CN110169984B - 一种发菜藻粉在调节肠道菌群结构中的应用 - Google Patents
一种发菜藻粉在调节肠道菌群结构中的应用 Download PDFInfo
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Abstract
本发明涉及一种发菜藻粉在调节肠道菌群结构中的应用。本应用为在调节肠道菌群结构中的应用,发菜藻粉可提高益生菌/致病菌的比值进而达到改善肠道健康的目的,这将有利于机体增强免疫力,预防和治疗高血压,高血脂及抗肿瘤。该法无任何副作用,适宜长期服用。
Description
技术领域
本发明属于天然产物应用技术领域,尤其是一种发菜藻粉在调节肠道菌群结构中的应用。
背景技术
人体是一个非常复杂的生态系统,肠道微生物是肠道微环境的主要构成部分,是动物体内复杂且重要的微生态系统。正常宿主肠道内定植的微生物包含上千种,其中以拟杆菌门与厚壁菌门丰度最高,占肠道微生物总量的90%以上。这些与宿主建立共生关系的微生物能影响多种生理功能。随着大量的肠道微生物研究的开展和深入,科学家发现其结构的失调与多种慢性疾病的发生发展关系密切,如糖尿病、肥胖、类风湿、帕金森病、心脑血管疾病及一些精神类疾病等都与肠道微生物相关。因此肠道微生物在宿主体内如何行使其重要功能越发成为研究的热点。近年来又有研究表明,肠道微生物的稳态对于调节宿主免疫的发育,维持机体正常免疫机能有不可或缺的作用。因此肠道健康与否将决定性地影响着我们的机体健康。
厚壁菌一拟杆菌一放线菌门为主微生物组合构成了成年人型菌群结构。人体的肠道微菌群结构直接影响了人体的内分泌系统,微生物结构的异常往往引起人体的代谢疾病,其中尤其与拟杆菌门和厚壁菌门二者间的比例有关,同时拟杆菌门/厚壁菌门比例也对肠道的消化吸收有影响,通过改善拟杆菌/厚壁菌门比例能调节血糖、血脂与体重。
阿卡曼氏菌(Akkermansia)是人体肠道中一种可降解粘蛋白的细菌,研究表明它与肥胖、糖尿病、炎症和代谢紊乱呈负相关,它发挥有益作用的机制可能是可以调节肠道内壁厚度和维持肠道屏障完整性,以及其他对内分泌的调节作用尤其对高血糖、肥胖有很好的调节作用。高血糖、肥胖人群的肠道中的含量不到普通人群的1/100,日前法国的Laurence Zitvogel实验室,给出了非常轰动的结果:阿卡曼氏菌在增加癌症免疫治疗效果上有非常显著的作用,赋予阿卡曼氏菌“抗癌新星”的称号。
发状念珠藻(Nostoc flagelliforme),俗名发菜,在植物分类系统中属于蓝藻门(Cyanophyta)、蓝藻纲(Cyanophyceae)、段殖体目(Hormogonales)、念珠藻科(Nostocaceae)、念珠藻属(Nostoc)。因其在生态上的特殊性和经济价值而备受关注。近年来发菜细胞因其所具有的多种生物活性而备受关注,目前所知的藻类所具有的活性主要表现在免疫调节、抗肿瘤、抗氧化、抗病毒、抗凝血等方面。但其在调节肠道微生物环境方面的应用还鲜有报道。
通过检索,发现如下三篇与本发明专利申请相关的专利公开文献:
1、专利公开号CN 108524749 A提供了一种用于改善肠道菌群分布的中药组合物及应用,该方法使用生地黄、茯苓、天冬,组合而成的中药成分,有效降低加了厚壁菌门/拟杆菌门的比例促进了肠道短链脂肪酸的分泌,从而达到增进肠道健康的作用,以及降低疾病的风险。但该方法所需的原材料较多对配比有一定要求,所涉及到的材料中草药均有一定的毒副作用,本方法利用的发菜是一种可食用性藻类安全性高无副作用,另外与该方法相比发菜藻粉不仅能降低厚壁菌门/拟杆菌门的比例,而且能够显著提高阿卡曼氏菌(Akkermansia)的丰度,这提示发菜藻粉不仅具有这些物质所展示的综合效果,且在预防和治疗肥胖及抗肿瘤方面有着独特的功效。
2、专利公开号CN 106962933 A提供了一种香水莲花提取物及其组合物在预防肥胖、改善肠道菌群方面的用途,该方法通过提取香水莲花不同部位的提取物及荷叶、绿茶、决明子、葡萄籽的提取物物并将其混合用于干预治疗,从而有效改善了肠道菌群且发现其在预防肥胖方面的作用显著,且所用到的材料均无毒副作用,但相较于本发明的发菜藻粉制备过程其提取工艺路线相对复杂,且其对阿卡曼氏菌的提高效果差。
