-HT，然后进入血液循环，作用于中枢神经系统，最终改善抑郁症状。同时肠道微生物的代谢产物短链脂肪酸也可调节肠5-HT的生产，改善抑郁症状。
国内外对于脑肠轴系统的问题，临床上主要的方法主要有抗抑郁药、抗精神药、情绪稳定剂等药物治疗。
发明内容
为了解决脑肠轴微生物系统失衡的表现特点，如腹泻、便秘、挑食、过敏等自闭症合并胃肠道不适引起的问题以及自闭症、睡眠障碍和情绪失控等脑肠轴神经系统引起的问题，依据现有临床及研究者发现结果，提出了一种可缓解自闭症并调节情绪的益生菌粉及其应用，具体如下：
本发明提供了一种可缓解自闭症并调节情绪的益生菌粉，由两歧双歧杆菌BGN4、长双歧杆菌BORI、乳双歧杆菌AD011、益生元和多种营养素组成；所述两歧双歧杆菌BGN4、长双歧杆菌BORI和乳双歧杆菌AD011为主要调节成分，益生元和多种营养素为辅助调节成分；其中：所述益生元为低聚果糖，所述多种营养素包括γ-氨基丁酸、酵母β-葡聚糖、维生素B12、维生素B6、维生素B1、维生素B2和维生素D。
在本发明的一种实施方式中，按照每袋2g的添加量计，上述益生菌粉各成分添加量如下所示：
两歧双歧杆菌BGN4 90亿CFU/袋(按活菌数计)
长双歧杆菌BORI 40亿CFU/袋(按活菌数计)
乳双歧杆菌AD011 90亿CFU/袋(按活菌数计)
低聚果糖1520mg/袋
γ-氨基丁酸0.39mg/袋
酵母β-葡聚糖0.6mg/袋
维生素B12 0.06μg/袋
维生素B6 0.0324mg/袋
维生素B1 0.03mg/袋
维生素B2 0.0294mg/袋
维生素D 0.03μg/袋
在本发明的一种实施方式中，上述益生菌的冻干菌粉的制备方法，包括如下步骤：
1)将两歧双歧杆菌BGN4、长双歧杆菌BORI、乳双歧杆菌AD011分别划线于MRS固体培养基上，37℃条件下培养48h，得到单菌落。
2)挑取单菌落分别接种于MRS液体培养基中，37℃条件下培养24～48h进行活化，得到一级种子液。
3)将一级种子液按接种量为3％(v/v)分别转接至种子培养基中得到二级种子液，培养条件为37℃，培养24～48h。
4)将二级种子液分别接入发酵培养基中进行高密度发酵，接种量为3％(v/v)，培养条件为35～37℃，培养24～48h。
5)待发酵液中菌体密度达到108～109CFU/mL，分别收集发酵液；将所述发酵液分别离心收集菌体。
6)收集菌体后分别用冻干保护剂重悬，得到重悬液。
7)将重悬液采用真空冷冻法进行冻干，得到两歧双歧杆菌BGN4、长双歧杆菌BORI、乳双歧杆菌AD011冻干菌粉。
在本发明的一种实施方式中，所述培养基为MRS培养基：蛋白胨10g、牛肉浸粉10g、葡萄糖20g、乙酸钠2g、酵母浸粉5g、柠檬酸氢二铵2g、K2PO4·3H2O 0.4g、MgSO4·7H2O 0.2g、MnSO40.05g、吐温80 1mL、琼脂15g，pH调至6.2～6.3。
在本发明的一种实施方式中，所述冻干保护剂按重量百分比计由以下成分制成：脱脂奶粉15％、海藻糖6％、甘油4％和木糖醇1.5％。
在本发明的一种实施方式中，上述益生菌粉的制备方法，包括如下步骤：
1)分别取两歧双歧杆菌BGN4冻干菌粉90亿CFU、长双歧杆菌BORI冻干菌粉40亿CFU和乳双歧杆菌AD011冻干菌粉90亿CFU后混合。
2)向上述益生菌冻干菌粉混合物中依次加入低聚果糖1520mg、γ-氨基丁酸0.39mg、酵母β-葡聚糖0.6mg、维生素B12 0.06μg、维生素B6 0.0324mg、维生素B1 0.03mg、维生素B2 0.0294mg和维生素D 0.03μg，搅拌均匀，充分混合后分装至袋装即得益生菌粉，所述袋装选用密封性好、安全的食品级PE包装材质，规格为2g。
