CN113521109A - 解纤维素拟杆菌在预防和/或治疗炎症性肠病中的应用 - Google Patents
解纤维素拟杆菌在预防和/或治疗炎症性肠病中的应用 Download PDFInfo
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- CN113521109A CN113521109A CN202110716399.3A CN202110716399A CN113521109A CN 113521109 A CN113521109 A CN 113521109A CN 202110716399 A CN202110716399 A CN 202110716399A CN 113521109 A CN113521109 A CN 113521109A
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Abstract
一种解纤维素拟杆菌在预防和/或治疗炎症性肠病中的应用,包括解纤维素拟杆菌用于制备预防和/或治疗炎症性肠病的药物、药物组合物、食品、保健品及食品添加剂等的应用。本发明经由活体内及体外的相关实验证实,解纤维素拟杆菌对炎症性肠病,包括溃疡性结肠炎和克罗恩病,具有优异的抵抗力且无毒副作用,可持久且有效地应用于制备预防和/或治疗炎症性肠病的药物、药物组合物、食品、保健品或食品添加剂等,该药物、药物组合物、食品、保健品或食品添加剂可用于预防和治疗炎症性肠病,具有重大应用价值。
Description
技术领域
本发明涉及微生物技术,特别是解纤维素拟杆菌在预防和/或治疗炎症性肠病中的应用,包括用于制备预防和/或治疗炎症性肠病的药物、药物组合物、食品、保健品及食品添加剂等的应用。
背景技术
炎症性肠病(Inflammatory bowel disease,IBD)是一组不明原因的慢性肠道炎症性疾病,包括溃疡性结肠炎(Ulcerative colitis,UC)和克罗恩病(Crohn's disease,CD)。前者又称非特异性溃疡性结肠炎,是一种原因不明的直肠和结肠的炎症,病变主要限于大肠黏膜与黏膜下层。后者为一种慢性肉芽肿性炎症,病变可累及胃肠道各部位,而以末段回肠及临近结肠为主,多呈节段性、非对称性分布(参见:蒋蔚茹.炎症性肠病的认识与治疗进展[J].上海医药,2010,05:207-210.)。炎症性肠病的发病机制尚未阐明,目前认为是基因上易感人群对肠道共生微生物产生过度的先天或后天免疫反应所致(参见:蒋蔚茹.炎症性肠病的认识与治疗进展[J].上海医药,2010,05:207-210.)。肠黏膜屏障功能损伤参与了IBD的发生(参见:毛靖伟,王英德.肠黏膜屏障在炎症性肠病中作用机制的研究进展[J].世界华人消化杂志,2010,07:695-698.)。
IBD在不同国家、地区、种族人群中的发病率不同,有显著的地域和种族差异。Molodecky等(Molodecky.NA,Soon IS,Rabi DM,et al.Increasing incidence andprevalence of the inflammatory bowel diseases with time,based on systematicreview[J].Gastroenterology,2012,142(1):46-54.)检索了1950-2010年有关IBD流行病学研究的文献,结果显示欧洲、亚洲、北美洲UC最高发病率分别为24.3/10万、6.3/10万、19.2/10万;CD最高发病率分别为12.7/10万、5.0/10万、20.2/10万。欧洲、北美洲UC最高患病率分别为505/10万、249/10万;CD最高患病率分别为322/10万、319/10万。可见IBD在亚洲的发病率低于欧美国家。据报道日本UC、CD的发病率分别为每年0.5人/10万和0.08人/10万(参见:陆星华.克罗恩病的诊断和治疗[J].中华消化内镜,2007,1(6):26—35.)。
