CN110393728A - 乳酸杆菌属、其医药组合物及可食用组合物于治疗、预防或改善骨质疾病的用途 - Google Patents
乳酸杆菌属、其医药组合物及可食用组合物于治疗、预防或改善骨质疾病的用途 Download PDFInfo
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Abstract
本发明公开一种乳酸杆菌属、其医药组合物及可食用组合物在用于治疗、预防或改善骨质疾病中的用途。前述乳酸杆菌属及其组合物可提高个体的血液钙质浓度、骨小梁骨体积与组织体积的比率、骨小梁厚度、骨小梁数目以及骨矿质密度，且可降低骨小梁分离度。
Description
技术领域
本发明关于一种乳酸杆菌属的用途，尤其是将乳酸杆菌属用于制备治疗、预防或改善骨质疾病的医药组合物及可食用组合物的用途。
背景技术
现今各国人口已逐渐迈入高龄化，与年龄相关的疾病日愈增加，也受到各国政府及民间的重视。其中一个与年龄高度相关的疾病为骨质疾病，例如骨质疏松症、骨缺损、骨折疾病等。
人体骨骼中主要由成骨细胞与蚀骨细胞进行骨质重塑作用，其中，成骨细胞为单核细胞，用以形成骨基质，而蚀骨细胞为多核巨噬细胞，用以吸收骨基质。一般而言，30～35岁左右的成年人的骨质密度达到颠峰，随着年龄增长，其骨质以每年0.5％至1％的速度流失，50 岁之后更以每年约1％至3％的速度流失。而女性的骨质于更年期以每年1％的速度迅速流失。停经妇女的骨质疏松症盛行率约为40％，这是因为女性停经后体内雌激素急剧减少，蚀骨细胞活性大幅增加，使得骨质流失造成脊椎压迫，或者髋骨、手腕骨折。
当成骨细胞进行骨质重塑作用的速率大于蚀骨细胞的作用时，骨骼将发展为较长、较宽、或较致密的型态。当蚀骨细胞过度活化、使其作用大于成骨细胞时，骨质将严重流失，骨骼孔隙变大且疏松，进而容易引发全身性骨量降低以及骨骼微细结构发生破坏的骨质疏松症，并且容易发生骨折。
骨质疏松症的发生通常没有任何外在症状，一旦产生症状往往是发生骨折，给患者带来莫大的困扰以及衍生相关后遗症。
骨质疏松症的高危险群包括：高龄、更年期或停经女性、身材体型较瘦小、甲状腺或副甲状腺功能异常以及家族中有骨质疏松症病史的人。而且，后天因素(例如饮酒过量、咖啡因或碳酸饮料摄取过量、缺乏运动、钙质及维他命D摄取不足、不当节食减肥造成异常经期停止、长期服用类固醇(例如气喘及风湿性关节炎患者))也会加速骨质疏松症的发生。
现行的骨质疏松症治疗药物依照骨质重塑机制分为以下几类：
1.抗骨质吸收剂：用以抑制蚀骨细胞活性，减少骨质的溶蚀，包括双磷酸盐类(bisphosphonate)、RANKL单株抗体、选择性雌激素受体调节剂(SERM)。其中，口服型双磷酸盐类包括福善美及瑞骨卓其吸收效果会受到食物影响，注射型双磷酸盐类包括骨维壮及骨力强则易引起恶心、呕吐、食道刺激、感冒、发烧或肌肉酸痛的副作用，长期使用双磷酸类可能发生下颚骨坏死或骨折。 RANKL单株抗体(例如denosumab)以模仿保骨素(osteoprotegerin，OPG)的作用而经皮下注射至骨质疏松症患者，RANKL单株抗体与RANKL结合，干扰蚀骨细胞成熟而减少骨质流失，但有低血钙、皮肤感染、颚骨坏死等副作用的风险。SERM包括钙稳抑钙激素(密钙息注射液(injection))，可选择性地作用于骨骼上的雌激素受体以抑制蚀骨细胞作用，但不会作用于子宫及乳房的雌激素受体而造成乳房细胞或子宫内膜细胞增生，但可能产生热潮红、深部静脉血栓、冠状动脉栓塞或脑中风的副作用，因此心血管疾病患者不建议使用。
2.促骨质合成药物：具有人工基因合成的副甲状腺素可刺激成骨细胞作用，达到骨质增生。市售的Teriparatide(骨稳注射液，)开始治疗后可明显增加骨质密度，但使用18个月后效果将减弱，其常见的副作用包括恶心、头痛、晕眩、关节痛、腿部抽筋等。