在本发明的一种实施方式中，上述益生菌粉的用法用量为：
对于全年龄层(包含幼儿和儿童)人群的食用建议为每天一袋，在10～20ml低于37℃的水、牛奶、粥或汤类中溶解后食用，饭后半小时内食用更佳，减少胃酸和胆汁的破坏力。
若服用抗生素期间，建议先用抗生素，间隔2～3小时再用益生菌粉。
本发明还提供了一种可缓解自闭症并调节情绪的益生菌粉在调节平衡脑肠轴微生物系统表现上的应用。
本发明的有益效果在于：
1)本发明提供了一种可缓解自闭症并调节情绪的益生菌粉，由两歧双歧杆菌BGN4、长双歧杆菌BORI、乳双歧杆菌AD011、益生元和多种营养素组成组成。此益生菌粉能够调节平衡脑肠轴微生物系统，具体体现在：这一益生菌粉可改善脑肠道微生物环境、能够很好地缓解自闭症，调节腹泻、便秘、挑食、过敏等自闭症合并的胃肠道不适问题，可有效缓解情绪、改善睡眠状态及自我认知。因此含有两歧双歧杆菌BGN4、长双歧杆菌BORI和乳双歧杆菌AD011的益生菌粉在调节平衡儿童脑肠轴微生物系统上具有很大的应用前景。
2)本发明中的两歧双歧杆菌BGN4、长双歧杆菌BORI、乳双歧杆菌AD011是从健康的母乳喂养婴儿的粪便中分离出来的。本发明中的益生元和多种营养素的搭配加入，符合国家GB/T 29602-2013及GB 14880-2012允许添加量。因此，本发明的益生菌粉对人体而言，健康且无毒副作用。
具体实施方式
本发明提供了一种可缓解自闭症并调节情绪的益生菌粉，由两歧双歧杆菌BGN4、长双歧杆菌BORI、乳双歧杆菌AD011、益生元和多种营养素组成。所述两歧双歧杆菌BGN4、长双歧杆菌BORI和乳双歧杆菌AD011为主要调节成分，益生元和多种营养素为辅助调节成分。其中：所述益生元为低聚果糖，所述多种营养素包括γ-氨基丁酸、酵母β-葡聚糖、维生素B12、维生素B6、维生素B1、维生素B2和维生素D。
下面对本发明的具体实施方式作进一步说明。在此需要说明的是，对于这些实施方式的说明用于帮助理解本发明，但并不构成对本发明的限定。此外，下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
下述实施例中涉及的培养基如下：
MRS培养基：蛋白胨10g、牛肉浸粉10g、葡萄糖20g、乙酸钠2g、酵母浸粉5g、柠檬酸氢二铵2g、K2PO4·3H2O 0.4g、MgSO4·7H2O 0.2g、MnSO40.05g、吐温80 1mL、琼脂15g，pH调至6.2～6.3。
实施例1：两歧双歧杆菌BGN4冻干菌粉的制备
1)两歧双歧杆菌BGN4划线于MRS固体培养基上，37℃条件下培养48h，得到单菌落。
2)挑取单菌落接种于MRS液体培养基中，37℃条件下培养24～48h进行活化，得到一级种子液。
3)将一级种子液按接种量为3％(v/v)分别转接至种子培养基中得到二级种子液，培养条件为37℃，培养24～48h。
4)将二级种子液分别接入发酵培养基中进行高密度发酵，接种量为3％(v/v)，培养条件为35～37℃，培养24～48h。
5)待发酵液中菌体密度达到108～109CFU/mL，分别收集发酵液；将所述发酵液分别离心收集菌体。
6)收集菌体后用冻干保护剂重悬(冻干保护剂按重量百分比计由以下成分制成：脱脂奶粉15％、海藻糖6％、甘油4％和木糖醇1.5％)，得到重悬液。
7)将重悬液采用真空冷冻法进行冻干，得到两歧双歧杆菌BGN4冻干菌粉。
实施例2长双歧杆菌BORI冻干菌粉的制备
1)长双歧杆菌BORI划线于MRS固体培养基上，37℃条件下培养48h，得到单菌落。
