CN114681493A - 动物双歧杆菌乳亚种的应用 - Google Patents
动物双歧杆菌乳亚种的应用 Download PDFInfo
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- CN114681493A CN114681493A CN202011640244.8A CN202011640244A CN114681493A CN 114681493 A CN114681493 A CN 114681493A CN 202011640244 A CN202011640244 A CN 202011640244A CN 114681493 A CN114681493 A CN 114681493A
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- Prior art keywords
- bifidobacterium animalis
- lactis
- animalis subsp
- bowel syndrome
- irritable bowel
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明公开了动物双歧杆菌乳亚种的应用,属于生物医药领域。本发明提供了双歧杆菌乳亚种BS‑1在制备治疗肠易激综合征的药物中的新应用,动物双歧杆菌乳亚种BS‑1在制备缓解肠易激综合征的保健品中的应用,动物双歧杆菌乳亚种BS‑1在制备缓解肠易激综合征的食品中的应用。研究证实动物双歧杆菌乳亚种的组合物治疗IBS疗效显著。
Description
技术领域
本发明属于生物技术领域,具体涉及动物双歧杆菌乳亚种的应用。
背景技术
乳酸菌作为一类能够利用糖类生长并产生乳酸的益生菌,因其具有保护人体肠道健康等有益作用引起了人们的广泛关注。乳杆菌属和双歧杆菌属被广泛应用于食品、药品、保健品产业中。目前已知乳杆菌属是一群广泛存在于人体肠道内的有益于宿主健康的微生物,能够发挥维持人体健康和调节免疫等作用。乳杆菌属的特定菌株已被发现能够定植于肠道粘膜,并协助维持宿主健康。目前国内许多企业利用动物双歧杆菌乳亚种冻干菌粉为原料生产生物制品,然而产品中菌粉的活菌数量是评价益生菌产品质量好坏的关键,鉴于不同的动物双歧杆菌乳亚种菌株特性之间的差异,而当前许多产品都不能有效地防止活菌数的衰减。所以,使产品能够保持足够多的活菌数量并延长菌种的保藏期,以便充分发挥其生理功能,降低成本,已成为动物双歧杆菌乳亚种活菌制剂产品研究开发及其应用的技术关键。
常用的治疗药物奥替溴铵主治胃肠道痉挛以及胃肠道蠕动功能障碍,如肠易激综合征、胃炎、肠炎、十二指肠等,可对胃肠道平滑肌产生解痉作用,可明显缓解腹痛。但也存在缺点,如当患者出现腹泻症状,则会大小便发作频繁,患者口服的奥替溴铵会很快随着大小便排出体外,从而降低药效,因此寻找安全有效的治疗试剂是迫在眉睫的需求。
肠易激综合征(IBS)是一种以腹痛或腹部不适伴腹泻为特征的功能性肠病。目前化药、中药中尚无一种药物能治愈IBS,大多数一线治疗方案主要针对其中一种症状进行改善,存在局限且有一定的副作用,文献报道,解痉药比较安全,但疗效不明显,仅略好于安慰剂,可溶性纤维对伴有便秘的患者比较有效,但麸糠及其他难溶性纤维则可能加剧症状;易蒙停能改善里急后重,减少大便次数"但可能加剧腹痛和腹部不适;拮抗剂能够改善全身症状、腹泻和腹痛等,但极少数情况下会引发不明原因的肠炎,所以寻找有效且安全无副作用的治疗肠易激综合征(IBS)的候选化合物是非常有必要的。
发明内容
