修回日期: 2007-03-01
接受日期: 2007-03-31
在线出版日期: 2007-07-18
尽管对溃疡性结肠炎的临床研究有100多年的历史, 但是他的真正病因尚不清楚, 多种因素可能促进这种疾病的发生和发展. 环境因素可能影响遗传易感性, 遗传易感性与异常的先天免疫反应性可能是溃疡性结肠炎的起始反应和持续反应的先决条件. 最近研究结果证实, 细菌物种可解释肠内生态失调可能是溃疡性结肠炎的一种促发因素. 溃疡性结肠炎的病因学研究对于提高疾病的治疗效果和改善患者的生存质量都具有重要意义.
引文著录: 桑力轩, 刘汉立, 姜敏. 溃疡性结肠炎发病机制研究进展. 世界华人消化杂志 2007; 15(20): 2249-2254
Revised: March 1, 2007
Accepted: March 31, 2007
Published online: July 18, 2007
Despite being known as a clinical entity for more than a century, the true origins of ulcerative colitis remain elusive. However, several factors are thought to contribute to the development of this condition. Environmental factors may interfere with inherent predispositions to ulcerative colitis. Genetic susceptibility, together with abnormal innate immunoreactivity, is probably the essential prerequisite for the initiation and perpetuation of ulcerative colitis. New investigative technology has recently clarified the role of bacterial species, which may account for intestinal dysbiosis, as a factor for triggering ulcerative colitis. The search for the pathogenesis of ulcerative colitis continues to have great significance, with the aim of achieving improvements in its treatment and in patient quality of life.
- Citation: Sang LX, Liu HL, Jiang M. Progress of research into the pathogenesis of ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2007; 15(20): 2249-2254
- URL: https://www.wjgnet.com/1009-3079/full/v15/i20/2249.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v15.i20.2249
溃疡性结肠炎是一种原因不明的非特异性炎症, 病变位于大肠, 呈连续性弥漫性分布, 多数累及直肠和乙状结肠, 溃疡性结肠炎一个典型的临床过程包括黏液脓血便和腹痛腹泻. 然而, 作为一种全身系统性疾病, 部分患者有肠外表现, 包括累及关节, 例如肠病性关节炎, 肝胆管的疾病,例如原发性硬化性胆管炎, 还可以出现眼和皮肤的损害[1-2]. 在世界范围内, 溃疡性结肠炎的发病率波动在十万分之0.5-24.5, 发病率和患病率与国家的经济状况相关, 在发展中国家发病率最低, 在北美和西欧中欧发病率最高, 目前, 溃疡性结肠炎的发病率在中欧和东欧有增长的趋势, 而在西欧和斯堪的那维亚人地区发病率稳定[3-4]. 1859年, 溃疡性结肠炎就被临床医生所了解, 但是病因学的秘密直到今天尚不完全清楚. 近几年来, 新的分子生物学机制的研究使本病在病因的研究方面取得了很大进步[5-6].
心理神经免疫学研究已经表明, 行为因素和情绪能对全身和局部的炎症反应和免疫系统产生影响[7-10]. 在1950年初期, 溃疡性结肠炎被称为心身疾病, 在文艺复兴时期这个方面的研究就开始增加, 如果患者显示出很高的抑郁分数, 疾病会显示出很大的恶化风险[11-13], 这些结果被临床实践所支持. 前瞻性研究表明, 情感的消极事件能引起溃疡性结肠炎的复发[14-20].
溃疡性结肠炎主要是影响不吸烟者. 与不吸烟者相比, 吸烟能改善疾病的过程, 能减少激素的需要量和结肠切除术发生率, 大样本的荟萃分析显示出一个优势比0.57 (95%CI: 0.38-0.85), 这是当前吸烟者和不吸烟者相比的全结肠切除术比率[21-23]. 吸烟对溃疡性结肠炎有利的影响的假定机制是: 香烟中的烟碱使黏蛋白合成增加, 致炎细胞因子的产生减少, 肠道平滑肌紧张度降低, 改善肠内对大分子的通透性[24-28]. 避孕药对溃疡性结肠炎的影响尚不十分清楚, 但是有数据表明口服药计划生育可能作为溃疡性结肠炎的一种触发因素, 荟萃分析显示: 避孕药和溃疡性结肠炎之间存在正相关[29-31]. 目前, 我们还没有明确的证据来建议溃疡性结肠炎的患者不使用避孕药.
