CN104955467A - 鼠李糖乳杆菌菌株用于降低身体脂肪积累 - Google Patents
鼠李糖乳杆菌菌株用于降低身体脂肪积累 Download PDFInfo
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Abstract
本发明涉及鼠李糖乳杆菌菌株CNCM I-3690用于降低身体脂肪积累并治疗由此产生的紊乱如超重、肥胖和与肥胖相关的紊乱的用途。
Description
本发明涉及益生菌领域，且更具体地涉及其用于调节脂质代谢的用途。
脂质代谢在能量平衡中发挥重要作用。食物中的能量可以作为脂质储备储存起来，该脂质储备能够在必需满足身体的能量需求时使用。由于体内脂肪积累，超出热量消耗的过量热量摄入引起体重增加，导致超重并且长期导致肥胖。身体质量指数(BMI)大于或等于25被认为是超重，身体质量指数大于或等于30被定义为肥胖。
由于肥胖是包括高血压、II型糖尿病、心血管疾病、肝脏疾病和许多癌症在内的多数疾病的一个重要的风险因素，它迅速成为一个主要的公共健康问题。自1980年，全球的肥胖人口的数量已增加超过一倍。在2008年，超过14亿的成人(20岁及以上)超重。这其中，有超过2亿男性和近3亿女性肥胖。
人们普遍认为，肥胖和相关代谢紊乱的目前频率的主要原因之一是日常生活中运动量减少与富含高脂肪和高蔗糖食物的西式饮食的结合。
然而，脂肪积累和体重在个体之间的差异还与其它因素，如遗传背景、健康状况、药物治疗、年龄或睡眠不足相关。
在这些因素中，肠道菌群是越来越使人感兴趣的焦点。近年来的大量研究表明，肥胖和与肥胖相关的代谢紊乱与肠道菌群组成的变化相关(参见TREMAROLI&BACKHED,Nature,489,242-9,2012；MARIK,FrontEndocrinol(Lausanne),3,87,2012；Burcelin,Physiology,27,300-7,2012)。
因此，曾有人建议，使用益生元、益生菌或合生元对肠道菌群的控制可能有助于降低肥胖和与肥胖相关的代谢紊乱(MALLAPPA等人，Indian JEndocrinol Metab,16,20-7,2012；DELZENNE等人，Nat Rev Endocrinol,7,639-46,2011)。
已报道某些益生菌菌株降低了脂肪积累和/或肥胖相关的代谢紊乱。LEE等人(Biochim Biophys Acta,1761,736-44,2006)已经表明，产生结合性亚油酸的鼠李糖乳杆菌菌株PL60(Lactobacillus rhamnosus strain PL60)在饮食诱导的肥胖小鼠中具有抗肥胖作用；加氏乳杆菌SBT2055(Lactobacillus gasseriSBT2055)已显示在成年人中降低腹部肥胖和体重(KADOOKA等人，Eur JClin Nutr,64,636-43,2010)，并且加氏乳杆菌BNR17(Lactobacillus gasseriBNR17)已显示在喂食高碳水化合物饮食的大鼠中减少体重增加(KANG等人，J Microbiol,48,712-4,2010)。ANDREASEN等人(Br J Nutr,104,1831-8,2010)报道了施用嗜酸乳杆菌NCFM(Lactobacillus acidophilus NCFM)对胰岛素抗性的改善。植物乳杆菌第14号菌株(Lactobacillus plantarum strain No.14)显示降低了喂食高脂肪饮食的小鼠中脂肪细胞的大小(TAKEMURA等人，Exp Biol Med(Maywood),235,849-56,2010)。ARONSSON等人(PLoS One,5,2010)报道，副干酪乳杆菌副干酪亚种菌株F19(Lactobacillus paracasei sspparacasei strain F19)能够通过提高血管生成素样4蛋白(ANGPTL4)的表达来降低脂肪储存。MA等人(J Hepatol,49,821-30,2008)报道，益生菌VSL#3通过增加肝NKT细胞改善了高脂肪饮食诱导的肝脂肪变性和胰岛素抗性。JI等人(Benef Microbes,3,13-22,2012)报道了鼠李糖乳杆菌GG(Lactobacillusrhamnosus GG)和沙克乳杆菌NR28(Lactobacillus sakei NR28)对鼠类菌群的调整，其伴随有抗肥胖作用。AN等人(Lipids Health Dis,10,116,2011)描述了在高脂肪饮食诱导的肥胖大鼠中双歧杆菌菌株混合物(假小链双歧杆菌(B.pseudocatenulatum)SPM 1204、长双歧杆菌(B.longum)SPM 1205和长双歧杆菌SPM 1207)的抗肥胖和降脂质作用。PCT申请WO 2007/043933提出了干酪乳杆菌F19(Lactobacillus casei F19)、嗜酸乳杆菌NCFB 1748(Lactobacillusacidophilus NCFB 1748)或乳酸双歧杆菌Bb12(Bifidobacterium lactis Bb12)用于降低食物摄入和脂肪沉积以及预防或治疗肥胖和胰岛素不敏感性的用途。
