CN116355815A - 一株降解精氨酸的地衣芽孢杆菌及其应用 - Google Patents
一株降解精氨酸的地衣芽孢杆菌及其应用 Download PDFInfo
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- CN116355815A CN116355815A CN202310561574.5A CN202310561574A CN116355815A CN 116355815 A CN116355815 A CN 116355815A CN 202310561574 A CN202310561574 A CN 202310561574A CN 116355815 A CN116355815 A CN 116355815A
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- bacillus licheniformis
- pharmaceutical product
- arginine
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Abstract
本发明公开了一株降解精氨酸的地衣芽孢杆菌及其应用。本发明提供的地衣芽孢杆菌已于2023年4月14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，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.27112。本发明提供的地衣芽孢杆菌可以显著降低精氨酸水平，具有缓解高精氨酸血症的治疗潜力，可以用于制备治疗和/或预防高精氨酸血症的药品或保健品。
Description
技术领域
本发明涉及一株降解精氨酸的地衣芽孢杆菌及其应用，属于微生物技术领域。
背景技术
精氨酸（Arg）是一种营养半必需的蛋白原性氨基酸，参与多种途径和多种生理过程。精氨酸在体内的来源主要有3种途径：食物中获取、内源途径合成以及自身蛋白转化合成。高精氨酸血症是尿素循环中精氨酸酶-1缺陷所导致的以血液中精氨酸异常升高为主要临床表现的常染色体隐性遗传疾病。
高精氨酸血症目前来说一般较难根治，但早发现早治疗，是可以有效控制其病情发展的。如果由于临床病症未及时发现，在诊断时就可能存在严重不可逆的神经系统损害，使得病情发生进行性加重，严重时危及生命。高精氨酸血症通过饮食与药物治疗后，相关症状可以得到有效控制和改善。饮食治疗为关键治疗方式，由于患者精氨酸酶的缺乏，日常可以通过限制精氨酸和蛋白质的摄入量为关键治疗方式，以糖类和脂肪的摄入来保证机体能量供应，所以一定要做到低精氨酸饮食，从而减少氮的摄入和分解代谢。通过饮食治疗，使血精氨酸维持在正常水平，减缓和避免疾病的进行性发展，以免患儿出现严重不可逆的神经系统症状。除饮食治疗外，若发生急性高氨血症，可用透析治疗，迅速降低血氨浓度；出现抽搐时，可给予抗癫痫药，如常见药物苯巴比妥、卡马西平等。也可考虑静脉或口服氮清除剂，如苯甲酸钠和苯丁酸钠进行脱氮治疗，促进内源性氨从尿液中排出。其他肝移植、干细胞移植、基因疗法等尚处在研究阶段。
肠道菌群组分和功能在许多代谢类疾病的发生发展中起重要作用，已逐渐成为疾病防治的新靶点，开发出了一系列益生菌。益生菌从实验室研究阶段到临床应用经历了多年的开发与探索，益生菌的种属类别、作用机制逐渐清晰，临床应用越发广泛。由于高精氨酸血症的发病机制尚未完全明了，临床治疗虽取得了一定的进展，但仍处于控制或缓解症状的阶段，尚无共识性的安全有效的治疗或治愈方法。因此，本领域迫切需要开发一种有效的新的，无毒副作用的，用于预防和治疗高精氨酸血症及其相关疾病的药物。
发明内容
为解决上述技术问题，本发明提供一株降解精氨酸的地衣芽孢杆菌及其应用，该地衣芽孢杆菌可以显著降低精氨酸水平，具有缓解高精氨酸血症的治疗潜力，可以用于制备治疗和/或预防高精氨酸血症的药品或保健品。
本发明的第一个目的是提供一株降解精氨酸的地衣芽孢杆菌，所述地衣芽孢杆菌，分类学命名为地衣芽孢杆菌Bacillus licheniformis，已于2023年4月14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，保藏编号为CGMCC No.27112，保藏地址为北京市朝阳区北辰西路1号院3号。
本发明的第二个目的是提供一种包含所述地衣芽孢杆菌的菌剂。
进一步地，所述菌剂通过如下方法制备：
将所述地衣芽孢杆菌菌种接种至培养基中培养，培养后收集菌体，将收集的菌体制备成所述菌剂。
进一步地，所述菌剂为液态菌剂或固态菌剂。
本发明的第三个目的是提供所述地衣芽孢杆菌或所述菌剂在制备治疗和/或预防高精氨酸血症的药品或保健品中的应用。
