CN117343874A - 副干酪乳酪杆菌iob413后生元提取物产品的制备方法及其应用 - Google Patents
副干酪乳酪杆菌iob413后生元提取物产品的制备方法及其应用 Download PDFInfo
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Abstract
本发明提供副干酪乳酪杆菌IOB413后生元提取物产品的制备方法,依据该方法所得到副干酪乳酪杆菌IOB413后生元提取物产品,以及其在制备抗幽门螺旋杆菌感染相关药物中的应用。通过本发明所述方法得到的副干酪乳酪杆菌IOB413后生元提取物产品对幽门螺杆菌感染的小鼠具有能够抑制幽门螺杆菌生长、缓解幽门螺杆菌感染、同时对菌群紊乱改善的显著作用,根据本发明记载的方法得到的副干酪乳酪杆菌IOB413后生元提取物产品,以及对该产品的功能验证,能够为辅助治疗幽门螺杆菌感染提供一定的药理学依据,为开发副干酪乳酪杆菌IOB413后生元提取物产品的在抗幽门螺旋杆菌治疗药物中的应用提供了有效思路。
Description
技术领域
本发明涉及微生物技术领域,尤其是保藏编号为CGMCC No.16022的副干酪乳酪杆菌(Lacticaseibacillus paracasei)IOB413的后生元提取物产品的制备方法,以及其在抗幽门螺杆菌方面的用途。
背景技术
幽门螺杆菌(Hp)是一种微嗜氧性、螺旋状、革兰氏阴性菌,主要定殖于胃粘膜,是慢性胃炎、消化性溃疡、胃癌、胃黏膜相关淋巴组织(MALT)淋巴瘤的主要致病因素,并与一些肠外疾病密切相关,幽门螺杆菌感染是全球卫生组织公认的感染性疾病,传染性高,并能在人体中长期存活,影响着全世界大约44亿人口。
对幽门螺杆菌治疗最普遍的疗法是采用抗生素联合用药,虽然治愈率较高,但抗生素会引起胃肠道微生态环境紊乱、增加人体的抗生素耐药率,带来诸多不良反应,不仅降低了幽门螺杆菌的根除率,更为患者的身体带来负担甚至难以预期的不良影响,为抗生素的日后其他疾病应用使用效果带来严重隐患。因此,亟需一种温和有效、对人体无伤害、减轻对抗生素依赖和耐药性潜在风险的幽门螺杆菌治疗方式。
后生元是指对宿主健康有益的遗传背景明确的灭活微生物和/或菌体成分,研究表明,通过后生元恢复肠道微生态平衡,能够达到有效辅助治疗疾病的目的,具有使用安全、无残留、无耐药性、促进营养物质吸收、抑制肠道病原菌生长、改善肠道微生态等诸多显著优点。
因此,寻找并开发一种改善肠道微生态平衡、有效抑制幽门螺杆菌生长、缓解其感染引起的各种症状的后生元微生态产品是解决减轻对抗生素依赖和耐药性潜在风险的幽门螺杆菌治疗问题的绝佳手段。
现有技术中,专利CN202110066239.9公开了抑制幽门螺旋杆菌感染的副干酪乳酪杆菌 JLPF-176 的应用及产品,专利CN202010678129.3公开了拮抗幽门螺旋杆菌的乳酸菌ZJUIDS03及其应用,专利CN202210694479.8公开了一株干酪乳杆菌M502及其与副干酪乳酪杆菌的复合制剂和在抗幽门螺杆菌药物中的应用。然而,上述专利文献中菌株在抗幽门螺杆菌方面的用途主要是通过制备抑制剂和复合剂实现菌株抑制幽门螺杆菌,辅助预防由其感染而导致的胃部疾病实现的,然而上述菌剂直接用于幽门螺旋杆菌抑制和疾病治疗的技术手段并未能考虑到菌剂的吸收、代谢,以及其肠道作用和进一步治疗效果优化的技术问题,因此,基于后生元产品的肠道吸收效率和肠道养护优势,亟需一种基于后生元产品的、抗幽门螺旋杆菌的副干酪乳酪杆菌发酵提取物。
