CN117070416B - 一株可缓解神经性贪食症的普拉梭菌及其应用 - Google Patents
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Abstract
本发明属于微生物技术领域以及医药技术领域,涉及一株可缓解神经性贪食症的普拉梭菌及其应用。本发明的普拉梭菌(F.prausnitzii)ATCC 27768能有效缓解神经性贪食症,具体体现在:对BN小鼠连续口饲F.prausnitziiATCC 2776811天后,小鼠BN相关脑区PVT的异常活跃得以恢复,贪食症状也得到显著改善。因此,口服补充F.prausnitziiATCC 27768恢复肠道微生物组正常功能可以达到从根源机制上治疗BN的目的,F.prausnitziiATCC 27768在制备预防和/或治疗神经性贪食症的产品中具有广阔的应用前景。
Description
技术领域
本发明涉及微生物技术领域以及医药技术领域,具体地,涉及一株可缓解神经性贪食症的普拉梭菌及其应用。
背景技术
神经性贪食症(Bulimianervosa,BN)是一类由不良饮食习惯发展而成的饮食失调疾病,发病特征主要表现为反复发作且不可抗拒的冲动性暴饮暴食,并伴随不当的补偿行为来缓解摄入过量的身心不适,如催吐、导泻、禁食及过度运动等。BN发病患者中年轻女性居多。除遗传因素外,压力因素对于BN的发病起到关键作用,包括生活压力、社会文化压力及心理压力等。BN的长期后果包括落齿、手麻手抖、晕厥、消化道损伤及心率失常等症状,严重情况下甚至有可能发生休克和心脏骤停。BN患者罹患各种癌症的风险因素也显著增加,包括结直肠癌、食管癌、肝癌和卵巢癌等。此外,BN患者也往往伴随出现一些神经精神障碍,如焦虑症、抑郁症、双相情感障碍及边缘型人格障碍等。据统计,BN患者的死亡率在所有精神类疾病(包括重型抑郁症)中是最高的。总之,BN对健康有较大危害,且逐渐成为当今社会环境下的一个普遍问题。
BN的治疗目标是减少患者暴饮暴食的频率并建立健康的饮食习惯。现阶段临床上对BN的治疗手段包括心理治疗及药物治疗,包括:(1)认知行为疗法(CBT),也是最早用于BN治疗的方法,该方法侧重帮助患者树立正常的体重认知,了解BN的负面影响,纠正对体重及形体的过分关注,以及合理的规划一日三餐,CBT对于有着强烈治疗愿望的患者来说短期内预后效果较好,但复发率较高;(2)人际关系疗法(IPT),这种方法侧重于改善BN患者的人际关系,通过建立更多的社交活动分散患者对食物的关注,因此IPT治疗周期长,见效时间较慢,容易出现患者依从性越来越差的问题;(3)行为治疗(BT),该方法侧重于提高患者的压力耐受程度,调节情绪以此降低暴饮暴食的欲望。与CBT和IPT相比,BT治疗患者的复发率最高。现阶段临床上没有针对BN的特效治疗药物,主要通过使用抗抑郁药(如各类5-HT再摄取抑制剂)、抗惊厥药物(如托吡酯)等去缓解BN症状。但这些药物往往伴有头痛、异常镇静、失眠、嗜睡、注意力不集中及心率和血压升高等不良反应。很多患者由于药物产生的副作用选择终止治疗,且在停药后,复发率依旧较高。由此可以看出,以上这些治疗方法均无法做到从根源机制上对BN的发病“对症下药”,导致治疗效果欠佳且容易反复。
人体的消化道中存在着大量的细菌,其功能或状态的改变与人体多种免疫性疾病、代谢性疾病等的发生、发展密不可分。在宿主健康和疾病的发生、发展中起到了重要的作用。普拉梭菌(Faecalibacteriumprausnitzii,F.prausnitzii)作为健康人类肠道共生菌一个重要组成部分,对人类的健康发挥着非常重要的作用。越来越多的研究发现,肠内F.prausnitzii水平的改变所导致的微生态失调与一些肠道疾病的发生密切相关。其发挥重要的抗炎、改善肠道黏膜屏障、对致病菌的抑制及对肥胖的调节作用(黄金莉,吕卉芸,李华军.普拉梭菌在肠道微生态中的功能及作用研究[J].胃肠病学和肝病学杂志,2019,028(003):245-249.)。由于BN的发病机制及治疗方案较复杂,相关科研人员尚未完全研究清楚,因此目前还未有通过服用F.prausnitzii来缓解或治疗BN的相关报道。
发明内容
本发明的目的是为了克服现有技术的上述不足,提供一株可缓解神经性贪食症的普拉梭菌(Faecalibacteriumprausnitzii,F.prausnitzii)ATCC 27768。
本发明的另一目的在于提供含有上述普拉梭菌ATCC 27768的产品。
本发明的另一目的在于提供上述普拉梭菌ATCC 27768在制备预防、缓解、改善和/或治疗神经性贪食症的药物中的应用。
本发明的另一目的在于提供含有上述普拉梭菌ATCC 27768的食品、饮品、保健品、肠内营养剂、膳食补充剂、兽药和/或饲料添加剂。
为了实现上述目的,本发明是通过以下方案予以实现的:
