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 care-givers 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 micro-biome and its effects on host metabolism, immune and mitochondrial function, and gene expression, hold great promise in ASD.