近20年来,IBD病例数在国内迅猛增加。1989-2007年间我国IBD文献报道病例数逐渐增多(Hu RW,Ouyang Q,Chen X et al.Analysis of the articles of inflammatorybowel disease in the literature China in recent fifteen years[J].Chin JGastroenterol,2007,12:74-77.)。Jiang等(Jiang XL,Cui HF.An analysis of10218ulcerative colitis cases in China[J].World J Gastroenterol,2002,8(1):158-161.)分析了1981-2000年国内文献报道的10218例UC患者,发现10年间病例数上升3.08倍。Wang等(Wang Y,Ouyang Q;APDW 2004Chinese IBD working group.Ulcerativecolitis in China:retrospective analysis of 3100hospitalized patients[J].JGastroenterol Hepatol,2007,22(9):1450-1455.)和中国IBD工作组(APDW 2004ChineseIBD Working Group.Retrospective analysis of 515cases of Crohn's diseasehospitalization in China:nationwide study from 1990to 2003[]].JGastroenterol Hepatol,2006,21(6):1009-1015.)对1990—2003年间IBD住院患者进行回顾性研究,共收集3100例UC和515例CD患者,结果显示我国IBD住院患者呈逐渐增加趋势,粗略推测UC患病率约为11.6/10万,CD约为1.4/10万,增长情况与日本、韩国、新加坡等国家相似。
西方国家IBD发病年龄多呈双峰状分布,UC第一个发病年龄高峰为30-39岁,CD为20-29岁,UC和CD第二个发病年龄高峰60-70岁,以第一个高峰病例数为多。亚洲国家IBD发病年龄第二高峰少见,UC和CD发病年龄高峰较西方国家延迟10年。
两项我国多中心研究显示,3100例UC患者19例(0.6%)死亡,515例CD患者7例(1.4%)死亡,死亡率明显低于西方国家。
炎症性肠病目前尚缺乏有效的治疗手段,其治疗药物包括以下几类:
(1)氨基水杨酸类制剂
从20世纪30年代以来,柳氮磺吡啶(Sulfasalazine,SASP)一直是治疗IBD的有效药物,但其代谢产物磺胺吡啶会产生不良反应。现已研究出新型制剂,如缓控释制剂、局部治疗制剂,提高其在结肠的浓度,从而发挥最大效益,并降低药物的毒副作用。
(2)肾上腺糖皮质激素(GCS)
GCS是单一应用最为有效的抑制急性活动性炎症的药物,近期疗效好,有效率可达90%,它能够控制炎症、抑制自身免疫反应、减轻中毒症状。常用药物有氢化可的松、地塞米松和泼尼松等,但该类药物长期使用易产生不良反应。目前已有新一代GCS制剂问世,如布地奈德(Budesonide)、二丙酸倍氯松和巯氢可的松等,此类药物抗炎作用强,而全身副反应少。另外IBD的治疗还有多种局部治疗剂,如灌肠剂、泡沫剂及栓剂,局部用药大大减轻了全身的副反应。
(3)免疫抑制剂
传统免疫抑制剂包括:硫唑嘌呤(AZA)、6-硫唑嘌呤(6-MP)及氨甲蝶呤(MTX)等。这些免疫抑制剂也可用于IBD的治疗,总体来说是有效的,但不是对所有IBD患者均有效,而且不良反应较多。新型免疫抑制剂,如环孢素A(CsA)、他克莫司(FK506)和霉菌酚(MMF)等对IBD有效,但其疗效和安全性尚有待于进一步评价。
(4)单克隆抗体
氨基水杨酸类制剂、肾上腺糖皮质激素和免疫抑制剂虽然对大多数病例有较好的疗效,但上述药物的有效性和安全性均具有一定程度的局限性,随着对IBD发病机制研究的深入,单克隆抗体治疗成为研究的新方向。
