CN110384719B - 可改善高血压的罗伊氏乳杆菌菌株gmnl-263及其组合物 - Google Patents
可改善高血压的罗伊氏乳杆菌菌株gmnl-263及其组合物 Download PDFInfo
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Abstract
本发明公开一种乳杆菌组合物,包含一罗伊氏乳杆菌(Lactobacillus reuteri)GMNL‑263,其中该罗伊氏乳杆菌(Lactobacillus reuteri)GMNL‑263为热灭杀死菌,透过抑制一促发炎细胞激素IL‑1β与提升一双歧杆菌属的生长,而具有降血压的功效,该乳杆菌组合物为医药组合物、营养补充品、保健食品或其组合。
Description
技术领域
本发明涉及微生物领域,特别是关于乳杆菌的组合物,用于改善高血压的应用。
背景技术
血压是藉由心脏的压缩与博动,进而令血液对于血管壁施加的压力。藉由血压的维持,而促进血液于全身循环,进而进行营养传输与废物的代谢;血压有两种,收缩压和舒张压,分别为心脏跳动时肌肉收缩(systole)或舒张(diastole) 时的测量值;正常血压范围为收缩压90–139mmHg(最高读数)和舒张压60–89mmHg(最低读数)。
高血压是一种动脉血压升高的慢性病,也是国内最常见的慢性病,当血压的升高使心脏推动血液在血管内循环时的负担增大,血压持续等于或高于 140/90毫米汞柱(mmHg)时则为高血压,由于很少显示症状,因此易于受到忽略,通常是通过筛查或者寻求解决其它健康问题时发现,部分患者有头痛、头晕、眩晕、耳鸣,一旦严重甚至会晕倒或是内部器官的损害,除了其症状不明常容易被忽视外,也常伴随着严重的并发症;随着年龄增长、高血压风险也随着增加,且高血压是让心血管疾病风险以倍数增加的重要因素,更为世界卫生组织所公布导致心血管疾病死亡的主要原因之一,而因其属于慢性病的一种,故患者须长期服药控制,对于时间或是金钱都是沉重的开销。
高血压分为原发性或继发性,原发性占了成因的90–95%,即没有明显病因;另一种则为继发性,表示由其它疾病所引发,占约5–10%,如糖尿病、肾脏疾病、内分泌疾病、胸腹部肥胖、甲状腺疾病及肢端肥大症或是生理的异常反应,例如促发炎细胞激素的大量产生(Krishnan et al.,2014)、肠胃道益生菌的减少(Li et al.,2017)等,均为引发或是加剧高血压的原因。
其中,长期罹患第二型糖尿病者(type 2diabetes mellitus,T2DM)为一典型的疾病与高血压连动的例子,由于糖尿病患者常衍生肾动脉和全身小动脉硬化的症状,进而使周边血管阻力与收缩压上升,造成血压升高,因此,二型糖尿病患者与高血压常相伴发生,而高血压还会加速血管病变,进而引起脑、眼、心、肾等器官的并发症,并显著提升心肌梗塞及中风风险。
目前以药物控制高血压,仍为主要治疗方式,然而,虽血压能稳定得到控制,但由于患者须长期服药,不仅时间、金钱均为沉重的负担外,服用不慎还会有风险。举例而言,部分药物会对孕妇或胎儿有害,而对原糖尿病患者而言,高血压药物可能会令影响血糖,造成糖尿病病情的恶化或是病情的错误评估;此外,随着药物本身的机制不同,如细胞受体的调控、抑制血脏搏动或是神经传导的降低等等,而有一定程度的副作用。因此,寻找其他有效而无副作用的降血压途径为解决以及预防当今高血压问题的必要之务,有许多研究,便针对如何透过健康食品控制、预防高血压。
人体的血压调节系统主要是经由肾素-血管收缩素系统 (Renin-AngiotensinSystem,RAS),以达血压、体液及电解质平衡,而在这个系统中,血管收缩素I-转化酵素(Angiotensin I-Converting Enzyme,ACE)则是血压调节中一重要的酵素,用以升高血压。