3.混合型机转药物：以同时刺激骨质生成及抑制骨质流失的双重机制来治疗骨质疏松症。现行药物为由阳离子锶(strontium)及有机酸(雷奈酸，ranelic acid)组成的补骨挺疏 (strontium ranelate)。锶以其物理性质与钙相似而对骨骼具有高度亲合性， strontium ranelate刺激钙敏感接受器，诱导成骨前驱细胞分化为成骨细胞，增加骨质生成，也刺激成骨细胞分泌蚀骨细胞抑制因子，以减少蚀骨细胞成熟，降低骨质再吸收。但可能产生腹泻、头痛、皮肤炎、胃炎、食道炎等副作用，也可能导致静脉血栓、冠状动脉栓塞。
目前临床试验尚无证据证实合并使用两种或更多种骨质疏松药物可以增加有效性，因此世界各国的骨质疏松防治指引均不建议并用两种或更多种抗骨质流失剂，或是并用抗骨质流失剂与促造骨剂。鉴于目前抗骨质疏松药物仍有许多副作用，且药物治疗需服用一年以上才有显著效果，目前合并药物治疗也缺乏有力的实验数据，因此有必要开发新颖产品以对抗骨质疏松症。
此外，另一种骨骼疾病为骨缺损，其成因为创伤、感染、肿瘤、骨髓炎手术清创及各种先天性疾病(例如，唇颚裂、耳缺损、鼻缺损等)。较小的骨缺损虽可自行愈合，但是较大的骨缺损或者较小骨骼上的骨缺损将难以完全愈合，将需要通过骨移植(包括自体骨移植、同种异体骨移植、异种骨移植)、人工骨(包括骨水泥、生物陶瓷)、组织工程骨、骨搬运技术等手术进行治疗。
因此，在面对各种不同成因的骨质疾病(例如，骨质疏松症、骨缺损、骨折疾病等)时，需给予不同药物或实施手术。因此，急需有新颖性及进步性的技术来克服骨质疾病。
发明内容
本发明公开一种具有新颖性及进步性的技术，克服现有骨质疾病治疗药物的缺陷。进一步地，本发明公开一种将乳酸杆菌属、其医药组合物及可食用组合物用于治疗、预防或改善骨质疾病的技术，所使用的乳酸杆菌菌株具有提高个体血液钙质浓度的能力。
因此，本发明公开一种将乳酸杆菌属用于制备治疗、预防或改善个体骨质疾病的医药组合物的用途，其中乳酸杆菌属具有提高所述个体血液钙质浓度的能力。前述骨质疾病可包括但不限于骨质疏松症、骨缺损及骨折疾病。
本发明还公开一种将乳酸杆菌属用于制备治疗、预防或改善个体骨质疾病的可食用组合物的用途，其中乳酸杆菌属具有提高所述个体血液钙质浓度的能力。
在一个具体实施例中，乳酸杆菌属为植物乳杆菌、副干酪乳酸杆菌或其组合。在一个具体实施例中，乳酸杆菌属可为植物乳杆菌，其品种选用Lactobacillus plantarumGKM3(保藏编号为CGMCC No.14565)。在一个具体实施例中，乳酸杆菌属可为副干酪乳酸杆菌，其品种选用Lactobacillus paracasei GKS6(保藏编号为CGMCC No.14566)。
本发明的乳酸杆菌属、其可食用组合物或医药组合物能够达到与市售治疗骨质疾病的药物相等、相仿、或近似的功效。进一步而言，骨质疾病产生于高龄、更年期、停经、体型瘦小、甲状腺或副甲状腺功能异常、骨质疏松症病史、饮酒过量、咖啡因或碳酸饮料摄取过量、缺乏运动、钙质及维他命D摄取不足、不当节食减肥造成异常经期停止、长期服用类固醇等。同时可与本发明比较的市售药物包括但不限于抗骨质吸收剂(例如，双磷酸盐类、RANKL单株抗体、SERM)、促骨质合成药物(例如，骨稳注射液)及/或混合型机转药物(例如，补骨挺疏)。
在本发明的一个具体实施例中，可比较的市售药物为福善美(又称为保骨锭、alendronate(简称Alen)或alendronic acid)，为焦磷酸盐的合成类似物，与骨骼中的羟磷辉石(hydroxyapatite)结合，作为对蚀骨细胞所引起的骨再吸收作用有效的专一性抑制剂，通常用于治疗停经妇女的骨质疏松症及男性的骨质疏松症。
本文用语“血钙”是指血中钙质的浓度。一般而言，当个体钙质摄取量不足时，经由副甲状腺的调节，骨骼即释放钙到血液中，使个体维持平衡及生理作用。相反地，当血钙浓度过高时，多余的钙质则沉积到骨骼中储存，或经肾脏尿以尿液排出体外。
本文用语“骨质疏松症”是指个体骨量减少，骨骼内孔隙增大，呈现中空疏松现象，导致骨骼强度减弱的疾病。本文用语“骨缺损”是指个体骨骼的结构完整性被破坏的疾病，而常见的骨缺损发生在胫骨。本文用语“骨折疾病”是指个体骨骼直接或间接地受到外力所造成的碎裂或变形。
