CN110652009B - 一种高纤维膳食补充剂用于预防及改善骨代谢相关疾病的新用途 - Google Patents
一种高纤维膳食补充剂用于预防及改善骨代谢相关疾病的新用途 Download PDFInfo
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Abstract
本发明公开了一种高纤维膳食补充剂用于预防及改善骨代谢相关疾病的新用途。本发明中高纤维膳食补充剂采用的原料是从玉米中获得的2型高直链玉米淀粉，通过对CIA小鼠骨关节评分、细胞因子表达和Micro‑CT对小鼠关节炎的严重程度进行评估，发现其可以改善CIA小鼠的骨关节病变情况。通过考察其对小鼠骨质疏松的改善作用，发现使用2型高直链玉米淀粉饲料的小鼠，血清钙、血清磷、甲状腺指数、脾指数、肝指数、子宫指数升高，骨小梁数目、骨密度均得到明显改善。说明2型高直链玉米淀粉具有一定改善骨代谢相关疾病的作用。可与辅料结合，制备改善骨代谢疾病症状的膳食补充剂。
Description
技术领域
本发明涉及一种用于预防及改善骨代谢相关疾病的高纤维膳食补充剂的新用途，属生物与新医药技术领域。
背景技术
人体是一个由自身细胞和共生微生物细胞组成的超级生物体。人体一切与外部相互作用的部位包括皮肤表面、口腔、肺泡、肠道、生殖道等都定植着微生物群体，而肠道是人体微生物密度最高、群落多样性最丰富的区域。肠道微生物的生长和繁殖需要大量的营养物质，这些物质主要来源于食物，少部分来自肠道分泌的黏蛋白、脱落的上皮细胞以及进入肠道的药物等。人体肠道菌群的组成被证实存在明显的个体间差异，然而菌群整体所具有的代谢功能(如碳水化合物和氨基酸代谢)往往趋于保守。研究显示，超过五天的全动物或者全植物产品饮食即可显著影响人体肠道菌群的构成，饮食因素对肠道菌群的塑造作用超越了个体菌群间的差异。目前发现饮食导致的肠道菌群变化可以影响多种疾病的病程。
骨代谢疾病是直接或间接由钙磷等代谢紊乱引起的全身性骨疾病，主要表现为骨形成和骨吸收两者之间的转换紊乱或异常，骨形成或骨吸收可减少或增加，骨基质形成可缺乏或增加，其矿化也可缺乏、不足或沉积过多，结果骨可显示疏松、软化、硬化或过度钙化，可兼具两种或两种以上的表现。越来越多的证据表明肠道菌群的失调与部分骨代谢疾病相关，如类风湿性关节炎、骨质疏松等。补充特殊肠道微生物或者益生元能够显著改善炎症或者激素引起的骨量丢失现象。
作为肠道菌群的重要影响因素，不同饮食模式以及饮食中的不同营养成分对骨代谢疾病的影响也受到了人们的关注。通常膳食纤维主要指代所有不能在胃和小肠中被吸收而进入大肠的碳水化合物成分，包括纤维素、半纤维素、各种植物胶质、糖醇、低聚糖类物质、抗性淀粉等。淀粉是人类膳食中主要的碳水化合物。根据淀粉在小肠内的生物利用度将其分为快速消化淀粉、缓慢消化淀粉和抗性淀粉(RS)。其中RS不同于前两者，它不能被小肠中的淀粉酶水解，本身或其降解产物能原封不动地到达结肠并被其中的微生物菌群发酵，继而发挥有益的生理作用，因此曾被看作是膳食纤维的重要组成成分。由于RS具备多种生理学特性，近年来成为了国际上新兴的食品研究领域。研究显示，RS具有控制体重、调节血糖水平、降低胆固醇和预防脂肪肝、促进锌、钙、镁离子的吸收和预防结肠癌的作用。同时，RS一方面是双歧杆菌和乳酸杆菌等有益菌繁殖的良好基质，另一方面可作为益生元在结肠内发酵产生对宿主有益的产物，如短链脂肪酸。