本发明的目的是为了提供一种双歧杆菌乳亚种BS-1的新应用,本发明提供了一种动物双歧杆菌乳亚种(Bifidobacterium animalis subsp.lactis)BS-1在制备治疗肠易激综合征的药物中的应用。
本发明还提供了一种动物双歧杆菌乳亚种(Bifidobacterium animalissubsp.lactis)BS-1在制备缓解肠易激综合征的保健品中的应用。
本发明还提供了一种动物双歧杆菌乳亚种(Bifidobacterium animalissubsp.lactis)BS-1在制备缓解肠易激综合征的食品中的应用。
上述的动物双歧杆菌乳亚种(Bifidobacterium animalis subsp.lactis)BS-1的保藏号为CGMCC NO.19079。
上述肠易激综合征为腹泻型肠易激综合征、便秘型肠易激综合征、混合型肠易激综合征或不确定型肠易激综合征。
上述包含动物双歧杆菌乳亚种(Bifidobacterium animalis subsp.lactis)BS-1的制剂剂型为片剂、胶囊剂、颗粒剂、散剂、液体制剂中的任意一种或其他可使动物双歧杆菌能够稳定存在的制剂剂型。
本发明利用的是首次从健康儿童的粪便中分离得到的动物双歧杆菌乳亚种BS-1,经过鉴定其为动物双歧杆菌乳亚种,进一步通过对该菌的生化特性进行鉴定后发现,该菌满足益生菌的众多指标,因此,该动物双歧杆菌乳亚种可以作为一种新型的益生菌。具体地,发明人发现该菌其对多种抗生素敏感,例如青霉素类(青霉素、氨苄西林、哌拉西林)、头孢菌素类(头孢唑啉、头孢克罗、头孢三曲松、头孢噻肟、头孢呋新、头孢他啶、头孢噻吩)、大环内酯类(红霉素、阿奇霉素、克拉霉素)、四环素类(四环素、米诺环素、多西环素)、醣肽类(万古霉素)、碳青霉烯类(美洛培南)、利福霉素类(利福平)、磺胺类抗生素是复方新诺明、氯霉素、呋喃妥因、克林霉素和大观霉素,经过试验证明,该动物双歧杆菌乳亚种对于动物例如小鼠没有毒性,小鼠服用该菌株后健康存活,体重正常增加,符合益生菌的质量标准要求;该动物双歧杆菌乳亚种能够抵抗胃液的酸性环境(例如pH1.5~4.5的人工胃液环境下,该菌株存活状况良好);该动物双歧杆菌乳亚种还能够抵抗肠道中的胆汁盐环境(例如在0.03~0.3%的胆汁盐浓度下,该菌存活状态良好)。发明所提供的动物双歧杆菌乳亚种可以在人体内定植,发挥益生作用。
根据本发明的实施例,所述动物双歧杆菌乳亚种BS-1具有高耐酸、耐胆盐特性表现在pH2.5~4.5的人工胃液环境或0.03~0.3%的胆汁盐浓度下,存活状况良好。动物双歧杆菌乳亚种BS-1对抗生素的具有敏感性。动物双歧杆菌乳亚种BS-1对人体胃酸和胆盐具有耐受性。动物双歧杆菌乳亚种BS-1对胆盐具有耐受性。
有益效果:
1.首先需要说明不是每株乳杆菌都能作为益生菌,需经科学方法验证后的菌株才能作为益生菌的候选菌株。以耐酸、耐胆盐特性为例,益生菌需具有较强的耐酸、耐胆盐特性,方可在进入胃肠道后耐受严苛环境在胃肠道发挥作用。本发明所提供的动物双歧杆菌乳亚种BS-1具有较好的耐酸、耐胆盐特性,可以在人体内定植,发挥益生作用。
2.本发明所提供的动物双歧杆菌乳亚种BS-1对多种抗生素敏感,菌株安全性高。
3.本发明所提供的动物双歧杆菌乳亚种BS-1菌株通过将所分离的细菌给小鼠喂食,发现全部小鼠均健康存活,体重正常增加,说明分离的动物双歧杆菌乳亚种BS-1无毒性,安全性高。
4.本发明所提供的动物双歧杆菌乳亚种BS-1常温条件下储藏稳定性较好,适用于制备多种剂型的益生菌制剂。
5.经过实验验证动物双歧杆菌乳亚种的组合物可以显著改善IBS鼠的临床症状、痛觉阈值和粪便含水率。
附图说明
图1为本发明提供的动物双歧杆菌乳亚种BS-1经革兰氏染色后的镜检照片,放大倍数为100倍的结果图;