在本文的乳酸杆菌被制备为医药组合物的过程中，可加入医药上可接受的载体或赋形剂，其包括但不限于二氧化硅粉末的微粒子、蔗糖脂肪酸酯、结晶纤维素/羧甲基纤维素钠、磷酸氢钙、淀粉类(小麦淀粉、米淀粉、玉米淀粉、马铃薯淀粉、糊精、环糊精等)、糖类(乳糖、葡萄糖、砂糖、还原麦芽糖、淀粉糖浆、低聚果糖、乳化寡糖等)、糖醇类(山梨糖醇、赤藻糖醇、木糖醇、乳糖醇、甘露糖醇等)。
在乳酸杆菌被制备为医药组合物的过程中，可加入医药上可接受的添加剂，其包括但不限于功能性原料、抗氧化剂、胶化剂、安定剂、增黏剂、保存剂、着色剂、呈味剂等。所加入的功能性原料包括但不限于各种维生素、泛酸、叶酸、生物素、锌、钙、镁、胺基酸、寡糖、蜂胶、蜂王浆、二十五碳五烯酸(EPA)、二十二碳六烯酸(DHA)、辅酶Q10(coenzyme Q-10)、软骨素、乳酸菌、乳铁素(lactoferrin)、异黄酮、干果李(prune)、几丁质、几丁聚糖、葡萄糖胺等。所加入的呈味剂包括但不限于各种水果香味的果汁萃取物、香料或香精。
在乳酸杆菌被制备为可食用组合物的过程中，可加入保护剂其包括但不限于海藻醣、奶粉、聚糊精、味精、焦磷酸盐、维他命及精氨酸。
依据待制备的可食用组合物的种类，例如：菌粉、流体乳品、浓缩牛奶、酸奶、酸乳、冷冻优格、乳酸杆菌发酵饮料、奶粉、冰淇淋、奶酪、干酪、豆浆、发酵豆浆、蔬果汁、果汁、运动饮料、甜点、果冻、糖果、婴儿食品、健康食品、动物饲料及膳食补充品，所属技术领域的技术人员可添加所述种类常用的添加物于乳酸杆菌属中，并符合法律规范。
附图说明
本发明的上述目的及优点在参阅以下详细说明及附图之后对那些所属技术领域的技术人员而言将变得更加明显和显而易见。
图1示出假手术对照组、去卵巢对照组(OVX+CMC)、去卵巢小鼠给予GKM3组 (OVX+M3)、去卵巢小鼠给予GKS6组(OVX+S6)以及去卵巢小鼠给予alendronate组 (OVX+Alen)的股骨骨小梁区域比率。
图2示出假手术对照组、去卵巢对照组(OVX+CMC)、去卵巢小鼠给予GKM3组 (OVX+M3)、去卵巢小鼠给予GKS6组(OVX+S6)以及去卵巢小鼠给予alendronate组(OVX+Alen)的股骨骨小梁厚度。
图3示出假手术对照组、去卵巢对照组(OVX+CMC)、去卵巢小鼠给予GKM3组 (OVX+M3)、去卵巢小鼠给予GKS6组(OVX+GKM3)以及去卵巢小鼠给予alendronate 组(OVX+Alen)的股骨骨小梁数目。
图4示出假手术对照组、去卵巢对照组(OVX+CMC)、去卵巢小鼠给予GKM3组 (OVX+M3)、去卵巢小鼠给予GKS6组(OVX+S6)以及去卵巢小鼠给予alendronate组 (OVX+Alen)的股骨骨小梁分离度。
图5示出假手术对照组、去卵巢对照组(OVX+CMC)、去卵巢小鼠给予GKM3组 (OVX+M3)、去卵巢小鼠给予GKS6组(OVX+S6)以及去卵巢小鼠给予alendronate组 (OVX+Alen)的股骨骨矿质密度。
具体实施方式
本案所提出的发明将可由以下的实施例说明而得到充分了解，使得所属技术领域的技术人员可以据以完成，然而下列实施例并不是对本案实施方式的限制，所属技术领域的技术人员仍可依据除已经公开的实施例之外的精神推导出其他实施例，这些推导出的实施例全都属于本发明的范围之内。
本发明公开一种将乳酸杆菌属、其医药组合物及可食用组合物用于治疗、预防或改善骨质疾病的用途，以及一种将乳酸杆菌属用于制备治疗、预防或改善骨质疾病的可食用组合物的用途，所述乳酸杆菌属具有提高个体血液钙质浓度的能力。
