CN107921057A - 用于预防和治疗炎性疾病的果胶组合物 - Google Patents
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Abstract
本发明一般地涉及用于对抗炎性疾病的组合物和方法,并且特别地涉及饲料或食品组合物用于预防、减轻和/或治疗炎性病症、疾病或不适的用途,其中所述组合物包含至少一种特定果胶。
Description
本发明一般地涉及用于对抗炎性疾病的组合物和方法,并且特别地涉及食品和/或饲料组合物用于预防、减轻和/或治疗炎性病症、疾病或不适的用途。
人的炎性疾病(或炎症相关病症)是例如以下疾病,例如阿尔茨海默病(Alzheimer's)、强直性脊柱炎、关节炎(骨关节炎、类风湿性关节炎(rheumatoidarthritis,RA)、银屑病关节炎)、哮喘、动脉粥样硬化、克罗恩氏病(Crohn's disease)、结肠炎、皮炎、憩室炎、纤维肌痛、肝炎、肠易激综合征(irritable bowel syndrome,IBS)、系统性红斑狼疮(systemic lupus erythematous,SLE)、肾炎(nephritism)、帕金森病(Parkinson’s disease)、溃疡性结肠炎、自身免疫病、哮喘、特应性(atopy)、心血管病、糖尿病、免疫衰老(immune senescence)、心脏或肾的缺血/再灌注损伤、猫传染性腹膜炎、乳腺炎、银屑病、脓毒症、系统性红斑狼疮(systemic lupus erymathosis)、肿瘤转移、以及内脏或皮肤利什曼病。它还可用于预防或治愈促炎事件(例如发生在使用细胞抑制剂进行癌症治疗期间)或在使用引起内脏损伤的药物期间的其他不适。
这些疾病中的大部分是普遍的。
例如,关节炎是美国最常见的残疾原因。多于2千万患有关节炎的个体在日常功能上受到严重限制。它可影响人以及动物。在本发明的上下文中,我们使用术语“患者”来描述目标个体。这些患者易患或患有炎性疾病。
风湿病(rheumatism)或风湿性疾病(rheumatic disorder)是影响关节和/或结缔组织的医学问题的非特定术语。术语“风湿病”仍然在口语和历史背景中使用,但通常不再用于医学或技术文献;不再有任何公认的疾病被简单地称为“风湿病”。该传统术语覆盖了如此大范围的不同问题,使得将其症状归于“风湿病”提得不多。“非关节性风湿病”(也被称为“局部疼痛综合征”或“软组织风湿病”)可引起明显的不适和困难。此外,关节炎和风湿病它们之间覆盖了至少200种不同的病症。
风湿病和关节炎是以炎症和疼痛为特征的急性和慢性病症的总称。风湿病是肌肉和关节中以炎症和疼痛为特征的一般病症类别,包括关节炎。关节炎的特征在于引起肿胀和疼痛的关节炎症。关节炎的类型包括骨关节炎、类风湿性关节炎、强直性脊柱炎(ankylosing spondylitis,AS)和系统性红斑狼疮(SLE)。风湿性病症包括感染性关节炎、类风湿性关节炎、由于风湿热引起的关节炎、由于创伤或退行性关节疾病引起的关节炎、肌炎、神经源性关节病、滑囊炎、纤维肌炎和关节积水。此类疾病的起因并不总是被完全了解,但可以是其他退行性疾病、创伤或自身免疫病(例如SLE)的结果。炎症还可作为对引起免疫应答的外来物质侵入宿主和机械创伤(例如微生物剂(例如细菌和病毒)、毒素、警报分子和瘤形成)的防御性应答而发生。
这些疾病和病症(炎性疾病的实例)共有的是炎症和引起的疼痛。现有的用于预防和治疗炎性疾病的方法通常集中在止痛和抗炎药物上。通常的方法集中在经口药物,例如甾体可的松衍生物和许多非甾体抗炎药(NSAID)。遗憾的是,这些药物几乎总是表现出不期望的副作用。其他努力集中在关节植入物(例如膝部或髋部植入物)上。这些方法是冗长且复杂的外科手术操作,迫使患者进行昂贵的侵入性手术和显著的需要严格且昂贵的物理治疗方案的恢复期。因此,需要新的用于预防和治疗炎性疾病的方法,其避免了先前用于预防和治疗炎性疾病之方法特有的不期望的副作用和昂贵的外科手术操作。
本发明可适用的另一个实例是控制或预防由不健康饮食或使用药物引起的疾病。例如,黏膜炎是由化学治疗(例如常用的多柔比星)引起的小肠中的炎症。这种药物导致黏膜损伤和释放细胞内分子,例如DNA、RNA和热休克蛋白(也被称为警报分子或危险相关分子模式),其引起严重的炎性应答,结果是黏膜炎。这可通过本发明来预防或减轻。这被认为是但不限于由于不健康饮食、使用药品或使用药物之炎性应答的一个实例。
在动物中,涉及炎性应答的胃肠紊乱是普遍的。在农场动物(猪、家禽和反刍类)中,这种现象造成大的经济损失。例如,在猪群中,在欧盟出生的所有小猪的总损失共计约17%,且这些损失中的大部分可与通过黏膜表面的感染相关(Lallès等,2007,Proc NutrSoc.66(2):260-268)。刚断奶的猪的短暂性厌食被认为是这些导致肠功能障碍、提高的肠感染敏感性和腹泻的问题的主要原因。伴随的病理生理变化包括与绒毛萎缩相关的黏膜重量降低20%至30%(Lallès等,2004,Animal Research 53,301-316)、肠屏障功能受损(Wijtten等,2011,Br J Nutr.105(7):967-981)、肠微生物区系(gut microbiota)稳态的紊乱(Bauer等,2006,Nutr Res Rev.19(1):63-78)以及免疫系统的解剖和功能发育的紊乱(Lallès等,2007,ProcNutr Soc.66(2):260-268)。同样在家禽中,由于动物表现受损、死亡率提高和鸟的健康福利降低,肠道疾病显著导致经济损失(Timbermont等,2011,AvianPathol.40(4):341-347)。非特异性肠炎、球虫病、病毒性感染、菌落失调症和细菌性感染已经被确定为在家禽中引起湿废弃物(wetlitter)的主要肠疾病(Hermans等,2006,VetRec.158(18):615-622)。虽然存在一些物种相关的差异,但是潜在的病理生理变化与猪的那些相当相似。例如,新孵化的肉用鸡(broiler)的小肠发育在低采食量水平下劣化(Wijtten等,2012,Acta Agriculturae Scandinavica Section A-Animal Science,62(1),1-12)。
过去,预防性使用饲料内抗生素生长促进剂来预防这类问题。目前,由于担心食品中的抗生素残留和病原体对抗生素的抗性提高,在农场动物中数种抗生素的预防性使用在欧盟被禁止或者在另一些国家(例如美国)处于高舆论压力下。因此,对于动物还需要新的用于预防和治疗涉及炎性应答的胃肠紊乱的方法。
令人惊讶地,发现了特定种类的果胶(关于其酯化度)可用于预防、减轻和/或治疗炎性病症、疾病或不适。
“预防、减轻和/或治疗炎性病症、疾病或不适”主要意指:
·使染上任何上述列举疾病的风险最小化,和/或
·减轻相关症状,和/或
·降低与任何上述列举疾病相关的疼痛或不适,和/或
