Rheumatology Division, Department of Medicine, University of California, San Francisco, CA 94143, USA; Department of Microbiology & Immunology, University of California, San Francisco, CA 94143, USA.
Department of Microbiology & Immunology, University of California, San Francisco, CA 94143, USA.
Cell Host Microbe. 2021 Mar 10;29(3):362-377.e11. doi: 10.1016/j.chom.2020.12.008. Epub 2021 Jan 12.
Immunomodulatory drugs can inhibit bacterial growth, yet their mechanism of action, spectrum, and clinical relevance remain unknown. Methotrexate (MTX), a first-line rheumatoid arthritis (RA) treatment, inhibits mammalian dihydrofolate reductase (DHFR), but whether it directly impacts gut bacteria is unclear. We show that MTX broadly alters the human gut microbiota. Drug sensitivity varied across strains, but the mechanism of action against DHFR appears conserved between mammalian and bacterial cells. RA patient microbiotas were sensitive to MTX, and changes in gut bacterial taxa and gene family abundance were distinct between responders and non-responders. Transplantation of post-treatment samples into germ-free mice given an inflammatory trigger led to reduced immune activation relative to pre-treatment controls, enabling identification of MTX-modulated bacterial taxa associated with intestinal and splenic immune cells. Thus, conservation in cellular pathways across domains of life can result in broad off-target drug effects on the human gut microbiota with consequences for immune function.
免疫调节药物可以抑制细菌生长,但它们的作用机制、作用范围和临床相关性尚不清楚。甲氨蝶呤(MTX)是一种治疗类风湿关节炎(RA)的一线药物,可抑制哺乳动物二氢叶酸还原酶(DHFR),但它是否直接影响肠道细菌尚不清楚。我们发现 MTX 广泛改变了人类肠道微生物群。药物敏感性在不同菌株之间存在差异,但针对 DHFR 的作用机制在哺乳动物和细菌细胞之间似乎是保守的。RA 患者的微生物群对 MTX 敏感,并且反应者和非反应者之间肠道细菌分类群和基因家族丰度的变化是不同的。将治疗后样本移植到给予炎症触发的无菌小鼠中,与治疗前对照相比,免疫激活减少,从而能够鉴定与肠道和脾脏免疫细胞相关的 MTX 调节细菌分类群。因此,生命领域的细胞途径的保守性可能导致广泛的针对人类肠道微生物群的药物脱靶效应,从而对免疫功能产生影响。