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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 gutbrain axis of disease is reasonably new, concepts are changing rapidly, and further investigation is much needed Abstract The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS)