Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH and GOSH, London, UK; Centre for Rheumatology Research, Division of Medicine, UCL, London WC1E 6JF, UK; Infection, Immunity and Inflammation Programme, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
Centre for Rheumatology Research, Division of Medicine, UCL, London WC1E 6JF, UK.
Cell Metab. 2020 Apr 7;31(4):837-851.e10. doi: 10.1016/j.cmet.2020.03.003. Epub 2020 Mar 25.
The differentiation of IL-10-producing regulatory B cells (Bregs) in response to gut-microbiota-derived signals supports the maintenance of tolerance. However, whether microbiota-derived metabolites can modulate Breg suppressive function remains unknown. Here, we demonstrate that rheumatoid arthritis (RA) patients and arthritic mice have a reduction in microbial-derived short-chain fatty acids (SCFAs) compared to healthy controls and that in mice, supplementation with the SCFA butyrate reduces arthritis severity. Butyrate supplementation suppresses arthritis in a Breg-dependent manner by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA), which activates the aryl-hydrocarbon receptor (AhR), a newly discovered transcriptional marker for Breg function. Thus, butyrate supplementation via AhR activation controls a molecular program that supports Breg function while inhibiting germinal center (GC) B cell and plasmablast differentiation. Our study demonstrates that butyrate supplementation may serve as a viable therapy for the amelioration of systemic autoimmune disorders.
肠道微生物衍生信号诱导的白细胞介素-10 产生调节性 B 细胞（Bregs）的分化有助于维持耐受。然而，微生物衍生代谢物是否可以调节 Breg 的抑制功能尚不清楚。在这里，我们证明与健康对照组相比，类风湿关节炎（RA）患者和关节炎小鼠的微生物衍生短链脂肪酸（SCFA）减少，而在小鼠中，补充 SCFA 丁酸可降低关节炎严重程度。丁酸补充通过增加血清素衍生代谢物 5-羟色胺-3-乙酸（5-HIAA）的水平以 Breg 依赖的方式抑制关节炎，该水平激活了芳基烃受体（AhR），这是 Breg 功能的新发现的转录标志物。因此，丁酸通过 AhR 激活补充剂控制支持 Breg 功能的分子程序，同时抑制生发中心（GC）B 细胞和浆母细胞分化。我们的研究表明，丁酸补充剂可能作为改善系统性自身免疫疾病的可行疗法。
