儿童孤独症谱系障碍患者的母亲肠道菌群组成特征及其对疾病预测价值的研究

目的　研究孤独症谱系障碍（Autism spectrum disorder, ASD）儿童的母亲肠道菌群组成的特点，基于微生物生态学方法发现具有早期ASD 临床辅助诊断意义的生物标志物。方法　回顾性分析了76 例ASD 儿童的母亲和47 例正常发育（Typical development, TD）儿童的母亲粪便中肠道菌群高通量测序数据。对数据进行质控、剪切、拼接和降噪，得到扩增序列变异（amplicon sequence variants, ASVs），基于ASVs 相对丰度的相关性建立具有生态学意义的17个丰度共变化群（co-abundance groups, CAGs），比较ASD 儿童母亲和TD 儿童母亲CAGs 的差异，判别两组人群的生物标志物。结果　基于ASVs 相对丰度的相关性建立的17 个CAGs，其中，CAG8 主要由属于Bacteroides 的肠道细菌组成，CAG10 主要由属于Collinsella 的肠道细菌组成，而CAG16 主要由属于Erysipelotrichaceae 和Lachnospiraceae的肠道细菌组成。比较这些CAGs 相对丰度的结果显示，ASD 儿童的母亲CAG10 的相对丰度（3.37±0.76）较TD 儿童的母亲（0.95±0.25）显著升高，差异具有统计学意义（U=1 393， P=0.038）；与TD 儿童的母亲相比，ASD 儿童的母亲CAG8（7.27±1.11 vs 12.98±2.14）和CAG16（0.7±0.06 vs 1.37±0.33）显著降低，差异具有统计学意义（U=1 252 和1 387，P=0.005，0.038）。基于这些变化的肠道细菌建立的肠道紊乱指数（gut dysbiosis index, GDI）具有区别ASD 儿童的母亲和TD 儿童的母亲的潜力，当GDI 以-1.073 为阈值时，其敏感度和特异度分别为93.4% 和80.9%。结论　 ASD 儿童的母亲肠道细菌组成失调，基于母亲的肠道菌群计算的生物标志物可用于ASD 儿童的早期诊断。

Characteristics of Maternal Gut Microbiota in Children with Autism Spectrum Disorder and Its Predictive Value for This Disease

Objective　To explore the gut microbial composition in mothers of children with autism spectrum disorder (ASD) based on biomarkers which had the significance of clinical auxiliary diagnosis of early ASD discovered by the microbial ecology method. Methods　This study analyzed gut microbial composition in 76 mothers of children with ASD and 47 mothers of children with typical development (TD). The data of gut microbiota was calculated as amplicon sequence variants (ASVs)which were then clustered into 17 co-abundance groups (CAGs) with ecological significance based on the correlation of relative abundances of ASVs. Compared the differences of CAGs between ASD children’s mothers and TD children’s mothers, and identified the biomarkers of the two groups. Results　17 CAGs were established based on the correlation of the relative abundance of ASVs. Among them, CAG8 was mainly composed of intestinal bacteria belonging to Bacteroides, CAG10 was mainly composed of intestinal bacteria belonging to Collinsella, and CAG16 was mainly composed of intestinal bacteria belonging to Erysipelotrichaceae and lachno spiraceae. The relative abundance of CAG10 in mothers of children with ASD (3.37±0.76) increased compared with mothers of children with TD (0.95±0.25), and the difference was statistically significant (U=1 393, P=0.038). Compared with mothers of children with TD, CAG8 (7.27±1.11 vs 12.98±2.14) and CAG16 (0.7±0.06 vs 1.37±0.33) decreased in mothers of children with ASD, the differences were statistically significant respectively (U=1 252, 1 387, P=0.005, 0.038). Based on these changes, gut dysbiosis index (GDI) established by intestinal bacteria had the potential to distinguish the mothers of ASD children and TD children. When GDI takes -1.073 as the threshold, its sensitivity and specificity were 93.4% and 80.9% respectively. Conclusion　The gut microbiota was altered in mothers of children with ASD. The biomarkers calculated by the alterations of maternal gut microbiota based on maternal gut microbiota based on microbiota may contribute to diagnose ASD children in early stage.