在一个具体实施例中，乳酸杆菌属(Lactobacillus)的菌种包括但不限于植物乳杆菌(L. plantarum)、副干酪乳酸杆菌(L.paracasei)、嗜酸乳酸杆菌(L.acidophilus)、短乳酸杆菌 (L.brevis)、干酪乳酸杆菌(L.casei)、德氏乳酸杆菌(L.delbrueckii)、德氏乳酸杆菌德氏亚种(L.delbrueckii subsp.delbrueckii)、德氏乳酸杆菌保加利亚种(L.delbrueckii subsp. bulgaricus)、德氏乳酸杆菌乳酸亚种(L.delbrueckiiisubsp.lactis)、鼠李糖乳酸杆菌(L. rhamnosus)、唾液乳酸杆菌(L.salivarius)、发酵乳酸杆菌(L.fermentum)、加氏乳酸杆菌 (L.gasseri)、瑞士乳酸杆菌(L.helveticus)、约氏乳酸杆菌(L.johnsonii)、戊糖乳杆菌(L. pentosus)及洛德乳酸杆菌(L.reuteri)。
在一个具体实施例中，植物乳杆菌的品种包括但不限于Lactobacillusplantarum GKM3 (其保藏编号为CGMCC No.14565)，且副干酪乳酸杆菌的品种包括但不限于Lactobacillus paracasei GKS6(其保藏编号为CGMCC No.14566)。
前述医药组合物或可食用组合物中，乳酸杆菌属菌株的种类可为一种或多种。例如，如以下实施例所言，将植物乳杆菌菌株GKM3用于医药组合物或可食用组合物中。或者，将副干酪乳酸杆菌菌株GKS6用于医药组合物或可食用组合物中。或者，同时将菌株GKM3 及菌株GKS6用于医药组合物中或可食用组合物中。
在一个具体实施例中，医药组合物或可食用组合物用于提高个体的血液钙质浓度、骨小梁骨体积与组织体积的比率、骨小梁厚度、骨小梁数目以及骨矿质密度，且所述医药组合物或可食用组合物用于降低骨小梁分离度。在一个具体实施例中，骨质疾病包括但不限于骨质疏松症、骨缺损及骨折疾病。
在一个具体实施例中，可食用组合物包括但不限于菌粉、流体乳品、浓缩牛奶、酸奶、酸乳、冷冻优格、乳酸杆菌发酵饮料、奶粉、冰淇淋、奶酪、干酪、豆浆、发酵豆浆、蔬果汁、果汁、运动饮料、甜点、果冻、糖果、婴儿食品、健康食品、动物饲料及膳食补充品。
试验物质来源：
本发明实施例所使用的植物乳杆菌Lactobacillus plantarum GKM3(CGMCCNo.14565) 及副干酪乳杆菌Lactobacillus paracasei GKS6(CGMCC No.14566)从中国微生物菌种保藏管理委员会普通微生物中心(CGMCC)取得。所属技术领域的技术人员亦可由所述中心或其他微生物菌株保存单位取得植物乳杆菌、副干酪乳杆菌及其亚种的菌株，例如台湾新竹财团法人食品工业研究所生物资源保存及研究中心(BCRC)编号为10069、10357、12327等的植物乳杆菌，BCRC编号为10358、14628、17005等的副干酪乳杆菌。
试验物质发酵：
菌株GKM3及GKS6的培养方式可分别参见发明专利申请号TW 106136134(2017年10月20日申请)及106137773(2017年11月1日申请)。菌株GKM3及GKS6的培养基中可选用的碳源包括但不限于葡萄糖、蔗糖、乳糖、果糖、甘露糖、山梨糖醇、甘油、糖蜜或其组合，前述成分在培养基中的重量份数及百分比可视情况调整。在一个具体实施例中，碳源为蔗糖。菌株GKM3及GKS6的培养基中可选用的氮源包括但不限于大豆蛋白、酵母抽提物、牛肉萃取物、酪蛋白粉、乳清蛋白粉、鱼蛋白水解物、植物萃取蛋白或其组合，前述成分在培养基中的重量份数及百分比可视情况调整。在一个具体实施例中，氮源为酵母抽提物。碳源及氮源相对于培养基总重量的添加比例对于培养成效有不同的影响，其添加比例分别为在1至10重量百分比(wt％)之间。在一个具体实施例中，碳源及氮源相对于培养基总重量的添加比例分别为在3wt％至7wt％之间。在一个具体实施例中，培养基包含蔗糖及酵母萃取物，且蔗糖及酵母萃取物相对于培养基总重量的添加比例分别为在1wt％至10wt％之间。在一个具体实施例中，培养基包含蔗糖及酵母萃取物，且蔗糖及酵母萃取物相对于培养基总重量的添加比例分别为在3wt％至7wt％之间。在一个具体实施例中，培养基仅包含蔗糖或仅包含酵母萃取物，且蔗糖或酵母萃取物相对于培养基总重量的添加比例为在1wt％至10wt％之间，或者为在3wt％至7wt％之间。