·延长可发生任何上述列举疾病的发作之间的时间,和/或
·改善人和动物的整体健康和福利。
果胶是陆生植物的初生细胞壁中含有的结构性杂多糖。它在商业上被制成白色至浅棕色粉末,主要从柑橘类水果中提取,且作为胶凝剂用于食品(特别是果酱和果冻)。它还用于填料(fillings)、药品(medicines)、甜品(sweets),用作果汁和乳饮料中的稳定剂,以及用作膳食纤维的来源。
梨、苹果、番石榴(guava)、榅桲(quince)、梅子(plum)、醋栗(gooseberry)、橙子和其他柑橘类水果包含大量果胶,而例如樱桃、葡萄和草莓的无核小果(soft fruit)包含少量果胶。除水果之外的其他植物来源也可包含果胶。例如,果胶可来源于马铃薯、大豆、糖用甜菜、菊苣(chicory)、胡萝卜、番茄、豌豆、欧洲防风(parsnip)和(绿色)豆类。
所有这些列表都不是穷举性的。仅列举了主要来源。
以下举例说明示出了果胶和(部分地)酯化的果胶的部分结构。
果胶(聚半乳糖醛酸)的结构
(部分地)甲基化的果胶的结构
在上述示出的式中,酯化为甲基化,但是也可使用其他基团(例如乙酰基)。在同一寡聚体结构中果胶可用一种基团(例如CH3或COCH3)或用多于一种基团酯化。乙酰化通常发生在2位和/或3位上的羟基中的氧处,而甲基化通常发生在5位上的羧基处。
在本发明的范围中,使用酯化度来描述主链中酯化果胶单体单元的百分比。
果胶是由α-1,4-连接的D-半乳糖醛酸(GalA)主链(所谓的同型半乳糖醛酸聚糖(homogalacturonan)或光滑区(smooth region))和以下区段构成的复杂多糖,所述区段由用阿拉伯聚糖、阿拉伯半乳聚糖和半乳聚糖的侧链分支的α-(1,2)-连接的L-鼠李糖基和α-1,4-连接的D-半乳糖醛酸基残基的交替序列组成(支链鼠李糖半乳糖醛酸聚糖(rhamnogalacturonan)或须状区(hairy region))。果胶被中性糖(neutral sugar,NS)修饰,所述中性糖主要是在主链中与鼠李糖部分连接的半乳糖和阿拉伯糖。
商业化果胶由于酸提取而通常包含少量的中性糖(中性糖含量为约5%)。果胶的其他结构元件是木糖半乳糖醛酸聚糖(xylogalacturonan)和鼠李糖半乳糖醛酸聚糖II。鼠李糖半乳糖醛酸聚糖II携带特殊的糖残基,例如Api(D-芹菜糖(D-apiose))、AceA(3-C-羧基-5-脱氧-L-木糖)、Dha(2-酮基-3-脱氧-D-来苏-庚酮糖酸)和Kdo(2-酮基-3-脱氧-D-甘露-辛酮糖酸)。这些不同结构元件的相对比例可因不同的植物来源和不同来源的商业化产品而显著不同。
果胶的多个结构元件可被酯化。酯化的主要类型为:O-甲基、O-乙酰基和O-阿魏酰基(O-feruloyl)。不排除任何其他类型的酯化。大多数酯化存在于GalA残基上的同型半乳糖醛酸聚糖区域中。因此,GalA残基可作为游离羧基或在一个或更多个羧基处酯化存在。酯化可以作为单酯化发生,但也可作为单个GalA残基的双重酯化发生。不排除任何其他数量的酯化。单个残基上的酯化可通过单一类型的烷基(即,甲基)或单一类型的酰基(即,乙酰基)。不排除任何混合型酯化。因此,GalA可被甲基化(导致每GalA残基0或1个甲基),或可被乙酰化(导致在C-2和/或C-3上羟基的氧上分别有0、1或2个乙酰基)。后者原样发生在糖用甜菜和马铃薯果胶中。
酯化度(degree of esterification,DE)定义为每100摩尔总半乳糖醛酸(游离GalA和经取代GalA加在一起)存在的酯的量(以摩尔计)。由于大多数商业化果胶实质上具有甲酯类型的酯化,因此经常将DE表示为甲基化度(degree of methylation,即DM)。在此情况下,酯化度定义为每100摩尔总半乳糖醛酸(游离GalA和经取代GalA加在一起)存在的甲酯的量(以摩尔计)。在酯化为乙酰基类型的情况下,通常将DE表示为乙酰化度(degreeof acetylation,即DA)。在此情况下,酯化度定义为每100摩尔总半乳糖醛酸(游离GalA和经取代GalA加在一起)存在的乙酰基酯的量(以摩尔计)。在单个果胶样品中多种类型酯化的情况下,通常将DE分开表示为甲基化度(即DM)和乙酰化度(即DA)。这些如上所述计算。或者,DE可表示为如下定义的酯化度:每100摩尔总半乳糖醛酸(游离GalA和经取代GalA加在一起)存在的用一种或更多种酯化修饰(为甲基或乙酰基类型)的半乳糖醛酸残基的量(以摩尔计)。
在本发明的上下文中,使用术语酯化度(DE),并且所述百分比总是基于通过酯化(即,甲基化)取代的GalA残基的量。50DE意指50%的所有可能的GalA残基被酯化(即,甲基化)。
以下专利申请涉及使用酯化果胶,更具体地涉及使用具有特定酯化度的酯化果胶。
在酯化果胶之间作出以下区分:
(i)低酯化果胶
(ii)高酯化果胶。
低酯化果胶的酯化度(DE)小于50%。这意指小于50%的可能位置被酯化。
高酯化果胶的DE大于50%。这意指大于50%的可能位置被酯化。
商业化HM-果胶的DE值通常为60%至75%,而LM-果胶的DE值为20%至40%(Sriamornsak,2003,Silpakorn University International Journal 3(1-2),206-228)。
如上所述,果胶存在于几乎所有的高等植物中。食品工业的数种副产物被用于其提取,例如柑橘果皮(柑橘汁生产的副产物)、苹果渣(苹果汁生产的副产物)、糖用甜菜(甜菜糖工业的副产物)以及在较小程度上,马铃薯纤维、向日葵盘(油生产的副产物)和洋葱(1990年5月,Carbohydr.Polymers,12:79-99)。从果渣或果皮中提取HM果胶的典型方法是在50℃至90℃下在pH 1至3的热的稀释的无机酸中3至12小时(Rolin,2002,In:Pectinsand their Manipulation;Seymour G.B.,Knox J.P.,Blackwell Publishing Ltd,222-239)。以干物质计,干柑橘果皮含有20%至30%的果胶,干苹果渣中存在更低的量(10%至15%)(Christensen,1986,Pectins.Food Hydrocolloids,3,205-230)。通过添加醇(通常为异丙醇,但也使用甲醇或乙醇)沉淀果胶。最后,对凝胶状物质进行压制、洗涤、干燥并研磨(1990年5月,Carbohydr.Polymers,12:79-99)。根据加工条件,获得了DM为55%至80%的果胶(Rolin,2002,In:Pectins and their Manipulation;Seymour G.B.,Knox J.P.,Blackwell Publishing Ltd,222-239)。
