Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome.
Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome.
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DOI：
10.3402/mehd.v26.27458
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发表时间：
2015
影响因子：
--
通讯作者：
MacFabe DF
中科院分区：
文献类型：
--
作者：
Frye RE;Rose S;Slattery J;MacFabe DF
自闭症谱系障碍（ASD）影响着世界范围内大量的个体，患病率持续增长。越来越清楚的是，一个大的ASD个体亚组表现出线粒体功能异常以及胃肠道（GI）症状。有趣的是，GI紊乱在患有线粒体疾病的个体中很常见，并且据报道在患有共同发生的ASD和线粒体疾病的个体中非常普遍。大多数患有ASD和线粒体疾病的个体并没有表现出原发性基因突变，这增加了他们的线粒体疾病是获得性的可能性，或者至少是遗传易感性与广泛的环境触发因素相互作用的组合的结果。线粒体对内源性和外源性环境应激源如毒物、医源性药物、免疫激活和代谢紊乱都非常敏感。这些相同的环境压力源中的许多与ASD相关，这表明线粒体可能是环境压力源和与ASD相关的神经代谢异常之间的生物学联系。本文综述了GI异常，线粒体和ASD之间的可能联系。首先，我们回顾胃肠道症状和线粒体功能异常之间的联系。其次，我们回顾了支持与ASD相关的环境压力因素也会对线粒体和GI功能产生不利影响的证据。第三，我们回顾了在ASD儿童中过度存在的肠道细菌，特别是梭菌，产生对线粒体有潜在毒性的短链脂肪酸代谢物。我们通过突出ASD的丙酸啮齿动物模型和支持这种动物模型的临床证据来提供这种肠-脑连接的例子。最后，我们讨论了可能有助于ASD和线粒体疾病中GI症状的潜在治疗方法。为此，本综述旨在帮助更好地了解与ASD相关的潜在病理生理学，可能与并发线粒体和GI功能障碍有关。
Autism spectrum disorder (ASD) affects a significant number of individuals worldwide with the prevalence continuing to grow. It is becoming clear that a large subgroup of individuals with ASD demonstrate abnormalities in mitochondrial function as well as gastrointestinal (GI) symptoms. Interestingly, GI disturbances are common in individuals with mitochondrial disorders and have been reported to be highly prevalent in individuals with co-occurring ASD and mitochondrial disease. The majority of individuals with ASD and mitochondrial disorders do not manifest a primary genetic mutation, raising the possibility that their mitochondrial disorder is acquired or, at least, results from a combination of genetic susceptibility interacting with a wide range of environmental triggers. Mitochondria are very sensitive to both endogenous and exogenous environmental stressors such as toxicants, iatrogenic medications, immune activation, and metabolic disturbances. Many of these same environmental stressors have been associated with ASD, suggesting that the mitochondria could be the biological link between environmental stressors and neurometabolic abnormalities associated with ASD. This paper reviews the possible links between GI abnormalities, mitochondria, and ASD. First, we review the link between GI symptoms and abnormalities in mitochondrial function. Second, we review the evidence supporting the notion that environmental stressors linked to ASD can also adversely affect both mitochondria and GI function. Third, we review the evidence that enteric bacteria that are overrepresented in children with ASD, particularly Clostridia spp., produce short-chain fatty acid metabolites that are potentially toxic to the mitochondria. We provide an example of this gut–brain connection by highlighting the propionic acid rodent model of ASD and the clinical evidence that supports this animal model. Lastly, we discuss the potential therapeutic approaches that could be helpful for GI symptoms in ASD and mitochondrial disorders. To this end, this review aims to help better understand the underlying pathophysiology associated with ASD that may be related to concurrent mitochondrial and GI dysfunction.