这些不同益生菌的作用是菌株特异性的，并且似乎是由不同的机制所介导。因此，仍然需要能够用于控制超重和肥胖以及与之相关的代谢疾病的发展的其它益生菌菌株。
本发明人使用线虫(Caenorhabditis elegans)作为体内模型，测试了益生菌菌株调节脂质代谢的能力。
脂肪调节途径中涉及的许多基因在线虫(C.elegans)和哺乳动物之间高度保守(ASHRAFI等人，Nature,421,268-72,2003)，因此使得线虫已成为用于研究肥胖相关的机制的流行模型(ASHRAFI,WormBook,1-20,2007；JONES&ASHRAFI,Dis Model Mech,2,224-9,2009)。
此外，线虫在其肠道内和其皮下细胞中以脂质小滴的形式储存脂肪。在用荧光染料如尼罗红染色后这些脂肪储备可以在完整的动物中容易地可视化和量化，使得可以容易地评估所测试的产品对身体脂肪积累的作用。
本发明人已发现，在所测试的益生菌菌株中，鼠李糖乳杆菌的菌株之一，菌株CNCM I-3690，降低脂质储备的程度与奥利司他(orlistat)相同，奥利司他是可逆的胃肠道脂酶抑制剂，其阻止膳食脂肪的吸收并广泛用作控制肥胖的药物。
这一作用是菌株特异性的，因为其没有在鼠李糖乳杆菌的另一个益生菌菌株CNCM I-4317中观察到(在PCT申请WO 2011/148355中有描述)。
菌株CNCM I-3690依据布达佩斯条约于2006年11月19日保藏于CNCM。该菌株在PCT申请WO 2009/122042中被公开，此申请报道了该菌株的抗微生物和免疫调节性质。该菌株还具有抗氧化性质，这在PCT申请WO 2011/083354中有描述。
因此，本发明涉及的主题是鼠李糖乳杆菌菌株CNCM I-3690或包含所述菌株的组合物用于降低受试者中的脂肪积累的用途。
具体的，本发明包括鼠李糖乳杆菌菌株CNCM I-3690或包含所述菌株的组合物，用于治疗、预防或缓解由过量的身体脂肪积累所导致的病症中的用途。
由过量的身体脂肪积累所导致的病症的实例是超重、肥胖和与肥胖相关的紊乱如2型糖尿病、非酒精性脂肪肝病(NAFLD)、高血压等。
鼠李糖乳杆菌菌株CNCM I-3690可以以活的或死的完整细菌的形式使用。或者，该菌株可以以细菌裂解物的形式或细菌级分(bacterial fraction)的形式使用；适合于此种用途的细菌级分可以例如通过测试其对线虫中脂质储备的性质来选择。
本发明还提供了用于治疗、缓解或防止有需要的受试者中过量的身体脂肪积累的方法，其中所述方法包括向所述受试者施用鼠李糖乳杆菌菌株CNCM I-3690或包含所述菌株的组合物。
本发明中使用的组合物可以是任何适合于给药尤其是口服给药的形式。这包括例如固体、半固体、液体和粉末。由于易于施用，通常优选液体组合物以，如作为饮料。
当细菌是活细菌的形式时，以组合物的每克干重计，所述组合物通常可以包含105至1013个菌落形成单位(cfu)，优选至少106cfu，更优选至少107cfu，还更优选至少108cfu，并且最优选至少109cfu。在液体组合物的情况下，这通常对应于104至1012个菌落形成单位(cfu)，优选至少105cfu，更优选至少106cfu，还更优选至少107cfu，并且最优选至少109cfu/ml。
本发明中使用的优选的组合物是营养组合物，包括食品并且具体是乳产品。这些营养组合物还包括食品补充剂和功能性食品。“食品补充剂”是指由通常在食品中所使用的化合物所制成的产品，但其形式是片剂、粉剂、胶囊剂、饮剂或通常与营养物无关的任何其它形式，且对人的健康具有有益作用。“功能性食品”是也对人的健康具有有益作用的营养物(aliment)。具体地，食品补充剂和功能性食品针对疾病，例如针对慢性疾病，具有生理学作用——防护或治疗性的作用。
适合用在本发明中的组合物的其它实例有药物组合物或化妆组合物。
除了菌株CNCM I-3690之外，本发明的组合物还可以包含益生性的或非益生性一个或多个其它的乳酸细菌的菌株，例如选自菌属乳杆菌(Lactobacillus)、乳球菌(Lactococcus)、链球菌(Streptococcus)和双歧杆菌(Bifidobacteria)的一个或多个细菌菌株。具体地，这个(这些)其它菌株可包括嗜热链球菌中的一个或多个菌株，和/或保加利亚乳杆菌中的一个或多个菌株。