菌株GKM3及GKS6可培养于固体培养基或液体培养基中，其培养温度介于32℃至42℃之间。在一个具体实施例中，培养温度介于35℃至40℃之间。在一个具体实施例中，培养温度为37℃。当培养于液体培养基时，培养容器或发酵槽的转速可设定为5rpm至50rpm，以使菌株GKM3及GKS6均匀地分布于液体培养基中培养，并将培养容器或发酵槽内的气体适度地溶入液体培养基中。在一个具体实施例中，转速介于10rpm至35rpm之间，或者为20rpm。
培养完成的菌株GKM3及GKS6可通过冷冻干燥技术脱去水分，以菌粉方式保存。替代地，可在冷冻干燥过程中加入保护剂，包括但不限于海藻糖、奶粉、聚糊精、味精、焦磷酸盐、维生素、精胺酸或其组合，成为可食用组合物，前述成分的重量份数可视情况调整。
替代地，冷冻干燥后的菌株GKM3及GKS6可以通常采用制药技术加入药学上可接受的载剂、赋形剂、稀释剂、辅剂、溶媒、分散剂、包衣、抗菌或抗真菌剂，并制备为锭剂、胶囊、颗粒、丸剂、片剂、粉剂、乳化剂、液状悬浮液、分散剂、溶剂及诸如此类。因此，菌株GKM3及GKS6可制备为菌粉、可食用组合物或医药组合物。
试验物质的制备：
本发明的动物实验可以以每千克小鼠体重喂食10mg至2000mg之间GKM3及GKS6 菌粉的方式进行。替代地，每千克小鼠体重喂食超过2000mg或低于10mg的GKM3及GKS6 菌粉的剂量也为本发明所欲保护的范围。而当除了小鼠以外的个体服用GKM3及GKS6菌粉、其医药组合物或可食用组合物时，则按照上述10mg～2000mg/kg个体体重适度调整。
在本实施例中，GKM3及GKS6菌粉各自以0.5％(w/v)羧甲基纤维素(CMC)溶液制备为浓度205mg/mL的悬浮液；溶媒组为0.5％(w/v)CMC溶液；阳性对照组-骨质疏松药物alendronate(Alen)以0.5％(w/v)CMC溶液制备为浓度0.25mg/mL的悬浮液。小鼠每10千克体重管喂给予0.1mL的GKM3悬浮液、GKS6悬浮液、0.5％(w/v)CMC溶液或Alen溶液。
实验动物及其处理：
由于骨质代谢与雌激素有密切关系，实验前以双侧卵巢切除方式作为模拟停经后动物的骨质疏松研究模型。实验动物卵巢切除后经1至2周的恢复期后，即开始进行试验物质的试验。
本实施例采用购自乐斯科生物科技股份有限公司(台湾台北)的8周龄雌性ICR小鼠，于9周龄时进行卵巢切除术(ovariectomy，简称OVX)去卵巢手术。实验组及阳性对照组小鼠在麻醉状态下切开卵巢处上方的背部两侧肌肉，并去除卵巢。假手术组(Sham)的小鼠也被切开卵巢处上方的背部两侧肌肉，但不摘除卵巢，而后缝合伤口。小鼠牺牲时，检查其卵巢组织，确认去除卵巢手术是否成功。手术失败的小鼠将不被采用作为数据的统计。
因此，雌性ICR小鼠分为假手术组(对照组)及去卵巢组。去卵巢组又分为去卵巢对照组(OVX+CMC)、去卵巢小鼠给予GKM3组(OVX+M3，205mg GKM3/kg小鼠体重)、去卵巢小鼠给予GKS6组(OVX+S6，205mg GKS6/kg小鼠体重)以及去卵巢小鼠给予 alendronate组(OVX+Alen，2.5mg Alen/kg小鼠体重)。各组小鼠在手术后4天开始给予试验物质，每天1次，连续28天。alendronate一周给予3次。试验物质(CMC、GKM3、GKS6 及alendronate)给予4周时以断颈方式牺牲小鼠，并取出股骨进行分析。
骨组织分析：
以微型计算机断层扫描仪(micro computed tomography(micro-CT)scanner；SkyScan 1076,Kontizh,Belgium)、18μm的分辨率拍摄ICR小鼠的右股骨远心端骨干的计算机断层扫描图，并以分析软件分析骨小梁区域的比率(骨体积与组织体积的比例(BV/TV))、骨小梁厚度、骨小梁数目及骨小梁分离度。分析的位置选择生长板下(往近心端)100片的不包含皮质骨的区域。骨矿质密度的分析选择包含皮质骨的相同区域。
骨密度分析：
