CN112933115B - Akkermansia muciniphila在治疗慢性胰腺炎方面的应用 - Google Patents
Akkermansia muciniphila在治疗慢性胰腺炎方面的应用 Download PDFInfo
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Abstract
本发明公开了Akkermansia muciniphila在治疗慢性胰腺炎方面的应用，属于益生菌的应用领域。本发明提供了Akkermansia muciniphila BAA‑835菌株在制备治疗慢性胰腺炎的产品中的应用，该菌株在活性状态或灭活状态下均可缓解胰腺萎缩症状，缓解腺泡细胞损伤及炎症浸润，减少促炎细胞因子的释放和巨噬细胞的浸润，减轻胰腺纤维化程度，可以用于制备治疗慢性胰腺炎的药物、药物组合物、功能性食品及饲料，具有广阔的应用前景。
Description
技术领域
本发明公开了Akkermansia muciniphila在治疗慢性胰腺炎方面的应用，特别涉及 Akkermansia muciniphila BAA-835菌株在治疗慢性胰腺炎方面的应用，属于益生菌的应用领域。
背景技术
慢性胰腺炎是一种由多因素引起的炎症性胰腺疾病，能够对胰腺组织和功能造成不可逆损伤。慢性胰腺炎的主要发病因素有酗酒、吸烟、高脂高蛋白饮食、遗传因素等。目前，慢性胰腺炎影响着世界1/2000的人口，而其中13％的慢性胰腺炎患者会进而恶化成胰腺癌，对患者生活造成严重的影响。在临床上慢性胰腺炎的表现多种多样，且发病机制尚未完全明确，因此尚无治疗慢性胰腺炎的有效药物。研究发现，将慢性胰腺炎患病小鼠的粪便菌群移植到健康小鼠体内，能让健康小鼠患病，表明菌群对慢性胰腺炎发病过程具有调节作用。
人体和动物肠道内存在数量庞大的微生物群，它们黏附在肠粘膜表面，构成生物屏障，宿主与肠道微生物群之间的相互作用一直是健康与疾病领域的研究热点。肠道菌群主要由专性厌氧菌、兼性厌氧菌和需氧菌组成，其中专性厌氧菌占99％以上。Akkermansiamuciniphila 是一种革兰氏阴性的严格厌氧菌，可在降解宿主粘蛋白的同时释放氨基酸或单糖，产生短链脂肪酸，为肠道中共生菌群提供营养，这提示Akkermansia muciniphila摄入对肠道菌群具有调节作用。已有研究表明，Akkermansia muciniphila具有缓解肥胖的作用，但Akkermansia muciniphila是否对慢性胰腺炎具有潜在调节作用，尚不清楚。
发明内容
本发明的目的是提供Akkermansia muciniphila BAA-835菌株在制备治疗慢性胰腺炎的产品中的应用；所述应用包括：
(1)缓解胰腺萎缩症状；
(2)缓解腺泡细胞损伤及炎症浸润；
(3)减少促炎细胞因子的释放和巨噬细胞的浸润；
(4)减轻胰腺纤维化程度。
在一种实施方式中，所述Akkermansia muciniphila BAA-835是具有生物活性的活细胞或经处理后获得的失活细胞。
在一种实施方式中，所述Akkermansia muciniphila BAA-835菌株以活菌制剂或经灭菌后的菌剂的形式使用。
在一种实施方式中，所述产品中Akkermansia muciniphila BAA-835的数量≥5×109CFU/g 或5×109CFU/mL。
在一种实施方式中，所述产品为功能性食品、保健品、饲料或药物。
在一种实施方式中，所述药物还含有药学上可接受的载体。
在一种实施方式中，所述药学上可接受的载体包括药物载体或药物辅料。
在一种实施方式中，所述药用辅料包含赋形剂和/或附加剂。
在一种实施方式中，所述药用辅料包含抗黏合剂、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、助滤剂以及释放阻滞剂。
在一种实施方式中，所述药物的剂型包含颗粒剂、胶囊剂、片剂、丸剂或口服液。
本发明的第二个目的是提供治疗慢性胰腺炎的药物，所述药物是含甘油的Akkermansia muciniphila BAA-835菌液。
在一种实施方式中，所述甘油的体积分数为3～30％。
本发明的有益效果为：
