Background: Autism Spectrum Disorders (ASD) have long been conceived as developmental disorder.
A growing body of data highlights a role for alterations in the gut in the pathoetiology and/or pathophysiology of
ASD. Recent work shows alterations in the gut microbiome to have a significant impact on amygdala development
in infancy, suggesting that the alterations in the gut microbiome may act to modulate not only amygdala
development but how the amygdala modulates the development of the frontal cortex and other brain regions.
Methods: This article reviews wide bodies of data pertaining to the developmental roles of the maternal and foetal
gut and immune systems in the regulation of offspring brain development.
Results: A number of processes seem to be important in mediating how genetic, epigenetic and environmental
factors interact in early development to regulate such gut-mediated changes in the amygdala, wider brain functioning
and inter-area connectivity, including via regulation of microRNA (miR)-451, 14-3-3 proteins, cytochrome
P450 (CYP)1B1 and the melatonergic pathways. As well as a decrease in the activity of monoamine
oxidase, heightened levels of in miR-451 and CYP1B1, coupled to decreased 14-3-3 act to inhibit the synthesis of
N-acetylserotonin and melatonin, contributing to the hyperserotonemia that is often evident in ASD, with consequences
for mitochondria functioning and the content of released exosomes. These same factors are likely to play
a role in regulating placental changes that underpin the association of ASD with preeclampsia and other perinatal
risk factors, including exposure to heavy metals and air pollutants. Such alterations in placental and gut processes
act to change the amygdala-driven biological underpinnings of affect-cognitive and affect-sensory interactions in
Conclusion: Such a perspective readily incorporates previously disparate bodies of data in ASD, including the
role of the mu-opioid receptor, dopamine signaling and dopamine receptors, as well as the changes occurring to
oxytocin and taurine levels. This has a number of treatment implications, the most readily applicable being the
utilization of sodium butyrate and melatonin.