发明内容
针对现有技术的不足,本发明目的在于提供一种有效抑制幽门螺杆菌生长、缓解幽门螺杆菌感染、改善并养护肠道微生态平衡的副干酪乳酪杆菌IOB413后生元提取物产品的制备方法与用途。
本发明使用的副干酪乳酪杆菌IOB413(Lacticaseibacillus paracasei)是自主筛选自天津市居民家中天然发酵酸面团,此菌株已经进行了菌株保藏和理化指标的检测,于2021年3月19日在中国食品发酵工业研究院有限公司进行了细菌鉴定检测,菌落为白色、圆形、表面湿润、不透明,边缘整齐的菌落,于2018年6月29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),其保藏编号为CGMCC No.16022。
本发明的技术方案如下:
本发明提供一种副干酪乳酪杆菌IOB413后生元提取物产品的制备方法,依据该方法所得到的生物发酵技术产品,以及其在制备抗幽门相关药物中的应用。
第一方面,本发明提供一种副干酪乳酪杆菌IOB413后生元提取物产品的制备方法,具体步骤为:
(1)副干酪乳酪杆菌IOB413(保藏编号CGMCC No.16022)菌株活化和培养;
(2)用所述活化后的副干酪乳酪杆菌IOB413以大豆粉为底物进行发酵,制备副干酪乳酪杆菌IOB413后生元,真空冷冻粉碎后得后生元粉;
(3)水浸提法处理后生元粉,将浸提后的后生元提取液进行冻干处理,获得的粉剂即为副干酪乳酪杆菌IOB413后生元提取物产品
优选地,步骤(1)中的培养温度为37±2℃,活化时间为20±2h;
优选地,步骤(2)中发酵参数是:料水比为1:1.75,接种量5×107CFU/mL,培养时间24±2h,最终获得固态发酵物的活性为6.78×1010CFU/g;
优选地,步骤(2)中真空冷冻粉碎的粉碎温度为-100℃,粉末细度为300目到500目;
优选地,步骤(3)中水浸提法提取时间为3-5h;
进一步地,还包括步骤(4):副干酪乳酪杆菌IOB413后生元提取物产品的营养成分测定;
优选地,步骤(4)中测定的成分为:大豆低聚糖、多糖、有机酸、长链脂肪酸、活性多肽,活性多肽的序列为SEQ ID NO:1。
进一步地,还包括步骤(5):副干酪乳酪杆菌IOB413后生元提取物产品对幽门螺杆菌的抑制作用的验证;
优选地,步骤(5)中采用SPF级昆明雄鼠分组建立幽门螺旋杆菌感染模型,以副干酪乳酪杆菌IOB413后生元提取物产品的高、低浓度灌胃作为验证试验;
优选地,步骤(5)中对实验小鼠的检测指标有:小鼠形态、小鼠体重、小鼠胃部炎症因子TNF-α、IL-1β表达水平变化、小鼠胃组织切片革兰氏染色分析、小鼠胃黏膜幽门螺杆菌的检测分析;
第二方面本发明提供一种上述方法制备的包含活性多肽的副干酪乳酪杆菌IOB413后生元提取物,其中包含活性多肽,其序列为SEQ ID NO:1。
第三方面一种包含活性多肽的副干酪乳酪杆菌IOB413后生元提取物在制备抗幽门螺旋杆菌感染相关药物中的应用。
有益效果:
(1)本发明提供一种副干酪乳酪杆菌IOB413后生元提取物产品的制备方法,通过最佳的活化方式和发酵参数,以大豆粉为底物,完成了副干酪乳酪杆菌IOB413后生元提取物的制备、纯化,并进一步处理形态得到方便使用的副干酪乳酪杆菌IOB413后生元提取物产品。