抗性淀粉是一种新型的可溶性膳食纤维，与其他种类经过物理或者化学改性制得的、主要用做添加剂的抗性淀粉不同，2型抗性淀粉广泛存在于马铃薯、香蕉、大米、玉米等天然食品中。本发明选用2型抗性淀粉(Type 2Resistant Starch，RS2)对胶原诱导关节炎(Collagen-induced arthritis，CIA)小鼠模型以及维甲酸诱导的小鼠骨质疏松模型进行研究，以评价这类可溶性膳食纤维对免疫炎性或代谢紊乱引起的骨质病变进程的影响。富含RS2的高纤维膳食补充剂，能有效改善胶原诱导的关节炎和维甲酸所引发的骨质破坏及骨量丢失，该方法可用于骨代谢疾病患者的日常对症治疗。
发明内容
本发明提供了一种用于预防及改善骨代谢相关疾病的高纤维膳食补充剂的新用途，即在制备改善骨代谢疾病症状的膳食补充剂中的应用。
高纤维膳食补充剂采用的原料是从玉米中获得的2型高直链玉米淀粉(RS2)。
一种高纤维膳食补充剂，可进一步包括营养制品学上和/或药学上可接受的载体和/或辅料组成。
所述的膳食补充剂被制成口服剂型；优选地，所述口服剂型是散剂、颗粒剂、胶囊剂或丸剂。
本发明的有益效果在于：
1、本发明对RS2发掘出了新的药用价值，将其用于骨代谢疾病，并可制备成预防、调理或改善骨代谢疾病的膳食补充剂和/或特殊医学用途食品，从而为RS2开拓一个新的用途。
2、本发明所提及的RS2治疗骨代谢疾病的药效试验通过考察其改善CIA小鼠的骨关节病变情况，通过对小鼠关节评分、组织病理学染色和Micro-CT对小鼠关节炎的严重程度进行评估。实验终点(第49天)，采用流式细胞术测定脾脏T细胞亚群(Treg、Th1、Th2、Th17)的比例。试验结果表明，摄入RS2可以加速CIA小鼠关节炎症的缓解，减少关节骨侵蚀。同时，CIA小鼠肠道固有层及脾脏调节性T(regulatory T，Treg)细胞百分比明显升高，血清中白细胞介素-10(IL-10)水平升高。而Th1、Th2、Th17细胞的含量不受RS2的影响。RS2治疗骨代谢疾病的药效试验通过考察其对小鼠骨质疏松的改善作用，采用维甲酸复制骨质疏松模型，与维甲酸处理组(RA)比较，使用RS2饲料的HFD组小鼠，血清钙、血清磷含量均不同程度地降低，甲状腺指数、脾指数和肝指数降低，子宫指数升高，骨小梁数目减少和骨密度降低程度得到明显改善。
下面结合具体实施例，进一步阐明本发明，应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或者制造厂商所建议的条件。
附图说明
图1.RS2对CIA小鼠体重变化的影响。
图2.RS2对CIA小鼠足爪关节外观对比图。
图3.RS2对CIA小鼠足爪关节炎症评分的影响。
图4.RS2对CIA小鼠膝关节H&E染色组织病理学的影响。
图5.RS2对CIA小鼠膝关节H&E染色组织病理学评分的影响。
图6.RS2对CIA小鼠小鼠足爪micro-CT及胫骨骨小梁结构的影响。
图7.RS2对CIA小鼠胫骨骨量的影响。
图8.RS2对CIA小鼠血清中IL-1β、IL-6、TNF、IL-17A及IL-10表达的影响。
图9.RS2对CIA小鼠脾脏Treg细胞表达的影响。(A)RS2对于脾脏Treg细胞影响的流式检测结果代表图例。(B)RS2对于Treg细胞影响的统计结果。