20世纪90年代英夫利昔(Infliximab,IFX)-人鼠嵌合型TNF-α单抗问世,10余年的临床应用证实其无论对活动性或缓解期CD在临床症状、内镜下病变改善、溃疡及瘘管愈合等方面均有卓越疗效。由于IFX在国内上市时间尚短,其应用适应证仅为CD及其并发症,但在国外已用于激素及免疫抑制剂无效或不能耐受的中、重度UC患者。随着IFX临床应用经验的不断积累以及纯人源化抗TNF-α的IgG单抗阿达姆(Adalimumab)、人源化抗α24整联蛋白(Integrin)的IgG4单抗Natalizumab和聚乙二醇化人抗TNF-α抗体Fab片段产品赛妥珠(Certolizumab Pegol)等新一代药物的出现,单克隆抗体的疗效越来越被人们所认同。许多大型临床对照研究均证实,单克隆抗体不但在诱导缓解方面疗效明显优于传统药物,而且在维持治疗中也有巨大的优势(Colombel JF,Kamm MA,Schwartz D,etal.Sustainability of adalimumab in fistula healing and response:2year datafrom CHARM and 12-month open-label extension follow-up study[J].Am JGastroenterol,2007,102(11):2541-2550.)。目前普遍的做法是:对于中、重度IBD和高危病人,若传统药物无效,则立即采用单克隆抗体诱导缓解。
限制单克隆抗体应用的原因除价格昂贵,潜在的危险性也是重要因素。如使用IFX的病人罹患结核或组织胞浆菌病等感染的可能性明显增加。此外,神经系统脱髓鞘病变、充血性心力衰竭以及淋巴瘤等疾病的患病率也有提高。
(5)抗生素
对有细菌感染的IBD患者和重症患者应选用抗生素,青霉素类、妥布霉素、新型头霉素和头孢菌素均可酌情选用。近年来,甲硝唑也广泛用于IBD的治疗,甲硝唑可抑制肠内厌氧菌并有免疫抑制、影响白细胞趋化等作用,对UC和CD均有良好效果,它能促进瘘管愈合和预防复发,不良反应有恶心、呕吐、肢端感觉异常等,目前作为二线药物在GCS或SASP无效时可考虑使用。
(6)微生态制剂
由于肠道菌群失调和腔内抗原刺激是IBD触发和复发的重要原因,近10年来开始应用微生态制剂以改善肠道微环境,恢复机体正常菌群、下调免疫反应,以达到控制肠道炎症及维持缓解的目的。微生态制剂包括益生菌、益生元和合生元制剂。益生菌为含有特定的充足数量活菌的制剂;益生元为功能性低聚糖,它不易被人体消化吸收,却可在肠道被肠道的有益菌双歧杆菌吸收和利用,起到促进双歧杆菌的作用;合生元是益生菌与益生元的混合制剂,或加入维生素、微量元素等。
人类应用益生菌虽有百余年历史,但真正应用于临床还是最近几十年才开始。Kruis等(Kruis W,Fric P,Pokrotnieks J,et al.Maintaining remission ofulcerative colitis with the probiotic Escherichia coli Nissle 1917is aseffective as with standard mwsalazine.Gut,2004.53:1617-1 623.)在327例UC患者维持治疗中比较美沙拉嗪和益生菌的治疗效果。两组患者分别口服美沙拉嗪(3次/day)和大肠埃希菌Nissle1917(1次/day)。两组的复发率、缓解天数及疾病活动指数相接近,说明益生菌治疗可取得与抗炎药物相似的疗效,且无药物副作用。给予18例活动期UC患者长双歧杆菌和菊粉、寡果糖治疗l个疗程后,治疗组的乙状结肠镜评分降低,而安慰剂组无改善,治疗组临床症状改善(Furrie E,Macfarlane S,Kennedy A,et al.Synbiotic therapy(Bifidobacterium longum/Synergy l)initiates resolution of inflamation inpatients with active ulcerative colitis:a randomised controlled pilottrial.Gut,2005.54:242—249.)。传统药物治疗无反应的34例轻、中度活动期UC患者接受一种益生菌制剂VSL#3治疗,缓解率为53%,24%患者有反应。说明VSL#3对UC有一定的治疗作用(Bibiloni R,Fedorak RN,Tannock GW,et al.VSL#3probiotic—mixture inducesremission in patients with active ulcerative colitis.Am J Gastroenterol,2005.100:1539-1546.)。