图2为不同pH对动物双歧杆菌乳酸亚种BS-1活菌数的影响结果,其中,横坐标是取样时间,纵坐标是活菌数量;
图3为不同浓度胆盐对动物双歧杆菌乳酸亚种BS-1活菌数的影响,其中,横坐标是取样时间,纵坐标是活菌数量;
图4为动物双歧杆菌乳酸亚种BS-1及市售动物双歧杆菌乳酸亚种MB-1、MB-2在20℃条件下储存12个月稳定性变化,其中,横坐标是取样时间,纵坐标是活菌数量;
图5为动物双歧杆菌乳酸亚种BS-1及市售动物双歧杆菌乳酸亚种MB-1、MB-2在25℃条件下储存12个月稳定性变化,横坐标是取样时间,纵坐标是活菌数量;
图6为动物双歧杆菌乳酸亚种BS-1的组合物对IBS大鼠痛觉阈值的影响,其中,横坐标是组别,纵坐标是痛觉阈值,Normal Control为正常对照组,Model Control为模型对照组,Positive Control为阳性对照组,Group A为A组,Group B为B组,Group C为C组。
具体实施例
本发明提供一种双歧杆菌乳酸亚种(Bifidobacterium animalissubsp.lactis),菌株号为BS-1,2019年12月4日,保藏于中国普通微生物菌种保藏管理中心(CGMCC),保藏地址为北京市朝阳区北辰西路1号院3号,保藏编号为CGMCC NO.19079。
Balb/c和SPF级BALB/c小鼠是商业购买的。
实验培养基:固体培养基TPY和液体TPY培养基都是购自青岛高科技工业园海博生物技术有限公司。
药敏纸片购自北京天坛生物技术开发公司。
实施例1.动物双歧杆菌乳亚种BS-1的分离纯化和鉴定
将采集到的健康婴儿新鲜粪便挑取5-10g,装入甘油管并转移至放有生物冰袋的冷藏箱中待用。在无菌操作台中将已厌氧保存的婴儿粪便样1g,转移至装有9ml的无菌生理盐水中并至均匀,依次进行10倍的梯度稀释至1×10-8,用移液枪吸取1×10-6、1×10-7、1×10-83个梯度的稀释液各100μL于固体选择培养基TPY中,每个稀释度3个平板。37℃恒温厌氧培养72小时后,挑取表面具备乳酸菌特性的菌落,分离单株菌后接种到TPY培养基中进行扩大培养。
基于细胞形态如图1所示、生理生化特征如表1所示和16S rRNA基因测序综合分析,参考《伯杰氏系统细菌学手册》以及International Jouranl of Systematic andEvelutionary Microbiology有关研究论文,鉴定所分离的菌株为一种新型的动物双歧杆菌乳亚种BS-1。动物双歧杆菌乳亚种BS-1与动物双歧杆菌乳亚种(Bifidobacteriumanimalis.strain)Probio-M8同源性为99.93%。
表1动物双歧杆菌乳亚种BS-1生理生化特征
实施例2.抗生素敏感性、菌株稳定性评价和小鼠毒性实验
2.1抗生素敏感性:发明人进一步采用K-B法(药敏纸片扩散法)测定了实施例1中所分离的动物双歧杆菌乳亚种BS-1菌株,并进行抗生素的敏感性的检测,结果表明动物双歧杆菌乳亚种BS-1对几乎全部种类的抗生素敏感。结果如表2所示。
表2动物双歧杆菌乳亚种BS-1的抗生素敏感性检测结果
备注:R表示抗性,S表示敏感。
2.2菌株稳定性评价:通过连续传代培养,对实施例1中所分离的动物双歧杆菌乳亚种BS-1的形态、理化等分类鉴定特征以及抗生素敏感性等性状,发现经过多次传代的分离的动物双歧杆菌乳亚种BS-1未发现可见的变化,说明分离的动物双歧杆菌乳亚种BS-1具有可稳定遗传的形状。
2.3小鼠毒性实验:
