肠道菌丛会诱发或恶化RA


  【24drs.com】类风湿性关节炎(RA)遗传易感因素与环境诱发因子之间的连结可能在于消化道菌丛。
  
  梅约诊所免疫科医师Veena Taneja博士领导的研究刊载于2012年4月的PloS ONE,首次提出HLA基因与肠道环境对于关节炎易感性的相互影响;研究者认为,肠道的微生物可以作为RA研究的生物标记。
  
  梅约诊所和伊利诺大学Urbana校区的研究者,参与「Mayo Illinois Alliance for Technology Based Healthcare」合作进行此次研究。
  
  Taneja博士表示,我们的研究率先指出,患有与肠道无关之疾病时,肠道可以改变免疫系统。没有单一的生物标记可以确认发生关节炎高风险者。我们的研究解释了宿主基因如何确认我们所带有的菌丛,以及他们是否可作为生物标记。再者,它促使我们了解,RA患者的免疫系统失调,可能与离实际病灶处有段距离的(肠胃道)有关。
  
  研究者使用了带有HLA-DR突变的拟人化HLA转殖基因老鼠,让牠们患有关节炎(*0401老鼠)或者对关节炎有抗性(*0402老鼠),以确认基因因素和肠道菌丛是否可预测后续发生关节炎。
  
  分析显示,*0401组老鼠的肠道菌丛主要是Clostridium类细菌,*0402组老鼠主要是Porphyromonadaceae 和Bifidobacteria属。根据研究者表示,后者这两属细菌与抗发炎反应有关,位于肠黏膜和周边免疫系统,作用是透过抑制T-细胞增生以及产生促发炎细胞激素,以及抑制细胞核因子kappa B(NF-κB)活化。
  
  此外,*0402组老鼠有动态的性别和年纪影响的肠道菌丛,*0401组老鼠的肠道菌丛并未显示年纪和性别差异,即使牠们并未出现肠道穿透性改变。细胞激素转录分析也显示,这两组老鼠有不同的TH17调节基因转录。
  
  Taneja博士表示,关键发现是,和肠道菌丛有关的HLA基因可能改变了免疫环境且造成关节炎易感性。*0401组基因易感性老鼠的肠道之clostridium类细菌浓度较高。这表示细菌菌种和宿主的基因环境有关,在这状况下可能改变了免疫环境与诱发自体免疫反应。我认为宿主基因对于确认肠道菌丛有很大的影响。肠道菌丛随著食物和其它环境而改变,可能会改变免疫反应。根据我们的研究,我们可以推测,与肠道菌丛有关的HLA基因对于确认关节炎易感性有所影响。
  
  研究者推测,Clostridia类细菌可能会干扰非致病性肠道共生菌的一般菌种,再加上肠道通透性增加,使梭状芽胞杆菌等细菌引起的疾病增加,产生了全身性免疫反应而导致基因易感者发生关节炎;研究者也指出,RA病患的滑膜液中曾发现某些口腔和肠道共生菌抗原。
  
  Taneja博士表示,很多人怀疑过肠道微生物对疾病易感性的作用,我们提出,在具有基因倾向者的细菌浓度与疾病发生之间的关联,这至少显示出,细菌是类风湿性关节炎的指标,相当有可能的是,用细菌来延迟或制止疾病发生与恶化。
  
  Taneja博士指出,我们肠道中的细菌可作为类风湿性关节炎易感性的微创生物标记,以及潜在的治疗标靶。我们现在探讨操控细菌浓度是否可以延缓疾病恶化或停止疾病发生。这篇研究显示出可以促成个人化医疗的一种可能方法。虽然人类的免疫系统更为复杂,这篇研究为调节疾病之观念的可能性又迈进一步。
  
  魁北克蒙特娄McGill大学健康中心、McGill宿主阻抗性研究中心医学副教授Marianna M. Newkirk博士曾研究细菌菌落模式和RA病患之风湿性因子的关联。
  
  Newkirk博士表示,发表的资料有一些问题,因此降低了它们对我的说服力;报告中有关细菌数量/类型的这部份,提到雄鼠和雌鼠的差异,不过,r值小于0.5 的意义要根据p值。p值意味著各个数据有多靠近(显著程度),而不是r值。我通常只有在r值大于等于0.5时假设它有意义,当然,它接近1.0时会令我更相信资料。他们的数据显然不是常态分布,所以我们确实需要非参数分析。
  
  细胞激素资料更为确实且显然更引人注目。r值大于0.5 (甚至达0.8,列于附录)。不过,这个不算新信息,因为我们已经知道,针对细胞激素是控制和处置RA的一个好的治疗方式。
  
  Newkirk博士结论表示,因为我并未全部相信肠道菌丛资料,我不急著改变类风湿性关节炎病患的饮食,因此,就我的观点,这个可能的发炎修改因子尚未定论。
  
  资料来源:http://www.24drs.com/professional/list/content.asp?x_idno=6872&x_classno=0&x_chkdelpoint=Y

Gut Flora Might Trigger or Worsen RA

By Janis C. Kelly
Medscape Medical News

June 28, 2012 — The bridge between genetic susceptibility for rheumatoid arthritis (RA) and environmental triggers might be the bacteria in the digestive tract.

