Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders

摘要

Recent evidence suggests potential, but unproven, links between dietary, metabolic, infective, and gastro-intestinal factors and the behavioral exacerbations and remissions of autism spectrum disorders (ASDs).Propionic acid (PPA) and its related short-chain fatty acids (SCFAs) are fermentation products of ASD-associated bacteria (Clostridia, Bacteriodetes, Desulfovibrio). SCFAs represent a group of compounds derivedfrom the host microbiome that are plausibly linked to ASDs and can induce widespread effects on gut, brain,and behavior. Intraventricular administration of PPA and SCFAs in rats induces abnormal motor movements,repetitive interests, electrographic changes, cognitive deficits, perseveration, and impaired social interactions.The brain tissue of PPA-treated rats shows a number of ASD-linked neurochemical changes, including innateneuroinflammation, increased oxidative stress, glutathione depletion, and altered phospholipid/acylcarnitineprofiles. These directly or indirectly contribute to acquired mitochondrial dysfunction via impairment incarnitine-dependent pathways, consistent with findings in patients with ASDs. Of note, common antibioticsmay impair carnitine-dependent processes by altering gut flora favoring PPA-producing bacteria and bydirectly inhibiting carnitine transport across the gut. Human populations that are partial metabolizers of PPAare more common than previously thought. PPA has further bioactive effects on neurotransmitter systems,intracellular acidification/calcium release, fatty acid metabolism, gap junction gating, immune function,and alteration of gene expression that warrant further exploration. These findings are consistent with thesymptoms and proposed underlying mechanisms of ASDs and support the use of PPA infusions in ratsas a valid animal model of the condition. Collectively, this offers further support that gut-derived factors,such as dietary or enteric bacterially produced SCFAs, may be plausible environmental agents that can triggerASDs or ASD-related behaviors and deserve further exploration in basic science, agriculture, and clinicalmedicine.