本发明的第四个目的是提供一种治疗和/或预防高精氨酸血症的药品，所述药品中包含所述地衣芽孢杆菌或所述菌剂。
进一步地，所述药品在使用时，按照所述地衣芽孢杆菌浓度为1×106~1×109CFU/g给药。
进一步地，所述药品中包括赋形剂、药品允许的媒介和载体。
进一步地，所述药品中还包括润滑剂、润湿剂、乳化剂、悬乳液稳定剂、防腐剂、甜味剂、香料中的一种或多种。
进一步地，所述药品的剂型为肠衣制剂。
本发明的有益效果是：
本发明提供的地衣芽孢杆菌已于2023年4月14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，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CGMCCNo.27112。本发明提供的地衣芽孢杆菌可以显著降低精氨酸水平，具有缓解高精氨酸血症的治疗潜力，可以用于制备治疗和/或预防高精氨酸血症的药品或保健品。
生物材料保藏
地衣芽孢杆菌，分类学命名为地衣芽孢杆菌Bacillus licheniformis，已于2023年4月14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，保藏编号为CGMCCNo.27112，保藏地址为北京市朝阳区北辰西路1号院3号。
附图说明
图1为地衣芽孢杆菌（Bacillus licheniformis）以Arg为唯一碳源的生长情况；
图2为坂口反应测定Arg含量标准曲线；
图3为厌氧肠液反应体系下芽孢杆菌对Arg的降解率；
图4为营养物质对于地衣芽孢杆菌（Bacillus licheniformis）降解Arg的影响；
图5为外源性13C-Arg精氨酸在小鼠体内代谢情况；
图6为内源性Arg精氨酸在小鼠体内代谢情况。
具体实施方式
下面结合具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
发明人经过广泛而深入的研究和实验，筛选得到一株具有预防和治疗高精氨酸血症的潜在治疗作用的地衣芽孢杆菌（Bacillus licheniformis）。对上述地衣芽孢杆菌（Bacillus licheniformis）纯培养菌种进行16S rRNA测序鉴定，与NCBI数据库Blast比对后，鉴定确认为Bacillus licheniformis。对应中文名称为地衣芽孢杆菌，该菌株已于2023年4月14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，保藏地址为北京市朝阳区北辰西路1号院3号，该菌株保藏编号为CGMCC No.27112，菌株命名为USS-BLI-23001。
首先经过一系列的体外实验表明，所述地衣芽孢杆菌（Bacillus licheniformis）与芽孢杆菌属的其他菌种相比，具有突出的精氨酸降解代谢能力。
其次，将含有地衣芽孢杆菌（Bacillus licheniformis）的活性菌剂饲喂实验对象C57BL/6J小鼠，小鼠通过灌胃13C-L-Arg区分食源性和内源性氨基酸。发现该菌剂能够有效降低外源性13C-L-Arg在小鼠体内的Cmax值，具备治疗、缓解高精氨酸血症的潜力。
本发明还提供了所述地衣芽孢杆菌（Bacillus licheniformis）在治疗高精氨酸血症等相关疾病方面的用途。
本发明菌剂可以片剂、针剂或胶囊的任一种形式给药，所述药品制剂包括赋形剂、药品允许的媒介或载体，这些物质可根据给药途径进行选择。本发明中的药品制剂还包含辅助的组分。
其中，乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、淀粉、阿拉伯胶、磷酸钙、 藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮(PVP)、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁或矿物油等都可用作本发明中药品的载体、赋形剂或稀释剂等。
此外，本发明的药品菌剂进一步包括润滑剂、润湿剂、乳化剂、悬乳液稳定剂、防腐剂、甜味剂和香料等。本发明的药品菌剂可通过多种公知的方法以肠衣制剂生产，以便于药品组合物的活性成分即微生物能顺利通过胃而不被胃酸所破坏。
本发明的药品制剂可制成肠衣片供口服使用。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1：以精氨酸为唯一碳源进行生长测定分析
实验以精氨酸（Arg）为唯一碳源对地衣芽孢杆菌（Bacillus licheniformis）进行生长情况测定。
