CN118021851A - 双歧杆菌在制备用于预防、治疗或辅助治疗矽肺病的药品或食品中的应用 - Google Patents
双歧杆菌在制备用于预防、治疗或辅助治疗矽肺病的药品或食品中的应用 Download PDFInfo
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Abstract
本发明属于微生物技术领域,具体涉及一种双歧杆菌在制备用于预防、治疗或辅助治疗矽肺病的药品或食品中的应用。本发明通过实验证明长双歧杆菌BB536,可以调节肠道菌群结构,增加乳杆菌属等益生菌的相对丰度,同时产生乙酸,通过血液循环将信号传到肺,降低促炎细胞因子和纤维化标志物的水平,通过AMPK/Sirt1信号通路发挥作用,从而缓解矽肺损伤。
Description
技术领域
本发明属于微生物技术领域,具体涉及一种双歧杆菌在制备用于预防、治疗或辅助治疗矽肺病的药品或食品中的应用。
背景技术
矽肺是由于长期吸入SiO2粉尘引起的以不可逆转的进行性肺纤维化为主的职业性疾病。矽肺早期表现为肺间质性炎症,晚期表现为进行性肺纤维化,患者表现为呼吸和循环功能障碍。矽肺患者机体处于高代谢、炎症反应等高耗状态,常伴有不同程度的营养不良,影响临床预后及生活质量。
矽肺病目前无法被治愈,只能通过肺移植或者服用药物和康复治疗等综合治疗方法缓解症状。矽肺患者一旦确诊往往需要长期用药,由于个体差异较大,用药方法和治疗效果因人而异,而且长期服用药物还会出现胃肠道反应和肝肾毒性等副作用。肺移植可以提高患者生存质量,但是费用昂贵技术复杂,移植后生存率不确定,在临床中难以实施。
肠道菌群是肠道内环境稳定的重要保障因素,它们能通过产生代谢物等方式影响远端器官,由于肠道与肺部还处于共同的黏膜免疫系统中,因此产生了“肠-肺轴”的概念。已有流行病学调查和实验证据显示,肠道菌群的改变可能促进了以全身性炎症反应为主的免疫反应,并可诱导肠屏障功能受损。肠道免疫反应的变化可加重肺部炎性和纤维化,肺部疾病如哮喘和慢性阻塞性肺病,通常与胃肠道疾病如炎症性肠病等一起发生。肺康复联合营养干预能够改善矽肺患者的呼吸功能及基础肺功能,缓解呼吸困难症状,增强呼吸肌力量及运动耐力,促进病情康复,进而改善患者的生活质量。
双歧杆菌是一种生理性的益生菌,它能够改善肠道菌群结构,维持肠道屏障,提高肠道免疫力,刺激免疫球蛋白分泌,具有良好的抗炎、抗氧化和免疫调节作用。同时,双歧杆菌分泌的短链脂肪酸等代谢物也有利于维持和调节肺组织免疫防御,提高机体抵抗感染的能力。世界胃肠道病学组织(WGO)已经公布了一部关于益生菌和益生元的临床应用指南,包括在中国、美国和欧盟等大多数国家,已经批准双歧杆菌可以作为药物用于临床上某些肠道疾病的治疗。大量动物实验支持双歧杆菌在呼吸系统疾病中的应用。例如乳双歧杆菌HY8002通过减轻炎性细胞浸润和ROS含量缓解PM2.5诱导的小鼠肺组织损伤,婴儿双歧杆菌通过上调产生IL-10的B细胞和树突状细胞来对抗小鼠鼻粘膜炎症;以上结果为双歧杆菌作为药物应用于肺部疾病的临床治疗提供了一定的实验数据支持。
因此,开发一种安全、可长期使用的用于预防、治疗或辅助治疗矽肺病的药品或食品,对于矽肺或其他类型尘肺病的辅助治疗具有重要的意义。
发明内容
针对上述问题,本发明提供一种双歧杆菌在制备用于预防、治疗或辅助治疗矽肺病的药品或食品中的应用。本发明提供的双歧杆菌,能够调节肠道菌群结构,缓解矽肺损伤,对于治疗矽肺病具有重要意义。
为了实现上述发明目的,本发明的技术方案如下:
本发明第一方面在于提供一种双歧杆菌在制备用于预防、治疗或辅助治疗矽肺病的药品或食品中的应用。
进一步地,所述双歧杆菌为长双歧杆菌。
进一步地,所述双歧杆菌单独使用或者与其他菌种联合应用。