本发明前期以啮齿类动物为研究对象,在小鼠上建立BN发病的动物模型,用于模拟BN患者的临床症状;通过对粪便微生物16S rDNA测序、免疫荧光染色、光遗传/化学遗传操纵、环路示踪、迷走神经横断、脑片电生理记录及粪菌移植等手段,解析了一条肠道微生物-迷走神经到中枢NTS-PVT的肠脑连接环路,该环路的功能失调介导小鼠BN症状的出现。进一步的,通过收集临床BN患者粪便并进行16S rDNA测序,发现BN患者肠道微生物组中一种重要的益生菌,普拉梭菌(Faecalibacterium Prausnitzii,F.prausnitzii)表现出显著缺失。对BN小鼠连续口饲F.prausnitziiATCC 2776811天后,小鼠BN相关脑区PVT的异常活跃得以恢复,贪食症状也得到显著改善。因此,相较于易复发的心理治疗与副作用大的药物治疗,口服补充F.prausnitziiATCC 27768恢复肠道微生物组正常功能可以达到从根源机制上治疗BN的目的,为临床推广治疗BN提供了新的方法。
因此,本发明请求保护一株普拉梭菌(Faecalibacterium Prausnitzii,F.prausnitzii)ATCC 27768。
在一种实施方式中,所述普拉梭菌ATCC 27768购买自ATCC公司,该菌株在LYHBHI培养基上的菌落呈半透明状。
本发明还请求保护含有上所述普拉梭菌ATCC 27768的产品。
优选地,所述产品为微生物制剂或药物。
更优选地,所述微生物制剂或药物中,所述普拉梭菌ATCC 27768的活菌数为不低于3.0×108CFU/mL或3.0×108CFU/g。
本发明还请求保护上述的普拉梭菌ATCC 27768在制备预防、缓解、改善和/或治疗神经性贪食症的药物中的应用。
优选地,所述药物还含有药物辅料。
更优选地,所述药物辅料包含抗黏合剂、渗透促进剂、缓冲剂、增塑剂、表面活性剂、消泡剂、增稠剂、包合剂、吸收剂、保湿剂、溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、pH值调节剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、整合剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、发泡剂、助悬剂、包衣材料、芳香剂、稀释剂、絮凝剂与反絮凝剂、助滤剂或释放阻滞剂。
优选地,所述药物的剂型为颗粒剂、胶囊剂、片剂、丸剂或口服液。
优选地,所述药物的应用对象包括但不限于人类或小鼠。
本发明还请求保护含有上所述普拉梭菌ATCC 27768的食品、饮品、保健品、肠内营养剂、膳食补充剂、兽药和/或饲料添加剂。
优选地,所述的食品、饮品、保健品、肠内营养剂、膳食补充剂、兽药和/或饲料添加剂中,所述普拉梭菌ATCC 27768的活菌数为不低于3.0×108CFU/mL或3.0×108CFU/g。
与现有技术相比,本发明具有以下有益效果:
本发明的普拉梭菌(F.prausnitzii)ATCC 27768能有效缓解神经性贪食症,具体体现在:对BN小鼠连续口饲F.prausnitziiATCC 2776811天后,小鼠BN相关脑区PVT的异常活跃得以恢复,贪食症状也得到显著改善。因此,口服补充F.prausnitzii ATCC 27768恢复肠道微生物组正常功能可以达到从根源机制上治疗BN的目的。与心理治疗相比,补充F.prausnitziiATCC 27768无需患者住院,节省人力物力财力,无需担心疗程结束后复发;与现有采用不对症的抗抑郁药或抗惊厥药相比,补充F.prausnitzii益生菌ATCC 27768产生的副作用远小于抗抑郁药或抗惊厥药带来的副作用。综上所述,F.prausnitziiATCC27768在制备预防和/或治疗神经性贪食症的产品中具有广阔的应用前景。
附图说明
图1为在小鼠上建立BN模型的示意步骤。其中,图1A为电击后不同时间段(post2h,8h,24h)后小鼠消耗chow和Oreo的重量;图1B为对照小鼠和BN小鼠在不同时间段chow/Oreo消耗重量的比值;图1C为对照小鼠和BN小鼠在不同时间段的热量摄入;图1D为对照小鼠和BN小鼠电击后靠近Oreo所需的潜伏时间。
图2为对照小鼠和BN小鼠肠道微生物测序结果分析对比。其中,图2A为对照小鼠和BN小鼠差异表达的肠道微生物种类;图2B-图2D为基于Bray-Curtis的PCoA分析对照组与BN组小鼠肠道微生物群落结构;图2E为对照小鼠和BN小鼠科级微生物群落相对丰度比较;图2F为基于Bray-Curtis的UPGMA树以比较对照小鼠和BN小鼠的微生物群落分类;图2G为LEfSE分析显示对照小鼠与BN小鼠存在显著差异的微生物类群;图2H-图2I为Metastats检验比较对照组小鼠与BN小鼠两个显著差异属微生物的相对丰度。.