Rembacken等(Rembackers BJ.Non-pathogenc escherichia coli versusmesalazine for the treatment of ulcerative colitis:a randomized trial[J].Lancet,1999,354(9):635-639.)在116例活动性UC患者中采用随机对照双模拟法比较了美沙拉嗪和大肠埃希菌的疗效和维持缓解的效果。结果美沙拉嗪组的缓解率为75%,大肠埃希菌组为68%;达到缓解的天数美沙拉嗪为44天,大肠埃希菌组为42天;复发率美沙拉嗪组为73%,大肠埃希菌组为67%;平均缓解天数美沙拉嗪组为206天(中位数为175天),大肠埃希菌组为221天(中位数)故提示在维持缓解方面,非致病性大肠埃希菌与美沙拉嗪同样有效。
综上,说明一些临床研究证实益生菌治疗IBD的疗效。肠道菌群与IBD发病密切相关,随着对肠道黏膜免疫系统及IBD遗传易感性研究的不断完善,微生态制剂在用与治疗IBD方面将非常有前景。
传统药物如氨基水杨酸类制剂、糖皮质激素、免疫抑制剂等不良反应较多,而单克隆抗体药物又价格昂贵;微生态制剂因其对其他细菌具有明显的调节作用和较少的毒副作用而逐渐成为IBD治疗的新手段,也成为目前研究的热点。
解纤维素拟杆菌((Bacteroides cellulosilyticus)是由Céline Robert等人首次描述的拟杆菌属新物种(Robert C,Chassard C,Lawson PA,Bernalier-DonadilleA.Bacteroides cellulosilyticus sp.nov.,a cellulolytic bacterium from thehuman gut microbial community.Int J Syst Evol Microbiol.2007Jul;57(Pt 7):1516-1520.)。其是降解纤维的革兰氏阴性杆状细菌,细胞无鞭毛,长约1.7μm,宽约0.9μm。严格厌氧。该细菌可以从人粪便分离,因此是人共生性微生物。暂无对其进行的安全性评价,但部分研究显示,相对脆弱拟杆菌,它具有较高的安全性。尽管这种细菌本身及其在食品中的应用已经被公布,但其在防治IBD中的应用尚未被公开。
发明内容
本发明所要解决的技术问题是提供一种解纤维素拟杆菌在预防和/或治疗炎症性肠病的应用,并提供用于预防和/或治疗炎症性肠病的药物、药物组合物、食品、保健品及食品添加剂,其均包含所述解纤维素拟杆菌。
为了实现上述目的,本发明提供了一种解纤维素拟杆菌在预防和/或治疗炎症性肠病中的应用。
为了更好地实现上述目的,本发明还提供了一种解纤维素拟杆菌在制备预防和/或治疗炎症性肠病的药物中的应用,其中,所述药物含有药学有效剂量的解纤维素拟杆菌和药学上可接受的载体。
上述的解纤维素拟杆菌在制备预防和/或治疗炎症性肠病的药物中的应用,其中,所述药学有效剂量为106-1010CFU。
上述的解纤维素拟杆菌在制备预防和/或治疗炎症性肠病的药物中的应用,其中,所述药学上可接受的载体包括奶粉、乳糖、环糊精、麦芽糖、葡萄糖、甘油、谷氨酸钠、维生素C、甘露糖、半乳糖、甘露聚醇和/或甲基纤维素。
上述的解纤维素拟杆菌在制备预防和/或治疗炎症性肠病的药物中的应用,其中,所述炎症性肠病为溃疡性结肠炎或克罗恩病。
为了更好地实现上述目的,本发明还提供了一种用于预防和/或治疗炎症性肠病的药物组合物,其中,所述药物组合物含有药学有效剂量的解纤维素拟杆菌。
上述的用于预防和/或治疗炎症性肠病的药物组合物,其中,所述药学有效剂量为106-1010CFU。
为了更好地实现上述目的,本发明还提供了一种用于预防和/或治疗炎症性肠病的食品,其中,所述食品含有解纤维素拟杆菌。
为了更好地实现上述目的,本发明还提供了一种用于预防和/或治疗炎症性肠病的保健品,其中,所述保健品含有解纤维素拟杆菌。
为了更好地实现上述目的,本发明还提供了一种用于预防和/或治疗炎症性肠病的食品添加剂,其中,所述食品添加剂含有解纤维素拟杆菌。