进一步地,所述其他菌种为乳杆菌或梭状芽胞杆菌中的一种或两种。
更进一步地,所述长双歧杆菌为长双歧杆菌BB536。长双歧杆菌BB536是肠道原籍菌,严格厌氧,活菌口服后能在人体肠道定植,在代谢过程中能在结肠中发酵糖类,产生乙酸和乳酸,使肠道内pH下降,形成化学屏障,抑制肠道有害菌的生长繁殖,修复肠粘膜损伤有修复作用。它还能产生消化酶,有助于食物的消化吸收,增强肠营养。该菌株已经通过临床和动物实验证明,被我国列入可用于婴幼儿食品名单,未发现由任何毒性反应和副作用。
所述矽肺病是由于吸入二氧化硅颗粒引起的纤维化和/或肺部炎症反应。
本发明第二方面在于提供一种用于预防、治疗或辅助治疗矽肺病的药品,所述药品中包括双歧杆菌,或者双歧杆菌与乳杆菌或梭状芽胞杆菌中的一种或两种;进一步地,所述双歧杆菌为长双歧杆菌BB536。
所述药品中双歧杆菌的活菌数不低于5×1010CFU。
进一步地,所述药品按照一定的制剂工艺,加入常规的赋形剂、调味剂、崩解剂、防腐剂、润滑剂、湿润剂、黏合剂、增稠剂、增溶剂等药物辅料中的一种或几种,制成任何一种适合于临床上使用的剂型,如粉末剂、混悬剂、糊剂、软膏剂、片剂、乳剂、口服液、注射剂、胶囊剂、颗粒剂或滴丸等;例如保健药品,肠内营养制剂等,但不限定于此,在此不过多赘述。
上述药品建议饭后0.5h后服用以降低胃酸的干扰,服用后1h内不要服用强酸、强碱和水果,胃药间隔1h,抗生素、感冒消炎药等杀菌药间隔3h;本发明中的药品在临床上的用量,因患者年龄、体重、症状、用药目的所决定的用药方式和方法、治疗效果及用药时间等因素而不同,具体的用量应该由医师来决定。
本发明第三方面在于提供一种用于预防、治疗或辅助治疗矽肺病的食品,所述食品中包括双歧杆菌,或者双歧杆菌与乳杆菌或梭状芽胞杆菌中的一种或两种;进一步地,所述双歧杆菌为长双歧杆菌BB536。
所述食品可以为面点类食品、乳制品类食品、肉食品类食品、调味品类食品、饮品或保健食品等,但不限定于此,在此不过多赘述。
所述食品中双歧杆菌的活菌数不低于5×1010CFU。
与现有技术相比,本发明的有益效果是:
本发明利用双歧杆菌,改善肠道菌群结构,调节循环短链脂肪酸水平,增加乳杆菌属等益生菌的相对丰度,产生大量的乙酸,并通过血液循环将信号传到肺,降低促炎细胞因子和纤维化标志物的水平,通过AMPK/Sirt1信号通路发挥作用,进而缓解矽肺损伤;本发明提供的双歧杆菌制备出的药品或食品安全、温和、无毒,可以有效减少因药物长期使用而产生的副作用,给药方式灵活,易于大规模推广生产。
附图说明
图1为对照组、模型组、长双歧杆菌BB536组矽肺大鼠的肺部炎性细胞浸润和胶原纤维沉积图;
图2为对照组、模型组、长双歧杆菌BB536组矽肺大鼠的肺部IL-1β、IL-6和TNF-α水平;
图3为对照组、模型组、长双歧杆菌BB536组矽肺大鼠的肺部Collagen III、Vimentin和α-SMA水平;
图4为对照组、模型组、乙酸钠组矽肺大鼠的肺部IL-1β、IL-6和TNF-α水平;
图5为对照组、模型组、乙酸钠组矽肺大鼠的肺部Collagen III、Vimentin和α-SMA水平;
图6为对照组、模型组、乙酸钠组、乙酸钠联合Sirt1抑制剂EX527组矽肺大鼠的肺部炎性细胞浸润和胶原纤维沉积图;
图7为对照组、模型组、乙酸钠组、乙酸钠联合Sirt1抑制剂EX527组矽肺大鼠的肺部IL-1β、IL-6和TNF-α水平;
图8为对照组、模型组、乙酸钠组、乙酸钠联合Sirt1抑制剂EX527组矽肺大鼠的肺部Collagen III、Vimentin和α-SMA水平;
图9为对照组、模型组、乙酸钠组、乙酸钠联合Sirt1抑制剂EX527组矽肺大鼠的肺部AMPK和Sirt1水平。