本发明提供了Akkermansia muciniphila BAA-835菌株在治疗慢性胰腺炎药物中的新用途，本发明通过实验，验证了Akkermansia muciniphila BAA-835菌株对缓解胰腺萎缩，缓解腺泡细胞损伤及炎症浸润，减轻胰腺纤维化程度，减少促炎细胞因子的释放和巨噬细胞的浸润方面的作用，且经巴氏灭菌的灭活菌制剂比活菌具有更优的效果。本发明提供的 Akkermansia muciniphila BAA-835菌株可作为现有药物的替代物，用于制备治疗慢性胰腺炎的益生菌药物、药物组合物、功能性食品及饲料，拓宽了Akkermansia muciniphilaBAA-835 菌株的应用领域。
附图说明
图1为Akkermansia muciniphila BAA-835应用于慢性胰腺炎小鼠后胰腺萎缩情况。其中， CON表示对照组，CAE表示炎症模型组，CAE+L表示Akkermansia muciniphilaBAA-835活菌处理组，CAE+K表示Akkermansia muciniphila BAA-835经巴氏消毒的灭活菌剂处理组。*： P＜0.05，**：P＜0.01，***：P＜0.001。
图2为Akkermansia muciniphila BAA-835应用于慢性胰腺炎小鼠后胰腺组织的病理变化。*：P＜0.05，**：P＜0.01，***：P＜0.001。
图3为Akkermansia muciniphila BAA-835应用于慢性胰腺炎小鼠后后胰腺的细胞因子和巨噬细胞的mRNA表达情况。*：P＜0.05，**：P＜0.01，***：P＜0.001。
图4为Akkermansia muciniphila BAA-835应用于慢性胰腺炎小鼠胰腺的纤维化程度。*： P＜0.05，**：P＜0.01，***：P＜0.001。
具体实施方式
菌株信息：Akkermansia muciniphila BAA-835菌株购买自美国ATCC公司，产品名称： Akkermansia muciniphila BAA-835。
实施例1 Akkermansia muciniphila菌剂制备
活性菌剂的制备：Akkermansia muciniphila BAA-835被严格厌氧培养在添加2％(m/v) Ⅲ型粘蛋白的脑心浸液培养基中。将对数生长期的菌液，4℃，8000g离心10min，去上清，用无菌生理盐水将菌泥洗涤2次，重悬菌泥于体积分数为30％(v/v)的甘油中，可选地，可于-80℃冰箱保存。
灭活菌剂的制备：Akkermansia muciniphila BAA-835被严格厌氧培养在添加2％(m/v) Ⅲ型粘蛋白的脑心浸液培养基中。将对数生长期的菌液，4℃，8000g离心10min，去上清，用无菌生理盐水将菌泥洗涤2次，重悬菌泥于体积分数为30％(v/v)的甘油中，取菌泥的甘油悬液于70℃加热30min进行巴氏消毒，加热后冻于-80℃冰箱保存。
可选地，使用前将活性菌剂或灭活菌剂用含3％(v/v)甘油的无菌生理盐水稀释至5×109 CFU/mL备用。
实施例2含Akkermansia muciniphila的药物的制备
将实施例1制备的含Akkermansia muciniphila BAA-835活细胞或灭活细胞的菌悬液与要用辅料混合，获得液体制剂；可选地，压制成型，制得片剂；可选地，将液体制剂干燥，获得粉剂；可选地，将粉剂作为填充物制备胶囊剂。
其中，所述药用辅料包含抗黏合剂、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、助滤剂以及释放阻滞剂。
实施例3 Akkermansia muciniphila BAA-835用于治疗慢性胰腺炎
(1)慢性胰腺炎模型的建立：
将8周龄左右的20-23g雌性C57BL/6J小鼠随机分为对照组(CON)，炎症模型组(CAE)， Akkermansia muciniphila BAA-835活菌处理组(CAE+L)，Akkermansiamuciniphila BAA-835 经巴氏消毒的灭活菌剂处理组(CAE+K)，每组8只，提供可控的饲养条件。采用腹腔注射雨蛙素的方式诱导慢性胰腺炎模型。将雨蛙素溶于生理盐水中，每小时注射一针雨蛙素(50 μg/kg体重)，连续注射6针，每周注射三天，连续注射四周。CON组小鼠给予等体积生理盐水。造模期间每天采用灌胃的方式给予CAE+L组每只小鼠含3％甘油的5×109CFU/mL的 Akkermansia muciniphila活菌菌液200μL，CAE+K组小鼠含3％甘油的5×109CFU/mL的 Akkermansia muciniphila巴氏消毒的灭活菌剂200μL。其余两组小鼠灌胃等量3％甘油。最后一针注射完三天后，向小鼠注射致死剂量的戊巴比妥钠并快速收集血液、胰腺等样品。
