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. 2013 Nov;2(6):52-66.
doi: 10.7453/gahmj.2013.089.

Autism: Metabolism, Mitochondria, and the Microbiome

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Free PMC article

Autism: Metabolism, Mitochondria, and the Microbiome

Derrick Macfabe. Glob Adv Health Med. .
Free PMC article

Abstract

New approaches are needed to examine the diverse symptoms and comorbidities of the growing family of neurodevelopmental disorders known as autism spectrum disorder (ASD). ASD originally was thought to be a static, inheritable neurodevelopmental disorder, and our understanding of it is undergoing a major shift. It is emerging as a dynamic system of metabolic and immune anomalies involving many organ systems, including the brain, and environmental exposure. The initial detailed observation and inquiry of patients with ASD and related conditions and the histories of their caregivers and families have been invaluable. How gastrointestinal (GI) factors are related to ASD is not yet clear. Nevertheless, many patients with ASD have a history of previous antibiotic exposure or hospitalization, GI symptoms, abnormal food cravings, and unique intestinal bacterial populations, which have been proposed to relate to variable symptom severity. In addition to traditional scientific inquiry, detailed clinical observation and recording of exacerbations, remissions, and comorbidities are needed. This article reviews the role that enteric short-chain fatty acids, particularly propionic (also called propanoic) acid, produced from ASD-associated GI bacteria, may play in the etiology of some forms of ASD. Human populations that are partial metabolizers of propionic acid are more common than previously thought. The results from pre-clinical laboratory studies show that propionic acid-treated rats display ASD-like repetitive, perseverative, and antisocial behaviors and seizure. Neurochemical changes, consistent and predictive with findings in ASD patients, including neuroinflammation, increased oxidative stress, mitochondrial dysfunction, glutathione depletion, and altered phospholipid/acylcarnitine profiles, have been observed. Propionic acid has bioactive effects on (1) neurotransmitter systems, (2) intracellular acidification and calcium release, (3) fatty acid metabolism, (4) gap junction gating, (5) immune function, and (6) alteration of gene expression that warrant further exploration. Traditional scientific experimentation is needed to verify the hypothesis that enteric short-chain fatty acids may be a potential environmental trigger in some forms of ASD. Novel collaborative developments in systems biology, particularly examining the role of the microbiome and its effects on host metabolism, immune and mitochondrial function, and gene expression, hold great promise in ASD.

我们需要新的手段来检查不断扩大的神经发育障碍,即自闭症谱系障碍(ASD)家族各种各样的症状和并存病症。ASD 最初被认为是一种静态的、可遗传的神经发育障碍,而我们对它的理解和认识正经历着重大的转变。它最初表现为代谢和免疫动态系统的异常,其中涉及众多器官系统,包括大脑和环境暴露。针对 ASD 和相关病症患者最初阶段的详细观察和调查,以及他们的护理人员和家庭成员的历史记录情况都是非常宝贵的资料。胃肠道(GI)因素与 ASD 的关系目前尚不明确。虽然如此,许多 ASD 患者都有过抗生素暴露或住院治疗的经历、有胃肠道症状、反常的饮食冲动和独特的肠道细菌种群,这些都可能与不同的症状严重度有关。除了传统的科学调查,还需要进行详细的临床观察并做好急性发作、缓解及并存病症的记录。本文综述了与 ASD 有关的 GI 细菌所制造的肠道短链脂肪酸(尤其丙酸)在某些类型 ASD 病因学中所起的作用。 丙酸部分代谢者人群比以前想象的要常见得多。临床前实验室研究的结果显示,接受丙酸治疗的老鼠表现出和 ASD 相似的重复、持续的反社会性行为和癫痫发作。研究观察到了与 ASD 患者身上的发现一致的影响神经系统的化学物质的变化,包括神经炎症、氧化压力增加、线粒体功能障碍、谷胱甘肽缺乏症和磷脂/酰肉碱属性改变等在内的现象。丙酸对(1)神经递质系统、(2)细胞内酸化和钙释放、(3)脂肪酸代谢、(4)缝隙连接门控、(5)免疫功能,以及(6)确证需要做进一步探索的基因表达的变化都具有生物活性效 应。关于肠道短链脂肪酸可能是某 些类型 ASD 潜在的环境诱因这一 假设,尚需要传统的科学实验加以 证明。系统生物学的新的合作进 展,尤其检查微生物组在宿主代 谢、免疫和线粒体功能,以及在基 因表达中所发挥的作用及其功效, 给 ASD 研究带来了巨大的希望。