3、专利公开号CN108403930 A提供了一种提高肠道中AKK菌/致病菌比值的复合制剂及制备方法与应用,其按一定比例将低聚糖、植物提取物、真菌提取物、牛磺酸钠、沙枣提取物复合成制剂,该法有效提高肠道中阿卡曼氏菌的丰度,降低致病菌的丰度,但相较于本发明该法工艺路线相对复杂,且未对其应用方式的多样性进行探究,有一定的局限性,产品的开发与利用还有待探究。
通过对比,本发明专利申请与上述专利公开文献存在本质的不同。
发明内容
本发明目的在于克服现有技术的不足之处,提供一种发菜藻粉在调节肠道菌群结构中的应用,该应用为在调节肠道菌群结构中的应用,发菜藻粉可提高益生菌/致病菌的比值进而达到改善肠道健康的目的,这将有利于机体增强免疫力,预防和治疗高血压,高血脂及抗肿瘤。该法无任何副作用,适宜长期服用。
本发明解决其技术问题所采用的技术方案是:
一种发菜藻粉在调节肠道菌群结构中的应用。
而且,所述发菜藻粉通过显著提高益生菌的数量、降低致病菌的数量,从而显著提高肠道微生物的丰度以改善肠道菌群结构;
或者,所述发菜藻粉中的发菜多糖、发菜藻胆蛋白在调节肠道菌群结构中的应用。
而且,所述益生菌包括:阿卡曼氏菌属(Akkermansia)、拟杆菌属(Bacteroides)、普雷沃菌属(Alloprevotella)、Blautia、ALllobaculum、普氏菌属(Prevotella)、Butyricimonas、双歧杆菌(Bifidobacterium)、瘤胃球菌(Desulfovibrio),所述致病菌为:脱硫弧菌(Desulfovibrio)、螺杆菌属(Helicobacter)、脲原体菌属(Ureaplasma)或变形菌门(proteobacteria)。
而且,所述发菜藻粉是由野生发菜经人工液体扩大培养后干燥粉碎获得的;
或者,所述发菜藻粉含有总质量20-30%的多糖、25-30%蛋白质以及1-2%的油脂;
或者,所述发菜藻粉的颗粒尺寸为60~150μm。
而且,所述野生发菜细胞的人工液体扩大培养条件为:温度:17-30℃,光照强度:100-5000Lux;人工液体扩大培养时使用的液体培养基,其成分满足发菜生长所需即可;
或者,所述干燥粉碎的方法能够达到粉碎的效果且不破坏发菜的结构及营养成分。
而且,所述发菜藻粉含量在30~90%(m/m),推荐使用量为:100~500mg发菜藻粉/kg。
一种发菜藻粉在制备调节肠道菌群结构的药物中的应用。
一种发菜藻粉在制备调节肠道菌群结构的食品中的应用。
而且,所述食品为饼干、面包、糖果、冰激凌、糕点、调味料、保健品或饮品。
而且,所述饮品为奶茶、果汁或发酵乳。
本发明取得的优点和积极效果为:
1、本发明提出了一种能够有效调节动物肠道菌群结构的手段。基于高通量测序技术以及统计学方法,本申请人发现了发菜藻粉具有调节肠道菌菌群的功能,发菜藻粉可提高益生菌/致病菌的比值进而达到改善肠道健康的目的,这将有利于机体增强免疫力,预防和治疗高血压,高血脂及抗肿瘤。该法无任何副作用,适宜长期服用。其中要特别强调的是,发菜藻粉的主要有效活性成分为发菜多糖及发菜藻胆蛋白,现阶段未见发菜藻粉及发菜多糖,发菜藻胆蛋白在调节肠道菌群结构方面的报道。
因而,本发明提供了发菜藻粉在调节肠道菌群结构中的用途。即将发菜藻粉以适当的形式、剂量对动物进行给药处理,经一段时间的干预后达到调节动物肠道菌群结构的目的,实验表明发菜藻粉能显著提高益生菌的数量,降低致病菌的数量,从而显著提高肠道微生物的丰度以改善肠道菌群结构,进而通过肠道菌群的作用而发挥增强免疫力、预防和治疗肥胖、高血压、高血脂,肿瘤等功效,为发菜藻粉在肠道菌群结构方面的开发和应用奠定了基础。
2、目前市场上常见的肠道微生物调节剂主要包括益生菌和益生元。补充益生菌虽然有益肠道健康,但外来的益生菌难以在肠道内长期定植及形成分布优势,因此效果不能持续。益生元日用量较大且需长期服用。发菜是一种天然的发状念珠蓝细菌,其富含丰富的蛋白质、多糖和钙、铁等。发菜藻粉的原料易获取且制备方式简单,安全性极高无毒副作用,将发菜藻粉的单独食用或与其他天然产物复配,均能有效改善肠道环境,提高有益菌的数量,降低致病菌的数量。
3、本发明中发菜及其加工产品均能降低厚壁菌门/拟杆菌门的比值,且显著增加阿卡曼氏菌(Akkermansia)的相对丰度,这将为发菜藻粉的抗癌,降血脂作用提供理论依据。