本发明的技术效果在于:
本发明通过对解纤维素拟杆菌,经由活体内及体外的相关实验证实,此菌株除了对抗生素相关性腹泻、肥胖及糖尿病、脑膜炎等具有良好的预防及治疗效果之外,还发现其对炎症性肠病,包括溃疡性结肠炎和克罗恩病,具有优异的抵抗力且无毒副作用,可持久且有效地应用于预防和/或治疗炎症性肠病。利用本发明的解纤维素拟杆菌可以制备成药物、药物组合物、食品、保健品或食品添加剂等形式。所述药物、药物组合物、食品、保健品或食品添加剂均含有解纤维素拟杆菌。该药物、药物组合物、食品、保健品或食品添加剂可用于预防和治疗炎症性肠病,具有重大应用价值。
以下结合附图和具体实施例对本发明进行详细描述,但不作为对本发明的限定。
附图说明
图1为本发明实施例一的解纤维素拟杆菌的镜检图;
图2为本发明实施例二的小鼠进食饮水量、毛发光泽度、精神状态及活动情况评分;
图3为本发明实施例二的各组小鼠DAI评分变化;
图4A、4B分别为本发明实施例二小鼠结肠促炎因子IL-17、INF-γ水平;
图5为本发明实施例三的各组大鼠DAI评分变化;
图6为本发明实施例三的各组大鼠结肠组织损伤评分变化。
具体实施方式
下面结合附图对本发明的结构原理和工作原理作具体的描述:
近年来我国的炎症性肠病患病率逐年增加,而目前该病的发病因素及致病机制尚未明确,是多种因素导致的病变,一般主要考虑与外界环境、基因遗传、免疫力以及感染等多方面综合因素相关。该病的主要临床表现为腹痛、腹泻、黏性血便等,如并发溃疡必须及时治疗,否则极易引发肠穿孔,威胁患者的生命安全。近年来有相关研究报道,IBD与肠道菌群失调有密切关系,人体肠道有大量的微生物,据不完全统计,数量高达400种以上,其中以双歧杆菌与嗜酸乳杆菌为主,大约占到微生物总量的98%以上,通常人体在正常情况下,肠道内的微生物处于相对平衡状态,可一旦失衡,菌群失调可导致相关疾病的发生。目前认为肠道菌群失调可能是IBD诱发及复发的关键因素。
本发明在多种疾病模型中对解纤维素拟杆菌(Bacteroides cellulosilyticus)的作用进行了检测和鉴定,第一次发现解纤维素拟杆菌对炎症性肠病具有优异的预防和/或治疗效果。本发明的解纤维素拟杆菌,在预防和/或治疗炎症性肠病中的应用,包括但不限于以下方面:
解纤维素拟杆菌在制备预防和/或治疗炎症性肠病的药物中的应用,其中,所述药物含有药学有效剂量的解纤维素拟杆菌和药学上可接受的载体。本实施例中,该药学有效剂量优选为106-1010CFU,该药学上可接受的载体包括奶粉、乳糖、环糊精、麦芽糖、葡萄糖、甘油、谷氨酸钠、维生素C、甘露糖、半乳糖、甘露聚醇和/或甲基纤维素等。其中,所述炎症性肠病通常为溃疡性结肠炎或克罗恩病。
另外,解纤维素拟杆菌还可用于制备预防和/治疗炎症性肠病的药物组合物,其中,所述药物组合物含有药学有效剂量的解纤维素拟杆菌,该药学有效剂量优选为106-1010CFU。
解纤维素拟杆菌还可用于制备预防和/或治疗炎症性肠病的食品、保健品及食品添加剂等,所述食品、保健品及食品添加剂等均可加入一定比例的解纤维素拟杆菌成分。
下面以具体实施例进一步说明本发明的解纤维素拟杆菌(Bacteroidescellulosilyticus)在预防和/或治疗炎症性肠病中的作用,下述实验动物及样品,如无特别说明,均可通过正常途径在市场上购买。
实施例一 解纤维素拟杆菌的培养
划线活化菌种:DSM 14838T解纤维素拟杆菌的菌种,用BHA(脑心浸液琼脂培养基)平板进行划线活化。厌氧,37℃恒温培养2-7天,得到单菌落。
菌落特征:解纤维素拟杆菌在BHA平板上培养48h后,呈现圆形微凸、半透明、白色、表面光滑的菌落特征。
显微镜下形态:解纤维素拟杆菌进行革兰氏染色镜检,为革兰阴性细菌,呈现典型的杆状,两端钝圆而浓染,菌体中间不着色部分形如空泡,参见图1。
菌泥制备:选取单个菌落接种于胰蛋白胨肉汤中进行发酵培养8小时(温度为37℃),所得菌液离心沉淀,转速3000r/min,离心15min,去上清,收集沉淀物,即得解纤维素拟杆菌菌泥。
实施例二 解纤维素拟杆菌治疗三硝基苯磺酸(TNBS)联合乙醇诱导的小鼠克罗恩病的药效实验
实验设计
