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

Key Points

  • The enteric nervous system (ENS) is the largest component of the autonomic nervous system and is uniquely equipped with intrinsic microcircuits that enable it to orchestrate gastrointestinal function independently of central nervous system (CNS) input

  • Because many neurotransmitters, signalling pathways and anatomical properties are common to the ENS and CNS, pathophysiological processes that underlie CNS disease often have enteric manifestations

  • Neuronal connections and the immune system might provide conduits that allow diseases acquired in the gut to spread to the brain

  • Transmissible spongiform encephalopathies, autistic spectrum disorders, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, and varicella zoster virus (VZV) infection are examples of disorders with both gastrointestinal and neurological consequences

  • VZV reactivations from latency in enteric and other autonomic neurons that lack cutaneous projections are occult causes of zoster without rash that lead to gastrointestinal disease, meningitis and strokes

  • Research on the gut–brain axis of disease is reasonably new, concepts are changing rapidly, and further investigation is much needed


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.

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Figure 1: Relationship between the ENS and components of the peripheral nervous system.
Figure 2: The ENS can regulate intestinal behaviours in the absence of CNS input.
Figure 3: Schematic of the peristaltic reflex microcircuit required for aboral propulsion of luminal contents.
Figure 4: Summary of primary disease interactions between the gut and brain.
Figure 5: Enteric manifestations of lytic VZV infection of the mucosa and latent VZV infection of the ENS.


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M.R. receives research support from Ivan and Phyllis Seidenberg, the Paul Marks Scholars Program, and the American Gastroenterological Association – Takeda Pharmaceuticals International Research Scholar Award in Neurogastroenterology. M.D.G. is supported by grant NS15547 from the NIH and the Einhorn Family Charitable Trust.

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The authors contributed equally to the review.

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Correspondence to Michael D. Gershon.

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Rao, M., Gershon, M. The bowel and beyond: the enteric nervous system in neurological disorders. Nat Rev Gastroenterol Hepatol 13, 517–528 (2016).

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