图10.RS2对CIA小鼠小鼠脾脏Th1、Th2、Th17细胞表达的影响。(A)RS2对于脾脏Th1、Th2、Th17细胞影响的流式检测结果代表图例。(B)RS2对于Th1、Th2、Th17细胞影响的统计结果。
图11.RS2对骨质疏松小鼠血清钙含量的影响。
图12.RS2对骨质疏松小鼠血清磷含量的影响。
图13.RS2对骨质疏松小鼠甲状腺指数的影响。
图14.RS2对骨质疏松小鼠脾指数的影响。
图15.RS2对骨质疏松小鼠肝指数的影响。
图16.RS2对骨质疏松小鼠子宫指数的影响。
图17.RS2对骨质疏松小鼠骨小梁数目的影响。
图18.RS2对骨质疏松小鼠骨密度的影响。
具体实施方式
根据下述实施例，可以更好地理解本发明。然而，实施例所描述的内容仅用于说明本发明，而不应当也不会限制权利要求书中所详细描述的本发明。
实施例1：RS2治疗CIA小鼠骨关节炎药效学研究
1.实验动物
DBA/1小鼠，6-7周，♂性，体重(20±2)g，无特定病原(Specific PathogenFree，SPF)级别，随机分为3组：
A.对照组(Naive Group)，不诱导CIA模型，常规饲料喂养，5只；
B.CIA组(CIA Group)，诱导CIA模型，常规饲料喂养，7只；
C.HF-CIA组(High-fiber CIA Group)，诱导CIA模型，从造模当天开始高纤维饲料喂养，5只。
3组动物同时饲养于四川大学华西科技园实验动物中心，室温稳定于22-25℃，12h昼夜交替，隔天补充食物及饮水，每周进行无菌垫料更换。
2.CIA小鼠模型建立
取CIA免疫乳化剂100μl于小鼠尾根部皮内注射。初次免疫当日定为第0天，于初次免疫后第21天再次皮内注射同等剂量的该乳化剂加强免疫，诱导CIA模型。于第49天处死小鼠，收集外周血、粪便、关节、脾脏、腹股沟淋巴结及肠道组织标本。
3.CIA关节炎评估
观察小鼠一般情况，从第0天开始每周记录体重变化，至第21天，隔天记录体重变化。根据小鼠足爪关节肿胀及活动情况进行足爪关节评分，记录小鼠关节病变的严重程度。四足按0-4五级评分，评分相加为小鼠的足爪关节评分，最高16分，评分标准如表1所示。
表1CIA足爪关节评分标准
注：day0开始每周进行足爪关节评分，day21开始隔天进行足爪关节评分
4.小鼠标本的收集
于第49天，腹腔注射水合氯醛麻醉小鼠，100-150μl/只。取血后将小鼠脱颈处死，左侧膝关节10％中性甲醛溶液固定，待做Micro-CT，后石蜡包埋行HE染色；左足10％中性甲醛溶液固定，待做Micro-CT，常温保存。
5.实验结果
(1)小鼠体重变化情况
CIA组及HF-CIA组小鼠在第21天进行二次免疫诱导CIA模型。以三组小鼠第21天的体重为基准，记录第21-49天小鼠体重变化情况。结果如图1显示，Naive组小鼠体重呈持续上升趋势。CIA组小鼠体重自第21天开始持续下降，第35天降至最低水平，之后缓慢回升。HF-CIA组小鼠体重略有下降，较CIA组小鼠下降幅度明显减小。
(2)小鼠足爪关节肿胀情况
在二次免疫24h后，CIA组及HF-CIA组小鼠陆续出现关节炎症，表现为精神萎靡、活动减少、体重下降及关节红肿等。小鼠关节肿胀情况如图2显示。三组小鼠隔天进行足爪关节评分，结果如图3显示，Naive组小鼠未见足爪关节肿胀。CIA组小鼠足爪关节评分于二次免疫后持续上升，至35天达高峰，后缓慢下降。HFD未显著影响CIA小鼠关节炎的急性发作，但HF-CIA组小鼠足爪关节评分最高值低于CIA组小鼠，且在关节炎缓解期即41-49天显著低于模型组小鼠。以上结果表明，RS2可以促进CIA小鼠关节炎更快速地缓解。
