The bowel and beyond: the enteric nervous system in neurological disorders

Abstract

The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS). An intact ENS is essential for life and ENS dysfunction is often linked to digestive disorders. The part the ENS plays in neurological disorders, as a portal or participant, has also become increasingly evident. ENS structure and neurochemistry resemble that of the CNS, therefore pathogenic mechanisms that give rise to CNS disorders might also lead to ENS dysfunction, and nerves that interconnect the ENS and CNS can be conduits for disease spread. We review evidence for ENS dysfunction in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease. Animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions. Moreover, the neurotropic pathogen, varicella zoster virus (VZV), unexpectedly establishes latency in enteric and other autonomic neurons that do not innervate skin. VZV reactivation in these neurons produces no rash and is therefore a clandestine cause of gastrointestinal disease, meningitis and strokes. The gut-brain alliance has raised consciousness as a contributor to health, but a gut-brain axis that contributes to disease merits equal attention.

Figure 1. Relationship between the ENS and components of the peripheral nervous system

The enteric nervous system (ENS) is a large division of the peripheral nervous system (PNS) that can control gastrointestinal behaviour independently of central nervous system (CNS) input. Mammalian neurons are located in either the CNS (brain and spinal cord) or PNS (cells with soma outside the brain and spinal cord). Afferent information from the periphery to the CNS is conveyed by neurons located in dorsal root or cranial nerve ganglia, which constitute the ‘sensory’ division of the PNS (yellow). Afferent information integrated by the CNS leads to efferent output through the ‘motor’ division of the PNS (blue). Efferent projections from the CNS target either skeletal muscle (skeletal motor) or the autonomic nervous system, which is divided into three parts: sympathetic, parasympathetic and enteric. In contrast to the neurons in sympathetic or parasympathetic ganglia, most enteric neurons receive no direct innervation from the CNS. Enteric neurons are organized in microcircuits that contain intrinsic primary afferent neurons that can respond intrinsically to local stimuli to integrate information and coordinate motor output. The ENS is therefore unique in having both sensory and motor properties (dotted line). Thus, ENS can mediate behaviour independently of the CNS; nevertheless, a two-way communication normally occurs between the bowel and the CNS, which influence one another.

Figure 2. The ENS can regulate intestinal behaviours in the absence of CNS input

The neurons and glia of the ENS form an extensive network that extends through the layers of the small and large intestine. a | Schematic of the small intestine illustrating the organization of the ENS in its location within the intestinal wall. The myenteric plexus is located between the longitudinal and circular layers of smooth muscle whereas the smaller submucosal plexus is located in the dense connective tissue of the submucosa, just underneath the mucosa. Note that no nerve fibres actually enter the enteric lumen or its epithelial lining. The extrinsic innervation reaches the bowel through the mesentery along with the vasculature. b | The major components of the gastrointestinal tract that allow the bowel to sense and respond to luminal conditions are listed. c | Organization of myenteric ganglia. A colonic segment from an adult PLP1-eGFP mouse immunostained with the neuronal cell body marker, ANNA-1 (red) and the PLP1-eGFP glial reporter (green). Scale bar = 50μm. d | Organization of the submucosal ganglia. A colonic segment from an adult PLP1-eGFP mouse immunostained with the neuronal cell body marker, ANNA-1 (red) and the PLP1-eGFP glial reporter (green). The asterisk indicates a non-immunostained crypt base encircled by mucosal glia (green). Scale bar = 50μm. e | A cross-section of ileum from a PLP1-eGFP mouse immunostained with the neuronal marker, PGP9.5, which identifies neurites as well as cell bodies (red). The extensive innervation of the intestine, as well as the presence of enteric glia (green) throughout the lamina propria of the mucosa, is illustrated. DAPI (blue) was used to stain cell nuclei. The image was obtained from a maximum intensity projection of a 20 μm confocal stack. Scale bar = 50 μm. 5-HT, 5-hydroxytryptamine or serotonin; ACh, acetylcholine; CGRP, calcitonin gene-related peptide; CNS, central nervous system; ENS, enteric nervous system; NO, nitric oxide; NPY, neuropeptide Y; VIP, vasoactive intestinal peptide.

Figure 3. Schematic of the peristaltic reflex microcircuit required for aboral propulsion of luminal contents

Luminal distention or distortion triggers direct activation of mechanoreceptive endings of intrinsic primary afferent neurons (IPANs), as well as indirect activation of IPANs upon serotonin (5-HT) release by enterochromaffin cells (ECs) in the epithelium. IPANs activate ascending and descending interneurons, which stimulate excitatory and inhibitory motor neurons, respectively. Motor neuron activity leads to oral contraction and anal relaxation of intestinal smooth muscle, which propels luminal contents in the proximal–distal direction. ACh refers to neurons that contain acetylcholine. SP refers to neurons that contain substance P. Enk refers to encephalin-expressing ascending interneurons. NO and VIP indicate inhibitory motor neurons secreting nitric oxide and vasoactive intestinal peptide. βNAD refers to inhibitory motor neurons secreting the purine, β-nicotinamide adenine dinucleotide. Secretomotor and vasomotor neurons of the submucosal plexus secrete ACh or VIP.

Figure 4. Summary of primary disease interactions between the gut and brain

Aβ, amyloid-beta; ALS, amyotrophic lateral sclerosis; ASD, autism spectrum disorder; PrP^Sc, prion protein scrapie.

Figure 5. Enteric manifestations of lytic VZV infection of the mucosa and latent VZV infection of the ENS

a | Mucosal biopsy sample from a patient with a perforated gastric ulcer. The patient’s saliva and stomach contained DNA encoding varicella zoster virus (VZV) gene products. The gastric epithelium has been infected and shows the immunoreactivity of gE (ORF68p; green) and ORF63p (red). DNA has been stained with bisbenzimide (blue). There is a slight superimposition of white light in interference contrast to allow all components of the tissue to be visualized. Newly infected cells (arrows) where the virus is spreading are mostly red fluorescent because ORF63 is an immediate early gene and gE is a late gene. The highly infected cells contain both gene products and are yellow. Scale bar = 20 μm. b | Ileum of a guinea pig injected with VZV-infected lymphocytes. The VZV expresses green fluorescent protein (GFP) under the control of the VZV promoter for ORF66. The red fluorescence is the immunoreactivity of β3-tubulin, a neuronal marker. Virtually all enteric neurons contain latent VZV. Note that the VZV is confined to nerve cell bodies and is not seen in neurites within the interganglionic connectives (red). Thus, the neurons are not actually producing viral particles. The restriction of ORF66-GFP to cell bodies is therefore an indicator of viral latency. DNA has been stained with bisbenzimide (blue). Scale bar = 20 μm.