(2)通过对副干酪乳酪杆菌IOB413后生元提取物产品对幽门螺杆菌抑制的研究,结果表明副干酪乳酪杆菌IOB413后生元提取物产品对幽门螺杆菌感染的小鼠具有能够抑制幽门螺杆菌生长、缓解幽门螺杆菌感染的药理性作用,上述作用是在没有进行任何抗生素辅助治疗以及其他菌剂辅助下完成的,相较于未发酵的菌剂以及普通发酵的菌剂而言,治疗效果更加显著,这为副干酪乳酪杆菌IOB413后生元提取物产品的药理学特性和价值提供了有效佐证,为副干酪乳酪杆菌IOB413后生元提取物产品的临床应用提供重要参考,证明了将微生物后生元提取物作为抗幽门螺旋杆菌治疗药物是可行的。
(3)副干酪乳酪杆菌IOB413后生元提取物产品不仅具有对幽门螺杆菌感染的小鼠具有能够抑制幽门螺杆菌生长、缓解幽门螺杆菌感染的作用,还具有对胃肠道菌群紊乱改善的显著功能,这使幽门螺旋杆菌感染患者的胃部损伤不再因治疗承受负担,并能够在抑制幽门螺旋杆菌感染、降低炎症反应和损伤的基础上,完成对胃部微环境的协同向好改善,缩短治疗周期、提高治疗效果。
附图说明
图1:本发明的不同组别小鼠体重变化;
图2:本发明的不同组别小鼠胃部炎症因子TNF-α、IL-1β表达水平变化;
图3:本发明的不同组别小鼠胃组织切片HE染色分析;
图4:本发明的不同组别小鼠胃黏膜幽门螺杆菌定量培养结果分析;
图5:本发明的不同组别小鼠胃黏膜幽门螺杆菌快速尿素酶检测结果分析;
图6:本发明的模型组小鼠胃黏膜幽门螺杆菌定量培养结果分析;
图7:本发明的模型组小鼠胃黏膜幽门螺杆菌快速脲酶检测结果;
图8:本发明的模型组小鼠胃组织切片革兰氏染色分析。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:副干酪乳酪杆菌IOB413后生元的制备方法
(1)菌株活化:将冻存管中的菌种接种至斜面培养基中,并放置到37±2℃培养,活化时间为20±2h。活化好的菌落为白色,圆形,表面湿润,不透明,边缘整齐,镜检菌体为杆状,个体均匀,粗壮;
活化后收获副干酪乳酪杆菌IOB413未发酵样品。
斜面培养基使用的是MRS培养基,其配方为:蛋白胨10 .0g,牛肉膏5 .0g,酵母粉4.0g,葡萄糖20 .0g,吐温80 1 .0mL,磷酸氢二钾(7H2O)2 .0,乙酸钠(3H2O)5 .0g,柠檬酸三铵2 .0g,硫酸镁(7H2O)0 .2,硫酸锰(4H2O)0 .05,琼脂15 .0g,pH=6 .2±0 .2,加水量为1L。
(2)种子液种龄的确定:取一环新鲜的斜面菌种接种于装有25mL 2%大豆粉的瓶子中,36±2℃,密闭静置培养,培养时间为20±2h。
(3)固态工艺参数的确定:采用副干酪乳酪杆菌IOB413在固体培养基上能获得的最高活菌数作为菌种生长活力的判断指标。采用不同料水比、接种量、固体发酵时间作为变量探究最佳培养条件,优选的料水比为1:1.75,优选的接种量5×107CFU/mL,优选的培养时间24±2h,最终获得固态发酵物的活性为6.78×1010CFU/g。
(4)后生元粉的制备工艺:将发酵后样品进行真空冷冻粉碎,粉碎温度-100℃,主机转速50Hz,风机38Hz,进料速度15Hz,出料25Hz,粉末细度300目到500目。
实施例2:副干酪乳酪杆菌IOB413后生元产品的制备方法
发酵后的后生元分离提取方法:后生元粉采用水浸提法,提取时间为3-5h,将浸提后的后生元提取液进行冻干处理,获得的粉剂即为后生元粉提取物产品。