可以由如下进一步描述的引用例示细菌菌株CNCM I-3690对脂质储备的作用的实施例，来更清楚地理解本发明。
实施例：鼠李糖乳杆菌CNCM I-3690抑制了线虫中的总脂肪堆积。
在尼罗红染色的线虫中通过荧光测量研究鼠李糖乳杆菌菌株CNCMI-3690和CNCM I-4317对线虫脂质包含物的影响。
鼠李糖乳杆菌菌株生长于MRS培养基中并在对数生长期(OD600＝1.5)回收。
用线虫的野生型N2株进行实验。通过从妊娠成虫分离卵，将卵M9培养基(10vol％MRS，110ug/ml氟脱氧尿嘧啶(fluorodexouridine)和5ug/ml胆固醇中孵化过夜，并将L1-期的线虫分离在微量滴定板的孔中,将线虫同步化。在25℃、80-85％相对湿度的三天期间，线虫在无晃动的情况下生长。将这些幼虫转移到含有M9培养基和胆固醇的板内并在25℃、80-85％湿度下孵育3天，同时进行对照或实验喂食。每个孔至少有50条线虫。
以标准饲料大肠杆菌OP50、大肠杆菌OP50和奥利司他(作为阳性对照)、鼠李糖乳杆菌CNCM I-3690或鼠李糖乳杆菌CNCM I-4317，喂食线虫。所有细菌按4×106cfu/ml的浓度使用。奥利司他按6μg/ml的浓度使用。加入30μg/ml的卡那霉素以防止大肠杆菌OP50或鼠李糖乳杆菌菌株在试验期间生长。
在喂食开始时，向板内加入尼罗红(0.05μg/mL，Sigma，St.Louis，美国)，浓度是0.05μg/ml。
使用VersaFluorTM荧光系统(Bio-Rad，Hercules，美国)通过荧光定量(λ激发＝480nm；λ发射＝571nm)测量脂肪堆积。每种情况分析总计180个蠕虫。实验一式三份。
结果示于图1，该图显示了所测试的每种条件下尼罗红染色的百分比：**p值＝0.001。
这些结果表明，当与标准饲料大肠杆菌OP50比较时，菌株CNCM I-4317对脂肪堆积无作用，菌株CNCM I-3690降低了34％的脂质包含物，其与用奥利司他所观察到的脂质包含物(lipid inclusion)的降低相当。
Claims (6)
1.鼠李糖乳杆菌(Lactobacillus rhamnosus)菌株CNCM I-3690，用于降低受试者中的身体脂肪积累。
2.权利要求1的用于所述用途的鼠李糖乳杆菌菌株CNCM I-3690，其中所述用途是用于处理、治疗、防止或缓解由过量的身体脂肪积累所导致的病症。
3.权利要求1或2中任一项的用于所述用途的鼠李糖乳杆菌菌株CNCMI-3690，其中所述病症选自超重、肥胖和与肥胖相关的紊乱。
4.权利要求1至3中任一项的用于所述用途的鼠李糖乳杆菌菌株CNCMI-3690，其中所述菌株包含于口服给药的组合物中。
5.权利要求4的用于所述用途的鼠李糖乳杆菌菌株CNCM I-3690，其中所述组合物是食品或食品补充剂。
6.权利要求5的用于所述用途的鼠李糖乳杆菌菌株CNCM I-3690，其中所述食品是发酵的乳产品。
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| KR101864347B1 (ko) * | 2017-09-06 | 2018-06-05 | 주식회사 지놈앤컴퍼니 | 락토바실러스 람노수스 lm1019 균주 및 이를 포함하는 비만 또는 당뇨병 예방 및 치료용 조성물 |
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| CA2890574A1 (en) | 2014-05-15 |
| US20150283186A1 (en) | 2015-10-08 |
| US9855304B2 (en) | 2018-01-02 |
| JP2016507216A (ja) | 2016-03-10 |
| EP2925333A1 (en) | 2015-10-07 |
| RU2015122728A (ru) | 2017-01-10 |
| MX2015005897A (es) | 2016-02-05 |
| WO2014072771A1 (en) | 2014-05-15 |
| AR093425A1 (es) | 2015-06-10 |
| BR112015010639A2 (pt) | 2017-07-11 |
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