(2)Akkermansia muciniphila BAA-835处理缓解胰腺萎缩
胰腺腺泡损伤导致的胰腺萎缩是慢性胰腺炎发生时胰腺组织最显著的标志之一，能够反映慢性胰腺炎的严重程度。小鼠处死前进行称重。小鼠处死后，分离新鲜胰腺组织，于分析天平称量。通过比较新鲜胰腺样品重量与体重的比值评估胰腺萎缩程度。结果表示为胰腺重量/体重(％)。如图1，与CON组相比，CAE组胰腺发生明显萎缩，胰腺重量/体重平均下降 0.29％(P<0.001)。而在CAE+L组中小鼠的胰腺重量较CAE组也有着显著上升，胰腺重量/ 体重平均上升0.09％(P<0.05)。同时CAE+K组的胰腺重量/体重较CAE组回升0.13％，表现为更为有效的缓解作用(P<0.01)。Akkermansia muciniphila BAA-835处理对胰腺重量/体重的下降的缓解作用优于20，40mg/kg/天剂量的异甘草素(参考文献为：Isoliquiritigenin ameliorates caerulein-induced chronic pancreatitis byinhibiting the activation of PSCs and pancreatic infiltration of macrophages，2020)。
(3)Akkermansia muciniphila BAA-835处理缓解腺泡细胞损伤及炎症浸润
用H&E染色的方法，将CON组、CAE组、CAE+L、CAE+K组胰腺经固定、脱水、染色、脱蜡、透明和封片等主要过程，观察胰腺组织的组织完整性、胰腺水肿程度和炎症细胞浸润程度。如图2，结果显示，CON组胰腺组织结构密实，无明显裂纹。CAE小鼠胰腺组显观察到腺泡细胞存在空泡和死亡情况，大量炎症细胞浸润，腺泡细胞向导管细胞转化，导管扭曲阻塞等情况，胰腺组织损伤明显。而CAE+L组相比于CAE组胰腺实质率提高12％ (P<0.05)，CAE+K组较CAE组胰腺实质率提高16％(P<0.01)，说明Akkermansia muciniphila BAA-835对小鼠慢性胰腺炎发挥了保护作用。Akkermansia muciniphila BAA-835处理对腺泡细胞损伤的缓解作用优于20mg/kg/天剂量的达沙替尼(参考文献为：Dasatinib ameliorates chronicpancreatitis induced by caerulein via anti-fibrotic and anti-inflammatorymechanism,2019)。
(4)Akkermansia muciniphila BAA-835处理抑制慢性胰腺炎小鼠中促炎细胞因子的释放和巨噬细胞的浸润
采用荧光定量PCR法(qPCR)测定小鼠胰腺中促炎因子TGF-β和MCP-1，巨噬细胞表型指标F4/80及M2型巨噬细胞标记物CD206的mRNA表达相对含量。组织样品通过使用高通量组织研磨机在Trizol中进行破碎，之后使用氯仿等进行抽提，离心后吸取上清，加入等体积的异丙醇进行沉淀RNA，离心后弃上清，用75％乙醇DEPC进行洗涤所得RNA。对得到的RNA进行浓度和纯度的测量后，使用Takara反转录试剂盒将组织样品中的RNA反转到 cDNA。根据mRNA设计的引物在正式实验前需进行qPCR测试其特异性和扩增效率，得到结果后，首先根据熔解曲线判断引物特异性，选择标准为单峰，峰形偏窄，无明显引物二聚体熔解曲线峰。引物验证结果良好后进行正式实验。
使用SYBR Green Mix进行相关基因的扩增检测。扩增程序为:55℃预热30秒；95℃5分钟；接下来循环39次：95℃30秒；58℃30秒；之后进行引物特异性检测，从65℃保持5秒之后每秒上升0.1℃至95℃，观察引物特异性。如通过对胰腺组织中TGF-β和MCP-1的mRNA 水平进行检测。如图3，与CON组相比，CAE组小鼠胰腺中TGF-β和MCP-1的表达显著上调，Akkermansia muciniphila BAA-835活菌处理后下调细胞因子TGF-β(P<0.05)与MCP-1 (P<0.05)，灭活菌剂处理同样显著下调TGF-β(P<0.01)与MCP-1(P<0.05)。对巨噬细胞的标记物F4/80的mRNA水平进行检测，结果显示，胰腺损伤后，机体募集了大量的巨噬细胞到受损的胰腺。同时CAE组小鼠相较于CON组，其胰腺中M2的标记物CD206和基因的相对表达量也明显提高。而Akkermansia muciniphila BAA-835活菌的处理也均明显下调了小鼠胰腺中F4/80(P<0.01)与CD206(P<0.01)的相对表达量，灭活菌液的处理后下调F4/80 (P<0.01)与CD206(P<0.001)。