实施例3:副干酪乳酪杆菌IOB413菌粉的制备
副干酪乳酪杆菌IOB413菌粉的制备方法如下:(1)菌株活化:将菌株按1:20接种于活化培养基中,37±2℃,静置,厌氧,培养36h,即得一级种子液,将一级种子按1:25接种于活化培养基中,37±2℃,静置,厌氧,培养36h,即得二级种子液;一级培养基为蛋白胨 10g,牛肉膏粉 3g,氯化钠 5g,使用蒸馏水1000ml溶解配置,将上述组分混合,并调节溶液pH为7.0-7.2,然后121℃灭菌25min。(2)发酵:按照1:50的接种量,将培养好的二级种子液接种到灭好菌的发酵液培养基中,发酵罐搅拌转速100r/min,37℃,厌氧培养48h,即得发酵液;发酵液培养基为:蛋白胨 10g,牛肉膏粉 3g,氯化钠 5g,使用蒸馏水1000ml溶解配置,将上述组分混合,并调节溶液pH为7.0-7.2,然后121℃灭菌25min。(3)菌粉:发酵液培养基离心,收集菌泥;将菌泥冷冻干燥,即可获得副干酪乳酪杆菌IOB413菌粉。
实施例4:副干酪乳酪杆菌IOB413后生元提取物产品的营养成分测定
后生元成分方法为:大豆肽的检测方法为GB/T 22492-2008 大豆肽粉;多糖的检测方法为SN/T 24260-2015 出口植物源食品中粗多糖的测定苯酚-硫酸法;有机酸为GB5009.157-2016 食品中有机酸的测定,检测结果参见表1。
表1 营养成分检测结果
由表1可知,在发酵过程中,产生的大豆低聚糖、多糖、有机酸、长链脂肪酸的含量逐渐积累,有机酸和长链脂肪酸会在一定程度上破坏幽门螺杆菌的生长环境,削弱其在胃上皮细胞上的定植,降低幽门螺杆菌感染率;大豆低聚糖具有促进双歧杆菌的增殖,改善肠道生态环境和肠道菌群平衡的作用;多糖具备调节肠道菌群、修复胃肠道黏膜免疫系统及增强胃肠道功能等多种胃肠保护功能,从而有效缓解由幽门螺杆菌感染引起的胃部不适等症状,因此,副干酪乳酪杆菌IOB413在发酵期间,不断积累产生的特定生物活性肽能促进肠道内有益菌的生长,增加抗体的分泌,抑制幽门螺杆菌生长,消除肠道菌群紊乱,调节肠道菌群平衡。
实施例5:
将本发明的样品进行蛋白质组学鉴定,采用LC-MS/MS分析、数据库比对,发现鉴定的序列未在数据库中找到相同或相似的序列。
测定序列为:
AGPELAGTYTGAMYREGOHKRLVAKPVFAORVPAIPSGLORPOGRDGPGQRPHGAGEGIDRVPAAPTFTLHGPSPSEVGLAIPSGKOAGPVGRQNATGWKGPSKSQPKSPEPKPONHGPHGDAGNTEANGGEGPSNTGEPPGSARNPDNAPAGAGTGAPA(SEQ IDNO:1)
实施例6:副干酪乳酪杆菌IOB413后生元提取物产品对幽门螺杆菌的抑制作用的验证
(1)实验材料:
实验动物:SPF级昆明雄鼠,体重25±2g。
实验产品:副干酪乳酪杆菌IOB413后生元提取物产品、副干酪乳酪杆菌IOB413菌粉、未发酵的实验对照样品。
(2)饲养环境:
12 h光照/12 h黑夜循环,温度 (22±2) ℃,湿度40%-60%,自由饮水饮食。
(3)小鼠建模与分组:
(3.1)小鼠建模:将小鼠随机分为空白组、模型组、实验对照组、实验1组、实验2组、实验3组,每组10只,为避免雌激素的影响,选择雄性鼠制备模型。
空白组的10只小鼠每天灌胃1次给予0.3 ml生理盐水;