低甲基化(low-methylated,LM)果胶可通过主要通过控制提取期间的酸度、温度和时间使高甲基化(high-methylated,HM)果胶脱酯化来获得。为了生产其他类型的果胶,可通过酸或碱的作用使酯水解,在提取前或期间、作为浓缩液体或在分离和干燥前的醇浆料中进行。当使用碱时,反应必须在低温和水溶液中进行以避免聚合物的β-消除降解(Kravtchenko等,,1992,Carbohydrate Polymers,19,115-124)。LM果胶还可用水性螯合剂(例如六偏磷酸盐)提取(例如,马铃薯果胶)(Voragen等,1995,In:Food polysaccharidesand their applications;Stephen A.M.,New York:Marcel Dekker Inc,287-339)。使用酶果胶甲基酯酶(pectinmethyl-esterase,PME)来生产LM果胶可以是化学提取的替代方案(Christensen,1986,Pectins.Food Hydrocolloids,3,205-230)。改变不同反应的条件和时间,产生不同DE(甚至低至DE为零)的果胶。
尽管商业化LM果胶几乎完全来源于HM果胶,但是存在LM果胶的天然来源,例如成熟的向日葵盘(Thakur等,1997,Critical Reviews in Food Science and Nutrition,37(l):47-73)。
DE可通过通常已知的方法来确定。
例如,酯化度可使用多种方法来确定,例如滴定(Food Chemical Codex,1981)、IR光谱法(Gnanasambandam&Proctor,2000,Food Chemistry,68,327-332;Haas&Jager,1986,Journal of Food Science,51(4),1087-1088;Reintjes等,1962,Journal of foodsciences,27,441-445)和NMR波谱法(Grasdalen等,1988,Carbohydrate Research,184,183-191)。已经开发了在果胶皂化后分析甲醇含量的使用HPLC(Chatjigakis等,1998,Carbohydrate Polymers,37,395-408;Levigne等,2002,Food Hydrocolloids,16(6),547-550;Voragen等,1986,FoodHydrocolloids,1(1),65-70)和GC-顶空(Huisman等,2004,FoodHydrocolloids,18(4),665-668;Walter等,1983,Journal of Food Science,48(3),1006-1007)的其他方法。已经开发了毛细管电泳(capillary electrophoresis,CE)法来确定聚合物原样的DM(Jiang等,2005,Food Chemistry,91,551-555;Jiang等,2001,ofAgricultural and Food Chemistry,49,5584-5588;Zhong等,1998,CarbohydrateResearch,308,1-8;Zhong等,1997,Carbohydrate Polymers,32(1),27-32)。CE法的优点在于不需要样品的GalA含量来计算DM,而按照GC顶空和HPLC法,在DM计算之前必须知道GalA值。
令人惊讶地发现使用DE小于65%的果胶能够预防、减轻和/或治疗炎性病症、疾病或不适。
根据本发明的果胶优选不是酰胺化的(果胶中不存在酰胺基团)。
此外,令人惊讶地,当与使用现有技术已知的果胶相比时,在较低的果胶浓度下达到该作用。这导致在制剂中的优势,因为较低浓度的当前果胶更容易配制成食品和/或饲料产品。
因此,本发明涉及用于在人和动物(即,患者)中治疗免疫介导的疾病和炎性疾病的酯化果胶或酯化果胶混合物,其中果胶的酯化度小于65%。
在本发明的情况中,酯化度优选通过HPLC法来确定,如A.G.J.Voragen、H.A.Schols和W.Pilnik在发表于Food Hydrocolloids,第1卷,第1期,第65-70页,1986中的题为“Determination of the degree of methylation and acetylation of pectins byh.p.l.c”的出版物中所述。
此外,本发明涉及通过向患者施用酯化果胶(或酯化果胶混合物)来预防、减轻和/或治疗炎性病症、疾病或不适(减轻炎性疾病)的方法(M),其中果胶的酯化度小于65%。
如实施例所示,具有更高酯化度(大于本发明的果胶;即,DE为75)的果胶效果低得多,并且仅在较高的果胶剂量下有效。
在本发明的情况中,果胶可以从任何已知的来源获得。合适来源的列表在上面给出。通过使用上述方法之一,获得了具有正确DE的果胶。
优选地,果胶(作为单一化合物或当在混合物中使用时)的DE小于60%,更优选小于55%,尤其优选小于50%。
因此,本发明还涉及用于治疗免疫介导的疾病和炎性疾病的酯化果胶或酯化果胶混合物,其中果胶的DE小于60%。
因此,本发明还涉及用于治疗免疫介导的疾病和炎性疾病的酯化果胶或酯化果胶混合物,其为酯化果胶或酯化果胶混合物,其中酯化果胶或酯化果胶混合物的DE小于55%。
因此,本发明还涉及用于治疗免疫介导的疾病和炎性疾病的酯化果胶或酯化果胶混合物,其为酯化果胶或酯化果胶混合物,其中酯化果胶或酯化果胶混合物的DE小于50%。
因此,本发明还涉及方法(M1),其为方法(M),其中果胶的DE小于60%。
因此,本发明还涉及方法(M1′),其为方法(M),其中果胶的DE小于55%。
因此,本发明还涉及方法(M1″),其为方法(M),其中果胶的DE小于50%。
通常果胶的DE为至少1%,优选至少2%,更优选至少3%。因此,存在1%至65%、2%至65%、3%至65%、1%至60%、2%至60%、3%至60%、1%至55%、2%至55%和3%至55%的范围。
商业化果胶可以是数个群体的混合物:取代基的分布可在分子内水平(在一个单个果胶聚合物链内)中或在分子间水平(在一个单个果胶样品内)中不同。这适用于所有取代基,因此糖和酯化,并且因此这两个类别在下文中均意指词语“取代基”。取代基可以完全随机地分布。这种随机分布可遵循均匀分布模式,当取代基在单个果胶聚合物链上规则分布时,导致更为同质的果胶聚合物链。如果单个果胶样品中的所有果胶聚合物链都是相同同质类型的,则样品也可以被称为同质的。
然而,单个同质果胶聚合物链可与其他同质果胶聚合物链一起存在于组合物中,但是分子内取代基分布不同(但仍是同质的)。在此情况下,果胶样品应被视为异质的。
此外,还可对根据本发明的酯化果胶进行修饰。其中可能的修饰之一是酰胺化。酰胺化果胶是果胶修饰形式。在这种情况下,用氨使一些半乳糖醛酸转化为羧酸酰胺。这是根据公知的方法完成的。存在的酰胺基通常位于酰胺化GalA残基的C-6位。如果果胶被酰胺化,则DE通常表示为酰胺化度(degree of amidation,即DAM)。在这种情况下,酯化度被定义为每100摩尔总半乳糖醛酸(游离GalA和经取代GalA加在一起)存在的酰胺的量(以摩尔计)。