4、本发明中发菜及其加工产品能够有效促进肠道短链脂肪酸的分泌,且能促进抑炎因子的产生,抑制炎症反应,这提示发菜藻粉对机体的免疫系统有积极作用。
5、本发明改善肠道菌群结构的方法所涉及到的发菜藻粉及可单独食用亦可作为添加剂用于药物、营养品、保健品、饮料、食品等领域。
6、本发明食品还具有所有原料源于天然,安全可靠,原料来源广泛易得,制备工艺简单,贮运和应用安全,生产成本低廉,质量稳定,可长期保存的优点。
附图说明
图1为本发明中发菜藻粉对小鼠体重的影响变化图;
图2为本发明中小鼠平均周体重变化图;
图3为本发明中发菜藻粉对肠道失调小鼠盲肠内短链脂肪酸含量的影响变化图。
具体实施方式
下面详细叙述本发明的实施例,需要说明的是,本实施例是叙述性的,不是限定性的,不能以此限定本发明的保护范围。
本发明中所使用的原料,如无特殊说明,均为常规的市售产品;本发明中所使用的方法,如无特殊说明,均为本领域的常规方法。
一种发菜藻粉在调节肠道菌群结构中的应用。
较优地,所述发菜藻粉通过显著提高益生菌的数量、降低致病菌的数量,从而显著提高肠道微生物的丰度以改善肠道菌群结构;
或者,所述发菜藻粉中的发菜多糖、发菜藻胆蛋白在调节肠道菌群结构中的应用。
较优地,所述益生菌包括:阿卡曼氏菌属(Akkermansia)、拟杆菌属(Bacteroides)、普雷沃菌属(Alloprevotella)、Blautia、ALllobaculum、普氏菌属(Prevotella)、Butyricimonas、双歧杆菌(Bifidobacterium)、瘤胃球菌(Desulfovibrio),所述致病菌为:脱硫弧菌(Desulfovibrio)、螺杆菌属(Helicobacter)、脲原体菌属(Ureaplasma)或变形菌门(proteobacteria)。
较优地,所述的发菜藻粉是由野生发菜经人工液体扩大培养后干燥粉碎获得的。
较优地,所述的野生发菜的选择不受地域的影响,所述的发菜细胞的人工液体扩大培养条件为,温度:17-30℃,光照强度:100-5000Lux。所涉及的液体培养基,其成分满足发菜生长所需即可。
较优地,所述的发菜细胞干燥粉碎方法不做具体约束,只要能达到粉碎的效果且不破坏发菜的结构及营养成分即可。
较优地,所述发菜藻粉主要含有碳水化合物以及少量脂质,包括20-30%的多糖,25-30%蛋白质以及1-2%的油脂。
较优地,所述发菜藻粉的颗粒尺寸为60~150μm,由此,有利于原料中的有效成分均匀分散,便于在所述动物的胃肠道吸收。从而更好地发挥其调节动物肠道菌群结构的作用。
较优地,本发明中所使用的表达方式“发菜藻粉在调节肠道菌群结构中的用途”中所指述“肠道”对其供体动物类型不受特别的限制,给药方式不受限制。即该动物可以为任何具有肠道器官的动物,优选哺乳动物,更优选大鼠、小鼠、人,最优选人;给药方式可根据不同的动物对象择优选择,如:灌胃,自由觅食,水服等。
较优地,本发明中所使用的表达方式“发菜藻粉在调节肠道菌群结构中的用途”中所述“适当的形式”包括发菜藻粉及利用发菜藻粉制备的药物、食品和饮品。
较优地,所述药物,须包含发菜藻粉;以及药学可接受的任意形式的赋形剂。任意地,药物形式可选自胶囊剂、丸剂、颗粒剂、口服液剂内服膏剂、气雾剂以及喷雾剂的至少一种形式。
较优地,发菜藻粉含量在30~90%(m/m),推荐使用量100~500mg发菜藻粉/kg。所用剂量应能够显著提高被给药动物肠道内益生菌数量,调节肠道菌群结构。
较优地,所述的食品,须包含发菜藻粉以及食品行业可以接受的添加剂。任意地,所述食品为选自饼干、面包、糖果、冰激凌、糕点、调味包的至少一种。
较优地,所述的饮品,须包含发菜藻粉提取物以及饮品行业可以接受的添加剂。任意地,所述饮品为奶茶、果汁、发酵乳的至少一种。
较优地,因发菜藻粉没有任何副作用,因而发菜藻粉在食品及饮品中的添加量不受特别限制,只要能提高食用者肠道的有益菌数量有效调节动物的肠道菌群结构,且保证风味可被人接受即可。需要说明的是,在本发明中所使用的术语“食品”应作广义理解,其可以是任何可被食用的形式,即除了常规的食品形式外,本发明的食品还可以为保健品,冰激凌等,有时也被称为“功能食品”。