(1)按现行版药典方法进行。取实施例1分离得到的动物双歧杆菌乳亚种BS-1,以生理盐水稀释至2.0×109cfu/ml的菌悬液,灌胃18-22g健康清洁级Balb/c小鼠,每组5只,试验前小鼠称重并做记录;每只小鼠灌胃菌液0.5ml,每天1次,连续3天,从第1天灌胃起逐日观察至第7天,观察小鼠健康状况,并在第7天记录小鼠体重。实验同时设立生理盐水对照组。
(2)为进一步考察实验菌株在小鼠体内安全性,参考文献中使用的灌胃剂量,采用高剂量1011cfu/ml菌液灌胃Balb/c小鼠,每组10只,每只小鼠灌胃0.1ml,每天1次,连续8天,观察小鼠健康状况,并记录第1、4、8天小鼠体重变化情况。实验设生理盐水对照组。
结果发现全部小鼠均健康存活,体重正常增加,说明分离的动物双歧杆菌乳亚种BS-1无毒性,安全性高。
实施例3.菌株的耐酸和耐胆盐实验
3.1菌株耐酸实验:按现行版药典方法进行配制人工胃液。取稀盐酸16.4ml,加水约800ml与胃蛋白酶10g,摇匀后,加水稀释成1000mL,即得人工胃液。考虑到细菌在液体状态下进入胃,排空较快,故在人工胃液中考察3小时以内的存活率。分别于0min、15min、30min、60min、90min、120min、180min取样计数。考虑到胃在饥饿和用餐后pH变化(1.5-4.5),分别于pH为1.5、2.5、3.5、4.5时取样计数,考虑到胃液在平常状态处于pH值约为2.5的状态,同时检测了市售动物双歧杆菌乳亚种MB和动物双歧杆菌乳亚种BS-1在pH值为1.5-4.5的状态下的存活情况。结果如表3和图2所示,结果表明实施例1中所分离纯化的动物双歧杆菌乳亚种BS-1具有较强的耐酸活
表3动物双歧杆菌乳亚种BS-1在人工胃液中的存活情况
备注:本发动物双歧杆菌乳亚种:BS-1;市售动物双歧杆菌乳亚种:MB。
3.2菌株耐胆盐实验:按现行版药典方法配制人工肠液。取磷酸二氢钾6.8g,加水500ml使溶解,用0.1mol/L氢氧化钠溶液调节pH值至6.8,另取胰酶10g,加水适量使溶解,将两液混合后,加水稀释至1000ml,即得人工肠液。考虑到细菌在液体状态下进入小肠,排空较快,故在人工肠液中考察3小时以内的存活率。分别于0min、15min、30min、60min、90min、120min、180min取样计数。考虑到人体小肠中胆汁盐含量在0.03%-0.3%内波动,分别设计胆汁盐在质量分数为0.03%、0.1%、0.2%、0.3%条件下进行实验和取样计数;考虑到胆汁在平常状态处于约0.2%的状态,胆汁在极端状态处于约0.3%的状态,同时检测了市售动物双歧杆菌乳亚种MB和动物双歧杆菌乳亚种BS-1在胆汁浓度为约0.03%-0.3%的状态下的存活情况。结果如表4和图3所示,结果表明实施例1中所分离纯化的动物双歧杆菌乳亚种BS-1具有较强的耐胆盐活性。
表4动物双歧杆菌乳亚种BS-1在人工肠液中的存活情况
备注:本发动物双歧杆菌乳亚种:BS-1;市售动物双歧杆菌乳亚种:MB。
实施例4.动物双歧杆菌乳亚种组合物的制备
动物双歧杆菌乳亚种BS-1片剂的制备:含动物双歧杆菌乳亚种BS-1组合物可以与药学上可接受的辅料制备成粉剂、片剂、胶囊剂及滴剂,制备成固体制剂、半固体制剂或液体制剂,本实施例子提供了一种含动物双歧杆菌乳亚种BS-1片剂的制备方法,步骤如下:
(1)原料菌粉制备:动物双歧杆菌乳亚种BS-1工作种子经活化、一级种子液培养、种子罐种子制作及发酵后,离心收集菌体,添加冻干保护剂进行菌体冷冻干燥获得动物双歧杆菌乳亚种BS-1菌粉。
(2)原辅料预处理:取动物双歧杆菌乳亚种BS-1菌粉及药学上可接受的辅料如润滑剂(硬脂酸镁、滑石粉、聚乙二醇6000、硬脂酸、十二烷基硫酸钠/镁、硬脂富马酸钠、山嵛酸甘油酯);助流剂(滑石粉、微粉硅胶、二氧化硅);填充剂(脱脂奶粉、麦芽糊精、蔗果低聚糖、预胶化淀粉、乳糖、葡萄糖、蔗糖、D-甘露醇、淀粉);甜味剂(甘露醇、葡萄糖、蔗糖、D-甘露醇、甜菊素、白糖)等进行预处理。