2)挑取单菌落接种于MRS液体培养基中，37℃条件下培养24～48h进行活化，得到一级种子液。
3)将一级种子液按接种量为3％(v/v)分别转接至种子培养基中得到二级种子液，培养条件为37℃，培养24～48h。
4)将二级种子液分别接入发酵培养基中进行高密度发酵，接种量为3％(v/v)，培养条件为35～37℃，培养24～48h。
5)待发酵液中菌体密度达到108～109CFU/mL，分别收集发酵液；将所述发酵液分别离心收集菌体。
6)收集菌体后用冻干保护剂重悬(冻干保护剂按重量百分比计由以下成分制成：脱脂奶粉15％、海藻糖6％、甘油4％和木糖醇1.5％)，得到重悬液。
7)将重悬液采用真空冷冻法进行冻干，得到长双歧杆菌BORI冻干菌粉。
实施例3乳双歧杆菌AD011冻干菌粉的制备
1)乳双歧杆菌AD011划线于MRS固体培养基上，37℃条件下培养48h，得到单菌落。
2)挑取单菌落接种于MRS液体培养基中，37℃条件下培养24～48h进行活化，得到一级种子液。
3)将一级种子液按接种量为3％(v/v)分别转接至种子培养基中得到二级种子液，培养条件为37℃，培养24～48h。
4)将二级种子液分别接入发酵培养基中进行高密度发酵，接种量为3％(v/v)，培养条件为35～37℃，培养24～48h。
5)待发酵液中菌体密度达到108～109CFU/mL，分别收集发酵液；将所述发酵液分别离心收集菌体。
6)收集菌体后用冻干保护剂重悬(冻干保护剂按重量百分比计由以下成分制成：脱脂奶粉15％、海藻糖6％、甘油4％和木糖醇1.5％)，得到重悬液。
7)将重悬液采用真空冷冻法进行冻干，得到乳双歧杆菌AD011冻干菌粉。
实施例4益生菌粉的制备
按照每袋2g的添加量计，益生菌粉各成分添加量如下所示：
两歧双歧杆菌BGN4 90亿CFU/袋(按活菌数计)
长双歧杆菌BORI 40亿CFU/袋(按活菌数计)
乳双歧杆菌AD011 90亿CFU/袋(按活菌数计)
低聚果糖1520mg/袋
γ-氨基丁酸0.39mg/袋
酵母β-葡聚糖0.6mg/袋
维生素B12 0.06μg/袋
维生素B6 0.0324mg/袋
维生素B1 0.03mg/袋
维生素B2 0.0294mg/袋
维生素D 0.03μg/袋
上述益生菌粉的制备方法，包括如下步骤：
1)分别取两歧双歧杆菌BGN4冻干菌粉90亿CFU、长双歧杆菌BORI冻干菌粉40亿CFU和乳双歧杆菌AD011冻干菌粉90亿CFU后混合。
2)向上述益生菌冻干菌粉混合物中依次加入低聚果糖1520mg、γ-氨基丁酸0.39mg、酵母β-葡聚糖0.6mg、维生素B12 0.06μg、维生素B6 0.0324mg、维生素B1 0.03mg、维生素B2 0.0294mg和维生素D 0.03μg，搅拌均匀，充分混合后分装至袋装即得益生菌粉，所述袋装选用密封性好、安全的食品级PE包装材质，规格为2g。
实施例5安全性试验
1.通过评估血细胞的溶血，粘蛋白降解，氨的产生，生物胺的产生，抗菌药的敏感性分析，抗生素耐药性的可转移性，抗生素抗性基因的PCR数据，基因组稳定性以及是否具有毒力因子/致病基因等多方面试验，对人体同源的两歧双歧杆菌BGN4、长双歧杆菌BORI和乳双歧杆菌AD011的安全性进行评估。
2.试验结果
1)三株菌均不显示溶血活性也不显示粘蛋白降解活性，没有发现生产氨的现象。
2)三株菌不生产5-戊二胺、组胺、酪胺，产生少量的腐胺，其含量与其他食物(例如菠菜，番茄酱，青豆，酸菜和香肠)相似或更低。
3)三株菌对庆大霉素及四环素的耐药性(敏感性)高于欧洲食品安全局(EFSA)的临界值。
4)在PCR分析研究中，未发现菌株的抗性基因。
