Blank Rebecca B, Bu Kevin, Chen Weixi, Cunningham Ian, Sokolove Jeremy, Lahey Lauren, Heguy Adriana, Medina Rhina, Ubeda Carles, Nayak Renuka R, Hu Jiyuan, Cantor Adam, Lee Jakleen, Clemente Jose C, Scher Jose U
Division of Rheumatology, NYU School of Medicine.
Dept. Genetics and Genomic Sciences, Precision Immunology Institute, Icahn School of Medicine at Mt. Sinai.
medRxiv. 2024 Dec 31:2024.12.30.24319783. doi: 10.1101/2024.12.30.24319783.
Although genetic factors have been identified in the pathogenesis of rheumatoid arthritis (RA), the concordance rate in monozygotic (MZ) twins is low, suggesting that other features contribute to disease development. Further, the relative contribution of such non-genetic elements in identical twins have not been characterized. Here, we aimed to measure differentiating host and microbial biomarkers of RA by studying MZ twins discordant for disease using a multi-omics approach.
Eight pairs of MZ twins discordant for RA (n=16) were enrolled. Gut microbiome was assessed using shotgun metagenomic sequencing. Autoantibodies, cytokines, and other plasma proteins were measured in both plasma and feces. Levels of short and medium-chain fatty acids from serum and feces were quantified using gas chromatography mass spectrometry (GC-MS).
While overall microbiome diversity and composition did not significantly differ between twins, we observed a decrease in in affected twins. Affected twins had higher concentrations of both fecal and plasma citrullinated and non-citrullinated autoantibodies, as well as significantly lower concentrations of fecal butyrate and propionate.
Multi-omics biomarkers differentiate MZ twins discordant for RA. , which is associated with reduced inflammatory cytokine expression, was decreased in RA twins. Similarly, short-chain fatty acids, known to have immune modulatory effects, were decreased in affected twins, suggesting further bi-directional interactions between inflammation at the gut barrier and disease state. If confirmed in other cohorts, exhaustive multi-omics approaches may improve our understanding of RA pathogenesis and potentially contribute to novel diagnostics and co-adjuvant therapies.
尽管在类风湿关节炎（RA）的发病机制中已确定了遗传因素，但同卵双胞胎（MZ）的疾病一致性率较低，这表明其他因素也参与了疾病的发展。此外，这些非遗传因素在同卵双胞胎中的相对作用尚未得到明确。在此，我们旨在通过多组学方法研究患RA不一致的MZ双胞胎，以测量RA的宿主和微生物差异生物标志物。
招募了8对患RA不一致的MZ双胞胎（n = 16）。使用鸟枪法宏基因组测序评估肠道微生物群。同时检测血浆和粪便中的自身抗体、细胞因子及其他血浆蛋白。采用气相色谱 - 质谱联用（GC-MS）对血清和粪便中的短链和中链脂肪酸水平进行定量。
虽然双胞胎之间的总体微生物群多样性和组成没有显著差异，但我们观察到患病双胞胎的[此处原文缺失相关内容]有所下降。患病双胞胎的粪便和血浆中瓜氨酸化和非瓜氨酸化自身抗体浓度均较高，而粪便中丁酸盐和丙酸盐的浓度则显著较低。
多组学生物标志物可区分患RA不一致的MZ双胞胎。在RA双胞胎中，与炎症细胞因子表达降低相关的[此处原文缺失相关内容]减少。同样，已知具有免疫调节作用的短链脂肪酸在患病双胞胎中减少，这表明肠道屏障炎症与疾病状态之间存在进一步的双向相互作用。如果在其他队列中得到证实，详尽的多组学方法可能会增进我们对RA发病机制的理解，并可能有助于新的诊断方法和辅助治疗。