剩余小鼠用抗生素混合液灌胃,0.3 mL/只,1次/天,共3天,清除所有细菌,第4天起,小鼠每次灌胃幽门螺杆菌前禁食24h,每只灌胃无菌3% NaHCO30.3 mL中和胃酸,20 min后使用制备的幽门螺杆菌菌液灌胃,0.5 mL/只,隔日1次,共3次,并于末次灌胃2周后随机选取3只小鼠,取胃组织分别进行细菌培养、快速尿素酶试验及组织学检查,观察小鼠感染情况,确定是否建模成功。
(3.2)小鼠验证实验:建模成功后将小鼠随机分为模型组、实验对照组、实验组1、实验组2、实验组3,每组10只。模型组灌胃生理盐水,0.3 mL/只,1次/天,连续灌胃4周;实验对照组,灌胃未发酵的实验样品,灌胃剂量为0.1 mL/只,1次/天,连续灌胃4周;实验组1为低剂量组,灌胃副干酪乳酪杆菌IOB413后生元提取物产品,灌胃剂量 0.02 mL/只,1次/天,连续灌胃4周;实验2组为高剂量组,灌胃副干酪乳酪杆菌IOB413后生元提取物产品,灌胃剂量为 0.1 mL/只,1次/天,连续灌胃4周;实验3组为副干酪乳酪杆菌IOB413菌粉,灌胃剂量为 0.1 mL/只,1次/d,连续灌胃4周。
(4)实验小鼠指标检测:
(4.1)小鼠形态观察:在实验期间内,每天灌胃之前观察小鼠的皮毛状态,体重、粪便等情况,并做好记录。(4.2)小鼠胃部炎症因子检测:使用试剂盒检测胃部血清炎症因子IL-1β和TNFα的含量。(4.3)小鼠胃组织切片革兰氏染色:观察小鼠胃黏膜炎症细胞浸润情况。(4.4)小鼠胃黏膜幽门螺杆菌的检测:通过胃黏膜幽门螺杆菌定量培养和快速尿素酶试验检测胃黏膜中幽门螺杆菌的存在。
(5)实验结果
5.1 幽门模型成型验证
中期杀鼠进行幽门模型验证,通过小鼠胃黏膜幽门螺杆菌定量培养、小鼠胃黏膜幽门螺杆菌快速脲酶检测、小鼠胃组织切片革兰氏染色分析可知,幽门模型建模成功,参见图6-8。
(5.1)小鼠形态:通过观察小鼠的活动和精神情况,空白组、模型组、实验组的小鼠活动正常,精神状态良好。
(5.2)小鼠体重:实验期间小鼠的死亡率为零,各组小鼠在实验期间均有所增加,且增加趋势一致如图1所示。
(5.3)小鼠胃部炎症因子TNF-α、IL-1β表达水平变化:
如图2所示,对比不同组别小鼠胃部炎症因子TNF-α、IL-1β表达水平变化发现,与模型组相比,经副干酪乳酪杆菌IOB413后生元提取物产品灌胃后,小鼠胃部炎症因子TNF-α、IL-1β表达水平明显下降,说明副干酪乳酪杆菌IOB413分后生元提取物产品对小鼠胃部炎症具有一定的缓解作用;但是未经发酵的菌剂样品以及普通发酵的菌剂样品均未能表现出显著的抗幽门螺旋杆菌感染和炎症抑制作用。
(5.4)小鼠胃组织切片革兰氏染色:
如图3所示,对比不同组别小鼠胃组织切片革兰氏染色结果可知,与模型组相比,经副干酪乳酪杆菌IOB413后生元提取物产品干预后,小鼠胃黏膜未出现大量白细胞浸润,胃部炎症明显降低,说明副干酪乳酪杆菌IOB413后生元提取物产品产品对小鼠胃部炎症可以降低小鼠胃部炎症,但是未经发酵的菌剂样品以及普通发酵的菌剂样品均未能表现出显著的抗幽门螺旋杆菌感染和炎症抑制作用。
(5.5)小鼠胃黏膜幽门螺杆菌的检测:
如图4和图5所示,通过胃黏膜幽门螺杆菌定量培养和快速尿素酶试验检测胃黏膜中幽门螺杆菌,对比不同组别小鼠胃黏膜幽门螺杆菌的检测结果可知,与模型组相比,经副干酪乳酪杆菌IOB413后生元提取物产品产品干预后,小鼠胃黏膜胃黏膜幽门螺杆菌的数量明显减少,尿素酶试剂依旧为黄色,说明副干酪乳酪杆菌IOB413后生元提取物产品可以抑制幽门螺杆菌的生长,缓解幽门螺杆菌感染,但是未经发酵的菌剂样品以及普通发酵的菌剂样品均未能表现出显著的抗幽门螺旋杆菌感染和炎症抑制作用。