另一些可能的果胶修饰是乙基或丙基。
优选地,果胶的酯化类型为甲基化和/或乙酰化,更优选甲基化。
因此,本发明还涉及用于治疗免疫介导的疾病和炎性疾病的如上所述的酯化果胶或酯化果胶混合物,其中果胶的酯化类型为甲基化和/或乙酰化。
因此,本发明还涉及用于治疗免疫介导的疾病和炎性疾病的如上所述的酯化果胶或酯化果胶混合物,其中果胶的酯化类型为甲基化。
因此,本发明还涉及方法(M1),其为方法(M),其中果胶的酯化类型为甲基化和/或乙酰化。
因此,本发明还涉及方法(M1′),其为方法(M),其中果胶的酯化类型为甲基化。
表征天然、经修饰和商业化的果胶的不同组分(即,GalA含量、中性糖含量、甲基酯化度、乙酰化度、酰胺化度、非甲基酯化GalA的分布、分子量)的方法在StéphanieGuillotin的PhD论文(Studies on the intra-and intermolecular distributions ofsubstituents in commercial pectins.Wageningen University,The Netherlands,2005.ISBN 90-8504-265-8)中很好地被描述。
如上所述,特定果胶用于对抗人或动物的炎性疾病。
术语“患者”意指可能发生或患有炎性疾病的人或其他动物,包括鸟(avian)、牛(bovine)、犬(canine)、马(equine)、鸡(galline)、猫(feline)、山羊(hircine)、兔(lapine)、鼠(murine)、鼬(musteline)、绵羊(ovine)、鱼(piscine)、猪(porcine)和狐狸(vulpine)动物。优选地,患者为人、牛、犬、猫、鸡、绵羊、猪或鸟。
根据本发明的特定果胶如上所公开地用于预防、减轻和/或治疗炎性病症、疾病或不适。该结果通过以下事实获得,根据本发明的特定果胶令人惊讶地能够结合TLR2,其参与许多疾病、肠屏障功能的调节和免疫应答的调节。
Toll样受体(Toll-like receptor,TLR)是在先天免疫系统中发挥关键作用的一类蛋白质。它们是通常在前哨细胞(例如巨噬细胞和树突细胞)中表达的单一跨膜非催化性受体,其识别来自于微生物的结构上保守的分子。一旦这些微生物突破了物理障碍(例如皮肤或肠道黏膜),它们被TLR识别,其激活免疫细胞应答。TLR包括TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12和TLR13。
令人惊讶地,发现仅具有低酯化度(即,低DE)的果胶能够以充分的方式结合TLR2。具体地,具有低甲基化度(即,低DM)的果胶能够以充分的方式结合TLR2。
根据本发明的特定果胶与TLR的相互作用用基于细胞的测定来测试。在本发明的情况中,使用HEK-BlueTM检测(来自InvivoGen)。HEK-BlueTM系统由多种特定细胞系和细胞培养基组成,该细胞培养基被开发成通过所谓的SEAP表达来提供快速且方便的监测分子相互作用的方法(详见实施例1)。这种细胞测定是可商购的。这些测试的结果在以下实施例中详尽公开。其表明低酯化(尤其是甲基化)的果胶显示出令人惊讶的有利作用!
所使用果胶的量可根据患者而不同。其必须是显示出充足效果的量。
被患者摄入的果胶可以是任何形式的。可原样或在与其他成分的混合物中使用果胶。当在混合物中使用时,在这种混合物中的量则取决于其他成分以及混合物的形式。
使用的成分通常根据混合物的用途来选择。所述成分可用于改善混合物的特性,或当混合物用于配制成最终组合物时用于改善最终组合物。
所述成分可用于一个或更多个目的。显然这样的成分必须是食品或饲料级(根据其用途)。
果胶还可以是食品或饲料产品中的一部分,然而食品或饲料产品可以是任何公知和常用的形式。
使用的果胶量可以不同(根据患者和/或所针对的炎性疾病)。这取决于体重。通常每千克体重每天0.01g至5g量的DE小于65%的果胶是期望的。
特定食品或饲料产品中的果胶量通常根据食品或饲料产品而不同。这还取决于消费者/动物吃这种食品或饲料产品的多少。在食品或饲料产品中的量应为使得通过该食品或饲料产品的平常消耗而消耗所需果胶剂量的量。
以下实施例用于举例说明本发明。
实施例
实施例1果胶抑制TLR2介导的NFκB活化
细胞系和培养
在具有10%经灭活补体的胎牛血清、50U/ml青霉素(Sigma,St.Louis,MO,USA)、50μg/ml链霉素(Sigma,St.Louis,MO,USA)和100μg/mlNormocin(InvivoGen,Toulouse,France)的DMEM培养基(Lonza,Basel,Switzerland)中培养细胞系。
使用表达人TLR2和SEAP(可溶性胚胎碱性磷酸酶)的HEK-BlueTMTLR2-CD14细胞(InvivoGen,Toulouse,France)。当TLR2被激动剂活化时,刺激NFκB和AP1移动到这些细胞系的细胞核。在此,SEAP基因处于NFκB/AP-1应答启动子的控制之下。表达后,在培养基中分泌SEAP基因产物,可使用Quantiblue(InvivoGen,Toulouse,France)溶液进行量化。根据活性,酶将粉红色转变成蓝色,这可用分光光度计测量。
向培养基添加1X HEK-BlueTM Selection(InvivoGen,Toulouse,France)以仅控制HEK-BlueTM TLR2-CD14细胞的生长。
果胶来源
所有的果胶均从柑橘分离。DE为0的果胶获自MP Biomcdicals,LLC。DE为7、22、45、60和75的果胶获自CP Kelko。
果胶抑制TLR2-1
用TLR2-1特异性激动剂Pam3CSK4活化HEK-BlueTM TLR2-CD14细胞。以0.5、1和2mg/ml添加不同DE值(0、7、22、45、60和75)的果胶。作为对照,仅用果胶孵育HEK-BlueTM TLR2-CD14细胞。
将HEK-BlueTMTLR2-CD14细胞以500,000个细胞/ml以每孔100μl的体积接种在96孔板中。使细胞培养过夜。第二天,用不同果胶在不同浓度下处理细胞以研究对TLR2的作用。与果胶孵育1小时后,以100ng/ml的浓度添加Pam3CSK4。与果胶和Pam3CSK4在37℃下孵育24小时后,确定SEAP基因的表达。使经孵育的细胞的上清液与QUANTI-Blue溶液以1:10的比例混合。SEAP的存在使QUANTI-Blue变蓝。NFκB活化通过使用ELISA读板器Versa Max(Molecular devices,Sunnyvale,CA,USA)测量在650nm处的颜色强度进行量化。该测定在96孔板中以8个技术重复进行。每个实验重复三次。
