腸道菌叢會誘發或惡化RA


  【24drs.com】類風濕性關節炎(RA)遺傳易感因素與環境誘發因子之間的連結可能在於消化道菌叢。
  
  梅約診所免疫科醫師Veena Taneja博士領導的研究刊載於2012年4月的PloS ONE,首次提出HLA基因與腸道環境對於關節炎易感性的相互影響;研究者認為,腸道的微生物可以作為RA研究的生物標記。
  
  梅約診所和伊利諾大學Urbana校區的研究者,參與「Mayo Illinois Alliance for Technology Based Healthcare」合作進行此次研究。
  
  Taneja博士表示,我們的研究率先指出,患有與腸道無關之疾病時,腸道可以改變免疫系統。沒有單一的生物標記可以確認發生關節炎高風險者。我們的研究解釋了宿主基因如何確認我們所帶有的菌叢,以及他們是否可作為生物標記。再者,它促使我們暸解,RA患者的免疫系統失調,可能與離實際病灶處有段距離的(腸胃道)有關。
  
  研究者使用了帶有HLA-DR突變的擬人化HLA轉殖基因老鼠,讓牠們患有關節炎(*0401老鼠)或者對關節炎有抗性(*0402老鼠),以確認基因因素和腸道菌叢是否可預測後續發生關節炎。
  
  分析顯示,*0401組老鼠的腸道菌叢主要是Clostridium類細菌,*0402組老鼠主要是Porphyromonadaceae 和Bifidobacteria屬。根據研究者表示,後者這兩屬細菌與抗發炎反應有關,位於腸黏膜和周邊免疫系統,作用是透過抑制T-細胞增生以及產生促發炎細胞激素,以及抑制細胞核因子kappa B(NF-κB)活化。
  
  此外,*0402組老鼠有動態的性別和年紀影響的腸道菌叢,*0401組老鼠的腸道菌叢並未顯示年紀和性別差異,即使牠們並未出現腸道穿透性改變。細胞激素轉錄分析也顯示,這兩組老鼠有不同的TH17調節基因轉錄。
  
  Taneja博士表示,關鍵發現是,和腸道菌叢有關的HLA基因可能改變了免疫環境且造成關節炎易感性。*0401組基因易感性老鼠的腸道之clostridium類細菌濃度較高。這表示細菌菌種和宿主的基因環境有關,在這狀況下可能改變了免疫環境與誘發自體免疫反應。我認為宿主基因對於確認腸道菌叢有很大的影響。腸道菌叢隨著食物和其他環境而改變,可能會改變免疫反應。根據我們的研究,我們可以推測,與腸道菌叢有關的HLA基因對於確認關節炎易感性有所影響。
  
  研究者推測,Clostridia類細菌可能會干擾非致病性腸道共生菌的一般菌種,再加上腸道通透性增加,使梭狀芽胞桿菌等細菌引起的疾病增加,產生了全身性免疫反應而導致基因易感者發生關節炎;研究者也指出,RA病患的滑膜液中曾發現某些口腔和腸道共生菌抗原。
  
  Taneja博士表示,很多人懷疑過腸道微生物對疾病易感性的作用,我們提出,在具有基因傾向者的細菌濃度與疾病發生之間的關聯,這至少顯示出,細菌是類風濕性關節炎的指標,相當有可能的是,用細菌來延遲或制止疾病發生與惡化。
  
  Taneja博士指出,我們腸道中的細菌可作為類風濕性關節炎易感性的微創生物標記,以及潛在的治療標靶。我們現在探討操控細菌濃度是否可以延緩疾病惡化或停止疾病發生。這篇研究顯示出可以促成個人化醫療的一種可能方法。雖然人類的免疫系統更為複雜,這篇研究為調節疾病之觀念的可能性又邁進一步。
  
  魁北克蒙特婁McGill大學健康中心、McGill宿主阻抗性研究中心醫學副教授Marianna M. Newkirk博士曾研究細菌菌落模式和RA病患之風濕性因子的關聯。
  
  Newkirk博士表示,發表的資料有一些問題,因此降低了它們對我的說服力;報告中有關細菌數量/類型的這部份,提到雄鼠和雌鼠的差異,不過,r值小於0.5 的意義要根據p值。p值意味著各個數據有多靠近(顯著程度),而不是r值。我通常只有在r值大於等於0.5時假設它有意義,當然,它接近1.0時會令我更相信資料。他們的數據顯然不是常態分佈,所以我們確實需要非參數分析。
  
  細胞激素資料更為確實且顯然更引人注目。r值大於0.5 (甚至達0.8,列於附錄)。不過,這個不算新資訊,因為我們已經知道,針對細胞激素是控制和處置RA的一個好的治療方式。
  
  Newkirk博士結論表示,因為我並未全部相信腸道菌叢資料,我不急著改變類風濕性關節炎病患的飲食,因此,就我的觀點,這個可能的發炎修改因子尚未定論。
  
  資料來源: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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