图3为发现BN病人F.prausnitzii菌丰度减少,以及BN小鼠回补F.prausnitziiATCC 27768可缓解BN症状。其中,图3A为PLS-DA聚类分析健康对照与BN病人肠道微生物群落差异;图3B为VIP分析表明健康对照与BN病人之间最具差异性的肠道微生物群(按重要性降序排列);图3C为火山图表明健康对照与BN病人相比差异性肠道微生物群(包括F.prausnitzii在内)的P值与倍数变化;图3D为LEfSE分析显示健康对照与BN病人F.prausnitzii菌群存在显著差异,BN病人F.prausnitzii菌群明显减少;图3E为未处理的BN小鼠与口饲补充F.prausnitziiATCC 27768的BN小鼠在第11天口饲结束后不同时间段chow/Oreo消耗重量的比值;图3F为未处理的BN小鼠与口饲补充F.prausnitzii ATCC27768的BN小鼠在第11天口饲结束后不同时间段的热量摄入。
具体实施方式
下面结合说明书附图及具体实施例对本发明作出进一步地详细阐述,所述实施例只用于解释本发明,并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
菌株:本发明所用F.prausnitzii ATCC 27768购买自ATCC公司,该菌株在LYHBHI培养基上的菌落呈半透明状。
实施例1在C57BL/6J小鼠上建立BN模型
整个模型由三个循环组成,每个循环11天,前4天为节食期,小鼠每天获得少于日均消耗量的鼠粮chow(约日均消耗量的60%);随后2天小鼠获得充足chow,并额外获得不限量的Oreo饼干;接下来撤去Oreo,小鼠进入4天的chow自由饮食期;在第11天对小鼠进行0.45mA足底电击,并记录电击后不同时间段(post 2h,8h,24h)后小鼠消耗chow和Oreo的重量(图1A)。通过计算chow/Oreo消耗重量的比值来反应其对高能食物的偏爱程度:chow/Oreo值越低,偏爱度越高,反之chow/Oreo值越高,偏爱度越低;以及摄入总卡路里数来反应贪食程度:卡路里值越高,贪食程度越强(图1B-D)。
实施例2BN小鼠肠道内包括瘤胃球菌科在内的微生物类群及丰度发生改变
通过16S rDNA扩增子测序技术对BN建模小鼠和对照组小鼠的肠道微生物种类和丰度进行检测。从新鲜粪便中获取的序列按照高于97%的相似性分类成操作单元OTU,再对组内微生物的组成进行分析。多样本分析中将OTU降维到PC1-3维度,再用Brary-Curtis距离矩阵两两比较获得三个PCoA样本分布点图。结果表明,BN小鼠肠道微生物群落组成与对照组相比发生稳定的变化(图2A-G)。组件群落差异分析发现,BN小鼠肠道微生物中益生菌类,如瘤胃球菌科的丰度下降,而拟杆菌门中的另枝菌属成为新的优势种(图2H-I)。
实施例3BN患者肠道内F.prausnitzii菌丰度降低
为了找出与BN发病密切相关的肠道微生物种属,招募了11名临床诊断为BN的女性患者,以及9名年龄、性别和体重指数相匹配的健康被试,并分别收集BN患者和健康被试的粪便进行16S rDNA测序。分析发现,在属水平上,BN患者表现出Faecalibacterium的缺失,这种细菌与小鼠粪便测序分析发现的Rumincocacea同属瘤胃球菌科(图3A、D)。VIP评分图表明,Faecalibacterium属中的Faecalibacteriumprausnitzii(F.prausnitzii)对组间差异贡献最大(图3B)。火山图也显示BN患者中F.prausnitzii丰度的显著降低(图3C)。
实施例4普拉梭菌对BN患者的影响
为了证明F.prausnitzii的减少可能是BN发病的关键原因,对BN小鼠进行口饲接种F.prausnitziiATCC 27768(每只鼠每天接受3.0×108CFU的F.prausnitzii菌量,连续口饲11天),结果与预期一致,肠道定植F.prausnitziiATCC 27768显著缓解了BN小鼠的贪食症状(图3E、F)。以上结果表明,补充F.prausnitziiATCC 27768为BN临床治疗提供了一个新思路。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,对于本领域的普通技术人员来说,在上述说明及思路的基础上还可以做出其它不同形式的变化或变动,这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明权利要求的保护范围之内。
Claims (3)
1.普拉梭菌(Faecalibacterium Prausnitzii)ATCC 27768在制备预防、缓解、改善和/或治疗神经性贪食症的药物中的应用,其特征在于,所述普拉梭菌ATCC 27768购买自ATCC公司。
2.根据权利要求1所述的应用,其特征在于,所述药物还含有药物辅料。
3.根据权利要求1或2所述的应用,其特征在于,所述药物的剂型为颗粒剂、胶囊剂、片剂、丸剂或口服液。
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