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施例,进一步阐明本发明。下述实施例中,若无特殊说明,所用的操作方法均为常规操作方法,所用设备均为常规设备,各个实施例所用设备材料均相同。
在本发明的具体实施方式中,所述长双歧杆菌BB536粉剂是来自日本森永乳业的膳食营养补充剂(商品编号:10025721204933)。
实施例1建模及检测
1、模型建立与分组
SPF级Wistar雄性大鼠150只,6-7周龄,适应环境1周后,随机分为对照组(Control)、模型组(Model)、长双歧杆菌BB536组(BB536)、乙酸钠组(NaAc)和乙酸钠联合Sirt1抑制剂EX527组(NA-EX)。模型组、BB536组、NaAc组和NA-EX组大鼠在无菌条件下以非暴露式气管滴注法一次性给予SiO2悬浮液(将微米级SiO2用生理盐水配制成SiO2混悬液,浓度为50mg/mL)建立矽肺模型,对照组大鼠以同样的方法给予等量的生理盐水。长双歧杆菌BB536粉剂和乙酸钠粉剂均使用生理盐水溶解,Sirt1抑制剂EX527溶解在含有10%的DMSO的生理盐水中,现用现配。
在矽肺模型建立后第二天开始干预,BB536组大鼠灌胃长双歧杆菌BB536溶液(300mg/kg),NaAc和NA-EX组大鼠灌胃乙酸钠溶液(200mg/kg),对照组和模型组大鼠给予等量的生理盐水,1次/日;NA-EX组大鼠接受EX527腹腔注射(5mg/kg),2次/周,系数均不超过1mL/200g。首次干预后第14、28和56天异氟烷麻醉处死大鼠,收集肺组织、盲肠内容物和血清。
2、肺组织病理学染色
分离大鼠右上肺,立即浸泡在4%多聚甲醛中,室温保存24h。脱水后,将肺组织包埋在石蜡中,以4μm的厚度切片,然后进行HE和Masson染色。在光学显微镜下观察病理肺组织变化。
3、肺组织细胞因子测定
称重肺组织,用PBS洗涤后研磨,然后用PBS和1mM PMSF匀浆。反复冻融破坏细胞膜后,将匀浆在4℃、5000g离心7min,然后收集上清液,在-80℃下保存。ELISA试剂盒检测IL-1β、IL-6和TNF-α浓度,酶标仪测量450nm处的吸光度值。
4、肺组织蛋白相对表达水平测定
在1mM PMSF的RIPA中裂解和匀浆肺组织,然后将匀浆在4℃、15000g下离心15min,收集上清液。通过BCA蛋白浓度测定试剂盒检测蛋白浓度,将提取的蛋白质在100℃的金属浴中变性10分钟。用10%SDS-PAGE分离蛋白质并电转印到PVDF膜上,牛奶封闭1h。Westernblot检测Collagen III、Vimentin、α-SMA、Sirt1、AMPK和p-AMPK的相对表达水平,ImageJ软件分析灰度值。
5、肠道菌群结构分析
无菌条件下收集大鼠的盲肠内容物并保存于-80℃。通过CTAB/SDS方法提取总基因组DNA,通过16S rRNA检测肠道菌群结构,R软件用于分析和可视化。
6、循环短链脂肪酸含量检测
收集心尖血,室温自然凝固30min,4℃、2000g离心15min分离血清。将100μL血清与含有20%磷酸的等体积水和500μL的50μg/mL的4-甲基戊酸混合均匀,然后以14000g离心20min,收集1μL上清液进行GC-MS分析,检测血清SCFAs的含量。
实施例2结果
1、长双歧杆菌BB536降低了肺系数
长双歧杆菌BB536降低了大鼠的肺系数,见表1;长双歧杆菌BB536减轻了矽肺大鼠肺泡壁损伤和胶原纤维沉积(见图1);长双歧杆菌BB536降低了肺部炎症标志物(IL-1β、IL-6和TNF-α)(见图2)和纤维化标志物(Collagen III、Vimentin和α-SMA)的水平(见图3)。
表1各组大鼠的肺系数变化
注:数值表示为MEAN±SD(n=6)。同模型组相比,*P<0.05,**P<0.01,***P<0.001。