另外,值得指出的是本发明中所表达的“发菜藻粉通过改变肠道菌群结构而具有的增强免疫力、预防和治疗肥胖、高血压、高血脂,肿瘤”是通过相关文献调研得出的结论。如:肠道中的优势菌:厚壁菌门与拟杆菌门的比例,有研究表明,厚壁菌门所占比例越大,拟杆菌门所占比例越小,机体体重越大。此外,一些肠道重要的微生物也与肥胖相关;再如阿卡曼氏菌属(Akkermansia)与脱硫弧菌(Desulfovibrio),研究表明,将阿卡曼氏菌(Akkermansia)移植到肥胖小鼠的肠道内,小鼠的肥胖症状得到改善。脱硫弧菌是革兰氏阴性菌,它能分泌内毒素,使机体产生炎症反应,进而导致机体非正常肥胖。
具体地,发菜藻粉的相关制备及应用如下:
一、发菜藻粉的制备
发菜细胞培养:将发菜细胞种子液接种于灭菌后的BG11培养基中,使初始菌体量达到10%(V/V),在温度为24℃,光照强度:100-5000Lux,光照周期24:0条件下通气培养25天。培养结束后4000r离心10min,收集发菜细胞。
发菜藻粉制备:将收集到的发菜细胞置于-20℃冷冻,将冷冻的发菜细胞置于冷冻干燥机中制得发菜干细胞,随后使用粉碎机粉碎发菜干细胞即可制得发菜藻粉。
二、发菜藻粉片剂的制备
原料:发菜藻粉、糖粉、淀粉、滑石粉、羧甲基淀粉钠。
制备方法:分别称取发菜藻粉、糖粉、淀粉、滑石粉、羧甲基淀粉钠,其中发菜藻粉的重量为所有物料总重量的20%,其它辅料按照制片标准添加。采用超粉碎设备进一步技工粉碎,过筛,获得颗粒粒径100微米左右的混合细粉,与适量的润滑剂混合,然后将所得物料置于单冲压片机中,按照现有片剂生产技术要求制成片剂。
三、发菜藻粉饼干的制备
原料:面粉、发菜藻粉、甜味剂、磷脂、调味剂、小苏打、植物油、奶粉、鲜鸡蛋、水
制备方法:将5重量份发菜藻粉、100重量份面粉混合均匀,加入4重量份糖、0.5重量份磷脂、1.0重量份精盐、0.2重量份小苏打、8.0重量份植物油、8.0重量份奶粉、2.0重量份鲜鸡蛋和20重量份饮用水,将上述原料混匀后,制成面团,放入冰箱冷却。从冰箱将冷却好的面团取出,放在操作台上,用搬面棍搬成3mm厚的面片,用花边圆戳子戳下来,摆放在烤盘上,上边刷蛋液,送入180℃烤炉大约10min烤熟。
四、发菜藻粉饮料的制备
原料:发菜藻粉、果糖浆、蔗糖、白冰糖、蜂蜜、柠檬汁、水
将发菜藻粉与水按质量比1:50-150混合,置于80℃水浴中处理3h,过滤,以得到发菜多糖粗提液。将粗提液稀释100倍,并向稀释液中添加1%(w/v)蔗糖脱腥,继续添加8%(w/v)的果浆糖,8%(w/v)的白冰糖,6%(v/v)的蜂蜜以及6%(v/v)的柠檬汁,以调整饮品的口味,充分溶解后过滤,杀菌,装罐后即制得所述发菜藻粉饮料。
本发明的相关检测:
以原材料“发菜藻粉”进行以下实验:
1.发菜藻粉改善小鼠肠道菌群结构实验
1.1实验设计思路
发菜藻粉的获得方式如下:向80L BG11培养基中接种10%(V/V)的发菜细胞。培养温度为24℃,光照强度:100-5000Lux,光照周期24:0,通气培养,培养15天。4000r离心10min,收集发菜细胞,使用冷冻干燥机制得发菜藻粉。
30只25日龄SPF级C57BL/6雄性小鼠,体重1~20g。饲养温度:22±2℃,湿度为30-70%的动物房适应性饲养一周后,随机分为3组,每组10只,即正常饮食组+生理盐水(NC),高剂量组(LL),低剂量组(LH),继续饲养或处理4周,具体处理方案如表1。
表1 灌喂方案
对照组(NC) | 饲料+水 | 灌胃生理盐水 |
高剂量组(LH) | 饲料+水 | 灌胃400mg/kg·bw |
低剂量组(LL) | 饲料+水 | 灌胃200mg/kg·bw |
实验过程中每日定点检测一次小鼠体重,实验结束前48小时取新鲜粪便,冷冻保存。8周后各组小鼠禁食12h,称重,摘眼球采血,随即颈椎脱臼处死,取肝脏、脾脏、胰腺,称重记录并冷冻。采用高通量测序对粪便菌群测定。
1.2发菜藻粉对小鼠肠道多样性的影响
表2 发菜藻粉对小鼠肠道微生物多样性指数的影响