令人惊讶地,果胶抑制TLR2,如NFκB活化SEAP基因表达后通过SEAP活性水平在650nm处的Quanti-blue颜色变化确定的。低DE果胶的抑制作用最高,但是发现在所有DE值下抑制作用取决于各果胶的浓度。具有较高DE值(45、60和75)的果胶的抑制作用明显地是浓度依赖性的,表明在较高浓度下局部DE<65%的分子内或分子间区域的绝对数量(由于在整个果胶分子和/或样品上可能的不规则或异质性的酯化GalA残基分布)变得更高,因此通过那些DE小于65之区域的TLR2的抑制作用提高。
HEK-BlueTM TLR2CD14的生存力不受添加的果胶影响(使用WST-1试剂测试)。
实施例2果胶与TLR2结合
TLR2胞外域-HA表达质粒的构建
使用 Mini试剂盒(Qiagen,Venlo,Netherlands)从HEK-BlueTMhTLR2-CD14细胞提取RNA。根据供应商的手册,使用OligodT引物(Lifetechnologies,Carlsbad,CA,USA)、dNTP混合物(Life technologies,Carlsbad,CA,USA)和SuperscriptTMIII逆转录酶(Life technologies,Carlsbad,CA,USA)合成cDNA。使用来自HEK-BlueTMhTLR2-CD14的cDNA,使用正向引物5'-GCGCACCGGTATGCCACATACTTTGTGGATGG-3′、反向引物5'-GCGCGGATCCGTGACATTCCGACACCGAGAG-3′和Pfu DNA聚合酶(Thermoscientific,Waltham,MA USA)合成了从密码子1至密码子586的TLR2。引物在5′端侧接GC双联体用于限制酶识别。AgeI和BamHI限制性位点分别包括在正向和反向引物中。用AgeI和BamHI限制酶(Thermo scientific,Waltham,MA USA)酶切消化PCR产物,以及酶切消化质粒pSELECT-CHA-blasti(InvivoGen,Toulouse,France)以产生黏性末端。使用T4DNA连接酶(Thermo scientific,Waltham,MA USA)连接PCR扩增的TLR2胞外域片段和线性质粒。使用经连接的质粒来转化One Shot TOP10化学感受态大肠杆菌(E.coli)(Life technologies,Carlsbad,CA,USA)。使用杀稻瘟菌素(blasticidin)琼脂培养基(InvivoGen,Toulouse,France)对经转化的大肠杆菌细胞进行选择。针对在质粒中正确定位的基因对所获得的菌落进行筛选。将所选择的正确菌落在杀稻瘟菌素液体培养基(InvivoGen,Toulouse,France)中培养,并使用Qiagen Midi prep试剂盒分离质粒。然后对质粒进行测序以选择未突变的克隆(Baseclear,Leiden,Netherlands)。
用TLR2胞外域-HA表达片段转染HEK293T
将HEK293T细胞以500,000个细胞/ml接种在12孔培养板中并孵育过夜。第二天,通过使用Lipofectamine (Lifetechnologies,Carlsbad,CA,USA)进行转染。用限制酶NotI(Fast digest,Thermo Scientific,Waltham,MA USA)使经序列验证的质粒线性化。将1μg纯化的线性质粒在低血清培养基Opti-(Life technologies,Carlsbad,CA,USA)中稀释并与3.5μlLipofectamine (Life technologies,Carlsbad,CA,USA)混合。将该转染混合物在室温下孵育30分钟,然后添加至培养基中的先前接种的细胞。用转染培养基混合物将细胞孵育24小时,并使用在具有10%经灭活补体的胎牛血清、50U/ml青霉素(Sigma,St.Louis,MO,USA)、50μg/ml链霉素(Sigma,St.Louis,MO,USA)和100μg/mlNormocin(InvivoGen,Toulouse,France)的DMEM培养基(Lonza,Basel,Switzerland)中的杀稻瘟菌素对经转染的细胞进行选择。分离单一细胞克隆以形成HEK293T TLR2胞外域-HA细胞系。
细胞培养
在具有10%经灭活补体的胎牛血清、50U/ml青霉素(Sigma,St.Louis,MO,USA)、50μg/ml链霉素(Sigma,St.Louis,MO,USA)、100μg/mlNormocin(InvivoGen,Toulouse,France)和50μg/ml杀稻瘟菌素(InvivoGen,Toulouse,France)的DMEM培养基(Lonza,Basel,Switzerland)中培养细胞系。
蛋白质免疫沉淀
使用1X RIPA裂解缓冲液(Merck Millipore,Billerica,MA,USA)在由AEBSF(4-(2-氨基乙基)苯磺酰氟盐酸盐)、抑酶肽(Aprotinin)、苯丁抑制素(Bestatin)、E-64、EDTA和亮抑蛋白酶肽(Sigma,St.Louis,MO,USA)组成的蛋白酶抑制剂混合物(proteaseinhibitor cocktail)的存在下将经过夜培养的HEK293T TLR2胞外域-HA细胞在4℃下裂解10分钟,然后在0%功率下进行两次超声处理5秒。在14000g下离心10分钟后分离上清液。在微量离心管中使用抗HA琼脂糖(Thermo scientific,Waltham,MA USA)对TLR2胞外域-HA标记的蛋白质进行免疫沉淀。使用HA合成肽(Thermo scientific,Waltham,MAUSA)通过在30℃下用单个床体积的HA合成肽孵育两次15分钟对蛋白质进行竞争性洗脱。将经分离的蛋白质脱盐,并且使用Zeba Spin脱盐柱和装置40KMWCO(Thermo scientific,Waltham,MA USA)除去HA肽。使用Thermo scientific BCA蛋白质测定试剂盒对经分离和脱盐的蛋白质进行量化。
用于TLR2和果胶结合的ELISA