过去研究发现,益生菌发酵乳具有调节血压的功效,益生菌可透过乳糖水解酵素分解酪蛋白,而产生不等量的血管收缩素I-转化酵素抑制胜肽(ACE inhibitory peptide,以下简称ACE抑制胜肽)(Yamamoto,1999)进而降血压;研究指出,Lactobacillushelveticus(L.helveticus)、Lactobacillus caseis(L. caseis)、Lactobacillusrhamnosus(L.rhamnosus)、Lactobacillus acidophilus(L. acidophilus)、Lactobacillus fermentum(L.fermentum)、Lactobacillus bulgaricus(L. bulgaricus)、Lactobacillus reuteri(L.reuteri)…等益生菌中,可筛选出特殊的活菌菌株,将菌株与ACE抑制胜肽添加于发酵乳中,藉由菌株能于发酵乳中产生更多的ACE抑制胜肽,进而对于高血压患者有降血压的功效 (Beltran-Barrientos et al.,2016)。
然而,此部分研究仅限于部分特殊活菌菌株,且在施行上仍有若干限制与不足,在有效服用菌量以及服用时间方面,均有相当高的门坎,而在关于益生菌产品降血压的系统性回顾性研究指出,人体需每天服用益生菌数超过1x1011 cfu(colony forming unit)超过八周,才能具有较佳血压调节的功效 (Khalesi et al.,2014)。
总体而言,现今的相关研究仍多仅止于体外或是动物实验,仅服用益生菌便能改善血压的人体临床试验数据不多,目前相关的人体数据,分别为针对高血压病人使用L.helveticus与Saccharomyces cerevisiae(S.cerevisiae)复合菌株发酵乳(Hata etal.,1996),或针对血压偏高的正常人给予L.helveticus CM4 发酵乳(Aihara et al.,2005),均具有降低血压的功效;而针对糖尿病危险群,使用包含益生质及同时包含以下菌株的产品L.casei、L.acidophilus、L. rhamnosus、L.bulgaricus、Bifidobacterium Breve(B.Breve)、B.longum、 Streptococcus thermophiles(S.thermophiles),结果均具有血压调节功能 (Mahboobi et al.,2014)。
目前利用活菌透过发酵乳发酵,产生ACE抑制胜肽,使用者藉由饮用而控制血压,为主要的途径。但因益生菌非为药物剂型,而是以健康食品型式,而少有人体数据支持,故对于饮用的有效剂量、频率等功效信息往往并不明确;此外,因活菌制备过程一旦当使用或保存不当,造成污染、过期等问题,便极易引发使用者健康风险;且因发酵乳组成往往做为乳酸菌的代谢基质以及调味的用途,故成分常具有糖分等添加物,对于可能具有其他并发症(例如:糖尿病),或是希望能控制热量摄取的使用者而言,并不是最适合的选择。
目前关于益生菌用于降血压的专利,主要仍着重于前述将活菌投予发酵乳的方式,并往往须结合若干种乳酸菌群的加成作用,相关专利兹简述于下。
中国台湾专利公开号TW 201305331以及中国专利公开号CN 102098923A揭示瑞士乳酸菌,其透过兽乳可代谢产生发酵产物 VPP(Valine-Proline-Proline,缬胺酸-脯胺酸-脯胺酸)及IPP (Isoleucine-Proline-Proline,异白胺酸-脯胺酸-脯胺酸),可抑制ACE,做为降血压剂;然而,此发明是藉由推论因VPP以及IPP被报导具有抑制ACE的能力,而有此发酵乳可用于降血压的结论,然而,并无试验数据支持,且此发明仍然以活菌型式投予,在功效以及活菌保存风险、发酵乳成份的可接受群体上,仍具有潜在性问题。
中国台湾专利公开号TW 200603741揭露一种含有ACE抑制剂的机能性发酵乳的制备方法,其步骤包含于一可供制备发酵乳的原料乳中接种适量的乳酸菌,该乳酸菌选自于乳杆菌属(Lactobacillus spp.)、链球菌属 (Streptococcus spp.)及双歧杆菌属(Bifidobacterium spp.)所组成的族群,该乳酸菌透过发酵乳,生产出ACE抑制胜肽,并经老鼠动物试验证实具有降血压的功效;然而,此发明因同样是藉由发酵乳的活菌型式投予,而仍具前述功效不明以及活菌保存、发酵乳成份的可接受群体有限的潜在风险,且仅有小鼠实验数据,并未有人体数据左证功效。