骨骼的骨密度(质量/体积)以微型计算机断层扫描仪进行检测。测定前先将小鼠麻醉，以俯卧姿势固定，利用两种不同能量的双能X光吸收剂量(DXA)测定仪扫瞄检查部位，再以闪烁侦测器接收经过受测部位的X光，以计算机分析数据，计算检查部位的骨骼质量、体积及骨密度。
统计方法：
本实施例实验所得的数据以单尾变异数分析(one-way analysis of variance,one-way ANOVA)，并进行邓式多距检定(Duncan’s multiple range test)，“*”表示组间具有统计上显著差异(p<0.05)。
实验结果：
1.血液钙质(血钙)浓度：
当个体内钙质摄取量均等而吸收较差、血钙浓度呈现偏低时，个体的钙质平衡机制会倾向将钙质由骨骼释放至血液，此不利于骨密度的增加或维持；相反地，当钙质吸收较佳、血钙浓度略偏高时，个体的钙质平衡机制倾向将钙质由血液送至骨骼，以沉积方式储存，以利于骨密度的增加或维持。
如表1及表2所示，管喂菌株GKM3及GKS6的小鼠，其血液中的钙离子浓度相较于对照组显著增加(p<0.05)，肌酸酐浓度无明显差异，然而钙/肌酸酐的比例相较于对照组亦显著增加(p<0.05)。根据文献(Yang et al.,Calcified Tissue International andMusculoskeletal Research,1994,55(5):335-341.)报导，较高的血清钙质及较高的钙/肌酸酐比例表明试验样品有助于钙质的吸收。因此，本发明的菌株GKM3及/或GKS6及其菌粉、可食用组合物或医药组合物有助于钙质吸收。
表1、试验期间各组雄鼠血液中钙、肌酸酐含量及钙/肌酸酐比例
数值以平均±平均值标准误(mean±S.E.M.)表示，并以单尾变异数分析(n＝6)
*表示与对照组具有统计上显著差异(p<0.05)
表2、试验期间各组雌鼠血液中钙、肌酸酐含量及钙/肌酸酐比例
数值以mean±S.E.M.表示，并以单尾变异数分析(n＝6)
*表示与对照组具有统计上显著差异(p<0.05)
2.股骨骨小梁区域比率：
将ICR小鼠于去卵巢后第32天断颈牺牲，并分析其股骨的各项参数。如表3及图1所示，去卵巢对照组(OVX+CMC)小鼠的右股骨骨小梁区域比率显著地小于假手术对照组，而OVX+M3组及OVX+S6组小鼠的右股骨骨小梁区域比率显著地高于OVX+CMC组(p< 0.05)，与OVX+Alen组接近，此表明服用本发明的菌株GKM3及/或GKS6、其菌粉、可食用组合物或医药组合物有助于治疗、预防或改善个体的股骨骨小梁区域比率。
表3、试验期间各组小鼠的股骨骨小梁区域比率
数值以mean±S.E.M.表示，并以单尾变异数分析(n＝6)
#表示与假手术对照组具有统计上显著差异(p<0.05)
*表示与OVX+CMC组具有统计上显著差异(p<0.05)
3.股骨骨小梁厚度：
如表4及图2所示，去卵巢对照组(OVX+CMC)小鼠的右股骨骨小梁厚度显著地小于假手术对照组，而OVX+M3组及OVX+S6组小鼠的右股骨骨小梁厚度显著地高于 OVX+CMC组(p<0.05)，与OVX+Alen组接近，此表明服用本发明的菌株GKM3及/或 GKS6、其菌粉、可食用组合物或医药组合物有助于治疗、预防或改善个体的股骨骨小梁厚度。
表4、试验期间各组小鼠的股骨骨小梁厚度
数值以mean±S.E.M.表示，并以单尾变异数分析(n＝6)
#表示与假手术对照组具有统计上显著差异(p<0.05)
*表示与OVX+CMC组具有统计上显著差异(p<0.05)
4.股骨骨小梁数目：
如表5及图3所示，去卵巢对照组(OVX+CMC)小鼠的右股骨骨小梁数目显著地小于假手术对照组，而OVX+M3组及OVX+S6组小鼠的右股骨骨小梁数目显著地高于 OVX+CMC组(p<0.05)，与OVX+Alen组接近，此表明服用本发明的菌株GKM3及/或 GKS6、其菌粉、可食用组合物或医药组合物有助于治疗、预防或改善个体的股骨骨小梁数目。
表5、试验期间各组小鼠的股骨骨小梁数目
数值以mean±S.E.M.表示，并以单尾变异数分析(n＝6)
#表示与假手术对照组具有统计上显著差异(p<0.05)