Research led by Mayo Clinic immunologist Veena Taneja, PhD, and published in the April 2012 issue of PloS ONE provides the first demonstration that HLA genes and the gut environment interact to affect arthritis susceptibility. The researchers suggest that the gut microbiome might be a useful biomarker in RA studies.

This study was conducted by Mayo Clinic and the University of Illinois at Urbana-Champaign researchers participating in the Mayo Illinois Alliance for Technology Based Healthcare.

Dr. Taneja told Medscape Medical News, "Our study brings to the fore that gut can change the immune system in diseases that do not actually involve gut. There is no single biomarker to define individuals at high risk for developing arthritis. Our study explains how host genetics may determine the bugs we carry and if together they can be used as biomarker. Further, it enhances our understanding that dysregulation of immune system in RA may also involve sites away from the actual affected tissues."

The researchers used humanized HLA transgenic mice that carried HLA-DR mutations making them either susceptible to arthritis (*0401 mice) or resistant to arthritis (*0402 mice) to determine whether genetic factors and gut flora would predict subsequent arthritis.

The analysis showed that the gut flora of the *401 arthritis-susceptible mice were dominated by a Clostridium-like bacterium, while those of the *0402 arthritis-resistant mice were enriched for Porphyromonadaceae species and for Bifidobacteria. The latter organism has been associated with anti-inflammatory response in the intestinal mucosal and peripheral immune systems via suppression of T-cell proliferation and production of pro-inflammatory cytokines, and inhibition of nuclear factor kappa B (NF-κB) activation, according to the researchers.

In addition, the resistant mice had a dynamic sex- and age-influenced gut microbiome, while the arthritis-susceptible mice did not show age and sex differences in gut flora, even though they did show altered gut permeability. Analysis of cytokine transcripts also showed different TH17 regulatory gene transcripts in the susceptible vs resistant mice.

Dr. Taneja said that the key finding was that HLA genes in association with the gut microbiome may both alter the immune environment and contribute to arthritis susceptibility. "We found higher concentrations of clostridium-like bacteria in the guts of genetically susceptible mice. This suggests that bacterial populations respond to the genetic environment of their host, which in this case is likely altering the immune environment and inducing autoimmune response. I think host genetics has a big role in determining gut flora. Gut flora does change with food and other environment, and that can alter immune response. Dependent on our study we can speculate that HLA genes in association with gut flora may have a role in determining susceptibility to arthritis," she said.

The researchers suspect that the Clostridia-like bacterium might disrupt the usual populations of nonpathogenic gut commensals. Coupled with the increased gut permeability, this raises the possibility that disease-causing bacteria such as Clostridia could produce a systemic immune response resulting in arthritis in those who are genetically susceptible. The researchers also point out that certain oral and gut commensal bacterial antigens have been found in synovial fluids of RA patients.

Dr. Taneja said, "Many have suspected that the gut microbiome plays a role in disease susceptibility. We were able to demonstrate a link between bacterial levels and disease onset in populations with a genetic predisposition. This shows, at the very least, that bacteria are indicators of rheumatoid arthritis. In all likelihood, bacteria can be manipulated to delay or stop disease onset and progression."

Dr. Taneja added, "The bacteria in our guts may make a minimally invasive biomarker for rheumatoid arthritis susceptibility, as well as a potential therapeutic target. We are now looking at whether manipulation of bacterial concentrations can slow disease progression or stop disease onset altogether. This study has raised a possible way that individualized medicine can be advanced. Although in humans, the immune system is more complicated, this study is a step closer to the concept that modulation of disease may be possible.”

Marianna M. Newkirk, PhD, associate professor of medicine at the McGill Centre for the Study of Host Resistance, McGill University Health Centre, Montreal, Quebec, reviewed the study for Medscape Medical News. Dr. Newkirk has studied the association of bacterial colonization patterns and rheumatoid factor status in RA patients.

Dr. Newkirk said, "There are some problems with the data presentation that make them less compelling to me. For the part of the paper where they present the data on the amounts/types of bacteria found in the males versus females of the two strains, unfortunately they are concluding that r values of less than 0.5 are meaningful based on a p value. The p value just indicates how close to the line the data points are and not that the r value is actually significant. I usually only assume that an r value is of meaning if it is at least 0.5 or greater and of course the closer to 1.0 it is the more I believe the data.... Their data though are clearly not normally distributed, so indeed non-parametric analyses were required.

"The cytokine data are much more solid and are clearly more compelling. The r values are above 0.5 (even up to almost 0.8, in the supplementary data). This information is less novel however, as we have known for a long time that targeting cytokines is a good therapeutic approach for the control and management of RA."

Dr. Newkirk concluded, "Since I am not totally convinced about their gut microbiome data, I would not be in a hurry to alter the diet of patients with rheumatoid arthritis. Thus from my perspective the jury is still out on this potential modifier of inflammation."

Drs. Taneja and Newkirk have disclosed no relevant financial relationships.

PloS ONE. 2012.

    
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