虽已有相关发明提出益生菌作为降血压的方法,但是因途径属于健康食品,故少有人体临床数据支持,且若需达至指定功效,则菌量需有相当的要求,并往往需合并ACE抑制胜肽,藉由发酵乳型式,以活菌投予;此外,目前除了 L.helveticus外,目前并无给予单一种活性菌株便可用以调节人体血压的相关人体临床研究,而前述关于L.helveticus的研究,也是须以活菌型式并结合 ACE抑制胜肽的机制的发酵乳才能达到降血压的功效,而因发酵乳又有活菌保存与污染风险,并且添加成份对于无法摄取多余糖分或是需控制热量者而言,仍非可行的方案。
有鉴于此,本案发明人深刻了解前案的不足与缺陷,乃亟思加以改良创新,并经多年苦心孤诣潜心研究后,终于成功完成本件利用热灭杀死菌的罗伊氏乳杆菌(L.reuteri)GMNL-263,即可降血压的发明。
参考文献
1.Krishnan,S.M.,Sobey,C.G.,Latz,E.,Mansell,A.,and Drummond,G.R.(2014)Br J Pharmacol 171,5589-5602
2.Li,J.,Zhao,F.,Wang,Y.,Chen,J.,Tao,J.,Tian,G.,Wu,S.,Liu,W.,Cui,Q.,Geng,B.,Zhang,W.,Weldon,R.,Auguste,K.,Yang,L.,Liu,X.,Chen,L.,Yang, X.,Zhu,B.,and Cai,J.(2017)Microbiome 5,14
3.Yamamoto,N.,and Takano,T.(1999)Nahrung 43,159-164
4.Beltran-Barrientos,L.M.,Hernandez-Mendoza,A.,Torres-Llanez,M.J.,Gonzalez-Cordova,A.F.,and Vallejo-Cordoba,B.(2016)J Dairy Sci 99, 4099-4110
5.Khalesi,S.,Sun,J.,Buys,N.,and Jayasinghe,R.(2014)Hypertension 64,897-903
6.Hata,Y.,Yamamoto,M.,Ohni,M.,Nakajima,K.,Nakamura,Y.,and Takano,T.(1996)Am J Clin Nutr 64,767-771
7.Aihara,K.,Kajimoto,O.,Hirata,H.,Takahashi,R.,and Nakamura,Y.(2005)J Am Coll Nutr 24,257-265
8.Mahboobi,S.,Iraj,B.,Maghsoudi,Z.,Feizi,A.,Ghiasvand,R.,Askari,G.,and Maayeshi,N.(2014)Int J Prev Med 5,1239-1246
发明内容
本发明是利用益生菌中的罗伊氏乳杆菌(L.reuteri)GMNL-263组合物,以预防高血压或是降血压。
为达前述发明目的,本发明是一种用于改善高血压的乳杆菌组合物,包含一罗伊氏乳杆菌(Lactobacillus reuteri,L.reuteri)GMNL-263,其中该罗伊氏乳杆菌为死菌。
为达前述发明目的,前述罗伊氏乳杆菌(L.reuteri)GMNL-263,寄存于中国台湾食品工业研究所,编号为BCRC 910452、中国典型培养物保藏中心 (CCTCC),寄存编号为CCTCCM 209263。
为达前述发明目的,其中该罗伊氏乳杆菌(L.reuteri)GMNL-263可用于糖尿病或是需控制糖量摄取族群。
为达前述发明目的,其中该乳杆菌组合物为医药组合物、营养补充品、保健食品或其组合。
为达前述发明目的,其中该乳杆菌组合物是以口服型式剂型投予。
为达前述发明目的,其中该医药组合物可进一步包含药学上可接受的载剂。
为达前述发明目的,其中该乳杆菌组合物可进一步包含一可食性材料,该可食性材料包含水、流体乳品、牛奶、浓缩牛奶、酸奶、酸乳、冷冻优格、乳杆菌发酵饮料、奶粉、冰淇淋、奶酪、干酪、豆奶、发酵豆奶、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、中草药材或膳食补充品。