*表示与OVX+CMC组具有统计上显著差异(p<0.05)
5.股骨骨小梁分离度：
如表6及图4所示，去卵巢对照组(OVX+CMC)小鼠的右股骨骨小梁分离度显著地高于假手术对照组，而OVX+M3组及OVX+S6组小鼠的右股骨骨小梁分离度显著地低于 OVX+CMC组(p<0.05)，此表明服用本发明的菌株GKM3及/或GKS6、其菌粉、可食用组合物或医药组合物有助于治疗、预防或改善及降低个体的股骨骨小梁分离度。
表6、试验期间各组小鼠的股骨骨小梁分离度
数值以mean±S.E.M.表示，并以单尾变异数分析(n＝6)
#表示与假手术对照组具有统计上显著差异(p<0.05)
*表示与OVX+CMC组具有统计上显著差异(p<0.05)
6.股骨骨矿质密度：
如表7及图5所示，去卵巢对照组(OVX+CMC)小鼠的右股骨骨矿质密度显著地小于假手术对照组，而OVX+M3组及OVX+S6组小鼠的右股骨骨矿质密度显著地高于 OVX+CMC组(p<0.05)，与OVX+Alen组接近，此表明服用本发明的菌株GKM3及/或 GKS6、其菌粉、可食用组合物或医药组合物有助于治疗、预防或改善个体的股骨骨矿质密度。
表7、试验期间各组小鼠的股骨骨矿质密度
数值以mean±S.E.M.表示，并以单尾变异数分析(n＝6)
#表示与假手术对照组具有统计上显著差异(p<0.05)
*表示与OVX+CMC组具有统计上显著差异(p<0.05)
综合上述，本发明的乳酸杆菌属、其医药组合物及可食用组合物经口服后能显著地提高个体血液中钙质浓度，提高钙/肌酸酐比例，有助于个体钙质吸收。另外，去除卵巢的小鼠在喂食本发明公开的乳酸杆菌、其医药组合物及可食用组合物后，显著地提高股骨骨体积与组织体积(BV/TV)的比率、骨小梁厚度、数目与骨矿质密度，并显著地降低骨小梁分离度，因此本发明公开的乳酸杆菌、其医药组合物及可食用组合物具有改善骨质疏松的功效。
在本发明中，小鼠食用菌株GKM3及/或GKS6后，其血液中钙离子浓度显著增加，将促进多余的钙质沉积到骨骼中储存。由于骨骼沉积的钙质增加，进而使得个体得以治疗或改善骨质疏松症等骨质疾病，或者预防骨质疏松症等骨质疾病的风险。
本文前述实验仅以小鼠以及去除卵巢的小鼠为对象，以模拟受雌激素分泌影响的骨质疏松症。然而，所属技术领域的技术人员通过以啮齿类动物(小鼠)为对象的众多实验及结果，已经能够推衍及实际应用至其他脊椎动物，例如哺乳类。因此，本发明所请求保护的范围包括脊椎动物，如包括哺乳类动物(例如，包括灵长类、啮齿类等)，其中灵长类包括人、猩猩、猿猴、猴等，啮齿类包括大鼠、小鼠、天竺鼠等。而模拟的骨质疏松症的适用范围也不限于受雌激素分泌影响的雌性动物，本发明的乳酸杆菌属、其医药组合物及可食用组合物亦适用于患有骨质疾病或患有骨质疾病风险的雄性动物。
本发明实属难能的创新发明，深具产业价值，援依法提出申请。此外，本发明可以由所属技术领域的技术人员做任何修改，但不脱离如所附权利要求所要求保护的范围。
Claims (9)
1.一种将乳酸杆菌属(Lactobacillus)用于制备治疗、预防或改善个体的骨质疾病的医药组合物的用途，其中所述乳酸杆菌属具有提高所述个体的血液钙质浓度的能力。
2.根据权利要求1所述的用途，其中所述乳酸杆菌属选自由以下菌种所组成的群组其中之一：
植物乳杆菌(Lactobacillus plantarum)、副干酪乳酸杆菌(Lactobacillusparacasei)、嗜酸乳酸杆菌(Lactobacillus acidophilus)、短乳酸杆菌(Lactobacillusbrevis)、干酪乳酸杆菌(Lactobacillus casei)、德氏乳酸杆菌(Lactobacillusdelbrueckii)、德氏乳酸杆菌德氏亚种(Lactobacillus delbrueckiisubsp.delbrueckii)、德氏乳酸杆菌保加利亚种(Lactobacillus delbrueckiisubsp.bulgaricus)、德氏乳酸杆菌乳酸亚种(Lactobacillus