5)三株菌对抗生素的耐药性均未通过与基因片段结合而转移。。
6)三株菌株的整个基因组序列已在GenBank中公开。
7)三株菌均不含有已知的产毒素基因和致病基因。
实施例6益生菌粉的安全性检测
1.检测依据及方法
根据食品安全国家标准食品中污染物限量GB 2762-2017、食品微生物学检验(菌落总数测定GB 4789.2-2016、大肠杆菌计数GB 4789.3-2016、沙门氏菌检验GB 4789.4-2016、霉菌检验GB 4789.15-2016)等标准方法对益生菌粉进行安全性检测。
2.检测结果
采用冷冻干燥微囊三层包埋技术制得的一种可缓解自闭症并调节情绪的益生菌粉，其色泽为淡黄色粉末，无正常视力可见的外来异物、无结块、无异味、无臭。且污染物铅、锡检测结果不活跃，菌落总数、大肠菌群、沙门氏菌、霉菌检测结果均通过。
实施例7具体病例
病例1：患者男，3岁4个月，诉求：有很严重的刻板行为，比如在拼板过程中不能有一点差错，必须按固定的顺序拼板，有情绪时就会大哭大叫，把随手拿到的东西往旁边的人身上丢，或者是爬到妈妈身上揪头发、掐胸口等，语言方面能清楚的说一个字或简单叠词，不主动交流，没有目光对视，不关心周围人和事等，经诊断为“自闭症”。食用本发明制备的益生菌粉，食用方法为将益生菌粉溶解在37℃左右温开水中，搅拌至完全溶解，饭后半小时内服用，早晚各一次，2袋/次。食用一周后与身边人能有简单的语言交流，呼其名字有反应，继续食用14日后至症状有所改善，而后减少食用量至每天食用1次，2袋/次，坚持3个月，随访3个月内情绪较稳定，语言表达能力有提升。
病例2：患者女，2岁8个月，诉求：因语言发育落后，目光常呆滞，睡眠不安，脾气暴躁，生长发育低于同龄人标准，矮小瘦弱，挑食厌食，同时还伴有便秘现象，经诊断为“自闭症”。食用本发明制备的益生菌粉，食用方法为将益生菌粉溶解在37℃左右温开水中，搅拌至完全溶解，饭后半小时内服用，早晚各一次，2袋/次。食用3天后排便逐渐通畅，进食量增加，继续食用15日后至症状有所改善，而后减少食用量至每天食用1次，2袋/次，坚持3个月，随访肠道问题改善，生长发育有改善，睡眠状态也好了。
病例3：患者男，11个月，诉求：因为11个月语言发育迟缓，连爸爸妈妈等简单的人称叠词也不能很好的说，经常目光呆滞，脾气暴躁，喜欢一种玩具，挑食严重，辅食添加困难，进行营养素干预无帮助，经诊断为“自闭症”。食用本发明制备的益生菌粉，食用方法为将益生菌粉溶解在37℃左右温开水中，搅拌至完全溶解，饭后半小时内服用，早晚各一次，2袋/次。食用3天后排便逐渐通畅，进食量增加，继续食用15日后至症状有所改善，而后减少食用量至每天食用1次，2袋/次，坚持3个月，随访辅食已顺利添加，语言发育良好，情绪稳定。
实施例8临床试验
1.研究对象
选择诊断为自闭症的儿童的40名。30名患者被分配到益生菌治疗组，其余10名患者被分配到安慰剂组。
2.治疗方法
治疗组为食用本发明制备的益生菌粉2袋，安慰剂组为不含益生菌的等量低聚果糖(安慰剂包)，在视觉上与益生菌包无区别。每位患者需在饭后30分钟内食用，每天两次，共持续30天。观察并记录治疗期间前后自闭症症状如抑郁、愤怒、敌意和焦虑方面是否有所改善。
3.效果评判标准
以治疗期间前后自闭症症状如抑郁、愤怒、敌意和焦虑方面匹配的情况来评判效果。有效：痊愈或自闭症表现症状有所改善；无效：治疗前后自闭症症状持续存在，无明显症状改善情况。
4.统计学方法
进行各组各症状有明显改善的儿童人数进行记录，研究期间前后自闭症症状如抑郁、愤怒、敌意和焦虑的改善情况。
5.试验结果
2组效果评价，结果见表1.