本发明的另一目的是提供一种乳杆菌用于制备改善高血压的组合物的新用途,其中该乳杆菌组合物包含一罗伊氏乳杆菌(L.reuteri)GMNL-263,其中该罗伊氏乳杆菌为死菌。
为达前述发明目的,其中改善高血压是透过抑制一促发炎细胞激素与提升一益生菌群的生长,使血压降低。
为达前述发明目的,其中该促发炎细胞激素为IL-1。
为达前述发明目的,其中该益生菌群是指双歧杆菌属(Bifidobacterium)。
为达前述发明目的,其中该用途特别指改善糖尿病族群的高血压。
为达前述发明目的,其中该糖尿病是指第二型糖尿病。
本发明实施例经由人体临床试验证明,组合物中以热灭杀型式存在的 GMNL-263,经由九个月的观察,证实具有降血压的功效,而同种的另一株菌 GMNL-89则并不具有此功效。
本发明另一实施例亦透过比对试验期间的受试者检体,证实GMNL-263 是透过降低人体促发炎细胞激素IL-,而具有降血压的功效。
本发明再一实施例亦证明,服用GMNL-263的确提升益生菌群中双歧杆菌属的表现,该双歧杆菌属表现提升与血压的净变化值呈现统计学中的显著负相关,表示服用GMNL-263而造成的双歧杆菌属表现提升,促进了降血压的功效。
本发明利用罗伊氏乳杆菌(L.reuteri)GMNL-263,透过热灭杀死菌的型式,达到降血压功效的发明;并进一步发现,其机制是藉由抑制促发炎细胞激素,以及提升益生菌群中双歧杆菌属(Bifidobacterium)的表现,有别于以往抑制 ACE的模式;本发明更经平行比较,证明即使同为罗伊氏乳杆菌,不同菌落(L. reuteri GMNL-89)便无法表现此降血压的功效。
本发明是为乳杆菌组合物,属于益生菌,因此使用上安全而无药物副作用,可应用于预防以及治疗高血压;且首度揭露以死菌方式投予,不需经发酵乳即可降血压;本发明进一步证实该GMNL-263降血压的功效并非普遍存在于同种罗伊氏乳杆菌中,需进一步进行临床测试方可确知;并首度提出抑制IL-1 以及提升双歧杆菌属表现可作为益生菌用以降血压的途径。
附图说明
图1A为人体临床试验分组图;
图1B为人体临床试验流程图;
图2为平均血压(Mean arterial pressure,MAP)与益生菌的双歧杆菌属的相关性分析图。
具体实施方式
本发明是以下面的实施例予以示范阐明,但本发明不受下述实施例所限制。本发明所使用的材料,除有特别指明者,皆为市售易于取得的材料,本发明所使用的罗伊氏乳杆菌(Lactobacilus reuteri,L.reuteri)GMNL-263[以下代称GMNL-263],寄存于中国台湾食品工业研究所,编号为BCRC 910452、中国典型培养物保藏中心(CCTCC),寄存编号为CCTCCM 209263。
实施例1、热灭杀的GMNL-263具有降血压的功效
本实施例为人体临床试验,有鉴于糖尿病第二型的患者往往好发高血压,因此患者以第二型糖尿病确诊超过6个月为主,其余纳入条件分别为:7%< HbA1c(醣化血色素,glycated hemoglobin)≦10%;年龄:25~70岁;BMI>18.5;排除条件为:怀孕/孕妇;3年内罹患重大疾病,如癌症(良性肿瘤且控制稳定除外)、肾衰竭/洗肾、心脏病、中风、自体免疫疾病、试验前四周与试验期间食用降血糖药物以外的改善血糖保健品、固定食用益生菌产品、固定使用抗生素、肝肾功能异常、肠胃道不健全、不能口服药物者。
本实施例于临床试验公开网站(Clinicaltrial.gov)登录号为 NCT02274272,进行于中国台湾彰化基督教医院,人类研究伦理审查委员会(Institutional Review Board,IRB)通过编号为No.140703。图1A以及图1B说明试验设计方式以及流程,为平行研究,具有对照组,采用双盲、随机分派的方法,入案74人,随机分配成三组执行,扣除离开试验者,最终分析数据的病人共为68人,分别为安慰剂组(placebo,N=22人),服用罗伊氏乳杆菌GMNL-89活菌组(以下代称GMNL-89)(GMNL-89,N=22人),以及服用罗伊氏乳杆菌GMNL-263热灭杀菌组(GMNL-263,N=24人)为两组益生菌试验组;此外,扣除一受试者遗失粪便检体,因此,粪便菌相分析数据为67人,在并用现行处方用药情况下,探讨基本生化值、血糖等代谢指标、肠道菌相以及促发炎细胞激素等,在服用前和服用益生菌六个月后及停止服用后三个月,总计九个月的变化。
