Autism: Metabolism, Mitochondria, and the Microbiome

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.

The Gut Microbiome and the Brain

“…98 Despite evidence of anti-inflammatory effects of propionic acid 88 and the recommendation of some researchers that increasing propionic acid synthesis in the colon may be of therapeutic value for metabolic disorders, 99 MacFabe has identified potential neurotoxicity of propionate and studied its possible role in autism. 100 His group found that pathological changes in the brains of animals exposed to intraventricular propionic acid were identical to abnormalities found in the brains of autistic children and adults. Depletion of glutathione and increased markers of oxidative stress accompanied neuroinflammation.…”

Microbiome Disturbances and Autism Spectrum Disorders

“…Health benefits ascribed to these compounds include energy supplementation for colonic epithelium, anti-inflammatory activity, and improved insulin regulation (Segain et al, 2000;Al-Lahham et al, 2010;De Preter et al, 2011). On the other hand, animal model and human epidemiologic studies suggest SCFAs may also induce neurotoxic effects, which might contribute to ASD development (MacFabe, 2013). Some of these detrimental effects are likely due to mitochondrial and epigenetic disruptions (discussed subsequently).…”

“…The MD observed in autistic cases is thought to be acquired rather than genetic in origin. The SCFAs, especially PPA, which are increased in ASD-associated gut microbes (Clostridia, Desulfovibrio, Sutterella, and Bacteroidetes), might contribute to mitochondrial dysfunction (MacFabe, 2012(MacFabe, , 2013Frye et al, 2013). One mechanism by which the bacterial metabolite PPA may disrupt mitochondria is through alteration of the tricarboxylic acid cycle via conversion of PPA to propionyl-CoA.…”

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

“…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 [350]. SCFA acts as gut-related environmental signals and are capable of altering host gene expression (including CREBdependent catecholaminergic neurotransmission), partly due to their histone deacetylase inhibitor activity and induced broad alterations in gene expression including neurotransmitter systems (monoaminergic pathways) neuronal cell adhesion molecules, inflammation, oxidative stress, lipid metabolism, and mitochondrial function, all of which have been implicated in ASD [351].…”