ELISA缓冲液由在pH 8.2的0.05M Tris缓冲液中的1mM CaCl2和150mM NaCl构成。缓冲液用于洗涤以及用于抗体和果胶的稀释剂。封闭缓冲液通过将3%乳粉(FrieslandCampina,Amersfoort,The Netherlands)溶解在ELISA缓冲液中制备。对于抗体溶液,使用封闭缓冲液与ELISA缓冲液的1∶2稀释液溶解抗体。用50μl的50μg/ml聚-L赖氨酸在37℃下处理ELISA板(Corning,Tewksbury,MA,USA)1小时。用400μlELISA缓冲液将孔洗涤一次。将果胶(0、7、22、45、60和75DE)以1mg/ml浓度溶解在ELISA缓冲液中,并将50μl添加至各孔。将板在37℃下孵育4小时以使果胶结合。然后用400μlELISA缓冲液洗涤各孔,并用100μl封闭缓冲液在4℃下封闭过夜。在封闭步骤后,用ELISA缓冲液将ELISA板洗涤一次。将TLR2胞外域-HA融合蛋白以每孔0.33μg、1μg、3μg和9μg浓度施加至果胶包被的孔。然后将ELISA板在37℃下孵育3小时。以每孔0.33μg、1μg、3μg和9μg浓度(与TLR2胞外域-HA融合蛋白相同)使用HA合成肽作为阴性对照。以1∶100稀释使用来自Plantprobes(Leeds,UK)的果胶结合抗体LM19(对DE 0和7具有特异性)和LM20(对DE 22、45、60和75具有特异性)作为果胶结合的阳性对照。此后,用400μl的ELISA缓冲液将孔洗涤5次,并用1∶200稀释的50μlHA标签的检测一抗(Cell Signaling,Danvers,MA,USA)孵育。将一抗在37℃下孵育2小时。一抗孵育后,再次用ELISA缓冲液将板洗涤5次。洗涤后,将50μl生物素标记的二抗(SouthernBiotech,Birmingham,AL,,USA)以1∶500稀释施加至各孔。将生物素标记的抗体在37℃下孵育1小时。该步骤后用400μl ELISA缓冲液洗涤5次。将链霉亲和素-HRP(Dako,Heverlee,Belgium)(100μl)以1∶1000稀释添加至各孔。在37℃下孵育1小时后,用400μlELISA缓冲液将板洗涤7次。最后,为了检测,将100μl的TMB底物(Cell Signaling,Danvers,MA,USA)施加至各孔,并在37℃下孵育30分钟。通过添加100μl终止溶液(Cell Signaling,Danvers,MA,USA)终止反应。在读板器Versa Max(Molecular devices,Sunnyvale,CA,USA)中在420nm处对ELISA板进行读取。为了清楚起见,从用TLR2胞外域-HA获得的值中减去阴性对照的值。
令人惊讶地,低DE果胶与TLR2胞外域直接结合,如在ELISA测试中获得的剂量依赖性值所示。
实施例3果胶仅抑制TLR2的促炎途径而不抑制其调节途径
细胞系
将HEK-BlueTM Null1(InvivoGen,Toulouse,France)以500,000个细胞/ml接种在12孔培养板中并孵育过夜。第二天,通过使用Lipofectamine (Lifetechnologies,Carlsbad,CA,USA)进行转染。用NotI(Thermo scientific,Waltham,MAUSA)使质粒pUNO3-hTLR2(InvivoGen,Toulouse,France)线性化。将1μg纯化的DNA在低血清培养基Opti-(Life technologies,Carlsbad,CA,USA)中稀释,并与3.5μlLipofectamine (Life technologies,Carlsbad,CA,USA)混合。将该转染混合物在室温下孵育30分钟,然后添加至培养基中的先前接种的细胞。用转染培养基混合物将细胞孵育24小时,使用在具有10%经灭活补体的胎牛血清、50U/ml青霉素(Sigma,St.Louis,MO,USA)、50μg/ml链霉素(Sigma,St.Louis,MO,USA)和100μg/ml Normocin(InvivoGen,Toulouse,France)的DMEM培养基(Lonza,Basel,Switzerland)中的Zeocin(100μg/ml)和潮霉素B(150μg/ml)对经转染的细胞进行选择。分离单一细胞克隆。由此获得的HEK-BlueTMNull1TLR2细胞系仅表达TLR2而不表达CD14。
TLR2活化和抑制测定
将HEK-BlueTMNull1 TLR2细胞以500,000个细胞/ml以每孔100μl的体积接种在96孔板中。使细胞培养过夜。第二天,用不同的果胶处理细胞以研究对TLR2的作用。用果胶孵育1小时后,以100ng/ml的浓度添加TLR2-6特异性激动剂FSL-1。用果胶和FSL-1在37℃下孵育24小时后,确定SEAP基因的表达。将经孵育细胞的上清液与QUANTI-Blue溶液以1∶10的比例混合。SEAP的存在使QUANTI-Blue变蓝。通过使用ELISA读板器Versa Max(Moleculardevices,Sunnyvale,CA,USA)测量在650nm处的比色读数对NFκB活化进行量化。该测定在96孔板中以10个技术重复进行。每个实验重复三次。
数据表明果胶不抑制TLR2-6信号传导途径,因为在HEK-BlueTMNull1 TLR2细胞中通过FSL-1的刺激不因果胶的存在而改变,而通过Pam3CSK4的刺激清楚地显示果胶抑制TLR2-1信号传导应答(实施例1)。
实施例4小猪饮食中的果胶导致肠紧密连接渗透性降低
小猪进食试验设置
年幼小猪的实验农场位于Flanders(Belgium),由8组(battery)组成,每组包含4个围栏(pen)。所研究的小猪是Topigs Piétrains的杂种,且在21天时断奶。断奶时和断奶后2周和4周对小猪各自称重。在称重的时候,对每围栏4只小猪记录采食量。在到达时,用新的Sanitel号为小猪加耳标(earmarked)。在试验期间,兽医和Felasa D认证人员根据法律EC/86/609中所述的国际准则监督所进行的小猪实验。
试验开始时,每个围栏(1.5m×1.5m)包含4只小猪。对每个围栏,安装一个用于膳食或颗粒的饲喂器(自由采食)。每个围栏安装一个饮用乳头。开始时的温度处于28±2℃,直至断奶后10天。此后,温度降至25±2℃。
给予商业化不加药饮食(non-medicated diet)。不加药意指在试验之前和期间小猪不接受任何治疗性抗生素。饮食以膳食的形式给予。分析所有饲料的营养含量。采用一式7份的四种处理(饮食A、B、C、D),每组4只小猪。在试验开始时,将小猪(约7kg体重)按重量分配至不同围栏。进行这种分配是为了每种处理和每个围栏具有相等的平均重量和相等的平均重量附近的标准偏差。对于微生物计数和取活检,小猪接受过量的巴比妥类药物(Nembutal),随后处死。此后,对小猪进行切片。立即处理用于微生物计数的样品,同时将用于进行组织化学实验而取得的样品固定用于以后的分析。
在整个试验期期间,除了微生物学计数期外,小猪随意进食。此时,在进行微生物学计数前三天,限制小猪进食。小猪每天接受仔细称重并记录的三次一定量的饲料。在8.00、13.00和18.00时给予饲料。必要时,对病猪单独进行处理(通过注射)。以下参数被考虑在内。(i)个体生长数据;(ii)每个围栏采食量数据(校正最终损失);(iii)断奶期间、起始和整个试验期的饲料转化率;(iv)粪便评分和临床评分;(v)紧密连接;(vi)微生物分析;(vii)组织化学分析。
饮食
饲料组成(以g/kg计):
*木聚糖酶/β-葡聚糖酶和植酸酶混合物(BASF)