(3)混合制备:将辅料过50-200目数的筛后加入批混机混匀,最后加入菌粉混匀,50分钟结束后放料。
(4)成型:将混合后的原辅料转入高速压片机中进行压片,在压片过程中应调节填充量及压力,保证素片重量差异、脆碎度、崩解度等符合质量标准要求,终产品动物双歧杆菌乳亚种BS-1活菌数≥1×106cfu/g,分别置于4℃、20℃、25℃条件下进行稳定性考察,确定动物双歧杆菌乳亚种BS-1在成品中的稳定性,稳定性考察结果显示,4℃条件下制剂中动物双歧杆菌乳亚种BS-1、市售动物双歧杆菌MB-1、市售动物双歧杆菌MB-2稳定性较好,存储12个月时基本没有下降,在20℃、25℃条件下稳定性结果比较如表5所示。
结果如表5、图4和图5所示,动物双歧杆菌乳亚种BS-1在成品制作成后的12个月时在20℃、25℃条件下稳定性分别能维持1.47E+08cfu/g、4.90E+07cfu/g的含量,而市售动物双歧杆菌MB-1在成品制作成后的12个月时在20℃仅能维持在4.30E+04cfu/g,在25℃条件下已无法检测活菌数,市售动物双歧杆菌MB-2在成品制作成后的12个月时在20℃仅能维持在4.70E+03cfu/g,在25℃条件下已无法检测活菌数。通过动物双歧杆菌乳亚种BS-1及市售菌株在成品中的稳定性说明动物双歧杆菌乳亚种BS-1在成品中的稳定性很高,高于市售的动物双歧杆菌在制成成品中的稳定性。本发明的动物双歧杆菌乳亚种在制备片剂中稳定性较好,在12个月的储藏期间有较好的稳定性。
表5动物双歧杆菌乳亚种BS-1及市售菌株在成品中的稳定性
备注:本发动物双歧杆菌乳亚种:BS-1;市售动物双歧杆菌乳亚种:MB-1;市售动物双歧杆菌乳亚种:MB-2。
实施例5.含动物双歧杆菌乳亚种的组合物治疗IBS(肠易激综合征)
1、动物:试验选用40只雄性SD大鼠,SPF级,6~7周。
2、模型制备:随机选取34只,采用醋酸灌肠结合改良夹尾刺激综合造模。大鼠禁食约6h,经SD大鼠肛门插入连接注射器的灌胃管,插入深度距肛门约2cm,灌入1%的醋酸1ml(灌胃管保留30s),每隔两天增加醋酸浓度0.5%,增加到2%时不再增加。灌肠后对大鼠进行夹尾和强光刺激,并敲打鼠笼等以减少大鼠休息时间,每天一次,每次持续30min,连续4周。模型制备约2周,模型组动物增加束缚刺激。造模过程观察大鼠粪便情况,造模4周后进行痛觉阈值的检测。模型组动物出现腹泻症状,且痛觉阈值明显低于正常对照组,表示造模成功。
3、分组:模型动物根据痛觉阈值随机分组,分为模型对照组、阳性对照组、供试品A、B、C和D组,阳性对照组、供试品A组每组5只,其他组每组6只,并选取6只正常大鼠作为正常对照。
4、给药:采用灌胃给药,正常对照组、模型对照组给予0.9%氯化钠注射液,阳性对照组给予奥替溴铵,给药剂量为25mg/kg/d,供试品A~D组分别给予不同浓度的双歧杆菌四联活菌菌粉悬液,给药容积皆为10ml/kg,每日给药1次,连续给药7天。
动物双歧杆菌乳亚种BS-1的组合物悬液的给药剂量见下表6。
表6菌粉悬液给药剂量
给药剂量(×10<sup>5</sup>CFU/kg) | A组 | B组 | C组 | D组 |
双歧杆菌乳亚种BS-1的组合物 | 4.7 | 470 | 4700 | 47000 |
5、指标检测
(1)临床症状评分:分别于给药前、给药结束观察各组动物症状,进行评分。评分标准记载在王伟岸,钱家鸣,潘国宗.肠易激综合症的诊断标准和鉴别诊断[J].胃肠病学和肝病学杂志(2):106-109.
