■细胞和分子生物学,结合对人类微生物组和代谢组的研究,为系统性硬化症(SSc)的发病机制提供了新的见解。然而,大多数关于SSc肠道菌群(GM)和代谢组的研究都是观察性研究。混杂因素和反向因果关系的影响导致不同的见解。为了阐明这件事,我们利用孟德尔随机化(MR)来确定GM/代谢物对SSc的因果效应.
■基于全基因组关联研究的汇总数据,双向双样本MR进行了涉及196GM,1400血浆代谢,和9,095SSc。逆方差加权(IVW)主要用于效果估计。
■前向MR分析发现,三种GM和两种血浆代谢物与SSc有因果关系。IVW结果显示小花科(科)(OR,1.469;95CI,1.099-1.963;p=0.009)和LachnospiraceaUCG004(属)(OR,1.548;95CI,1.020-2.349;p=0.04)是SSc的危险因素。相反,Prevotella7(属)(OR,0.759;95CI,0.578-0.997;p=0.048)是SSc的保护因素。血浆代谢物的结果表明,孕二醇二硫酸酯(C21H34O8S2)水平(OR,1.164;95CI,1.006-1.347;p=0.041)是SSc的危险因素,而神经鞘磷脂(d18:1/19:0,d19:1/18:0)水平(OR,0.821;95CI,0.677-0.996;p=0.045)是SSc的保护因素。反向MR分析未发现SSc与上述GM/血浆代谢物之间的因果关系。
■我们的结果揭示了GM/血浆代谢物与SSc之间的因果关系。这些发现为SSc的机制提供了新的见解。特别是,我们证明了Prevotella7是SSc的保护因子,尽管在以前的研究中它在SSc中的作用存在争议。
UNASSIGNED: Cellular and molecular biology, combined with research on the human microbiome and metabolome, have provided new insights into the pathogenesis of systemic sclerosis (SSc). However, most studies on gut microbiota (GM) and metabolome in SSc are observational studies. The impact of confounding factors and reverse causation leads to different insights. To shed light on this matter, we utilized Mendelian randomization (MR) to determine the causal effect of GM/metabolites on SSc.
UNASSIGNED: Based on summary-level data from genome-wide association studies, bidirectional Two-sample MR was conducted involving 196 GM, 1400 plasma metabolism, and 9,095 SSc. Inverse Variance Weighting (IVW) was mainly used for effect estimation.
UNASSIGNED: Forward MR analysis found that three GM and two plasma metabolites are causally related to SSc. IVW results showed Victivallaceae (family) (OR, 1.469; 95%CI, 1.099-1.963; p = 0.009) and LachnospiraceaeUCG004 (genus) (OR, 1.548; 95%CI, 1.020-2.349; p = 0.04) were risk factor of SSc. Conversely, Prevotella7 (genus) (OR, 0.759; 95%CI, 0.578-0.997; p = 0.048)was a protective factor of SSc. The results on plasma metabolites indicated that Pregnenediol disulfate (C21H34O8S2) levels (OR, 1.164; 95%CI, 1.006-1.347; p = 0.041)was a risk factor of SSc, while Sphingomyelin (d18:1/19:0, d19:1/18:0) levels (OR, 0.821; 95%CI, 0.677-0.996; p = 0.045)was a protective factor of SSc. Reverse MR analysis did not find causally relationship between SSc and the above GM/plasma metabolites.
UNASSIGNED: Our results revealed the causally effect between GM/plasma metabolites and SSc. These findings provided new insights into the mechanism of SSc. In particular, we demonstrated Prevotella7 was a protective factor of SSc despite its controversial role in SSc in previous researches.