综上所述,本发明研究了副干酪乳酪杆菌IOB413后生元提取物产品对幽门螺杆菌抑制的研究,结果表明副干酪乳酪杆菌IOB413后生元提取物产品对幽门螺杆菌感染的小鼠具有能够抑制幽门螺杆菌生长、缓解幽门螺杆菌感染、同时对菌群紊乱改善的显著作用,根据本发明记载的方法得到的副干酪乳酪杆菌IOB413后生元提取物产品,以及对该产品的功能验证,能够为辅助治疗幽门螺杆菌感染提供一定的药理学依据,为开发副干酪乳酪杆菌IOB413后生元提取物产品的在抗幽门螺旋杆菌治疗药物中的应用提供了有效思路。
本发明可用其他的不违背本发明的精神或主要特征的具体形式来概述。因此,无论从哪一点来看,本发明的上述实施方案都只能认为是对本发明的说明而不能限制本发明,权利要求书指出了本发明的范围,而上述的说明并未指出本发明的范围,因此,在与本发明的权利要求书相当的含义和范围内的任何改变,都应认为是包括在本发明的权利要求中。
Claims (9)
1.一种包含活性多肽的副干酪乳酪杆菌IOB413后生元提取物产品的制备方法,具体步骤为:
(1)副干酪乳酪杆菌IOB413,保藏编号CGMCC No.16022,菌株活化和培养;
(2)用所述活化后的副干酪乳酪杆菌IOB413以大豆粉为底物进行发酵,制备副干酪乳酪杆菌IOB413后生元,真空冷冻粉碎后得后生元粉;
(3)水浸提法处理后生元粉,将浸提后的后生元提取液进行冻干处理,获得的粉剂即为副干酪乳酪杆菌IOB413后生元提取物产品;
所述步骤(1)中,培养温度为37±2℃,活化时间为20±2h;
所述步骤(2)中,发酵参数是:料水比1:1.75,接种量5×107CFU/mL,培养时间24±2h,最终获得固态发酵物的活性为6.78×1010CFU/g;
对其发酵产物分离获得的活性多肽测序,获得序列为SEQ IDNO:1的活性多肽。
2.根据权利要求1所述的制备方法,其特征在于:所述步骤(2)中,真空冷冻粉碎的粉碎温度为-100℃,粉末细度为300目到500目。
3.根据权利要求1所述的制备方法,其特征在于:所述步骤(3)中,水浸提法提取时间为3-5h。
4.根据权利要求1所述的制备方法,其特征在于:还包括步骤(4),副干酪乳酪杆菌IOB413后生元提取物产品的营养成分测定。
5.根据权利要求4所述的制备方法,其特征在于:所述步骤(4)中,测定的成分为:大豆低聚糖、多糖、有机酸、长链脂肪酸、活性多肽。
6.根据权利要求1所述的制备方法,其特征在于:还包括步骤(5),副干酪乳酪杆菌IOB413后生元提取物产品对幽门螺杆菌的抑制作用的验证。
7.根据权利要求6所述的制备方法,其特征在于:步骤(5)中对实验小鼠的检测指标有:小鼠形态、小鼠体重、小鼠胃部炎症因子TNF-α、IL-1β表达水平变化、小鼠胃组织切片革兰氏染色分析、小鼠胃黏膜幽门螺杆菌的检测分析。
8. 一种包含活性多肽的副干酪乳酪杆菌IOB413后生元提取物,其特征在于,根据利用权利要求1-7任一项所述的方法制备得到,活性多肽的序列为SEQ ID NO:1。
9.一种如权利要求8所述的后生元提取物在制备抗幽门螺旋杆菌感染相关药物中的应用。
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