将上述地衣芽孢杆菌（Bacillus licheniformis）菌株接种于液体LB培养基（胰蛋白胨 10g/L；酵母提取物 5g/L；氯化钠 10g/L）中，37℃有氧发酵培养16h后收集菌体，用灭菌的 0.9 % NaCl 溶液清洗菌体2次后加入灭菌的蒸馏水，重悬后置于 37℃的恒温培养箱中静置培养 48 h，得到饥饿培养后的菌悬液。精氨酸母液采用 0.22 µm 水系滤膜过滤除菌后单独加入培养基中。将氮源基础培养基，121℃高压灭菌20min，冷却后，加入精氨酸母液，使培养基中精氨酸浓度达到5g/L，此培养基为精氨酸代谢筛选培养基。所述氮源基础培养基成分为Na2HPO4 33.90 g/L，KH2PO4 15.00 g/L，NaCl 2.50 g/L，NH4Cl 5.00 g/L。调整菌株菌悬液的 OD600=1.0±0.1 后，以接种量为1%的比例接种到100mL的液体精氨酸代谢筛选培养基中。37℃摇床培养，在菌株培养的间隔时间取样，用紫外分光光度计测定菌株的OD600值，记录菌株的生长情况。其中上述地衣芽孢杆菌（Bacillus licheniformis）在以精氨酸为唯一碳源的培养基中生长情况良好，绘制菌株的生长曲线如图1所示。
实施例2：地衣芽孢杆菌（Bacillus licheniformis）的基因组分析和体外代谢精氨酸功能解析
被测菌株为地衣芽孢杆菌（Bacillus licheniformis）USS-BLI-23001，(简写：BLI)，对BLI进行基因组分析，发现菌株具有代谢精氨酸的相关功能基因arcA，speA，arcR等。
检测方法
实验建立了坂口反应（Sakaguchi test）定量检测Arg的方法。坂口试验是检测单取代基胍的特征性试验，广泛用于精氨酸的分析与测定的一种方法。实验原理是利用精氨酸在碱性溶液中与次氯酸钠和α-萘酚作用产生红色的产物。通过分光光度法测定不同浓度的Arg的紫外吸收，建立标准曲线，用于分析反应体系中剩余的Arg含量。坂口反应各体系浓度体积如表1所示。
表1 坂口反应测试Arg含量各体系组分
坂口反应操作如下：向2 mL一定稀释倍数的待检测样品中加入400 µL NaOH和200µL α-萘酚，充分振荡混匀，加入30 µL NaClO，充分振荡混匀，室温反应1min，加入400 µL尿素中止反应。振荡混匀后每个样品取200 µL用于测定，用酶标仪（杭州奥盛FlexA-200）在495nm下检测吸光值。
精氨酸（Arg）标准曲线的绘制
Arg标准溶液浓度梯度为0.01 g/L；0.025 g/L；0.035 g/L；0.05 g/L；0.075 g/L，坂口反应测试其在495nm下的吸光值，以OD495和Arg浓度做标准曲线，标准曲线如图2。
实验测试芽孢杆菌属不同种菌株对于Arg的体外降解效率：
外来菌株除经过胃消化后需经过小肠的消化转运才能到达它们的目的地发挥作用。因此，本研究反应体系为人工肠液，同步对菌株的肠液耐受能力进行测定分析。实验所用的人工小肠液为北京酷来搏科技有限公司(Coolaber) 的SL6610 人工小肠液（除菌，含酶）。试剂参照中国药典表述，主要由磷酸二氢钾、胰酶等组成，经无菌处理。
实验所用菌株为：地衣芽孢杆菌（Bacillus licheniformis）为本专利保藏菌株，保藏编号为CGMCC No. 27112、枯草芽孢杆菌（Bacillus subtilis）购自中国普通微生物菌种保藏管理中心，菌株编号为CGMCC No. 1.9086、蜡样芽孢杆菌（Bacillus cereus）购自中国普通微生物菌种保藏管理中心，菌株编号为CGMCC No. 1.9067、解淀粉芽孢杆菌（Bacillus amyloliquefaciens）购自中国普通微生物菌种保藏管理中心，菌株编号为CGMCC No. 1.10901以及凝结芽孢杆菌（Bacillus coagulans）购自中国普通微生物菌种保藏管理中心，菌株编号为CGMCC No. 1.10。
所用培养基为LB培养基（胰蛋白胨 10g/L；酵母提取物 5g/L；氯化钠 10g/L），37℃发酵培养16h后收集菌体，用无菌生理盐水清洗重悬。采用紫外分光光度计测定菌液的OD600（本实验中的菌浓OD600均采用紫外分光光度计（尤尼柯UV-2365）测定，后文不再重复说明），调整各菌株的菌浓为OD600=2.0，对应菌量为109CFU/ml。反应体系为人工肠液，向反应体系中添加Arg，使反应体系的Arg浓度为0.2g/L (1.1mM)，37℃无氧条件下静置反应，在1h、2h反应时间取样，测定反应体系中剩余的Arg含量，计算菌株对Arg的降解率。实验结果如图3所示。
实验测试不同营养物质对于地衣芽孢杆菌（Bacillus licheniformis）降解Arg的体外抑制作用：
材料：葡萄糖（货号：2106011）购自西陇科学股份有限公司，胰蛋白胨（货号：3256061）购自OXOID，酪蛋白水解物（货号：A603080-0100）购自上海生工Sangon公司。