样本多样性分析(Alpha-diversity)可以反映肠道微生物的丰度与多样性。其中OTU(Operational Taxonomic Units,操作分类单元)是在系统发生学或群体遗传学中,人们根据某一个分类水平设置的标志,在本实验中把有效序列相似性在97%以上的归为1个OTU,Chao与Ace与是反映肠道微生物丰度的指数,Chao值与Ace值越大,说明肠道微生物丰度越高;(香农指数)Shanon与Simpson(辛普森指数)是反映肠道微生物多样性的指数,Shanon数值越大,说明肠道微生物多样性越高,而Simpson数值越大,说明肠道微生物多样越低;Coverage(测序覆盖度)则是反映测序深度的指数,其数值越,说明越能反映肠道微生物的真实情况。
表2反映了不同剂量灌胃后小鼠肠道微生物丰度与多样性的变化情况。在本次实验中,各组Coverage值均大于0.99,表示本次实验能反映小鼠肠道微生物的真实情况。由Chao值与Ace值可知,发菜藻粉能使小鼠肠道微生物丰度升高。由值Shanon与Simpson值可知,不同剂量的发菜藻粉均使高脂膳食小鼠肠道微生物多样性增加。此外,高剂量的发菜藻粉比低剂量的发菜藻粉对肠道菌群的丰度及多样性的提高效果更好。
1.3发菜藻粉对小鼠肠道生物菌群结构组成的影响
表3 发菜藻粉对肠道菌群分布(门分类水平)的影响
门 | NC | LH | LL |
拟杆菌门 | 68.89 | 71.32 | 70.28 |
厚壁菌门 | 27.49 | 25.89 | 26.41 |
放线菌门 | 2.75 | 3.01 | 2.98 |
变形菌门 | 0.54 | 0.57 | 0.76 |
疣微菌门 | 1.49 | 1.3=25 | 1.38 |
无壁菌门 | 0.04 | 0.03 | 0.02 |
F/B | 0.40 | 0.36 | 0.37 |
从菌群结构中可知,每组小鼠肠道内包含的主要肠道微生物菌门均为厚壁菌门(Firmicutes)、拟杆菌门(Bacteroidetes)、变形菌门(Proteobacteria)、放线菌门(Actinobacteria)、变形菌门(proteobacteria)、疵微菌门(Verrucomicrobia)和无壁菌门(Tenericutes),其中优势菌群均为Firmicutes与Bacteroidetes,这与前人报道一致。然而五组小鼠肠道微生物菌群在门分类水平上的比例分布有较大的差异。相比于正常对照组,LH和LL组F/B值都有不同程度的降低。相关资料显示,厚壁菌门与拟杆菌门的比值值与肥胖有着密切的关系,F/B值与个体体重呈正相关。因此,通过结合体重变化曲线图1推测发菜藻粉能通过调节肠道微生物菌群结构来起到一定的肥胖降脂作用。
表4 发菜藻粉对几种常见肠道有益菌及有害菌(属分类水平)的影响
种 | NC | LH | LL |
乳酸杆菌 | 0.55 | 0.61 | 0.58 |
双歧杆菌 | 0.12 | 0.17 | 0.15 |
阿卡曼氏菌 | 0.15 | 0.24 | 0.22 |
脱硫弧菌 | 0.011 | 0.08 | 0.09 |
天然产物能通过改变肠道微生物的菌群构成(包括肠道有益菌与肠道有害菌)对健康产生积极作用。发菜藻粉对几种常见肠道有益菌及有害菌的影响见表4,其中乳酸杆菌(Lactobacillus)、双歧杆菌(Bifidobacterium)、阿卡曼氏菌(Akkermansia)是肠道益生菌,脱硫弧菌(Desulfovibrio)是肠道有害菌。乳酸杆菌,因能发酵糖产生大量乳酸得名,它能通过释放抗菌物质乳酸、过氧化氢、细菌素,竞争黏附位点、竞争营养物质,诱导劲液素分泌、保护上皮细胞,调控肠道免疫功能来改善宿主健康。双歧杆菌是人体肠道内重要的益生菌,它不产生内毒素、治病物质以及有害气体,具有调节肠道菌群结构、降低胆固醇、抗肿瘤、延迟集体衰老等作用。阿卡曼氏菌是寄居在宿主肠道粘液层并能降解劲蛋白。前人研究发现该菌能使肥胖小鼠在不改变膳食的前提下,改善小鼠代谢紊乱状况,包括抗肿瘤,减少脂肪量,代谢内毒素及改善脂肪组织炎症与胰岛素抵抗等。脱硫弧菌是肠道有害菌,它能在宿主体内代谢硫酸盐产生硫化氢,过量的硫化氢会使肠上皮粘膜受到损害,且它能产生内毒素造成机体炎症反应,而机体炎症与肥胖有极大的相关性。
相对于正常对照组,LH与LL组能提高小鼠肠道内乳酸杆菌、双歧杆菌、菌数量,减少脱硫弧菌数量。推测发菜藻粉对提高机体免疫及抗肿瘤也有一定的效果。
1.4发菜藻粉对小鼠免疫系统的影响