GMNL-89活菌菌粉及GMNL-263热灭杀菌菌粉是由景岳生物科技公司发酵生产制备,GMNL-89活菌剂量为4×109cfu(colony forming unit)/天, GMNL-263剂量为2×1010cells/天,每天持续服用,共计六个月。
各项统计分析方面,基本资料的比较是利用卡方试验(Chi-quare test) 或双样本t检验(two sample t-test);而用药记录及高血压比较则是利用费舍尔精确检验(Fisher exact test),其他部分则是利用双样本t检验。
首先进行病人基本数据分析,表1为三组受试者在试验开始时的各项基本数据的比较,三组并无明显差异;表2显示三组受试者高血压的比例无统计上的差异,表示三组受试者的背景条件接近,且在血压方面,虽然这些受试者均有以药物控制血压,然研究过程中所使用的药物种类三组并无统计上差异,因此不具有药物造成的实验误差的可能,但收缩压(systolic blood pressure, SBP)仍是较偏高的,表示血压控制不良。
表1、三组受试者的基本数据
表2、三组受试者的疾病史及用药纪录
实验结果显示,经过六个月,服用GMNL-89活菌组的糖尿病病人的糖化血色素(HbA1c)的净变化值(代表第六个月扣除第一个月的值,net change value:6M-0M)有明显的降低(-0.39±0.80,P<0.05);而GMNL-263热灭杀菌组则与安慰剂组无太大差异(0.24±0.93),表示服用GMNL-263热灭杀菌组不会影响糖尿病患者的血糖值。
而在血压方面(表3),服用GMNL-263热灭杀菌组,其收缩压(SBP) 及平均血压(mean blood pressure)的净变化值明显下降,并呈现统计上的显著差异(P<0.05),表示GMNL-263具有降血压的功效;然而,同为罗伊氏乳杆菌的GMNL-89,各种血压测定值均无显著变化,表示不具有调节血压的功效。此对比也显示,降血压功效需于罗伊氏乳杆菌菌种中的特定菌株才具有,并非普遍存在且易于推知,须经实验证实才能确认。
表3、三组受试者经六个月试验后的血压净变化值
实施例2、热灭杀的GMNL-263透过降低促发炎细胞激素IL-1β,而具降血压的功效
为测试GMNL-263是透过何种机制达到降血压的功效,进一步进行细胞激素的含量变化分析。首先,收集三组受试者在试验开始(0M)以及六个月后 (6M)的血液检体,利用ELISA套组进行各种细胞激素的含量分析,包含人 IL-6(Cat#900-K16,PeproTech,USA)、人IL-10(Cat#900-K21,PeproTech,USA)、人TNF-α(Cat#50-114-2609,eBioscience,USA)、人IL-1β(Cat#437005, Biolegend,USA),数据处理为六个月(6M)减掉开始(0M)的净变化值,并进一步以双样本t试验进行统计分析。
结果呈现,服用GMNL-263六个月后,病人血中IL-1β与安慰剂组相比,呈现统计上显著意义地明显下降,反观其他细胞激素则没有太大的差异(表4),表示GMNL-263是透过令IL-1β下降,调控全身慢性发炎反应,进而达到降血压的目的。
表4、三组受试者经六个月试验的血中细胞激素变化
实施例3、热灭杀的GMNL-263透过提升肠道双歧杆菌属表现,而具降血压的功效
为厘清GMNL-263的降血压功效是否与肠道益生菌群的调控有关,收集受试者于试验开始(0M)及六个月(6M)的粪便检体,以定量聚合酶链锁反应 (Quantitativepolymerase chain reaction,Q-PCR)分析粪便菌相中的DNA,计算服用益生菌六个月后的菌相消长变化,其计算方式为,(服用六个月的粪便 DNA利用Q-PCR所得的CT(Thresholdcycle)值-总菌的CT值)=△Ct,△ Ct-(尚未服用者的粪便DNA利用Q-PCR所得的CT值-总菌的CT值)=△△Ct;将其换算为2-△△Ct,即为服用益生菌六个月后的菌相的消长变化。
