Luna Ruth Ann, Oezguen Numan, Balderas Miriam, Venkatachalam Alamelu, Runge Jessica K, Versalovic James, Veenstra-VanderWeele Jeremy, Anderson George M, Savidge Tor, Williams Kent C
Texas Children's Microbiome Center, Department of Pathology, Texas Children's Hospital, Houston, Texas; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas.
Department of Psychiatry, Columbia University, New York, New York.
Cell Mol Gastroenterol Hepatol. 2016 Dec 11;3(2):218-230. doi: 10.1016/j.jcmgh.2016.11.008. eCollection 2017 Mar.
BACKGROUND & AIMS: Emerging data on the gut microbiome in autism spectrum disorder (ASD) suggest that altered host-microbe interactions may contribute to disease symptoms. Although gut microbial communities in children with ASD are reported to differ from individuals with neurotypical development, it is not known whether these bacteria induce pathogenic neuroimmune signals.
Because commensal clostridia interactions with the intestinal mucosa can regulate disease-associated cytokine and serotonergic pathways in animal models, we evaluated whether microbiome-neuroimmune profiles (from rectal biopsy specimens and blood) differed in ASD children with functional gastrointestinal disorders (ASD-FGID, n = 14) compared with neurotypical (NT) children with FGID (NT-FGID, n = 15) and without abdominal pain (NT, n = 6). Microbial 16S ribosomal DNA community signatures, cytokines, and serotonergic metabolites were quantified and correlated with gastrointestinal symptoms.
A significant increase in several mucosa-associated Clostridiales was observed in ASD-FGID, whereas marked decreases in and , as well as , were evident. Stratification by abdominal pain showed multiple organisms in ASD-FGID that correlated significantly with cytokines (interleukin [IL]6, IL1, IL17A, and interferon-γ). Group comparisons showed that IL6 and tryptophan release by mucosal biopsy specimens was highest in ASD children with abdominal pain, whereas serotonergic metabolites generally were increased in children with FGIDs. Furthermore, proinflammatory cytokines correlated significantly with several Clostridiales previously reported to associate with ASD, as did tryptophan and serotonin.
Our findings identify distinctive mucosal microbial signatures in ASD children with FGID that correlate with cytokine and tryptophan homeostasis. Future studies are needed to establish whether these disease-associated Clostridiales species confer early pathogenic signals in children with ASD and FGID.
关于自闭症谱系障碍（ASD）肠道微生物群的新数据表明，宿主与微生物相互作用的改变可能导致疾病症状。虽然据报道，患有ASD的儿童的肠道微生物群落与神经发育正常的个体不同，但尚不清楚这些细菌是否会诱导致病性神经免疫信号。
由于共生梭菌与肠黏膜的相互作用可调节动物模型中与疾病相关的细胞因子和血清素能通路，我们评估了患有功能性胃肠疾病的ASD儿童（ASD-FGID，n = 14）与患有功能性胃肠疾病的神经发育正常儿童（NT-FGID，n = 15）以及无腹痛的神经发育正常儿童（NT，n = 6）相比，其微生物组-神经免疫特征（来自直肠活检标本和血液）是否存在差异。对微生物16S核糖体DNA群落特征、细胞因子和血清素能代谢产物进行了定量分析，并与胃肠道症状进行了关联。
在ASD-FGID中观察到几种与黏膜相关的梭菌目显著增加，而在[具体菌名未给出]以及[另一种具体菌名未给出]中明显减少。按腹痛分层显示，ASD-FGID中有多种微生物与细胞因子（白细胞介素[IL]6、IL1、IL17A和干扰素-γ）显著相关。组间比较显示，有腹痛的ASD儿童黏膜活检标本中IL6和色氨酸释放最高，而功能性胃肠疾病儿童的血清素能代谢产物普遍增加。此外,促炎细胞因子与先前报道的几种与ASD相关的梭菌目显著相关，色氨酸和血清素也是如此。
我们的研究结果确定了患有功能性胃肠疾病的ASD儿童独特的黏膜微生物特征，这些特征与细胞因子和色氨酸稳态相关。未来需要开展研究，以确定这些与疾病相关的梭菌目物种是否会在患有ASD和功能性胃肠疾病的儿童中产生早期致病信号。