60只SPF级健康BALB/c小鼠,雌性,平均体重18~22g,平均周龄6-8周。适应性喂养1周后,随机分组如下:空白组、模型组、美沙拉嗪组、解纤维素拟杆菌(BC)低、中、高剂量组。
造模:除空白组外,每周一次,3%水合氯醛2.0mL腹腔注射,麻醉后,采用12mm规格小鼠灌肠器灌肠给予2.0mgTNBS/50%乙醇混合灌肠液0.1mL。空白组每周一次,灌肠给予生理盐水0.1mL。连续6周给药。
给药:造模6周后,除模型组外,每天给予各组小鼠相对应药量:美沙拉嗪组0.2mg/kg.d-1,解纤维素拟杆菌低剂量106CFU/只,中剂量108CFU/只,高剂量1010CFU/只。连续给药14天,每天一次。造模及给药期间,每日观察小鼠体重变化、进食饮水情况、毛发光泽度、精神状态及活动情况等,并根据Ganta等制定的标准进行小鼠DAI评分。
给药14天后,于第15天处死小鼠,解剖,提取结肠组织,进行细胞因子检测。
实验结果:
1、小鼠进食饮水、毛发光泽度、精神状态及活动情况
以空白组进食饮水量、毛发光泽度、精神状态及活动情况作为满分(100)参照,对模型组及各给药组进行评分。结果如图2所示。
模型组的进食饮水量、毛发光泽度、精神状态和活动情况都显著低于空白组,造模成功。尽管毛发光泽度没有明显改善,但阳性药美沙拉嗪明显改善了小鼠进食饮水量、精神状态和活动能力。解纤维素拟杆菌的效果与美沙拉嗪相似,且不具有剂量依赖性。
2、小鼠DAI评分,评分基准如下表:
表1 DAI评分标准
DAI=体重减失率分数+大便潜血/肉眼血便分数,0-8分。
结果如图3所示。
模型组得分远超空白组(8/0分),美沙拉嗪改善了血便和稀便的情况(5分),解纤维素拟杆菌的得分与美沙拉嗪相似,解纤维素拟杆菌组内不存在剂量相关性。可见解纤维素拟杆菌缓解克罗恩病小鼠的药效与美沙拉嗪相似。
3、细胞因子检测:
采用luminex技术检测BALB/c鼠结肠中IL-17、INF-γ细胞因子的水平。由图4A、4B可知,模型组IL-17、INF-γ远高于空白组,阳性药美沙拉嗪降低了促炎因子的水平;解纤维素拟杆菌低、中、高各剂量也能使小鼠促炎因子水平下降,这种效果稍优于美沙拉嗪,但不具有显著性。说明解纤维素拟杆菌能够降低促炎因子水平,具有一定抑制炎症的作用。
综上所述,解纤维素拟杆菌对克罗恩病具有一定的治疗作用,这种作用与美沙拉嗪相似,且不具有剂量依赖性。
实施例三 解纤维素拟杆菌治疗硫酸葡聚糖钠盐(DSS)诱导大鼠慢性溃疡性结肠炎的药效实验
实验设计:
选健康成熟的SD大鼠60只,雌雄各半,体质量200±20g,购自广东省实验动物中心,饲养于SPF级动物房,随机分成6组,每组10只,所有大鼠实验前适应环境1周,喂食普通大鼠饲料。
采用5%硫酸葡聚糖钠盐(dextran sulfate sodium,DSS),购自美国西格玛公司)溶液诱导大鼠慢性溃疡性结肠炎模型,60只SD大鼠随机分为如下6组:
正常对照组、模型组、美沙拉嗪组、BC低剂量组、BC中剂量组、BC高剂量组,采用DAI积分及组织损伤学评分检测各干预组疗效。动物分组表如下:
表3动物分组表
编号 | 造模 | 分组 | 动物只数 |
A | 否 | 正常对照组 | 10 |
B | 是 | 模型组 | 10 |
C | 是 | 美沙拉嗪组 | 10 |
D | 是 | BC低剂量组 | 10 |
E | 是 | BC中剂量组 | 10 |
F | 是 | BC高剂量组 | 10 |
1、实验动物模型:
50gDSS加入1000mL蒸馏水中,充分溶解,配制成5%DSS溶液,每日新鲜配制。依据Cooper等的研究方法(Cooper,H.S.,Murthy,S.N.,Shah,R.S.,Sedergran,D.J.,1993.Clinic opathologic study of dextran sulfate sodium experimental murinecolitis.Laboratory Investigation 69,238–249.),大鼠自由饮用5%DSS溶液7天,正常饮水10天,以上为1个循环,反复4个循环,建立大鼠慢性溃疡性结肠炎模型。10只SD大鼠为正常对照组,其余50只大鼠采用随机抽签的方法将大鼠分为6组,每组10只,分别为模型组、美沙拉嗪组、BC低剂量组、BC中剂量组、BC高剂量组,剂量设计:BC低剂量(106CFU/只)、BC中剂量(108CFU/只)、BC高剂量(1010CFU/只);美沙拉嗪,0.4g/Kg.d-1;模型组只造模不给药;造模成功后开始给药,每天灌胃1次,连续灌胃1周。