利用Q-PCR分析粪便菌相,可分为抽DNA以及进行Q-PCR分析两部分,首先,粪便检体抽DNA的方法,是利用DNA套组(QIAamp DNAStool Mini Kit,QIAGEN,Lot.51504),将病人粪便去除RNA later保护剂后,加入 Buffer ASL,而后置于70℃加热板中加热5分钟,再加入0.1mm灭菌后的微珠(型号:BioSpec Products 0.1MM ZIRCONIA/SILICA BEADS,cat.No.11079101z)强烈震荡至少15秒,直至粪便全部混匀搅碎;以13,000rpm离心1分钟,取上清,接续进行DNA的萃取,并将萃取后的DNA,调整为 1ng/μl备用。
而后,进行粪便Q-PCR分析,将上述萃取出的DNA当作模板进行 Q-PCR,每一份反应试剂以5μl的2x Rotor-Gene SYBR Green PCR Master Mix(QIAGEN,Cat.204076),加入2μl粪便DNA后,再加入3μl的待测菌相引子(0.66μM正向引物(F)+反向引物(R)),使总体积为10μl,以PCR机器(型号QIAGEN:Rotor-Gene Q 2Plex)执行实时Q-PCR。
菌相变化数据以双样本t试验进行统计分析;而菌相变化与血压变化的相关性分析,则是利用统计软件PASW Statistics 18Software(SPSS Inc)进行斯皮尔曼相关系数分析(Spearman's rho correlation)。
结果呈现,服用热灭杀GMNL-263六个月后可以观察到受试者益生菌群中的双歧杆菌属表现增加,与安慰剂组相较,据统计上的显著差异(表5);为了厘清菌相与血压变化的关联,且进一步利用相关性统计分析,发现双歧杆菌属的含量提升与平均血压净变化值呈负相关(R=-0.268、P=0.028,图2),表示当双歧杆菌属含量多时,会促进血压降低。因此,证明热杀灭GMNL-263能经由增加粪便中的益生菌中的双歧杆菌属,达到调降血压的功效。
表5、三组受试者经六个月实验后的微生物态变化
本发明证明服用热灭杀罗伊氏乳杆菌GMNL-263,六个月后可帮助有高血压症状的糖尿病病人调降收缩压及平均血压,且不影响血糖值,对于需控制糖分或热量摄取的群体或是糖尿病病患十分有帮助;该菌是经热灭杀处理,可制成胶囊或粉包,具有稳定性高、以及简便的优势;此外,因为乳杆菌属于益生菌,为健康食品,因此并无安全的疑虑,一般人也可使用,以预防或是控制高血压,使用族群无限制,可应用范围极广;本发明进一步由相关性统计分析,证实热灭杀罗伊氏乳杆菌GMNL-263同时经由降低促发炎细胞激素IL-1β,并且调节病人肠道菌相,以增加益生菌中的双歧杆菌属的方式,达到降血压的效果;且藉由相同菌种的对照组GMNL-89证明,并非所有罗伊氏乳杆菌均可用于降血压,需特定菌株,并经临床试验才可证实。上述罗伊氏乳杆菌 GMNL-263用于降血压的发明,均为益生菌用于降血压应用领域的首度发现,并破除了前案的形式以及使用群体限制。
本案不仅于技术思想上确属创新,并具备习用的传统方法所不及的多项功效,已充分符合新颖性及进步性的法定发明专利要件。
【符号说明】
无
【生物材料寄存】
寄存国家-中国、寄存机构-中国典型培养物保藏中心(CCTCC)、寄存日期-2009年11月13号、寄存标号-CCTCC M 209263。
Claims (4)
1.一种乳杆菌用于制备改善高血压的组合物的用途,其中该乳杆菌组合物包含罗伊氏乳杆菌(L.reuteri),所述罗伊氏乳杆菌(L.reuteri)的寄存编号为CCTCC M 209263,其中该罗伊氏乳杆菌为死菌,所述高血压为二型糖尿病继发的高血压。
2.根据权利要求1所述的用途,其特征在于,所述改善高血压是通过 抑制促发炎细胞激素与提升益生菌群的生长,使血压降低。
3.根据权利要求2所述的用途,其特征在于,所述促发炎细胞激素为IL-1。
4.根据权利要求2所述的用途,其特征在于,所述益生菌群是指双歧杆菌属(Bifidobacterium)。
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