(3)关节组织病理学观察
在第49天收集实验各组小鼠后肢膝关节，HE染色后观察局部炎症及骨质破坏情况。HE染色结果如图4显示，与Naive组相比，CIA组小鼠存在明显的关节炎症，表现为炎性细胞浸润，滑膜增生，软骨层结构不完整及骨质破坏等；相较CIA组，HF-CIA组小鼠膝关节中炎性细胞浸润、滑膜增生情况未显著改善，但骨质破坏明显减轻。三组组织病理学评分图5显示，HF-CIA组较CIA组骨侵蚀评分明显降低。
(4)Micro-CT及骨量分析
小鼠足爪Micro-CT三维成像及胫骨骨小梁结构如图6所显示。从中可见，相较Naive组，CIA组小鼠存在明显的骨质破坏及骨量减少。与CIA组相比，HF-CIA组小鼠骨质破坏较轻，且骨量丢失不明显。从BV/TV、BS/BV、Tb.Th、Tb.Sp、Tb.N五个方面评价各组的骨量变化，结果如图7显示，CIA组小鼠相较Naive组小鼠骨小梁体积分数及骨小梁数量明显下降，而予以RS2的HF-CIA组小鼠较CIA组小鼠骨小梁体积分数及骨小梁数量显著增加。
实施例2：RS2治疗CIA小鼠骨关节炎作用机制研究
1.实验动物
DBA/1小鼠，6-7周，♂性，体重(20±2)g，无特定病原(Specific PathogenFree，SPF)级别，随机分为3组：
A.对照组(Naive Group)，不诱导CIA模型，常规饲料喂养，5只；
B.CIA组(CIA Group)，诱导CIA模型，常规饲料喂养，7只；
C.HF-CIA组(High-fiber CIA Group)，诱导CIA模型，从造模当天开始高纤维饲料喂养，5只。
3组动物同时饲养于四川大学华西科技园实验动物中心，室温稳定于22-25℃，12h昼夜交替，隔天补充食物及饮水，每周进行无菌垫料更换。
2.CIA小鼠模型建立
取CIA免疫乳化剂100μl于小鼠尾根部皮内注射。初次免疫当日定为第0天，于初次免疫后第21天再次皮内注射同等剂量的该乳化剂加强免疫，诱导CIA模型。于第49天处死小鼠，收集外周血、粪便、关节、脾脏、腹股沟淋巴结及肠道组织标本。
3.小鼠标本的收集
于第49天，腹腔注射水合氯醛麻醉小鼠，100-150μl/只。收集外周血至抗凝EP管中(约1ml左右)，3000rpm离心15mins，取上清，-80℃保存，检测血清中IL-1β、IL-6、TNF、IL-17A及IL-10。取血后将小鼠脱颈处死，摘取小鼠脾脏，PBS溶液暂存，流式细胞(Flowcytometry，FCM)分析T细胞亚群含量。
4.实验结果
(1)外周血细胞因子检测
第49天留取小鼠血清，利用CBA试剂盒检测代表Th1、Th2、Th17的7种细胞因子，包括IL-2、IL-4、IL-6、IFN-γ、TNF、IL-17A及IL-10；利用ELISA试剂盒检测其中的IL-1β。血清中的IL-2、IL-4、IFN-γ低于检测水平，对其余细胞因子进行比较及统计学分析，结果如图8显示。实验终点CIA组小鼠血清中IL-6水平较Naive组小鼠明显上升。HF-CIA组小鼠血清中IL-10的表达水平较Naive组及CIA组小鼠均明显升高。
(2)脾脏Treg、Th1、Th2和Th17的流式细胞学检测
