Häupl Thomas, Sörensen Till, Smiljanovic Biljana, Darcy Marine, Scheder-Bieschin Justus, Steckhan Nico, Hartmann Anika M, Koppold Daniela A, Stuhlmüller Bruno, Skriner Karl, Walewska Barbara M, Hoppe Berthold, Bonin Marc, Burmester Gerd R, Schendel Pascal, Feist Eugen, Liere Karsten, Meixner Martin, Kessler Christian, Grützkau Andreas, Michalsen Andreas
Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Berlin, 10117 Berlin, Germany.
Institute of Social Medicine, Epidemiology and Health Economics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Berlin, 10117 Berlin, Germany.
J Clin Med. 2023 Jun 28;12(13):4359. doi: 10.3390/jcm12134359.
Rheumatoid arthritis (RA) synovitis is dominated by monocytes/macrophages with inflammatory patterns resembling microbial stimulation. In search of triggers, we reduced the intestinal microbiome in 20 RA patients (open label study DRKS00014097) by bowel cleansing and 7-day fasting (≤250 kcal/day) and performed immune monitoring and microbiome sequencing. Patients with metabolic syndrome ( = 10) served as a non-inflammatory control group. Scores of disease activity (DAS28/SDAI) declined within a few days and were improved in 19 of 20 RA patients after breaking the fast (median ∆DAS28 = -1.23; ∆SDAI = -43%) or even achieved remission (DAS28 < 2.6/ = 6; SDAI < 3.3/ = 3). Cytometric profiling with 46 different surface markers revealed the most pronounced phenomenon in RA to be an initially increased monocyte turnover, which improved within a few days after microbiota reduction and fasting. Serum levels of IL-6 and zonulin, an indicator of mucosal barrier disruption, decreased significantly. Endogenous cortisol levels increased during fasting but were insufficient to explain the marked improvement. Sequencing of the intestinal microbiota indicated that fasting reduced potentially arthritogenic bacteria and changed the microbial composition to species with broader metabolic capabilities. More eukaryotic, predominantly fungal colonizers were observed in RA, suggesting possible involvement. This study demonstrates a direct link between the intestinal microbiota and RA-specific inflammation that could be etiologically relevant and would support targeted nutritional interventions against gut dysbiosis as a causal therapeutic approach.
类风湿性关节炎（RA）滑膜炎以单核细胞/巨噬细胞为主，其炎症模式类似于微生物刺激。为了寻找触发因素，我们通过肠道清洁和7天禁食（≤250千卡/天）减少了20例RA患者（开放标签研究DRKS00014097）的肠道微生物群，并进行了免疫监测和微生物群测序。患有代谢综合征的患者（n = 10）作为非炎症对照组。疾病活动评分（DAS28/SDAI）在几天内下降，20例RA患者中有19例在禁食结束后病情改善（中位∆DAS28 = -1.23；∆SDAI = -43%），甚至达到缓解（DAS28 < 2.6/n = 6；SDAI < 3.3/n = 3）。用46种不同表面标志物进行的细胞分析显示，RA中最明显的现象是单核细胞周转率最初增加，在微生物群减少和禁食后几天内有所改善。血清白细胞介素-6和zonulin（粘膜屏障破坏的指标）水平显著下降。禁食期间内源性皮质醇水平升高，但不足以解释明显的改善。肠道微生物群测序表明，禁食减少了潜在的致关节炎细菌，并将微生物组成改变为具有更广泛代谢能力的物种。在RA中观察到更多的真核生物，主要是真菌定植者，提示可能参与其中。这项研究证明了肠道微生物群与RA特异性炎症之间的直接联系，这可能在病因学上具有相关性，并支持针对肠道菌群失调的靶向营养干预作为一种因果治疗方法。