**预混物包含芳香剂(aroma's)、额外的微量矿物质、维生素(维生素N.V.)
果胶来源
DE 33和55的果胶分离自柑橘,且获自Herbstreith&Fox(Neuenbürg/Württingen,Germany)。大豆粉(Soy Bean Meal,SBM)来源于南美洲(来自阿根廷、巴西和/或巴拉圭的混合物),并且通过使SBM与自来水以33%干物质混合并在120℃下高压灭菌30分钟进行加工以提取存留的果胶。冷却后,将所得材料冷冻干燥并研磨,并原样用于饮食中。
甘露醇-乳果糖测试
通过在动物中进行甘露醇-乳果糖测试对回肠渗透性进行量化。乳果糖不能通过整个小肠,这被认为是积极的,因为在全身感染和免疫问题上的机会较低。
甘露醇是代谢上惰性的单糖,其通过肠黏膜被动吸收。任何吸收的甘露醇都在几小时内完全排泄到尿中。通过胃泵将甘露醇以0.3g甘露醇/kg体重施用于小猪(解剖前4小时)。乳果糖是代谢上惰性的二糖,其通常不被吸收,除非黏膜屏障受损。任何吸收的乳果糖在6小时内完全排泄到尿中。通过胃泵将乳果糖以0.75g乳果糖/kg体重施用于小猪(解剖前4小时)。
然后在解剖期间收集小猪尿。在具有健康肠的小猪中,平均乳果糖吸收小于所施用剂量的1%。尿中>1%的乳果糖回收率表明二糖渗透性过高。
在具有健康肠的小猪中,平均甘露醇吸收为所施用剂量的>14%。
尿中<14%的甘露醇回收率表明碳水化合物吸收不良。较低的乳果糖/甘露醇比例(L/M比例)表明饮食的积极作用。
如所示,所有果胶(且尤其是具有DE 33和55果胶的果胶导致降低的L/M比例,因此在年幼猪的小肠中具有积极作用。
实施例5饮食中的果胶导致绒毛与隐窝比例提高
小猪进食试验设置如实施例4中所述。
用于组织学的样品制备
取样:取十二指肠和/或回肠的样品,用生理水(0.9%NaCl)冲洗。储存在20ml福尔马林缓冲液(1ml甲醛(37%)/升、4.5g NaH2PO4+10.4g Na2HPO4)中。
包埋:使容器中的石蜡溶液不足(未完全装满),并将肠样品垂直放置在容器内。在4℃下固化,并完全填充容器。使其在-3℃下固化。
活检(Biopt):用10%二甲苯清洁手术刀,并使其干燥。用刷和针将切出物(coupe)转移至50%醇。切成片并用刷和显微镜载玻片转移至蒸馏水(65℃)。将样品置于显微镜载玻片上并在60℃下孵育一晚。
在环境温度下的苏木精-曙红(H&E)染色步骤:
1)脱蜡
·用10%二甲苯洗涤3次(5分钟)
·用100%乙醇洗涤2次(3分钟)
·用90%乙醇洗涤1次(3分钟)
·用70%乙醇洗涤1次(3分钟)
·用水洗涤1次(3分钟)
·用水洗涤1次(3分钟)
2)染色
·在Mayers苏木精中孵育(6分钟)
·用水洗涤1次(5分钟)
3)复染
·在10%曙红中孵育(5分钟)
·用水洗涤10次(每次30秒)
4)脱水
·用90%乙醇洗涤10次(每次30秒)
·用70%乙醇洗涤10次(每次30秒)
·用100%酒精洗涤2次(5分钟)
·用10%二甲苯洗涤3次(5分钟)
·
绒毛长度和隐窝深度的量化
通过Olympus显微镜分析上述包埋的组织学样品,并测量绒毛长度(mm)和隐窝(深度)。
较长的绒毛意味着较高的吸收能力,而较长的隐窝意味着相反。因此,较高的绒毛与隐窝比例被认为是饮食的积极作用,而较低的绒毛与隐窝比例被认为是使用相应饮食的负面缺陷。如所示,尤其是具有DE 33和55果胶的饮食在十二指肠和回肠二者中具有提高的绒毛-隐窝比例,这证明了这两种果胶改善胃肠健康的潜力。
实施例6果胶在多柔比星诱导的黏膜炎中作为抗炎剂发挥作用
黏膜炎(也被称为黏膜屏障损伤)是放疗和化疗治疗中最严重的副作用之一。黏膜屏障的炎症和凋亡二者导致其不连续性,从而促进细菌移位。黏膜炎的病理生理学中的五个阶段是重要的:(1)在起始阶段期间导致核因子κB(nuclear factor kappa B,NFκB)活化的活性氧类(reactive oxygen species)的形成,(2)在上调/信息产生阶段期间信使分子(例如肿瘤坏死因子α(tumor necrosis factor alpha,TNFα))的诱导,导致治疗相关的组织炎症和凋亡,(3)扩增/信号传导阶段中信使分子的扩增,导致更多的炎症和凋亡,(4)在溃疡阶段期间由于凋亡导致的上皮屏障的不连续性,从而促进细菌移位,以及(5)以细胞增殖为特征的自发性愈合阶段(Sonis,2004,Semin Oncol Nurs.20(1):11-5);Van Vliet等,2010,PLoSPathog.6(5):e1000879)。
小鼠
C57BlL/6雌性小鼠(7至10周龄)购自Janvier laboratories,France。格罗宁根大学动物伦理委员会批准了动物的实验用途。在实验开始之前,使所有小鼠适应2.5周。通过施用多柔比星(Sigma,St.Louis,MO,USA)诱导黏膜炎。
饮食向小鼠供应随意RMH-B饮食(AB diets,Woerden,The Netherlands)。供应商指定的饮食成分为小麦、肉粉(meat meal)(80%消毒)、黄色马齿型玉米(yellow dentcorn)、全燕麦、麦麸(wheat middlings)、苜蓿、大豆油、干酵母、磷酸二钙、碳酸钙、NaCl、dl-甲硫氨酸、维生素和微量元素。向小鼠供应饮用自来水,且水瓶每周更换一次。
果胶来源
DE为7的果胶获自CP Kelko。
诱导黏膜炎和读出
将多柔比星溶解在无菌0.9%氯化钠中,并在4℃下以等分试样储存。将果胶(7DM)溶解在无菌水中,并通过管饲法施用于小鼠10或11天,每天两次,3mg/天。在第8天,以10mg/kg的浓度腹膜内注射多柔比星。在第10天(48小时多柔比星)或第11天(72小时多柔比星)处死小鼠。通过管饲法接受水的动物用作对照。收集组织样品后,通过颈脱位法(cervicaldislocation)处死小鼠。
小鼠中的TLR2阻断
在多柔比星处理之前1小时,以10mg/kg IP施用TLR2阻断抗体,克隆T2.5(InvivoGen,Toulouse,France)。
中性粒细胞计数
用2ml PBS收集腹膜灌洗液以收集腹膜中性粒细胞内流。使用ZTMSeries coulter(Beckman Coulter,Brea,CA,USA)对腹膜灌洗液中的活细胞总数进行计数。将灌洗液以500,000个细胞/ml稀释,并使用100μl细胞液用于cytospin制备物。在室温下用吉姆萨染色(Merck Millipore,Billerica,MA,USA)将cytospin载玻片染色1小时。在Hamamatsu载玻片扫描仪(Hamamatsu photonics,Japan)中对经染色的载玻片进行扫描,并使用形态特征在250个细胞中对中性粒细胞进行计数。使用腹膜中的总细胞计数和从cytospin制备物的中性粒细胞计数计算中性粒细胞的总数。
从数据可以看出,多柔比星诱导的黏膜炎使中性粒细胞计数提高了56倍。通过TLR2阻断抗体克隆T2.5或果胶DE7阻断TLR2显著降低了中性粒细胞计数,表明果胶作为抗炎剂发挥作用。
实施例7果胶对有益健康的微生物具有积极作用
消化物收集
在实验饮食饲喂期间在第14天和第28天收集猪粪便样品(实施例4)。在粪便收集期后,麻醉动物并使其安乐死。从末端回肠、近端结肠、中段结肠和远端结肠收集消化物样品。将各消化物的一部分储存在1.5mLEppendorf管中用于分析微生物区系组成和SCFA。立即将这些管在液氮中冷冻并储存在-80℃下。将剩余量的消化物立即储存在-20℃下,直至进一步分析。
DNA提取和微生物区系分析