遗传易感性在炎症性肠病的病因学中具有重要作用. 溃疡性结肠炎和克罗恩病都有复杂的遗传基础, 存在多重的联合基因和不纯一性. 在过去的10 年中, 十多个基因组的筛选和不同的连锁研究已经描绘出至少9个炎症性肠病(IBD)的易感位置, 许多研究已经证明NOD2/CARD15多态现象和溃疡性结肠炎不相关[41]. 然而, 研究人员已经开始研究其他的基因是否与溃疡性结肠炎相关, 研究已经发现, 多元抗药性基因1(MDR1)缺陷的老鼠发展成结肠炎. 另外, 临床研究发现, MDR1的两个多晶型物(C3435T和G2677T/C)和溃疡性结肠炎相关. 人类多元抗药性基因密码对于P-糖蛋白而言是形成一个抵抗外源性化学物质的屏障, 这个基因的多态现象引起低蛋白表达, 在防御肠内细菌方面似乎很重要[42-45]. 然而, 其他的病例对照研究不能证实这个结果, 正在进行的关于IBD3和IBD6的研究有望证实这个结果, IBD3位于6号染色体上, 包含主要组织相容性复合物基因, 根据前人的研究结果, 人体白细胞抗原等位基因和IBD似乎是相关的. IBD6包括一种抗抑郁成分和膜蛋白质结合的基因密码, 这对于免疫细胞的吸附和运输是很重要的[46]. 核因子kB(NF-κB)家族成员的多态现象和IBD的关系非常密切[47], 相关的研究聚焦在人类4号染色体的NF-κB1基因启动子区的多态现象, 他在溃疡性结肠炎的发病过程中参与许多调控进程[48]. 研究人员发现, 与对照组对比, 荷兰人高加索人的患者NF-κB1启动因子94ATTG多态现象缺失频率增加. 此外, 一个94ATTG缺失的纯合子患者比不是纯和子的患者发病要年轻. 关于溃疡性结肠炎的与NF-κB1基因相关疾病易感性的确切机制尚不清楚, 一种解释是由于转录蛋白水平很低, 对细菌抗原的免疫反应很弱, 导致菌株入侵黏膜并且诱发慢性炎症. 当前研究主要是集中在基因编码TLR4和TLR9修饰肠腔内抗原应答反应[49]. 尽管新的实验都证明, 与克罗恩病相比, 遗传易感性在溃疡性结肠炎中相对较弱, 但是我们推测, 加强溃疡性结肠炎遗传方面的研究将会使疾病的诊断和治疗水平有很大的提高.
在局部和系统的免疫反应中消化道内细菌刺激上皮细胞和肠道淋巴组织, 先天免疫的激活作用使肠内上皮细胞和细菌与黏膜稳定的紧密接触, 通过形成的膜感受器(TLR)或者细胞内的NOD族感受器对细菌抗原进行快速识别. 导致肠道疾病的细菌通过激活相关的转录基因刺激促炎症反应细胞因子的产生. 至于健康人黏膜存在非致病微生物的入侵, 免疫活性细胞产生调控细胞因子. 值得强调的是, 一些菌株调控释放促炎症细胞因子并且诱导有活性的淋巴细胞凋亡[50].
上皮细胞不仅在先天免疫的形成中起重要作用, 而且在诱导后天免疫的记忆途径上也有重要作用. 后天免疫反应主要是发生在peyer's斑和淋巴结. 为了使同源T细胞或B细胞增殖, 专门化树状突细胞传递细菌抗原给淋巴组织. 未致敏的T细胞分化为Th1, Th2, T调控细胞, 这些淋巴细胞亚群效应器能力有显著的不同[51]. 1990年代, 研究发现克罗恩病和溃疡性结肠炎细胞之间的调停主要是被Th1和Th2细胞所解释. 真实情况似乎更加复杂, 在两种疾病之间有严格的分化, 理解还远不完善[52-53]. 共生菌株和免疫间隔之间的肠道内黏膜免疫的失调和相互作用的缺陷能导致免疫调节的紊乱, 包括炎症性肠病. 由于发达国家卫生标准很高, 在儿童期细菌和免疫活性细胞的接触显著减少, 结果, 细菌抗原耐受性的减少可能导致后来的慢性肠病, 这样的一种解释被称为"卫生学假说"[54].