(2)痛觉阈值:分别于给药前、给药结束进行痛觉阈值的检测。
(3)粪便含水率:分别于给药前、给药结束收集各组动物24h粪便,称量粪便湿重和干重,计算粪便含水率的变化。
6、结果
(1)组合物对IBS大鼠临床症状的改善
结果如表7所示,给药前,与正常对照组相比,其余各组大鼠临床症状评分显著升高(P<0.01),表现为稀样便、肛周及腹部淋漓污浊。给药结束后,大鼠临床症状得到改善,评分降低,B、C、D组与模型对照组比较,具有显著差异(P<0.05)。
表7组合物对IBS大鼠临床症状的影响(MEAN±SD)
备注:模型对照组与正常对照组比较,##P<0.01;各给药组与模型对照组比较,*P<0.05
(2)组合物对IBS大鼠痛觉阈值的影响
结果如表8和图6所示,给药前,与正常对照组相比,其余各组大鼠痛觉阈值显著降低(P<0.01)。给药结束后,大鼠痛觉阈值升高,腹痛得到缓解,与模型对照组比较,具有显著差异(P<0.01)。
表8组合物对IBS大鼠痛觉阈值的影响(MEAN±SD)
备注:模型对照组与正常对照组比较,##P<0.01;各给药组与模型对照组比较,**P<0.01
(3)组合物对IBS大鼠粪便含水率的影响
结果如表9所示,给药前,与正常对照组相比,其余各组大鼠粪便含水率显著升高(P<0.01),呈稀样便。给药结束后,与模型对照组相比,治疗组大鼠粪便含水率显著降低(P<0.01)。
表9组合物对IBS大鼠粪便含水率的影响(MEAN±SD)
备注:模型对照组与正常对照组比较,##P<0.01;各给药组与模型对照组比较,**P<0.01
综上所述,该组合物可显著改善IBS大鼠的临床症状、痛觉阈值和粪便含水率。
SEQUENCE LISTING
<110> 杭州远大生物制药有限公司
<120> 动物的双歧杆菌乳亚种的应用
<130>
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 1440
<212> DNA
<213> 16S
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Claims (7)
1.动物双歧杆菌乳亚种(Bifidobacterium animalis subsp.lactis)BS-1在制备治疗肠易激综合征的药物中的应用。
2.动物双歧杆菌乳亚种(Bifidobacterium animalis subsp.lactis)BS-1在制备缓解肠易激综合征的保健品中的应用。
3.动物双歧杆菌乳亚种(Bifidobacterium animalis subsp.lactis)BS-1在制备缓解肠易激综合征的食品中的应用。
4.根据权利要求1-3任意一项所述的应用,其特征在于,所述动物双歧杆菌乳亚种(Bifidobacterium animalis subsp.lactis)BS-1的保藏号为CGMCC NO.19079。
5.根据权利要求1-3任意一项所述的应用,其特征在于,所述肠易激综合征为腹泻型肠易激综合征、便秘型肠易激综合征、混合型肠易激综合征或不确定型肠易激综合征。
6.根据权利要求1所述的应用,其特征在于,所述药物的剂型为片剂、胶囊剂、颗粒剂、散剂、液体制剂中的任意一种。
7.根据权利要求2所述的应用,其特征在于,所述保健品的剂型为片剂、胶囊剂、颗粒剂、散剂、液体制剂中的任意一种。
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CN116121128A (zh) * | 2022-12-23 | 2023-05-16 | 深圳保时健生物工程有限公司 | 一种动物双歧杆菌乳亚种菌株goldgut-bb69及用途 |
CN116083324A (zh) * | 2023-03-21 | 2023-05-09 | 微康益生菌(苏州)股份有限公司 | 一种能够改善或治疗肠易激综合征的动物双歧杆菌乳亚种ba79及其培养方法和应用 |
CN116083324B (zh) * | 2023-03-21 | 2023-10-31 | 微康益生菌(苏州)股份有限公司 | 一种能够改善或治疗肠易激综合征的动物双歧杆菌乳亚种ba79及其培养方法和应用 |
CN117568202A (zh) * | 2023-09-21 | 2024-02-20 | 广东正当年生物科技有限公司 | 一株促肠蠕动的动物双歧杆菌乳亚种bl-g75及其应用 |
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