2、大鼠疾病活动度积分的计算:
参照Hamamoto等标准(Murano M,MaemuraK,HirataI,ToshinaK,NishikawaT,Hamamoto N,Sasaki S,Saitoh O,Katsu K.The rapeutic effect of intracolonicallyadministered nuclear factor kappa B(p65)antisense oligonucleotide on mousedextran sulphate sodium(DSS)-inducedcolitis.Clin Exp Immunol 2000;120:51-58),每日观察大鼠的体质量、大便性状和隐血情况,计算每只大鼠的疾病积分活动(DAI)积分,评估结肠炎活动程度。
3、病理学观察:
预冷生理盐水将大肠洗净,于大肠末端距离肛门1cm处剪取0.5cm大肠,4%多聚甲醛浸泡,石蜡包埋,切片,HE染色做病理检查。其余部分结肠组织进行组织病理学评分。组织学损伤程度用炎症、病变深度、隐窝破坏及病变范围评分的乘积表示,取平均值作为结肠组织学损伤计分。
实验结果
1、实验观察指标:
造模成功后予以美沙拉嗪、BC低剂量、BC中剂量、BC高剂量,治疗1周,整个实验过程中无大鼠死亡,观察结果如下:
(1)模型组大鼠食量降低,毛色干枯、拱背和拖尾,出现稀便,部分肛周可见血迹;
(2)美沙拉嗪组大鼠毛色欠光滑、精神欠活跃、反应不灵活,但好于模型组;
(3)BC低、中、高剂量组大鼠毛色欠光滑、精神欠活跃、反应不灵活,与美沙拉嗪组相似。
以上结果显示:BC低、中、高剂量组改善慢性溃疡性结肠炎的效果与美沙拉嗪组相似。
2、大鼠疾病活动度的变化参考Hamamoto等的方法(Murano M,Maemura K,HirataI,Toshina K,Nishikawa T,Hamamoto N,Sasaki S,Saitoh O,Katsu K.The rapeuticeffect of intracolonically administered nuclear factor kappa B(p65)antisenseoligonucleotide on mouse dextran sulphate sodium(DSS)-induced colitis.ClinExp Immunol 2000;120:51-58)对每只大鼠的体质量下降、大便性状和粪便隐血情况进行综合评分。结果如下:
(1)正常对照组DAI评分始终稳定在零水平;
(2)模型组大鼠炎症逐渐加重;
(3)美沙拉嗪组、BC各剂量组及联合组大鼠DAI评分也逐渐升高,但明显低于模型组,参见图5。
以上结果显示:BC低、中、高剂量组综合评分明显优于模型组,与美沙拉嗪组相似。这表明BC各剂量组改善慢性溃疡性结肠炎小鼠体重减轻及血便程度与阳性药美沙拉嗪相似。
3、结肠黏膜损伤组织病理变化参照Dieleman等的评分标准(DielemanL A,PalmenMJ,AkolH,etal.Chronic experimental colitis induced by dextran sulfatesodium(DSS)is characterized by Th1 and Th2 Cytokines[J].Clinical&ExperimentalImmunology,1999,114(3):385-91.)
对每只大鼠的结肠病理切片进行组织损伤学评分。参见图6,具体为各组大鼠第7天的结肠炎症浸润评分、病变深度评分、隐窝破坏及总体组织损伤评分直方图。正常对照组大鼠组织学损伤评分为0分,模型组评分9.40分。美沙拉嗪组、BC低剂量组、BC中剂量组、BC高剂量组组织学损伤评分分别为6.89、6.65、7.35、7.47,BC各剂量组与模型组差异显著(P<0.01),低剂量效果略优于美沙拉嗪,但这种差异不具有显著性。