通过使用粪便DNA提取方案(Salonen A, J,Jalanka-Tuovinen J,Immonen O, M,Kekkonen RA,Palva A&de VosWM.2010.Comparative analysis of fecal DNA extraction methods withphylogenetic microarray:Effective recovery of bacterial and archaeal DNAusing mechanical cell lysis.Journal of Microbiological Methods,81:127-134)从250mg消化物中提取微生物DNA。通过连续沉淀分离DNA,并最后通过根据制造商的推荐使用QIAamp DNA Stool Mini试剂盒柱(Qiagen,Hilden,Germany)进行纯化。将16S rRNA基因扩增并通过使用MiSeq平台(Illumina)以配对末端模式(paired-end mode)进行测序。
序列分析
使用QIIME 1.9.0对原始的Illumina fastq文件进行解复用(demultiplexed)、质量过滤和分析。
*相对丰度是通过Illumina测序获得的总数据集中普雷沃菌属16S rRNA数据的%
**相对提高是总数据集中普雷沃菌属16S rRNA的%提高的倍数,即确定的特定果胶饲喂样品的相对丰度除以对照样品。
令人惊讶地,向饮食添加果胶导致普雷沃菌属物种在肠中的普遍性(这是一项健康指标,参见Wu GD,Chen J,Hoffmann C,Bittinger K,Chen YY,Keilbaugh SA,Bewtra M,Knights D,Walters WA,Knight R,Sinha R,Gilroy E,Gupta K,Baldassano R,Nessel L,Li H,Bushman FD&Lewis JD.2011.Linking long-term dietary patterns with gutmicrobial enterotypes.Science 334:105-108)提高。
所有这些实施例清楚且令人惊讶地表明特定果胶显示出显著的改善。
序列表
<110> 营养科学股份有限公司
皇家农业企业集团有限公司
<120> 用于预防和治疗炎性疾病的饲料组合物
<130> NUSC-020-EP
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 32
<212> DNA
<213> 人
<400> 1
gcgcaccggt atgccacata ctttgtggat gg 32
<210> 2
<211> 31
<212> DNA
<213> 人
<400> 2
gcgcggatcc gtgacattcc gacaccgaga g 31
Claims (13)
1.用于在患者中治疗免疫介导的疾病和炎性疾病的酯化果胶或酯化果胶混合物,其特征在于所述酯化果胶或所述混合物中酯化果胶的酯化度(DE)小于65%。
2.根据权利要求1所述的酯化果胶,其中所述果胶的DE小于60%。
3.根据权利要求1所述的酯化果胶,其中所述果胶的DE小于55%。
4.根据权利要求1所述的酯化果胶,其中所述果胶的DE小于50%。
5.根据权利要求1所述的酯化果胶,其中所述果胶不是酰胺化的。
6.根据前述权利要求中任一项所述的酯化果胶,其中所述果胶的DE为至少1%,优选至少2%,更优选至少3%。
7.根据前述权利要求中任一项所述的用于治疗免疫介导的疾病和炎性疾病的酯化果胶或酯化果胶混合物,其中所述免疫介导的疾病和炎性疾病由包含紧密连接的组织的过度或不期望渗透性所导致的TLR2活化引起。
8.根据前述权利要求中任一项所述的酯化果胶或酯化果胶混合物,其用于预防药物的不良副作用。
9.根据前述权利要求中任一项所述的用途,其中所述患者意指可能发生或患有炎性疾病的人或其他动物。
10.根据前述权利要求中任一项所述的酯化果胶或酯化果胶混合物,其用于在患者中治疗免疫介导的疾病和炎性疾病以及用于在患者中预防药物的不良副作用,其中所述患者是人、鸟、牛、犬、马、鸡、猫、山羊、兔、鼠、鼬、绵羊、鱼、猪和狐狸动物,优选地所述患者是人、牛、犬、猫、鸡、绵羊、猪或鸟。
11.至少一种酯化度小于65%的果胶在食品或饲料制剂中的用途。
12.制剂,其包含至少一种酯化度(DE)小于65%的果胶。
13.根据权利要求12所述的制剂,其为食品或饲料制剂。
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EP15176285.3 | 2015-07-10 | ||
PCT/EP2016/066351 WO2017009257A2 (en) | 2015-07-10 | 2016-07-08 | Feed compositions for preventing and treating inflammatory diseases |
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EP (2) | EP3319616B1 (zh) |
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BR (1) | BR112018000520A2 (zh) |
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CN107847518A (zh) * | 2015-07-10 | 2018-03-27 | 帝斯曼知识产权资产管理有限公司 | 用于预防和治疗炎性疾病的食物和/或饲料组合物 |
WO2022222899A1 (zh) * | 2021-04-20 | 2022-10-27 | 涛护集团有限公司 | 果胶在制备保健品或药物中的应用 |
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CN112533486A (zh) | 2018-03-16 | 2021-03-19 | 味之素株式会社 | 饲料用添加剂及饲料 |
EP3895710A1 (en) * | 2020-04-15 | 2021-10-20 | DSM IP Assets B.V. | Food and/or feed compositions to manage immune homeostasis |
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- 2016-07-08 ES ES16738129T patent/ES2894834T3/es active Active
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WO2022222899A1 (zh) * | 2021-04-20 | 2022-10-27 | 涛护集团有限公司 | 果胶在制备保健品或药物中的应用 |
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HUE056154T2 (hu) | 2022-01-28 |
WO2017009257A3 (en) | 2017-02-23 |
WO2017009257A2 (en) | 2017-01-19 |
ES2894834T3 (es) | 2022-02-16 |
EP3319616B1 (en) | 2021-09-01 |
US20190008890A1 (en) | 2019-01-10 |
US10639323B2 (en) | 2020-05-05 |
DK3319616T3 (da) | 2021-10-18 |
EP3319616A2 (en) | 2018-05-16 |
EP3939598A1 (en) | 2022-01-19 |
PL3319616T3 (pl) | 2022-01-10 |
BR112018000520A2 (pt) | 2018-09-18 |
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