表1 2组效果评价
从表1中可以看出，采用本发明的益生菌粉在改善自闭症症状方面具有显著效果。且试验中的患病儿童在试验前后均有进行肠道菌群细菌的检测，发现服用本发明的益生菌粉有助于改善肠道菌群的紊乱，提高自闭症患者的肠胃抵抗能力，改善肠胃不适症状，进而实现对自闭症的有效治疗。
本发明提供了一种可缓解自闭症并调节情绪的益生菌粉及其应用，所述益生菌粉由两歧双歧杆菌BGN4、长双歧杆菌BORI、乳双歧杆菌AD011、益生元和多种营养素组成。此益生菌粉能够调节平衡脑肠轴微生物系统，具体体现在：这一益生菌粉可改善脑肠道微生物环境、能够很好地缓解自闭症，调节腹泻、便秘、挑食、过敏等自闭症合并的胃肠道不适问题，可有效缓解情绪、改善睡眠状态及自我认知。其中，两歧双歧杆菌BGN4在老年人精神灵活性、缓解压力和改善肠道健康应用方向上得以验证，且与长双歧杆菌BORI混合在改善认知能力和肠道健康(肠胀气、腹部痉挛等)问题上均得到了临床数据验证。两歧双歧杆菌BGN4、长双歧杆菌BORI和乳双歧杆菌AD011混合菌株在临床上通过脑肠轴改善认知障碍和抑郁障碍得到证实。因此含有两歧双歧杆菌BGN4、长双歧杆菌BORI和乳双歧杆菌AD011的益生菌粉在调节平衡儿童脑肠轴微生物系统上具有很大的应用前景。
以上所述，只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人了解本发明内容并加以实施，本申请的保护范围并不受这些具体实施例的限制。对于本领域技术人员来说，本申请可以有各种更改和变化。凡在本申请的技术思想和原理之内所作的任何修饰修改、等效变化、等同替换、改进等，均应包含在本申请的保护范围之内。
Claims (7)
1.一种可缓解自闭症并调节情绪的益生菌粉，其特征在于，所述益生菌粉由两歧双歧杆菌BGN4、长双歧杆菌BORI、乳双歧杆菌AD011、益生元和多种营养素组成；所述两歧双歧杆菌BGN4、长双歧杆菌BORI和乳双歧杆菌AD011为主要调节成分，益生元和多种营养素为辅助调节成分；其中：所述益生元为低聚果糖，所述多种营养素包括γ-氨基丁酸、酵母β-葡聚糖、维生素B12、维生素B6、维生素B1、维生素B2和维生素D。
2.如权利要求1所述的一种可缓解自闭症并调节情绪的益生菌粉，其特征在于，按照每袋2g的添加量计，所述益生菌粉各成分添加量如下所示：
两歧双歧杆菌BGN4 90亿CFU/袋(按活菌数计)
长双歧杆菌BORI 40亿CFU/袋(按活菌数计)
乳双歧杆菌AD011 90亿CFU/袋(按活菌数计)
低聚果糖1520mg/袋
γ-氨基丁酸0.39mg/袋
酵母β-葡聚糖0.6mg/袋
维生素B12 0.06μg/袋
维生素B6 0.0324mg/袋
维生素B1 0.03mg/袋
维生素B2 0.0294mg/袋
维生素D 0.03μg/袋
所述益生菌粉的制备方法，包括：
1)冻干菌粉的制备
保护剂与活化后的单一纯菌株、菌液分别混合，倒入容器置于真空冷冻干燥机中，制得3种单一益生菌冻干菌粉。
2)配方菌粉制备
分别取上述配方量3种单一益生菌冻干菌粉后混合，再依次加入上述配方量的低聚果糖、γ-氨基丁酸、酵母β-葡聚糖、维生素B12、维生素B6、维生素B1、维生素B2和维生素D混合，搅拌均匀，分装至袋装即得益生菌粉。
3.如权利要求2所述的一种可缓解自闭症并调节情绪的益生菌粉，其特征在于，所述保护剂按重量百分比计由以下成分制成：脱脂奶粉15％、海藻糖6％、甘油4％和木糖醇1.5％。
4.如权利要求2所述的一种可缓解自闭症并调节情绪的益生菌粉，其特征在于，所述益生菌粉包装袋选用密封性好、安全的食品级PE包装材质。
5.如权利要求2所述的一种可缓解自闭症并调节情绪的益生菌粉，其特征在于，所述益生菌粉的用法用量为：每天一袋，在10～20ml低于37℃的水、牛奶、粥或汤类中溶解后食用，饭后半小时内食用更佳。
6.如权利要求2所述的一种可缓解自闭症并调节情绪的益生菌粉，其特征在于，所述益生菌粉的食用建议为：服用抗生素期间，先用抗生素，间隔2～3小时再用益生菌粉。
7.如权利要求1或2所述的一种可缓解自闭症并调节情绪的益生菌粉在调节平衡脑肠轴微生物系统表现上的应用。
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