Data_Sheet_1_Intestinal metabolites and the risk of autistic spectrum disorder: A two-sample Mendelian randomization study.pdf

BackgroundObservational studies have reported a strong association between autistic spectrum disorder (ASD) and intestinal metabolites. However, it is unclear whether this correlation is causally or violated by confounding or backward causality. Therefore, this study explored the potential causal relationship between intestinal metabolites and dependent metabolites on ASD.
MethodsWe used a two-sample Mendelian random analysis and selected variants closely related to intestinal flora-dependent metabolites as instrumental variables. MR-Egger, inverse variance weighted (IVW), MR-PRESSO, maximum likelihood, and weighted median were performed to reveal their causal relationships. Ten metabolites were studied, which included trimethylamine-N-oxide, betaine, carnitine, choline, glutamate, kynurenine, phenylalanine, serotonin, tryptophan, and tyrosine. Sensitivity tests were also performed to evaluate the robustness of the MR study.
ResultsThe IVW method revealed that serotonin may increase the ASD risk (OR 1.060, 95% CI: 1.006–1.118), while choline could decrease the ASD risk (OR 0.925, 95% CI: 0.868–0.988). However, no definite causality was observed between other intestinal metabolites (e.g., trimethylamine-N-oxide, betaine, and carnitine) with ASD. Additionally, neither the funnel plot nor the MR-Egger test showed horizontal pleiotropy, and the MR-PRESSO test found no outliers. Cochran’s Q test showed no significant heterogeneity among the studies, suggesting the robustness of the study.
ConclusionOur study found potential causality from intestinal metabolites on ASD. Clinicians are encouraged to offer preventive measures to such populations.

研究背景
已有观察性研究报道孤独症谱系障碍（autistic spectrum disorder, ASD）与肠道代谢物之间存在显著关联。然而目前尚不清楚该相关性是否为真正的因果关联，亦或是受混杂因素或反向因果关系误导而产生的虚假关联。因此，本研究旨在探索肠道代谢物与孤独症谱系障碍之间的潜在因果关联。

研究方法
本研究采用两样本孟德尔随机化（two-sample Mendelian random, 2SMR）分析方法，选取与菌群依赖性代谢物密切相关的遗传变异作为工具变量。依次采用MR-Egger法、逆方差加权（inverse variance weighted, IVW）法、MR-PRESSO法、极大似然法以及加权中位数法，以揭示二者的因果关联。本研究共纳入10种代谢物进行分析，分别为氧化三甲胺（trimethylamine-N-oxide）、甜菜碱（betaine）、肉碱（carnitine）、胆碱（choline）、谷氨酸（glutamate）、犬尿氨酸（kynurenine）、苯丙氨酸（phenylalanine）、5-羟色胺（serotonin）、色氨酸（tryptophan）以及酪氨酸（tyrosine）。同时开展敏感性检验以评估本孟德尔随机化研究结果的稳健性。

研究结果
逆方差加权法分析结果显示，5-羟色胺可能升高孤独症谱系障碍的发病风险（比值比OR=1.060，95%置信区间CI：1.006~1.118），而胆碱则可能降低该疾病的发病风险（OR=0.925，95%CI：0.868~0.988）。但其余肠道代谢物（如氧化三甲胺、甜菜碱及肉碱）与孤独症谱系障碍之间未观察到明确的因果关联。此外，漏斗图与MR-Egger检验均未发现水平多效性，MR-PRESSO检验也未检出异常值。Cochran Q检验显示本研究不存在显著的异质性，进一步证实了研究结果的稳健性。

研究结论
本研究证实了肠道代谢物与孤独症谱系障碍之间存在潜在因果关联，建议临床医师为高风险人群采取相应的预防干预措施。