Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.
Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.
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DOI：
10.1016/j.medj.2021.04.013
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发表时间：
2021-07-09
期刊：
影响因子：
--
通讯作者：
Mauri C
中科院分区：
文献类型：
--
作者：
Matei DE;Menon M;Alber DG;Smith AM;Nedjat-Shokouhi B;Fasano A;Magill L;Duhlin A;Bitoun S;Gleizes A;Hacein-Bey-Abina S;Manson JJ;Rosser EC;ABIRISK Consortium;Klein N;Blair PA;Mauri C
有证据表明，肠道微生物群失调在类风湿关节炎（RA）的发展中起重要作用。肠道细菌的变化和关节炎症的发展之间的联系是缺失的。在这里，我们讨论肠道环境是否有变化，以及它们如何促进关节炎的发病机制。我们分析了RA患者外周血和血清中肠道通透性、损伤和炎症标志物的变化。采用免疫荧光/组织学、ELISA和流式细胞术分析自发性关节炎的K/BxN小鼠或野生型、转基因白介素(IL)-10R - / -或cladin -8 - / -小鼠的血清、肠道和淋巴器官。RA患者表现出肠道通透性和损伤的血清标志物以及细胞肠道归巢标志物水平升高，这两个参数都与疾病严重程度呈正相关。关节炎小鼠在疾病早期表现出肠道通透性增加，以及细菌易位，炎症性肠道损伤，干扰素γ (IFNγ)+增加和IL-10+肠道浸润白细胞频率降低，以及肠上皮IL-10R表达减少。从机制上讲，关节炎细菌和白细胞都需要破坏肠道屏障的完整性。我们发现，将肠道类器官暴露于IFNγ会降低上皮细胞的IL-10R表达，缺乏上皮细胞IL-10R的小鼠表现出肠道通透性增加和关节炎加重。肠道通透性增加的Claudin-8−/−小鼠也会发生更严重的关节疾病。用AT-1001（一种阻止肠道通透性发展的分子）治疗小鼠，可以改善关节炎。我们认为肠道屏障完整性的破坏有助于关节炎的发展，并提出恢复肠道屏障稳态作为治疗RA的新方法。由Versus Arthritis（21140和21257）和UKRI/MRC （MR/T000910/1）资助。类风湿关节炎是一种以慢性关节炎症为特征的自身免疫性疾病。类风湿关节炎是一种以慢性关节炎症为特征的自身免疫性疾病。类风湿关节炎是一种以慢性关节炎症为特征的自身免疫性疾病。越来越多的证据表明，肠道细菌组成的变化可能是导致关节炎症的原因。目前，尚不清楚细菌或其产物如何指导免疫系统细胞变得有害并诱发关节炎。伦敦大学学院（University College London）的研究人员发现，关节炎患者的肠壁受到严重损害，肠壁无法正常发挥屏障的作用，而且肠道中白细胞的积累会导致炎症。作者表明，在关节炎中，细菌穿过肠道内壁的禁止边界，用特定的药物修复肠道渗透性缺陷可以抑制关节炎症。肠道细菌的变化与关节炎的发展有关；然而，与疾病的机制联系尚不清楚。Matei等人发现了关节炎中肠道组织的病理变化，包括肠道屏障完整性的丧失和炎症细胞的浸润，并表明肠道稳态的恢复可以改善疾病。
Evidence suggests an important role for gut-microbiota dysbiosis in the development of rheumatoid arthritis (RA). The link between changes in gut bacteria and the development of joint inflammation is missing. Here, we address whether there are changes to the gut environment and how they contribute to arthritis pathogenesis. We analyzed changes in markers of gut permeability, damage, and inflammation in peripheral blood and serum of RA patients. Serum, intestines, and lymphoid organs isolated from K/BxN mice with spontaneous arthritis or from wild-type, genetically modified interleukin (IL)-10R−/−or claudin-8−/−mice with induced arthritis were analyzed by immunofluorescence/histology, ELISA, and flow cytometry. RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters positively correlating with disease severity. Arthritic mice display increased gut permeability from early stages of disease, as well as bacterial translocation, inflammatory gut damage, increases in interferon γ (IFNγ)+and decreases in IL-10+intestinal-infiltrating leukocyte frequency, and reduced intestinal epithelial IL-10R expression. Mechanistically, both arthritogenic bacteria and leukocytes are required to disrupt gut-barrier integrity. We show that exposing intestinal organoids to IFNγ reduces IL-10R expression by epithelial cells and that mice lacking epithelial IL-10R display increased intestinal permeability and exacerbated arthritis. Claudin-8−/−mice with constitutively increased gut permeability also develop worse joint disease. Treatment of mice with AT-1001, a molecule that prevents development of gut permeability, ameliorates arthritis. We suggest that breakdown of gut-barrier integrity contributes to arthritis development and propose restoration of gut-barrier homeostasis as a new therapeutic approach for RA. Funded by Versus Arthritis (21140 and 21257) and UKRI/MRC (MR/T000910/1). Serum gut-permeability markers LPB, LPS, and I-FABP are increased in RA Mice with arthritis have increased gut permeability and intestinal inflammation Both bacteria and leukocytes are needed to disrupt gut-barrier integrity Prevention of gut-barrier dysfunction in arthritis ameliorates joint inflammation Rheumatoid arthritis is an autoimmune disorder characterized by chronic joint inflammation. Accumulating evidence suggests that changes in the composition of the bacteria residing in the gut could be responsible for joint inflammation. Currently, it is unclear how bacteria or their products instruct cells of the immune system to become harmful and induce arthritis. Researchers at University College London have shown that, in arthritis, there is profound damage to the gut lining, which fails to work properly as a barrier, as well as an accumulation in the gut of white blood cells that cause inflammation. The authors show that, in arthritis, bacteria cross the prohibited border of the intestinal lining and that repairing gut permeability defects with specific drugs inhibits joint inflammation. Changes to the gut bacteria have been associated with the development of arthritis; however, the mechanistic connection with disease remains unknown. Matei et al. identify pathological changes to the gut tissue in arthritis, including loss of gut-barrier integrity and inflammatory-cell infiltration, and show that restoration of gut homeostasis ameliorates disease.
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