Son necesarios nuevos enfoques que examinen los diversos síntomas y comorbilidades de la creciente familia de trastornos del desarrollo neurológico que reciben el nombre de trastorno del espectro autista (TEA). En sus comienzos se pensó que el TEA era un trastorno estático y hereditario del desarrollo neurológico, pero nuestra comprensión del mismo está cambiando sustancialmente. Se está revelando como un sistema dinámico de anomalías metabólicas e inmunitarias en el que están involucrados numerosos sistemas orgánicos, incluido el cerebro, y la exposición ambiental. La detallada observación inicial y las investigaciones sobre los pacientes con TEA y enfermedades relacionadas, así como las historias de sus cuidadores y familiares, han sido inestimables. Aún no está clara la forma en que los factores gastrointestinales (GI) se relacionan con el TEA. Sin embargo, hay muchos pacientes con TEA que tienen antecedentes de exposición previa a antibióticos o de hospitalización, síntomas gastrointestinales, antojos anormales de comida y poblaciones bacterianas intestinales únicas, que se ha sugerido están relacionados con la gravedad variable de los síntomas.Además de la investigación científica tradicional, es necesaria una detallada observación clínica y el registro de exacerbaciones, remisiones y comorbilidades. En este artículo se revisa el papel que pueden desempeñar en la etiología de algunas formas de TEA los ácidos grasos de cadena corta intestinales, en particular el ácido propiónico (también denominado propanoico), que se produce por la acción de bacterias GI asociadas al TEA. Las poblaciones humanas que son metabolizadoras parciales del ácido propiónico son más frecuentes de lo que se pensaba anteriormente. Los resultados de estudios preclínicos de laboratorio revelan que las ratas tratadas con ácido propiónico muestran unos comportamientos repetitivos, perseverativos y antisociales, así como convulsiones, similares a los del TEA. Se han observado cambios neuroquímicos, de valor pronóstico y coherentes con los hallazgos en pacientes con TEA, que incluyen la neuroinflamación, el aumento del estrés oxidativo, la disfunción mitocondrial, la disminución de glutatión y la alteración de los perfiles de fosfolípidos y acilcarnitina. El ácido propiónico tiene efectos bioactivos sobre (1) los sistemas neurotransmisores, (2) la acidificación intracelular y la liberación de calcio, (3) el metabolismo de los ácidos grasos, (4) la activación/desactivación de las uniones intercelulares comunicantes, (5) la función inmunitaria y (6) la alteración de la expresión génica, los cuales justifican una exploración con mayor detalle. Es necesaria la experimentación científica tradicional para verificar la hipótesis de que los ácidos grasos de cadena corta intestinales puedan potencialmente representar un desencadenante ambiental en algunas formas de TEA. Los desarrollos colectivos novedosos en biología de sistemas, en particular los que examinan el papel del microbioma y sus efectos sobre el metabolismo anfitrión, la función inmunitaria y mitocondrial, y la expresión génica, constituyen una gran esperanza en el TEA.

Keywords: Autism spectrum disorder; animal model; carnitine; clostridia; fatty acids; gap junctions; gastrointestinal tract; microbiome; mitochondria; neuropsychiatric disorder; propanoic acid; propionic acid.

Figures

Figure 1
Figure 1
Behavioral videos of propionic acid infusions in rats. Single intracerebroventricular (ICV) infusions (4 μL of 0.26 M solution over 4 min) of propionic acid (PPA), a metabolic end product of autism-associated enteric bacteria, produce bouts of reversible hyperactive and repetitive behavior (A) in adult rats, compared with phosphate-buffered saline (PBS) vehicle–infused control rat (B). Rat pairs infused with PPA show markedly reduced social interaction and play behavior (C) compared with pairs of rats infused with PBS vehicle (D), which show typical social behavior. Ethovision behavioral tracking of control (left) and PPA-treated (right) rat pairs (E), showing further evidence of PPA-induced hyperactive, repetitive, and antisocial behavior. PPA-treated rat displays fixation on objects (F) and a specific object preference (ie, block vs sphere). PPA-infused rats also show turning, tics, dystonia, and retropulsion and electrographic evidence of complex partial seizures and basal ganglial spiking consistent with findings in patients with autism spectrum disorders. Modified with permission from MacFabe 2012, Microbial Ecology in Health and Disease.
Figure 2
Figure 2
Neuropathology (avidin–biotin complex immunohistochemistry) and semiquantitative image densitometry of coronal brain sections of dorsal hippocampus (CA2) and external capsule of adult rats with 14-day twice daily intracerebroventricular infusions of propionic acid (PPA) or phosphate-buffered saline (PBS). Propionic acid induced significant reactive astrogliosis (anti-GFAP) and microglial activation (anti-CD68) without apoptotic neuronal cell loss (anti-cleaved caspase 3) in rat hippocampus, similar to findings in autopsied brain from patients with autism. Nuclear translocation of anti-CREB and an increase of anti-phospho-CREB immunoreactivity are observed in neural, glial, and endovascular epithelia by propionic acid treatment, suggestive of gene induction. Propionic acid increases monocarboxylate transporter 1 (MCT1) immunoreactivity, primarily in white matter external capsule, suggestive of alterations in brain short–chain fatty acid transport/metabolism. Black bars indicate propionic acid–treated animals; white bars indicate PBS (vehicle)–treated animals. Horizontal measurement bar = 100 μ. Reproduced with permission from MacFabe (2012), Microbial Ecology in Health and Disease.
Figure 3
Figure 3
Metabolism of the tricarboxylic-acid cycle during (a) typical metabolism and (b) with high levels of propionic acid (PPA). PPA is metabolized to propionyl-CoA, which inhibits the proximal portion of the tricarboxylic-acid cycle and enhances the distal portion of the tricarboxylic-acid cycle (see discussion for details). Modified from Frye, Melnyk, and MacFabe 2013, Translational Psychiatry. Abbreviations: FADH2, flavin adenine dinucleotide; NADH, nicotinamide adenine dinucleotide.

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