注意缺陷多动障碍儿童肠道菌群特征的横断面研究与孟德尔随机化分析

Cross-sectional study and Mendelian randomization analysis of gut microbiota characteristics in children with attention-deficit hyperactivity disorder

目的分析注意缺陷多动障碍(attention-deficit hyperactivity disorder,ADHD)儿童与健康儿童的肠道菌群差异,并通过孟德尔随机化(Mendelian randomization,MR)分析评价肠道菌群与ADHD的因果关系,探索ADHD的发病机制。方法2019年1~12月对解放军总医院第一医学中心儿科门诊收集的25例ADHD患儿和25例健康儿童的粪便标本进行宏基因组测序,以评估2组之间肠道菌群组成和功能的差异。并利用PGC数据库进行双向MR分析,采用逆方差加权(inverse-variance weighting,IVW)法、MR-Egger回归法、加权中位数(weighted median estimator,WME)法3种回归模型对肠道菌群与ADHD的因果关系进行分析。统计学方法采用χ^(2)检验、独立样本t检验。结果ADHD组与健康儿童组肠道菌群的α和β多样性有显著性差异[Shannon指数,P=0.018;置换多元方差分析(permutation multivariate analysis of variance,PERMANOVA)检验,P=0.026]。有21个菌种与ADHD显著相关,其中14个菌种在ADHD中富集(包括瘤胃球菌),7个菌种在ADHD中降低。正向MR分析结果提示,有13种细菌可能是ADHD的危险因素,其中包括瘤胃球菌(OR=1.149,95%CI:1.035~1.276,P=0.009);反向MR分析结果并未发现任何细菌与ADHD有统计学差异,提示ADHD可能不是导致菌群失调的原因。结论ADHD儿童与健康儿童的肠道菌群组成及功能之间存在差异,瘤胃球菌可能是ADHD的危险因素。

Objective To analyze the differences in gut microbiota between children with attentiondeficit hyperactivity disorder(ADHD)and healthy children,and evaluate the causal relationship between gut microbiota and ADHD using Mendelian randomization(MR)analysis,aiming to investigate the pathogenesis of ADHD.Method From January to December 2019,fecal samples were collected from 25 children with ADHD and 25 healthy children at the Department of Pediatric Outpatient the First Medical Center of Chinese PLA General Hospital,metagenomic sequencing was performed to evaluate the differences in composition and function of gut microbiota between the two groups.Two-way MR analysis was conducted using the PGC database,and three regression models,including inverse-variance weighting(IVW),MR-Egger regression,and weighted median estimator(WME)were used to analyze the causal relationship between gut microbiota and ADHD.Statistical methods performed byχ^(2) test and independent samples t-test.Result There were significant differences inαandβdiversity of gut microbiota between the ADHD and healthy children groups[Shannon index,P=0.018;permutation multivariate analysis of variance(PERMANOVA)test,P=0.026].Twenty-one bacterial species were significantly associated with ADHD,with 14 bacterial species enriched in the ADHD(including Ruminococcus)and 7 bacterial species reduced in ADHD.The positive MR analysis results suggested that 13 bacterial species may be risk factors for ADHD,including Ruminococcus(OR=1.149,95%CI:1.035-1.276 P=0.009).However,the reverse MR analysis results did not show any statistically significant differences in bacteria associated with ADHD,suggesting that ADHD may not be the cause of gut dysbiosis.Conclusion There are differences in composition and function of gut microbiota between children with ADHD and healthy children,and Ruminococcus may be a risk factor for ADHD.