外周血液的血清中存在着大量的免疫相关因子,因此研究外周血液中慢性免疫因子的分泌水平能在一定程度上反应机体的免疫能力,发菜藻粉对小鼠外周血液中免疫因子浓度影响见表5,结果表明:发菜藻粉能降低促炎因子(IL-1β)的浓度,而升高促炎因子TNF-α、INF-γ浓度,另外分泌型免疫球蛋白SigA的浓度显著升高,这均在一定程度说明发菜藻粉对小鼠的免疫系统有一定的性影响,TNF-α是一种能够直接杀伤肿瘤细胞而对正常细胞无明显毒性的细胞因子,是迄今为止所发现的直接杀伤肿瘤作用最强的生物活性因子之一,IFN-γ是一类糖蛋白,具有一定的抗病毒、抑制细胞增殖、调节免疫及抗肿瘤作用。分泌型IgA(SIgA)是机体粘膜防御系统的主要成分,覆盖在鼻、咽、气管、肠和膀胱粘膜的表面,它能抑制微生物在呼吸道上皮附着,减缓病毒繁殖,是粘膜重要屏障,对某些病毒、细菌和—般抗原具有抗体活性,是防止病原体入侵机体的第一道防线。外来抗原进入呼吸道或消化道,局部免疫系统受到刺激后,无需中央免疫系统的参与,自身就可进行免疫应答,产生分泌型抗体,即SIgA。已有研究证明,呼吸道分泌液中SigA含量的高低直接影响呼吸道粘膜对病原体的抵抗力,两者呈正相关。因此我们认为发菜藻粉对小鼠的免疫效果是积极的。
表6展示了发菜藻粉对小鼠免疫器官指数的影响,有研究表明机体的免疫能力与免疫器官指数呈正相关,根据表5可知,LH组与对照组相比免疫器官指数明显上升这也反应了发菜藻粉对小鼠免疫机能有一定的提高作用。
表5 发菜藻粉对小鼠外周血液中免疫因子(IL-1β、TNF-α、IFN-γ)及肠道内容物中SigA的影响
指标 | NC(μg/mL) | LH(μg/mL) | LL(μg/mL) |
IL-1β | 512.12±17.56 | 310.45±10.49 | 390.45±9.87 |
TNF-α | 50.46±5.56 | 121±10.52 | 85±7.83 |
IFN-γ | 112.48±20.1 | 260.85±15.22 | 213.89±1.85 |
SigA | 17.57±2.98 | 26.22±4.53 | 25.71±2.65 |
表6 发菜藻粉对小鼠免疫器官指数的影响
组 | n | Thymusindex | Spleenindex |
NC | 10 | 1.55±0.12 | 4.03±0.13 |
LH | 10 | 1.99±0.28 | 4.59±0.34 |
LL | 10 | 1.63±0.19 | 4.09±0.21 |
综上所述,发菜藻粉在动物改善肠道菌群结构方面的效果显著。通过进一步的论证也为其在增强免疫力、预防和治疗肥胖、高血压、高血脂,肿瘤等方面提供了指导性的意见。
二、发菜藻粉对菌群失调模型小鼠的影响
2.1实验设计
发菜藻粉的获得方式如下:向80LBG11培养基中接种10%(V/V)的发菜细胞。培养温度为24℃,光照强度:100-5000Lux,光照周期24:0,通气培养,培养15天。4000r离心10min,收集发菜细胞,将收集到的发菜细胞于40℃下烘干,并使用粉碎机粉碎,制得发菜藻粉。
40只25日龄的SPF级C57BL/6雄性小鼠,体重17~20g,饲养温度为22±2℃,湿度为30-70%的动物房适应性饲养一周后,取10只小鼠灌胃生理盐水作为正常组,另取30只小鼠灌胃头孢拉定和庆大霉素抗生素混合液构建菌群失调模型,均按计量0.4mL/次,2次/天,连续造模10天,确保造模小鼠出现粪便稀软等抗生素相关性腹泻(AAD)症状。
将预处理后的小鼠随机分为4组,每组10只,即正常饮食组、模型组、实验Ⅰ组、实验Ⅱ组。各组小鼠给予发菜的方式、灌胃体积和天数,见表7实验期为30天,饲养条件与适应性实验一致。
实验过程中每周定点检测一次小鼠体重,实验结束前48小时取新鲜粪便,冷冻保存。4周后各组小鼠禁食12h,称重。采用高通量测序对粪便菌群测定。采用气相色谱仪对盲肠中的短链脂肪酸进行测定。
表7 小鼠的灌喂方案的实验设计
2.2发菜对小鼠体重的影响
连续30d灌胃发菜藻粉,记录各组小鼠给药后每周的平均体质量差值,结果如2图所示。结果显示,各发菜灌胃实验组小鼠给药后体重较模型组均显著增加,且高剂量组对体重的增加效果要优于低剂量组,经过4周的发菜藻粉给予后小鼠体重基本恢复正常。以上结果证明发菜藻粉能够有效促进菌群失调小鼠的生长,帮助小鼠恢复体质。