溃疡性结肠炎和传染性肠炎有很多类似的方面, 因此, 许多研究者怀疑是否存在某种微生物触发肠道的慢性炎症, 然而, 直到现在, 尚未证实某种微生物与该病有关. 许多论点反对该病存在一个感染的病因. 例如在溃疡性结肠炎的患者之间缺乏传染证据. 溃疡性结肠炎高发的国家, 感染性肠病的发病率却很低. 在卫生条件很差的国家, 消耗未被加工的食物却是保护性因素. 在儿童期频繁应用抗生素增加溃疡性结肠炎的发病风险. 在溃疡性结肠炎的治疗中, 缺乏有效的抗微生物制剂. 在溃疡性结肠炎患者的粪便中培养出结果亦不一致[55]. 已经有大量的证据表明, 在溃疡性结肠炎的患者中, 肠道细菌与黏膜之间存在异常的黏膜免疫反应. 分子生物学技术已经表明一个成人肠道内空间能容纳多于500种不同的细菌, 许多菌株沿小肠逐渐增加, 革兰氏阴性菌占主要地位, 大肠中细菌的数量在肠腔内每公分达到大约1012, 当前条件下多于50%的菌株还不能被人工培养. 在成人粪便的细菌组成是宿主专化和稳定的, 菌株波动很少达到20%[56-57].
肠道细菌能刺激淋巴细胞克隆增殖并且阻止淋巴细胞凋亡[58], 革兰氏阳性菌优先刺激白细胞介素12的产生, 然而革兰阴性菌诱导白细胞介素4的产生, 革兰阴性菌和革兰阴性菌细胞壁的主要成分对于诱导口服免疫耐受是很重要的. 虽然标准的培养技术能检测达到30%的微生物群, 新的技术(包括细菌的16s核糖体核糖核酸分析, 多聚酶链式反应, 原位杂交, 流式细胞计量术, 脱氧核糖核酸微点阵, 薄片分析)已经显著的增加了检出率, 有益的菌株诸如双歧杆菌和乳酸杆菌, 在活动性溃疡性结肠炎患者肠黏膜中是缺失的[59]. 另一个方面, 革兰氏阴性厌氧菌, 特别是大肠杆菌, 变形梭杆菌, 拟杆菌在黏膜中浓度增加, 消化链球菌属有一个很高的侵袭频率. 研究证实, 与健康人相比, 溃疡性结肠炎患者的结肠样本中黏膜存在严重的细菌感染[60-63]. 在炎症性肠病的患者中, 细菌黏膜入侵与免疫球蛋白G和细菌性抗原的滴定度是相对应的, 他们中的一些可以用来区分溃疡性结肠炎和克罗恩病[63-64]. 由于遗传对照提出了肠内菌丛的测定, 在炎症性肠病患者的健康亲属中发现了粪便菌丛的改变[65], 然而, 问题就是在溃疡性结肠炎的患者中生态失调是疾病的原因还是结果仍然缺乏一个满意的答案. 肠道细菌在溃疡性结肠炎的发病机制中的作用被总结如下: (1)在溃疡性结肠炎患者中菌丛的组成和空间分布与对照组存在明显差异; (2)在肠道免疫系统中, 一些共生菌株在黏膜内环境稳态和成熟方面起重要作用[66-67]; (3)不同的细菌存在变异的能力来诱导慢性肠炎. 微生物制剂或抗生素有疗效主要是归因于对细菌群落的控制[50,68].