方法：菌株通过口服进入人体，在人体肠道发挥作用，由于人体肠道内营养成分复杂，可能会影响菌株对于Arg的降解。为了验证复杂营养成分是否会抑制菌株降解Arg，实验设计在原有Arg反应体系中添加葡萄糖（G）、胰蛋白胨（Typ）和酪蛋白水解物（Ltm）对比测定Arg的降解情况，反应体系的Arg浓度设定为0.2 g/L，G、Typ和Ltm的添加浓度为5g/L。反应体系菌浓调整为OD600=2.0，37℃无氧静置反应，反应时间为1h。实验结果如图4所示。
实施例3：动物实验验证
材料：
被测菌株为：地衣芽孢杆菌（Bacillus licheniformis）USS-BLI-23001，(简写：BLI)。
灌胃BLI菌剂浓度为2×1010CFU/ml，灌胃BLI菌剂为冻存菌液，菌剂buffer (简写：BLI-f)为：15%甘油，KH2PO4，K2HPO4, 调节pH=7.5。灌胃前将BLI冻存菌液37℃水浴解冻，并充分混悬。
C57BL/6J小鼠购自北京维通利华实验动物有限公司，温度20-26℃，恒湿 40-70％，光照12小时(07:00-19:00)，隔音，自由摄食、饮水，适应环境一周后进行实验。
稳定性同位素标记13C-Arg精氨酸（货号MBBB4331V）购自Sigma公司。
方法：
雌性C57BL/6J小鼠6-8周，体重18-20克，共24只，分为3组进行实验。
(1)空白组：雌性C57BL/6J小鼠6-8周，体重18-20克，8只，13C-Arg灌胃量10µl/g，灌胃剂量为15mpk；
(2)实验组：雌性C57BL/6J小鼠6-8周，体重18-20克，8只，13C-Arg灌胃量5µl/g，灌胃剂量为15mpk；BLI灌胃量为5µl/g，先灌胃BLI菌剂后灌胃13C-Arg。
(3)对照组：雌性C57BL/6J小鼠6-8周，体重18-20克，8只，13C-Arg灌胃量5µl/g，灌胃剂量为15mpk；BLI-f灌胃量为5µl/g，先灌胃BLI-f后灌胃13C-Arg。
菌剂和13C-Arg灌胃完成后，5min，10min，30min，60min取血样，采用LC-MS的方法检测血液中外源性13C-Arg和内源性Arg含量，末次取样后麻醉处死小鼠。
结果：与空白组和对照组比较，BLI菌株可以显著降低血液中外源性13C-Arg的含量，可对13C-Arg的Cmax降低66.3%，结果如图5所示，对内源性Arg无显著影响，结果如图6所示。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换，均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。
Claims (10)
1.一株降解精氨酸的地衣芽孢杆菌，其特征在于，所述地衣芽孢杆菌已于2023年4月14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，保藏编号为CGMCC No.27112，保藏地址为北京市朝阳区北辰西路1号院3号。
2.一种包含权利要求1所述地衣芽孢杆菌的菌剂。
3.根据权利要求2所述菌剂，其特征在于，所述菌剂通过如下方法制备：
将所述地衣芽孢杆菌菌种接种至培养基中培养，培养后收集菌体，将收集的菌体制备成所述菌剂。
4.根据权利要求2所述菌剂，其特征在于，所述菌剂为液态菌剂或固态菌剂。
5.权利要求1所述地衣芽孢杆菌或权利要求2~4任一项所述菌剂在制备治疗和/或预防高精氨酸血症的药品或保健品中的应用。
6.一种治疗和/或预防高精氨酸血症的药品，其特征在于，所述药品中包含权利要求1所述地衣芽孢杆菌或权利要求2~4任一项所述菌剂。
7.根据权利要求6所述药品，其特征在于，所述药品中所述地衣芽孢杆菌浓度为1×106~1×109CFU/g。
8.根据权利要求6所述药品，其特征在于，所述药品中包括赋形剂、药品允许的媒介或载体。
9.根据权利要求8所述药品，其特征在于，所述药品中还包括润滑剂、润湿剂、乳化剂、悬乳液稳定剂、防腐剂、甜味剂、香料中的一种或多种。
10.根据权利要求6所述药品，其特征在于，所述药品的剂型为肠衣制剂。
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| CN117815160A (zh) * | 2023-11-08 | 2024-04-05 | 首都医科大学附属北京潞河医院 | 一种黄芪散饮片的制备及其在治疗慢性肾功能不全中的应用 |
| CN117815160B (zh) * | 2023-11-08 | 2024-05-28 | 首都医科大学附属北京潞河医院 | 一种黄芪散饮片的制备及其在治疗慢性肾功能不全中的应用 |
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