Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders

Abstract

Autism-spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive patterns of behavior. ASD is, however, often associated with medical comorbidities and gastrointestinal (GI) dysfunction is among the most common. Studies have demonstrated a correlation between GI dysfunction and the degree of social impairment in ASD. The etiology of GI abnormalities in ASD is unclear, though the association between GI dysfunction and ASD-associated behaviors suggest that overlapping developmental defects in the brain and the intestine and/or a defect in communication between the enteric and central nervous systems (ENS and CNS, respectively), known as the gut-brain axis, could be responsible for the observed phenotypes. Brain-gut abnormalities have been increasingly implicated in several disease processes, including ASD. As a critical modulator of ENS and CNS development and function, serotonin may be a nexus for the gut-brain axis in ASD. This paper reviews the role of serotonin in ASD from the perspective of the ENS. A murine model that has been demonstrated to possess brain, behavioral and GI abnormalities mimicking those seen in ASD harbors the most common serotonin transporter (SERT) based mutation (SERT Ala56) found in children with ASD. Discussion of the gut-brain manifestations in the SERT Ala56 mice, and their correction with developmental administration of a 5-HT₄ agonist, are also addressed in conjunction with other future directions for diagnosis and treatment.

Keywords: Autism spectrum disorder; Enteric nervous system; Gut-brain-microbiome axis; Serotonin; Serotonin 4 receptor; Serotonin reuptake transporter.

Figure 1.. Schematic of the synthesis, inactivation and degradation of 5-HT in the intestinal epithelium and ENS.

5-HT is synthesized in the intestinal epithelium by enterochromaffin (EC) cells from tryptophan (Trp) by the rate-limiting tryptophan hydroxylase 1 (TPH1). Luminal distention results in the basal release of 5-HT into the interstitial space of the lamina propria, leading to activation of 5-HT receptors on intrinsic primary afferent neurons (IPANs) in both the submucosal and myenteric plexuses. 5-HT is inactivated through the actions of the serotonin reuptake transporter (SERT), which is expressed by intestinal epithelial cells. Once intracellular, 5-HT is degraded by monoamine oxidase (MAO) into 5-hydroxyindoleacetic acid (5-HIAA). Platelets also express SERT; they are thought to reflect stores of intestinal epithelial 5-HT that are picked up as platelets pass through enteric circulation. The ENS contains serotonin-synthesizing neurons. Enteric neurons utilize a different isoform of tryptophan hydroxylase, TPH2, to synthesize serotonin from tryptophan, which is then stored in synaptic vesicles. Secreted 5-HT activates post-synaptic receptors and is then inactivated through pre-synaptic reuptake by SERT, where it can be packaged into vesicles once again for release or degraded by MAO into 5-HIAA.