20多年来, 溃疡性结肠炎在病因、发病机制、应用现代的治疗方法上尽管有很大进步, 但是许多问题还是没有满意的答案. 现在, 任何一种单独的治疗方法成功应用于溃疡性结肠炎患者中似乎都是不太可能的. 前景有待于个体化治疗的应用. 靶向作用于刺激抗原, 纠正特殊的遗传缺陷, 修复被破坏的黏膜屏障, 消除肠腔内的抗原, 这些都有待于细菌群落的操纵, 或者免疫抑制分子的传递来阻断扩大的黏膜免疫活性, 我们希望益生元, 生物制剂或者是局部应用抗生素能广泛的应用, 还有新的分子靶向作用,抑制促炎因子, 或者希望在不久的将来有新的治疗方法.
1859年, 人类就了解了溃疡性结肠炎, 但是至今真正病因仍不十分清楚, 目前已知的环境因素, 遗传因素, 免疫因素, 感染因素可能促进该病的发生和发展.
关于溃疡性结肠炎发病机制中免疫因素的研究较多, 免疫因素的研究对疾病的治疗也具有重要意义.
本文对溃疡性结肠炎发病机制中的4个方面做了详尽的分析, 对临床上分析该病的有一定的帮助.
细菌物种可解释肠内生态失调可能是溃疡性结肠炎的一种促发因素. 溃疡性结肠炎的病因学研究对于提高和疾病的治疗效果和改善患者的生存质量都具有重要意义.
本文综述了溃疡性结肠炎发病机制进展, 内容广泛, 层次清楚, 对溃疡性结肠炎的研究有重要参考价值.
编辑:王晓瑜 电编:张敏
1. | Park SH, Kim YM, Yang SK, Kim SH, Byeon JS, Myung SJ, Cho YK, Yu CS, Choi KS, Chung JW. Clinical features and natural history of ulcerative colitis in Korea. Inflamm Bowel Dis. 2007;13:278-283. [PubMed] |
2. | Brandt LJ, Boley SJ, Mitsudo S. Clinical characteristics and natural history of colitis in the elderly. Am J Gastroenterol. 1982;77:382-386. [PubMed] |
3. | Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: up or down? World J Gastroenterol. 2006;12:6102-6108. [PubMed] |
4. | Lakatos L, Lakatos PL. Is the incidence and prevalence of inflammatory bowel diseases increasing in Eastern Europe? Postgrad Med J. 2006;82:332-337. [PubMed] |
5. | Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640. [PubMed] |
6. | Kirsner JB. Inflammatory bowel diseases at the University of Chicago-early experiences: a personal historical account. Inflamm Bowel Dis. 2005;11:407-416. [PubMed] |
7. | Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47:861-869. [PubMed] |
8. | Grundy D, Al-Chaer ED, Aziz Q, Collins SM, Ke M, Tache Y, Wood JD. Fundamentals of neuro-gastroenterology: basic science. Gastroenterology. 2006;130:1391-1411. [PubMed] |
9. | Heinrichs SC, Tache Y. Therapeutic potential of CRF receptor antagonists: a gut-brain perspective. Expert Opin Investig Drugs. 2001;10:647-659. [PubMed] |
10. | Glavin GB, Murison R, Overmier JB, Pare WP, Bakke HK, Henke PG, Hernandez DE. The neurobiology of stress ulcers. Brain Res Brain Res Rev. 1991;16:301-343. [PubMed] |
11. | Filipovic BR, Filipovic BF, Kerkez M, Milinic N, Randelovic T. Depression and anxiety levels in therapy-naive patients with inflammatory bowel disease and cancer of the colon. World J Gastroenterol. 2007;13:438-443. [PubMed] |
12. | Szigethy E, Carpenter J, Baum E, Kenney E, Baptista-Neto L, Beardslee WR, Demaso DR. Case study: longitudinal treatment of adolescents with depression and inflammatory bowel disease. J Am Acad Child Adolesc Psychiatry. 2006;45:396-400. [PubMed] |
13. | Mittermaier C, Dejaco C, Waldhoer T, Oefferlbauer-Ernst A, Miehsler W, Beier M, Tillinger W, Gangl A, Moser G. Impact of depressive mood on relapse in patients with inflammatory bowel disease: a prospective 18-month follow-up study. Psychosom Med. 2004;66:79-84. [PubMed] |
14. | Bitton A, Sewitch MJ, Peppercorn MA, deB Edwardes MD, Shah S, Ransil B, Locke SE. Psychosocial determinants of relapse in ulcerative colitis: a longitudinal study. Am J Gastroenterol. 2003;98:2203-2208. [PubMed] |
15. | Langhorst J, Anthonisen IB, Steder-Neukamm U, Luedtke R, Spahn G, Michalsen A, Dobos GJ. Patterns of complementary and alternative medicine (CAM) use in patients with inflammatory bowel disease: perceived stress is a potential indicator for CAM use. Complement Ther Med. 2007;15:30-37. [PubMed] |
16. | Kunzendorf S, Jantschek G, Straubinger K, Heberlein I, Homann N, Ludwig D, Benninghoven D. The Luebeck interview for psychosocial screening in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:33-41. [PubMed] |
17. | Vidal A, Gomez-Gil E, Sans M, Portella MJ, Salamero M, Pique JM, Panes J. Life events and inflammatory bowel disease relapse: a prospective study of patients enrolled in remission. Am J Gastroenterol. 2006;101:775-781. [PubMed] |
18. | Bernstein CN, Walker JR, Graff LA. On studying the connection between stress and IBD. Am J Gastroenterol. 2006;101:782-785. [PubMed] |
19. | Mawdsley JE, Rampton DS. Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut. 2005;54:1481-1491. [PubMed] |
20. | Jantschek G, Zeitz M, Pritsch M, Wirsching M, Klor HU, Studt HH, Rasenack J, Deter HC, Riecken EO, Feiereis H. Effect of psychotherapy on the course of Crohn's disease. Results of the German prospective multicenter psychotherapy treatment study on Crohn's disease. German Study Group on Psychosocial Intervention in Crohn's Disease. Scand J Gastroenterol. 1998;33:1289-1296. [PubMed] |
21. | Birrenbach T, Bocker U. Inflammatory bowel disease and smoking: a review of epidemiology, pathophysiology, and therapeutic implications. Inflamm Bowel Dis. 2004;10:848-859. [PubMed] |
22. | Cosnes J. Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice. Best Pract Res Clin Gastroenterol. 2004;18:481-496. [PubMed] |
23. | Boyko EJ, Perera DR, Koepsell TD, Keane EM, Inui TS. Effects of cigarette smoking on the clinical course of ulcerative colitis. Scand J Gastroenterol. 1988;23:1147-1152. [PubMed] |
24. | McGilligan VE, Wallace JM, Heavey PM, Ridley DL, Rowland IR. Hypothesis about mechanisms through which nicotine might exert its effect on the interdependence of inflammation and gut barrier function in ulcerative colitis. Inflamm Bowel Dis. 2007;13:108-115. [PubMed] |
25. | Scott DA, Martin M. Exploitation of the nicotinic anti-inflammatory pathway for the treatment of epithelial inflammatory diseases. World J Gastroenterol. 2006;12:7451-7459. [PubMed] |
26. | Ingram JR, Rhodes J, Evans BK, Thomas GA. Preliminary observations of oral nicotine therapy for inflammatory bowel disease: an open-label phase I-II study of tolerance. Inflamm Bowel Dis. 2005;11:1092-1096. [PubMed] |
27. | Sandborn WJ, Tremaine WJ, Leighton JA, Lawson GM, Zins BJ, Compton RF, Mays DC, Lipsky JJ, Batts KP, Offord KP. Nicotine tartrate liquid enemas for mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy: a pilot study. Aliment Pharmacol Ther. 1997;11:663-671. [PubMed] |
28. | Sandborn WJ, Tremaine WJ, Offord KP, Lawson GM, Petersen BT, Batts KP, Croghan IT, Dale LC, Schroeder DR, Hurt RD. Transdermal nicotine for mildly to moderately active ulcerative colitis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1997;126:364-371. [PubMed] |
29. | Jantchou P, Monnet E, Carbonnel F. Environmental risk factors in Crohn's disease and ulcerative colitis (excluding tobacco and appendicectomy). Gastroenterol Clin Biol. 2006;30:859-867. [PubMed] |
30. | Garcia Rodriguez LA, Gonzalez-Perez A, Johansson S, Wallander MA. Risk factors for inflammatory bowel disease in the general population. Aliment Pharmacol Ther. 2005;22:309-315. [PubMed] |
31. | Godet PG, May GR, Sutherland LR. Meta-analysis of the role of oral contraceptive agents in inflammatory bowel disease. Gut. 1995;37:668-673. [PubMed] |
32. | Fernandez-Banares F, Hinojosa J, Sanchez-Lombrana JL, Navarro E, Martinez-Salmeron JF, Garcia-Puges A, Gonzalez-Huix F, Riera J, Gonzalez-Lara V, Dominguez-Abascal F. Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Spanish Group for the Study of Crohn's Disease and Ulcerative Colitis (GETECCU). Am J Gastroenterol. 1999;94:427-433. [PubMed] |
33. | Magee EA, Edmond LM, Tasker SM, Kong SC, Curno R, Cummings JH. Associations between diet and disease activity in ulcerative colitis patients using a novel method of data analysis. Nutr J. 2005;4:7. [PubMed] |
34. | Jowett SL, Seal CJ, Pearce MS, Phillips E, Gregory W, Barton JR, Welfare MR. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut. 2004;53:1479-1484. [PubMed] |
35. | Tilg H, Kaser A. Diet and relapsing ulcerative colitis: take off the meat? Gut. 2004;53:1399-1401. [PubMed] |
36. | Winawer SJ. Screening of colorectal cancer. Surg Oncol Clin N Am. 2005;14:699-722. [PubMed] |
37. | Russel MG, Engels LG, Muris JW, Limonard CB, Volovics A, Brummer RJ, Stockbrugger RW. Modern life' in the epidemiology of inflammatory bowel disease: a case-control study with special emphasis on nutritional factors. Eur J Gastroenterol Hepatol. 1998;10:243-249. [PubMed] |
38. | Jiang L, Xia B, Li J, Ye M, Deng C, Ding Y, Luo H, Ren H, Hou X, Liu H. Risk factors for ulcerative colitis in a Chinese population: an age-matched and sex-matched case-control study. J Clin Gastroenterol. 2007;41:280-284. [PubMed] |
39. | Sonntag B, Stolze B, Heinecke A, Luegering A, Heidemann J, Lebiedz P, Rijcken E, Kiesel L, Domschke W, Kucharzik T. Preterm birth but not mode of delivery is associated with an increased risk of developing inflammatory bowel disease later in life. Inflamm Bowel Dis. 2007;. [PubMed] |
40. | Koutroubakis IE, Vlachonikolis IG. Appendectomy and the development of ulcerative colitis: results of a metaanalysis of published case-control studies. Am J Gastroenterol. 2000;95:171-176. [PubMed] |
41. | Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005;19 Suppl A:5-36. [PubMed] |
42. | Ho GT, Moodie FM, Satsangi J. Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease? Gut. 2003;52:759-766. [PubMed] |
43. | Ardizzone S, Maconi G, Bianchi V, Russo A, Colombo E, Cassinotti A, Penati C, Tenchini ML, Bianchi Porro G. Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:516-523. [PubMed] |
44. | Ho GT, Soranzo N, Nimmo ER, Tenesa A, Goldstein DB, Satsangi J. ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach. Hum Mol Genet. 2006;15:797-805. [PubMed] |
45. | Schwab M, Schaeffeler E, Marx C, Fromm MF, Kaskas B, Metzler J, Stange E, Herfarth H, Schoelmerich J, Gregor M. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology. 2003;124:26-33. [PubMed] |
46. | Ahmad T, Armuzzi A, Neville M, Bunce M, Ling KL, Welsh KI, Marshall SE, Jewell DP. The contribution of human leucocyte antigen complex genes to disease phenotype in ulcerative colitis. Tissue Antigens. 2003;62:527-535. [PubMed] |
47. | Vermeire S, Rutgeerts P, Van Steen K, Joossens S, Claessens G, Pierik M, Peeters M, Vlietinck R. Genome wide scan in a Flemish inflammatory bowel disease population: support for the IBD4 locus, population heterogeneity, and epistasis. Gut. 2004;53:980-986. [PubMed] |
48. | Borm ME, van Bodegraven AA, Mulder CJ, Kraal G, Bouma G. A NFKB1 promoter polymorphism is involved in susceptibility to ulcerative colitis. Int J Immunogenet. 2005;32:401-405. [PubMed] |