2.3发菜藻粉对肠道失调小鼠菌群丰度的影响
表8 肠道微生物多样性指数
样本多样性分析(Alpha-diversity)可以反映肠道微生物的丰度与多样性。其中OTU(Operational Taxonomic Units,操作分类单元)是在系统发生学或群体遗传学中,人们根据某一个分类水平设置的标志,在本实验中把有效序列相似性在97%以上的归为1个OTU,Chao与Ace与是反映肠道微生物丰度的指数,Chao值与Ace值越大,说明肠道微生物丰度越高;香农指数)Shanon与Simpson(辛普森指数)是反映肠道微生物多样性的指数,Shanon数值越大,说明肠道微生物多样性越高,而Simpson数值越大,说明肠道微生物多样越低;Coverage(测序覆盖度)则是反映测序深度的指数,其数值越,说明越能反映肠道微生物的真实情况。
肠道菌群失调小鼠在给予发菜藻粉灌胃后肠道微生物丰度与多样性的变化情况见表8。在本次试验中,各组Coverage值均大于0.99,表示本次实验能反应小鼠肠道微生物的真实情况。由Ace值与Chao值均可知,建模会导致小鼠肠道微生物丰度降低,而不同剂量的发菜藻粉均能使肠道菌群失调的小鼠微生物多样性增加。
2.4发菜藻粉对肠道失调小鼠菌群结构的影响
结果如表9所示,从菌群结构中可知,每组小鼠肠道内包含的主要肠道微生物菌门均为厚壁菌门(Firmicutes)、拟杆菌门(Bacteroidetes)、变形菌门(Proteobacteria)、放线菌门(Actinobacteria)、变形菌门(proteobacteria)、疵微菌门(Verrucomicrobia)和无壁菌门(Tenericutes),其中优势菌群均为Firmicutes与Bacteroidetes,这与前人报道一致。然而五组小鼠肠道微生物菌群在门分类水平上的比例分布有较大的差异。相比于正常对照组,模型组的拟杆菌门相对丰度显著下降,厚壁菌门的相对丰度显著升高。而相对于模型对照组,发菜藻粉干预的实验组则出现拟杆菌门升高,厚壁菌门下降的现象,且其相对丰度更接近与对照组,这证明发菜藻粉的灌胃有助于小鼠肠道菌群结构的恢复。
此外,孢拉定和庆大霉素抗生素混合液严重扰乱了小鼠肠道微生物菌群结构,它导致模型对照组小鼠肠道内放线菌门微生物数量猛增,其比例高达8.78%(正常对照组为2.75%)变形菌门微生物数量提高,可达到4.06%(正常对照组为0.54%)。前人研究表溃疡性结肠炎等肠道疾病患者微生物多样性降低,放线菌门与变形菌门微生物增多。这证明建模的成功,另外发现发菜藻粉干预组能有效降低这几种菌门的相对丰度。
表9 发菜藻粉对肠道微生物菌群分布(门分类水平)的影响
门 | Nomal group | Model group | Ⅰgroup | Ⅱgroup |
拟杆菌门 | 68.89 | 36.89 | 67.71 | 62.23 |
厚壁菌门 | 27.49 | 47.58 | 33.15 | 34.25 |
放线菌门 | 2.75 | 8.78 | 0.89 | 0.78 |
变形菌门 | 0.54 | 4.056 | 0.98 | 1.58 |
疣微菌门 | 1.49 | 2.51 | 0.98 | 1.38 |
无壁菌门 | 0.04 | 0.03 | 0.04 | 0.02 |
表10 发菜藻粉对肠道菌群分布(属门类水平)的影响
种 | Nomal group | Model group | Ⅰgroup | Ⅱgroup |
乳酸杆菌 | 0.55 | 0.17 | 0.58 | 0.60 |
双歧杆菌 | 0.12 | 0.05 | 0.08 | 0.11 |
阿卡曼氏菌 | 0.05 | 0.00 | 0.22 | 0.29 |
脱硫弧菌 | 0.01 | 0.89 | 0.09 | 0.10 |