delbrueckiiisubsp.lactis)、鼠李糖乳酸杆菌(Lactobacillus rhamnosus)、唾液乳酸杆菌(Lactobacillus salivarius)、发酵乳酸杆菌(Lactobacillus fermentum)、加氏乳酸杆菌(Lactobacillus gasseri)、瑞士乳酸杆菌(Lactobacillus helveticus)、约氏乳酸杆菌(Lactobacillus johnsonii)、戊糖乳杆菌(Lactobacillus pentosus)、洛德乳酸杆菌(Lactobacillus reuteri)及其组合。
3.根据权利要求2所述的用途，其中所述植物乳杆菌的品种为Lactobacillusplantarum GKM3，其保藏编号为CGMCC No.14565。
4.根据权利要求2所述的用途，其中所述副干酪乳酸杆菌的品种为Lactobacillusparacasei GKS6，其保藏编号为CGMCC No.14566。
5.根据权利要求1所述的用途，其中所述医药组合物用于提高所述个体的骨小梁骨体积与组织体积的比率、骨小梁厚度、骨小梁数目以及骨矿质密度，且所述医药组合物用于降低骨小梁分离度。
6.根据权利要求1所述的用途，其中所述骨质疾病选自由骨质疏松症、骨缺损及骨折疾病所组成的群组其中之一。
7.一种将乳酸杆菌属(Lactobacillus)用于制备治疗、预防或改善个体的骨质疾病的可食用组合物的用途，其中，所述乳酸杆菌属具有提高所述个体的血液钙质浓度的能力。
8.根据权利要求7所述的用途，其中所述可食用组合物系选自由菌粉、流体乳品、浓缩牛奶、酸奶、酸乳、冷冻优格、乳酸杆菌发酵饮料、奶粉、冰淇淋、奶酪、干酪、豆浆、发酵豆浆、蔬果汁、果汁、运动饮料、甜点、果冻、糖果、婴儿食品、健康食品、动物饲料及膳食补充品所组成的群组其中之一。
9.根据权利要求7所述的用途，其中所述乳酸杆菌属为植物乳杆菌、副干酪乳酸杆菌中至少其中之一，当所述乳酸杆菌属为所述植物乳杆菌时，所述植物乳杆菌的品种为Lactobacillus plantarum GKM3，其保藏编号为CGMCC No.14565，且当所述乳酸杆菌属为所述副干酪乳酸杆菌时，所述副干酪乳酸杆菌的品种为Lactobacillus paracasei GKS6，其保藏编号为CGMCC No.14566。
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| GB201905386D0 (en) * | 2019-04-16 | 2019-05-29 | Probi Ab | Probiotic compositions and uses thereof |
| US20220072070A1 (en) * | 2019-06-25 | 2022-03-10 | Synbio Tech Inc. | Method for improving walking capacity of elderly subjects |
| TWI825362B (zh) * | 2020-11-13 | 2023-12-11 | 葡萄王生技股份有限公司 | 乳酸菌醱酵產物用於製備促進皮膚創傷癒合之外用組成物的用途 |
| CA3238788A1 (en) * | 2021-11-22 | 2023-05-25 | Eric Michael Schott | Methods and compositions for treating musculoskeletal diseases, treating inflammation, and managing symptoms of menopause |
| CN115806898A (zh) * | 2022-08-10 | 2023-03-17 | 重庆第二师范学院 | 一种植物乳杆菌ksfy04及其应用 |
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