49. | Franchimont D, Vermeire S, El Housni H, Pierik M, Van Steen K, Gustot T, Quertinmont E, Abramowicz M, Van Gossum A, Deviere J. Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut. 2004;53:987-992. [PubMed] |
50. | Borruel N, Carol M, Casellas F, Antolin M, de Lara F, Espin E, Naval J, Guarner F, Malagelada JR. Increased mucosal tumour necrosis factor alpha production in Crohn's disease can be downregulated ex vivo by probiotic bacteria. Gut. 2002;51:659-664. [PubMed] |
51. | Mudter J, Neurath MF. Mucosal T cells: mediators or guardians of inflammatory bowel disease? Curr Opin Gastroenterol. 2003;19:343-349. [PubMed] |
52. | Rogler G. Update in inflammatory bowel disease pathogenesis. Curr Opin Gastroenterol. 2004;20:311-317. [PubMed] |
53. | Hanauer SB. Update on the etiology, pathogenesis and diagnosis of ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2004;1:26-31. [PubMed] |
55. | Guarner F. Microecology as a target for therapeutic intervention in inflammatory bowel disease. IDrugs. 2003;6:868-873. [PubMed] |
56. | Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, Weber J, Hoffmann U, Schreiber S, Dietel M. Mucosal flora in inflammatory bowel disease. Gastroenterology. 2002;122:44-54. [PubMed] |
57. | Katz JA, Itoh J, Fiocchi C. Pathogenesis of inflammatory bowel disease. Curr Opin Gastroenterol. 1999;15:291-297. [PubMed] |
58. | Marteau P, Lepage P, Mangin I, Suau A, Dore J, Pochart P, Seksik P. Review article: gut flora and inflammatory bowel disease. Aliment Pharmacol Ther. 2004;20 Suppl 4:18-23. [PubMed] |
59. | Kleessen B, Kroesen AJ, Buhr HJ, Blaut M. Mucosal and invading bacteria in patients with inflammatory bowel disease compared with controls. Scand J Gastroenterol. 2002;37:1034-1041. [PubMed] |
60. | Macfarlane S, Furrie E, Cummings JH, Macfarlane GT. Chemotaxonomic analysis of bacterial populations colonizing the rectal mucosa in patients with ulcerative colitis. Clin Infect Dis. 2004;38:1690-1699. [PubMed] |
61. | Tamboli CP, Neut C, Desreumaux P, Colombel JF. Dysbiosis in inflammatory bowel disease. Gut. 2004;53:1-4. [PubMed] |
62. | Furrie E, Macfarlane S, Cummings JH, Macfarlane GT. Systemic antibodies towards mucosal bacteria in ulcerative colitis and Crohn's disease differentially activate the innate immune response. Gut. 2004;53:91-98. [PubMed] |
63. | Ohkusa T, Sato N, Ogihara T, Morita K, Ogawa M, Okayasu I. Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody. J Gastroenterol Hepatol. 2002;17:849-853. [PubMed] |
64. | Mow WS, Vasiliauskas EA, Lin YC, Fleshner PR, Papadakis KA, Taylor KD, Landers CJ, Abreu-Martin MT, Rotter JI, Yang H. Association of antibody responses to microbial antigens and complications of small bowel Crohn's disease. Gastroenterology. 2004;126:414-424. [PubMed] |
65. | Van de Merwe JP, Schroder AM, Wensinck F, Hazenberg MP. The obligate anaerobic faecal flora of patients with Crohn's disease and their first-degree relatives. Scand J Gastroenterol. 1988;23:1125-1131. [PubMed] |
66. | Peluso I, Pallone F, Monteleone G. Interleukin-12 and Th1 immune response in Crohn's disease: pathogenetic relevance and therapeutic implication. World J Gastroenterol. 2006;12:5606-5610. [PubMed] |
67. | Sartor RB. Intestinal microflora in human and experimental inflammatory bowel disease. Curr Opin Gastroenterol. 2001;17:324-330. [PubMed] |
68. | Kruis W. Review article: antibiotics and probiotics in inflammatory bowel disease. Aliment Pharmacol Ther. 2004;20 Suppl 4:75-78. [PubMed] |