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. 2015 May 29:26:28177.
doi: 10.3402/mehd.v26.28177. eCollection 2015.

Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders

Derrick F MacFabe  1
Affiliations

Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders

Derrick F MacFabe. Microb Ecol Health Dis. .

Abstract

Clinical observations suggest that gut and dietary factors transiently worsen and, in some cases, appear to improve behavioral symptoms in a subset of persons with autism spectrum disorders (ASDs), but the reason for this is unclear. Emerging evidence suggests ASDs are a family of systemic disorders of altered immunity, metabolism, and gene expression. Pre- or perinatal infection, hospitalization, or early antibiotic exposure, which may alter gut microbiota, have been suggested as potential risk factors for ASD. Can a common environmental agent link these disparate findings? This review outlines basic science and clinical evidence that enteric short-chain fatty acids (SCFAs), present in diet and also produced by opportunistic gut bacteria following fermentation of dietary carbohydrates, may be environmental triggers in ASD. Of note, propionic acid, a major SCFA produced by ASD-associated gastrointestinal bacteria (clostridia, bacteroides, desulfovibrio) and also a common food preservative, can produce reversible behavioral, electrographic, neuroinflammatory, metabolic, and epigenetic changes closely resembling those found in ASD when administered to rodents. Major effects of these SCFAs may be through the alteration of mitochondrial function via the citric acid cycle and carnitine metabolism, or the epigenetic modulation of ASD-associated genes, which may be useful clinical biomarkers. It discusses the hypothesis that ASDs are produced by pre- or post-natal alterations in intestinal microbiota in sensitive sub-populations, which may have major implications in ASD cause, diagnosis, prevention, and treatment.

Keywords: antibiotic; autism spectrum disorder; carnitine; epigenetics; food preservative; gap junctions; gastrointestinal; glutathione; lipids; microbiome; mitochondria; neurexin; neuroinflammation; oxidative stress; short-chain fatty acids.

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Figures

Fig. 1
Fig. 1
Behavioral videos of propionic acid infusions in rats (click headings to view videos). 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 and PPA-treated rat pairs (E), showing further evidence of PPA-induced hyperactive, repetitive, and antisocial behavior. PPA-treated rat displays fixation on objects (F) and specific object preferences (i.e. block vs. sphere). PPA-infused rats also show turning, tics, dystonia, and retropulsion and electrographic evidence of complex partial seizures and basal ganglia spiking, consistent with findings in patients with autism spectrum disorders. With permission from MacFabe (6).
Fig. 2
Fig. 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 BID ICV infusions of propionic acid (PPA) or phosphate-buffered saline (PBS). PPA-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 finding in autopsy brain from patients with autism. Nuclear translocation of anti-CREB and an increase of anti phosphoCREB immunoreactivity are observed in neural, glial, and endovascular epithelium by PPA treatment, suggestive of gene induction. PPA increases monocarboxylate transporter 1 immunoreactivity, primarily in white matter external capsule, suggestive of alterations in brain short-chain fatty acid transport/metabolism. Black bars indicate PPA-treated animals; white bars indicate PBS (vehicle)-treated animals. Horizontal measurement bar = 100 µ. With permission from MacFabe (6).
Fig. 3
Fig. 3
Effects of the enteric bacterial metabolite propionic acid (PPA) on the tricarboxylic acid cycle during (A) typical metabolism and (B) with high levels of 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. Effects of PPA on the citric acid cycle in the PPA rodent model of autism are consistent with those found in a subset of patients with ASD, along with further abnormalities in mitochondrial redox function, phospholipid, and acylcarnitine profiles. FADH2, flavin adenine dinucleotide; NADH, nicotinamide adenine dinucleotide. With permission from Ref. (74).
Fig. 4
Fig. 4
Broad physiological effects of enteric short-chain fatty acids on host physiology and brain function and behavior. These effects which are dose, tissue and temporally specific may be physiologically adaptive (immune/cellular energy regulation, food seeking, learning and memory, intra species social interaction), but may be pathological with increased production, decreased breakdown or increased early exposure of these bacterial metabolites during key periods of neurodevelopment.
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