(5)Akkermansia muciniphila BAA-835处理缓解胰腺纤维化程度
胰腺纤维化被认为是慢性胰腺炎另一个主要的表观特征。纤维化通常被定义为过量的细胞外基质蛋白的累积。在正常情况下，胰腺的结构是由细胞外基质合成和降解间的平衡所维持的，因此，纤维化可以被看作是这种平衡被打破的结果。普遍认为纤维化并不仅仅是慢性损伤的终产物，而是标志着这种情况下在胰腺中发生的活跃、动态和持续的过程。
胰腺的纤维化通常使用马松三色染色法检验。图4，CON组形态正常，无蓝色胶原蛋白区域，CAE组小鼠相较于CON组小鼠，其胰腺组织可以观察到明显的管状复合物及被染成蓝色的胶原蛋白，CAE+L组相比于CAE组纤维化区域，由0.38显著下降至0.28 (P<0.01),CAE+K组较CAE组也明显改善胰腺纤维化程度，纤维化区域由0.38降低至0.32 (P<0.05)。
虽然本发明已以较佳实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可做各种的改动与修饰，因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (13)
1.Akkermansia muciniphila BAA-835在制备缓解慢性胰腺炎的产品中的应用。
2.根据权利要求1所述的应用，其特征在于，所述缓解慢性胰腺炎包括（1）~（4）中的至少一种：
（1）缓解胰腺萎缩症状；
（2）缓解腺泡细胞损伤及炎症细胞浸润；
（3）减少促炎细胞因子TGF-β和MCP-1的释放和巨噬细胞的浸润；
（4）减轻胰腺纤维化程度。
3.根据权利要求1或2所述的应用，其特征在于，所述Akkermansia muciniphila BAA-835是具有生物活性的活细胞或经灭活处理后的失活细胞。
4.根据权利要求1或2所述的应用，其特征在于，所述产品为饲料。
5.根据权利要求3所述的应用，其特征在于，所述产品为饲料。
6.根据权利要求1或5所述的应用，其特征在于，所述产品中AkkermansiamuciniphilaBAA-835的数量≥5×109 CFU/g或5×109 CFU/mL。
7.根据权利要求4所述的应用，其特征在于，所述产品中AkkermansiamuciniphilaBAA-835的数量≥5×109 CFU/g或5×109 CFU/mL。
8.根据权利要求1、2、5任一所述的应用，其特征在于，所述产品是Akkermansiamuciniphila BAA-835和含细胞保护剂的组合物；所述细胞保护剂为甘油。
9.根据权利要求6所述的应用，其特征在于，所述产品是Akkermansia muciniphilaBAA-835和含细胞保护剂的组合物；所述细胞保护剂为甘油。
10.Akkermansia muciniphila BAA-835在制备治疗慢性胰腺炎的药物中的应用，其特征在于，所述药物含有Akkermansia muciniphila BAA-835和药学上可接受的载体。
11.根据权利要求10所述的应用，其特征在于，所述药学上可接受的载体包括药物载体或药物辅料。
12.根据权利要求11所述的应用，其特征在于，所述药用辅料包含赋形剂和/或附加剂。
13.根据权利要求10~12任一所述的应用，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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| Regulation of Gut Microbiota and Metabolic Endotoxemia with Dietary Factors;Nobuo Fuke，et al;《Nutrients》;20190723;第2277卷(第11期);第1-38页 * |
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