以上结果显示:BC各剂量组药效基本与阳性药美沙拉嗪相似,其对慢性溃疡性结肠炎治疗具有显著作用。这种治疗效果或源于解纤维素拟杆菌通过上调肠道局部的免疫功能,促进机体免疫恢复,从而有效纠正了抑炎和抗炎动态失衡,降低炎症反应,减少了炎性因子的释放的能力。
实施例四一种解纤维拟杆菌散剂的制备
处方如下,其中解纤维拟杆菌菌粉细胞为1×1011Cell/g。
其制备方法如下:
(1)将市购药用级麦芽糊精、二氧化硅、硬脂酸镁充分烘干后分别粉碎并过100目筛备用;
(2)取实施例1所得解纤维拟杆菌菌泥,冻干得到解纤维拟杆菌菌粉,将其及烘干后的其余辅料,按上述处方表的重量比例进行称取;
(3)混料罐设定混料频率为35Hz,加入二氧化硅、硬脂酸镁与麦芽糊精,进行初步混合10分钟,得混合物I;将解纤维拟杆菌菌粉加入混料罐中,混合25分钟,得散剂半成品粉末;
(4)设置分装机参数,装量范围1.40~1.60g,将半成品粉末分装成散剂条包,即得解纤维拟杆菌散剂。
实施例五一种解纤维拟杆菌片剂的制备
处方如下,其中解纤维拟杆菌菌粉细胞为1×1011Cell/g。
其制备方法如下:
(1)将市购药用级乳糖、麦芽糊精、羟甲基淀粉钠、二氧化硅与硬脂酸镁充分烘干后备用;
(2)取实施例1所得解纤维拟杆菌菌泥,冻干得到解纤维拟杆菌菌粉,将其及烘干后的其余辅料,按上述处方表的重量比例进行称取;
(3)混料罐设定混料频率为35Hz,加入二氧化硅与解纤维拟杆菌菌粉,进行初步混合3分钟,过40目筛后得混合物I;依次将乳糖、麦芽糊精、羟甲基淀粉钠加入混料罐中,混合40分钟,得混合物II;加入硬脂酸镁,混合10分钟,得压片前中间体粉末;
(4)设置压片机参数:预压0.6KN,主压50KN,转速15转/分钟,将压片前中间体粉末压片成型,即得解纤维拟杆菌片剂。
实施例六一种解纤维拟杆菌硬胶囊剂的制备
处方如下,其中解纤维拟杆菌菌粉细胞为1×1011Cell/g。
其制备方法如下:
(1)将市购药用级淀粉、微晶纤维素、硬脂酸镁充分烘干后备用;
(2)取实施例1所得解纤维拟杆菌菌泥,冻干得到解纤维拟杆菌菌粉,将其及烘干后的其余辅料,按上述处方表的重量比例进行称取;
(3)混料罐设定混料频率为35Hz,依次加入微晶纤维素、淀粉、硬脂酸镁、解纤维拟杆菌菌粉,混合40分钟,得胶囊填充物;
(4)使用全自动胶囊填充机与1#羟甲基纤维素胶囊壳将上述胶囊填充物进行分装,即得解纤维拟杆菌硬胶囊。
当然,本发明还可有其它多种实施例,在不背离本发明精神及其实质的情况下,熟悉本领域的技术人员当可根据本发明作出各种相应的改变和变形,但这些相应的改变和变形都应属于本发明所附的权利要求的保护范围。
Claims (10)
1.一种解纤维素拟杆菌在预防和/或治疗炎症性肠病中的应用。
2.一种解纤维素拟杆菌在制备预防和/或治疗炎症性肠病的药物中的应用,其特征在于,所述药物含有药学有效剂量的解纤维素拟杆菌和药学上可接受的载体。
3.如权利要求2所述的解纤维素拟杆菌在制备预防和/或治疗炎症性肠病的药物中的应用,其特征在于,所述药学有效剂量为106-1010CFU。
4.如权利要求2或3所述的解纤维素拟杆菌在制备预防和/或治疗炎症性肠病的药物中的应用,其特征在于,所述药学上可接受的载体包括奶粉、乳糖、环糊精、麦芽糖、葡萄糖、甘油、谷氨酸钠、维生素C、甘露糖、半乳糖、甘露聚醇和/或甲基纤维素。
5.如权利要求1、2或3所述的解纤维素拟杆菌在制备预防和/或治疗炎症性肠病的药物中的应用,其特征在于,所述炎症性肠病为溃疡性结肠炎或克罗恩病。
6.一种用于预防和/或治疗炎症性肠病的药物组合物,其特征在于,所述药物组合物含有药学有效剂量的解纤维素拟杆菌。
7.如权利要求6所述的用于预防和/或治疗炎症性肠病的药物组合物,其特征在于,所述药学有效剂量为106-1010CFU。
8.一种用于预防和/或治疗炎症性肠病的食品,其特征在于,所述食品含有解纤维素拟杆菌。
9.一种用于预防和/或治疗炎症性肠病的保健品,其特征在于,所述保健品含有解纤维素拟杆菌。
10.一种用于预防和/或治疗炎症性肠病的食品添加剂,其特征在于,所述食品添加剂含有解纤维素拟杆菌。
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