天然产物能通过改变肠道微生物的菌群构成(包括肠道有益菌与肠道有害菌)对健康产生积极作用。发菜藻粉对几种常见肠道有益菌及有害菌的影响见表10,其中乳酸杆菌(Lactobacillus)、双歧杆菌(Bifidobacterium)、阿卡曼氏菌(Akkermansia)是肠道益生菌,脱硫弧菌(Desulfovibrio)是肠道有害菌。乳酸杆菌,因能发酵糖产生大量乳酸得名,它能通过释放抗菌物质乳酸、过氧化氢、细菌素,竞争黏附位点、竞争营养物质,诱导劲液素分泌、保护上皮细胞,调控肠道免疫功能来改善宿主健康。双歧杆菌是人体肠道内重要的益生菌,它不产生内毒素、治病物质以及有害气体,具有调节肠道菌群结构、降低胆固醇、抗肿瘤、延迟集体衰老等作用。阿卡曼氏菌是寄居在宿主肠道粘液层并能降解劲蛋白。前人研究发现该菌能使肥胖小鼠在不改变膳食的前提下,改善小鼠代谢紊乱状况,包括抗肿瘤,减少脂肪量,代谢内毒素及改善脂肪组织炎症与胰岛素抵抗等。脱硫弧菌是肠道有害菌,它能在宿主体内代谢硫酸盐产生硫化氢,过量的硫化氢会使肠上皮粘膜受到损害,且它能产生内毒素造成机体炎症反应,而机体炎症与肥胖有极大的相关性。另外我们发现发菜藻粉能够显著提高阿卡曼氏菌
相对于正常对照组,肠道失调的小鼠肠道乳酸杆菌、双歧杆菌数量减少,Akk.菌没有检出,脱硫弧菌数量增多。相对于模型对照组,发菜藻粉灌胃实验组能显著提高小鼠肠道内的乳酸杆菌、双歧杆菌Akk.菌数量,减少脱硫弧菌的数量。另外本申请人发现发菜藻粉能够显著提高阿卡曼氏菌这是其他物质所不具备的一种特性,这意味着发菜藻粉对增加肠道菌群失调小鼠肠道内的有益菌有积极作用,对其肠道内的有害菌有抑制作用。
2.5发菜藻粉对小鼠盲肠短链脂肪酸含量的影响
短链脂肪酸一般是指乙酸、丙酸、丁酸、异丁酸、戊酸和异戊酸,它们由肠道微生物通过厌氧发酵肠道中纤维和抗性淀粉而产生。短链脂肪酸中,乙酸可迅速被肠上皮吸收进入外周血液并为宿主供能,丙酸经上皮吸收后进入肝脏,用于糖原合成,丁酸是结肠上皮细胞的能源物质,能促进肠道上皮细胞增值与发育,肠道微生物也可以通过利用乳酸和丙酸转化为丁酸。短链脂肪酸还可以降低肠道pH,促进有益菌如比双歧杆菌等的增殖,并抑制特定病原菌的定植。因此,肠道短链脂肪酸含量的增加有益于肠道健康,有利于动物生长。结果如图3所示,结果显示,相较于对照组模型组的小鼠盲肠内短链脂肪酸(乙酸、丙酸、丁酸)含量显著下降,另一方面发菜藻粉能够显著提高肠道菌群失调小鼠大肠内短链脂肪酸的产量。且高剂量组基本能够使小鼠盲肠内的短链脂肪酸含量恢复至与正常对照组同一水平。
综上所述发菜藻粉对肠道菌群失调的小鼠的肠道环境有一定的调节作用,能够改善肠道菌群结构,恢复小鼠体重,增加肠道内短链脂肪酸的含量,这些指标均有利于肠道的健康。且通过增加的有益菌的种类与数量,本申请人推测其在增强免疫力、预防和治疗肥胖、高血压、高血脂,肿瘤等方面将有一定的疗效。
尽管为说明目的公开了本发明的实施例,但是本领域的技术人员可以理解:在不脱离本发明及所附权利要求的精神和范围内,各种替换、变化和修改都是可能的,因此,本发明的范围不局限于实施例和附图所公开的内容。
Claims (4)
1.一种发菜藻粉在调节小鼠肠道菌群结构中的应用,其特征在于:所述发菜藻粉通过显著提高益生菌的数量、降低致病菌的数量,从而显著提高肠道微生物的丰度以改善肠道菌群结构;
所述益生菌包括:阿卡曼氏菌(Akkermansia)、双歧杆菌(Bifidobacterium), 所述致病菌为:脱硫弧菌(Desulfovibrio);
所述发菜藻粉是由野生发菜经人工液体扩大培养后干燥粉碎获得的;
所述发菜藻粉含有总质量20-30%的多糖、25-30%蛋白质以及1-2%的油脂;
所述发菜藻粉的颗粒尺寸为60~150μm;
所述野生发菜的人工液体扩大培养条件为:温度:17-30℃,光照强度:100-5000Lux;人工液体扩大培养时使用的液体培养基,其成分满足发菜生长所需即可;
所述干燥粉碎的方法能够达到粉碎的效果且不破坏发菜的结构及营养成分;
所述应用为发菜藻粉在制备调节肠道菌群结构的药物、食品中的应用。
2.根据权利要求1所述的应用,其特征在于:所述食品为饼干、面包、糖果、冰激凌、糕点、调味料、保健品或饮品,所述食品中发菜藻粉含量在30~90%(m/m)。
3.根据权利要求1所述的应用,其特征在于:所述食品中发菜藻粉的使用量为:100~500mg发菜藻粉/kg。
4.根据权利要求1所述的应用,其特征在于:所述饮品为奶茶、果汁或发酵乳。
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