2、长双歧杆菌BB536改善了肠道菌群结构
长双歧杆菌BB536改变了矽肺大鼠的肠道菌群结构,增加了梭状芽胞杆菌和乳杆菌等产生SCFAs的益生菌的相对丰度,降低了瘤胃球菌的水平,见表2。
表2各组大鼠盲肠内容物菌群结构变化
3、长双歧杆菌BB536增加了循环乙酸水平
我们重点关注乙酸的水平,因为它是双歧杆菌属的主要产物,并且在体循环中含量较高,见表3。长双歧杆菌BB536在第14和56天提高了矽肺大鼠血清的乙酸水平,短链脂肪酸含量变化见表4。
表3各组大鼠血清乙酸含量变化
注:数值表示为MEAN±SD(n=6)。同模型组相比,*P<0.05,**P<0.01,***P<0.001。
表4各组大鼠血清短链脂肪酸含量变化
注:数值表示为MEAN±SD(n=6)。同模型组相比,*P<0.05,**P<0.01,***P<0.001。
4、乙酸钠NaAc减轻了矽肺损伤
乙酸具有抗炎和抗纤维化的潜力,在体内主要以盐的形式存在。乙酸钠降低了大鼠的肺系数(见表1),显著降低了矽肺大鼠肺部促炎细胞因子(IL-1β、IL-6和TNF-α)(见图4)和纤维化标志物(Collagen III、Vimentin和α-SMA)的相对表达水平(见图5)。
5、Sirt1的抑制削弱了乙酸钠对矽肺的保护作用
当Sirt1被EX527抑制时,乙酸钠对矽肺大鼠肺泡结构的保护作用减弱(见图6)。同乙酸钠组相比,NA-EX组大鼠肺部的促炎细胞因子(IL-1β、IL-6和TNF-α)(见图7)和纤维化标志物(Collagen III、Vimentin和α-SMA)的相对表达水平更高(见图8)。
6、乙酸钠的保护作用依赖于AMPK/Sirt1信号通路的激活
乙酸盐显著上调了矽肺大鼠肺部Sirt1的表达水平,并提高了AMPK的磷酸化程度,但当Sirt1被EX527抑制时,这种作用被削弱(见图9)。
综上所述,长双歧杆菌BB536能够降低肺部促炎细胞因子和纤维化标志物的水平,有效改善矽肺。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.双歧杆菌在制备用于预防、治疗或辅助治疗矽肺病的药品或食品中的应用,其特征在于,所述双歧杆菌为长双歧杆菌。
2.根据权利要求1所述的应用,其特征在于,所述双歧杆菌单独使用或者与其他菌种联合应用。
3.根据权利要求2所述的应用,其特征在于,所述其他菌种为乳杆菌或梭状芽胞杆菌中的一种或两种。
4.根据权利要求1-3任一项所述的应用,其特征在于,所述长双歧杆菌为长双歧杆菌BB536。
5.根据权利要求1所述的应用,其特征在于,所述矽肺病是由于吸入二氧化硅颗粒引起的纤维化和/或肺部炎症反应。
6.一种用于预防、治疗或辅助治疗矽肺病的药品,其特征在于,所述药品中包括双歧杆菌,或者双歧杆菌与乳杆菌或梭状芽胞杆菌中的一种或两种,其中,所述双歧杆菌为长双歧杆菌BB536。
7.根据权利要求6所述的用于预防、治疗或辅助治疗矽肺病的药品,其特征在于,所述药品的剂型为粉末剂、混悬剂、糊剂、软膏剂、片剂、乳剂、口服液、注射剂、胶囊剂、颗粒剂或滴丸。
8.根据权利要求6所述的用于预防、治疗或辅助治疗矽肺病的药品,其特征在于,所述药品中双歧杆菌的活菌数不低于5×1010CFU。
9.一种用于预防、治疗或辅助治疗矽肺病的食品,其特征在于,所述食品中包括双歧杆菌,或者双歧杆菌与乳杆菌或梭状芽胞杆菌中的一种或两种;其中,所述双歧杆菌为长双歧杆菌BB536。
10.根据权利要求9所述的用于预防、治疗或辅助治疗矽肺病的食品,其特征在于,所述食品中双歧杆菌的活菌数不低于5×1010CFU。
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