The enteric nervous system deficits in autism spectrum disorder

Abstract

Gastrointestinal (GI) disorders are common comorbidities in individuals with autism spectrum disorder (ASD), and abnormalities in these issues have been found to be closely related to the severity of core behavioral deficits in autism. The enteric nervous system (ENS) plays a crucial role in regulating various aspects of gut functions, including gastrointestinal motility. Dysfunctional wiring in the ENS not only results in various gastrointestinal issues, but also correlates with an increasing number of central nervous system (CNS) disorders, such as ASD. However, it remains unclear whether the gastrointestinal dysfunctions are a consequence of ASD or if they directly contribute to its pathogenesis. This review focuses on the deficits in the ENS associated with ASD, and highlights several high-risk genes for ASD, which are expressed widely in the gut and implicated in gastrointestinal dysfunction among both animal models and human patients with ASD. Furthermore, we provide a brief overview of environmental factors associated with gastrointestinal tract in individuals with autism. This could offer fresh perspectives on our understanding of ASD.

Keywords: autism spectrum disorder; enteric nervous system; environmental factor; genetical factor; gut motility.

Figure 1

Schematic representation of the enteric nervous system (ENS). The ENS comprises a sophisticated network of neurons and glia organized into two ganglionated plexuses in mammals. The submucosal plexus is situated between the muscularis mucosa and circular muscle, while the outer myenteric plexus is located between the circular and longitudinal muscle layers. Herein, we present an enumeration of the principal cell types within the enteric system: 1, Myenteric/submucosal intrinsic primary afferent neuron; 2, Ascending interneuron; 3, Descending interneuron; 4, Excitatory motor neuron for circular/longitudinal muscles; 5, Inhibitory motor neuron for circular/longitudinal muscles; 6, Vasodilator neuron; 7, Secretomotor neuron; 8, Protoplasmic type I glia; 9, Fibrous type II glia; 10, Subepithelial type III glia; 11, Intramuscular type IV glia. Additionally, the ENS is also innervated by extrinsic nerves, including the vagal and spinal nerves. This figure was created with BioRender.com, with permission.

Figure 2

Schematics illustrating the fundamental circuitry regulating gut contraction and relaxation in normal condition, as well as possible mechanisms for gastrointestinal dysmotility in animal models with certain ASD—associated gene mutation. (A) The essential neuronal network responsible for coordinating peristalsis, a classic gastrointestinal motility pattern, comprises a five-neuron unit featuring an intrinsic sensory or primary afferent neuron (IPAN) that detects mechanical or chemical stimuli from the intestinal lumen. Subsequently, this IPAN activates excitatory or inhibitory motor neurons through ascending or descending interneurons. Consequently, an oral contraction of the intestinal muscle and distal relaxation occur in response to the stimulus. Additionally, enteric glia actively participate in regulating intestinal motility. (B) Potential mechanisms underlying gastrointestinal dysmotility in animal models with specific gene mutations associated with ASD. They include: (i) serotonergic signaling pathway: a reduction in serotonin-positive enteroendocrine cells, as well as alterations in SERT activity, may potentially impact the 5-HT signaling pathway that regulates enteric neuronal development and gastrointestinal motility ①; (ii) inhibitory pathway: aberrant innervation of GI smooth muscle by nNOS neurons, or an increase in the number of nNOS+ neurons or varicosities may lead to elevated levels of NO in the ENS, potentially contributing to gastrointestinal dysmotility in animal models of autism ②③④; (iii) GABA receptor pathway: activation of GABA and GABA_A receptors may potentially contribute to gastrointestinal motility, including the modulation of sensitivity toward GABA_A receptor modulators, such as alterations in the abundance and/or composition of GABA_A receptors ⑤. Additionally, (iv) Alterations in glia activity and an imbalance in the ratio between excitatory and inhibitory neurons within the enteric nervous system may contribute to gastrointestinal dysmotility observed in animal models of autism ⑥⑦. Ach, acetylcholine; ATP, adenosine triphosphate; ChAt, Choline acetyltransferase; GABA_A, γ-aminobutyric acid A; NO, nitric oxide; nNOS, neuronal nitric oxide synthase; VIP, vasoactive intestinal peptide; 5-HT, serotonin. This figure was created with BioRender.com, with permission.