实验第49天摘取小鼠脾脏，流式细胞术检测Treg、Th1、Th2和Th17的表达情况。实验结果如图9显示，CIA组小鼠脾脏Treg细胞的表达较Naive组小鼠明显下降；而予以RS2的HF-CIA组小鼠脾脏Treg的表达较CIA组小鼠明显增加。如图10显示，脾脏Th1、Th2、Th17表达三组间未见明显差异。
实施例3：RS2对维甲酸致小鼠骨质疏松模型的影响
1.实验动物
昆明种小鼠，雌雄各半，体重(22±2)g，无特定病原(Specific Pathogen Free，SPF)级别，随机分为3组：
A.Control组(Control Group)，不诱导骨质疏松模型，常规饲料喂养，6只；
B.RA组(RA Group)，维甲酸诱导骨质疏松模型，常规饲料喂养，6只；
C.HFD组(High-fiber diet Group)，维甲酸诱导骨质疏松模型，从造模当天开始高纤维饲料喂养，6只。
3组动物同时饲养于四川大学华西科技园实验动物中心，室温稳定于22-25℃，12h昼夜交替，隔天补充食物及饮水，每周进行无菌垫料更换。
2.维甲酸致小鼠骨质疏松模型建立
除Control组外，其余各给药组小鼠ig维甲酸CMC悬液70mg/kg·d，连续给造模药14d，复制骨质疏松模型。对照组ig等体积生理盐水，实验过程中每周称重1次。
3.小鼠标本的收集
(1)于实验第15d摘眼球取血，以1000×g离心15min，分离血清，按照试剂盒说明书操作，检测血清钙、血清磷含量。取血完成后处死小鼠，取肝、脾、胸腺，称质量，计算脏器指数：脏器指数(mg/g)＝脏器质量(mg)/体质量(g)。选择雌性小鼠，将HE染色切片置于10倍镜下，随机选择6个视野，应用Image-Pro Plus显微测量系统，进行子宫、阴道形态计量学相关参数的测定，分别测定子宫上皮厚度、子宫腔径、子宫肌层厚度、管径厚度，统计子宫腺体个数，以及对阴道上皮厚度、阴道壁厚度进行测量。
(2)取右侧股骨，中性福尔马林浸泡，常规脱钙，切片，苏木精-伊红(HE)染色后，通过多功能真彩色细胞图像分析管理系统对骨小梁数目进行分析。剥离好的股骨利用XR-36双能X射线骨密度仪扫描小鼠并测定其股骨骨密度。
4.实验结果
(1)血清钙、血清磷含量及重要脏器指数
如图11-12显示，与Control组比较，RA组小鼠血清钙、血清磷含量增加(P＜0.05)；与RA组比较，HFD组小鼠血清钙、血清磷含量均不同程度地降低。如图13-16显示，与对照组比较，RA组小鼠甲状腺、脾指数和肝指数升高(P＜0.05或P＜0.01)，子宫指数降低(P＜0.05)；与RA组比较，HFD组小鼠甲状腺、脾指数和肝指数降低(P＜0.05或P＜0.01)，子宫指数升高(P＜0.05)。
(2)骨小梁面积数目和骨密度
如图17显示，与Control组比较，RA组小鼠骨小梁数目减少(P＜0.01)；与RA组比较，HFD组骨小梁数目减少程度得到明显改善(P＜0.05)。如图18显示，与Control组比较，RA组小鼠骨密度降低(P＜0.05)；与RA组比较，HFD组骨密度降低程度得到明显改善(P＜0.05)。
Claims (1)
1.一种高纤维膳食补充剂用于制备预防、改善骨代谢相关疾病的药品的用途；其中，所述高纤维膳食补充剂为从玉米中获得的RS2型高直链玉米淀粉，所述骨代谢相关疾病为骨关节炎或骨质疏松。
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