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Disorders of the enteric nervous system — a holistic view

Nature Reviews Gastroenterology & Hepatology volume 18, pages 393–410 (2021)Cite this article

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Abstract

The enteric nervous system (ENS) is the largest division of the peripheral nervous system and closely resembles components and functions of the central nervous system. Although the central role of the ENS in congenital enteric neuropathic disorders, including Hirschsprung disease and inflammatory and functional bowel diseases, is well acknowledged, its role in systemic diseases is less understood. Evidence of a disordered ENS has accumulated in neurodegenerative diseases ranging from amyotrophic lateral sclerosis, Alzheimer disease and multiple sclerosis to Parkinson disease as well as neurodevelopmental disorders such as autism. The ENS is a key modulator of gut barrier function and a regulator of enteric homeostasis. A ‘leaky gut’ represents the gateway for bacterial and toxin translocation that might initiate downstream processes. Data indicate that changes in the gut microbiome acting in concert with the individual genetic background can modify the ENS, central nervous system and the immune system, impair barrier function, and contribute to various disorders such as irritable bowel syndrome, inflammatory bowel disease or neurodegeneration. Here, we summarize the current knowledge on the role of the ENS in gastrointestinal and systemic diseases, highlighting its interaction with various key players involved in shaping the phenotypes. Finally, current flaws and pitfalls related to ENS research in addition to future perspectives are also addressed.

Key points

  • As a potent modulator of gut barrier function and enteric homeostasis, the enteric nervous system (ENS) is a key player in disease pathogenesis.

  • The role of the ENS in human health and disease has largely been neglected and gastrointestinal symptoms have been overlooked.

  • In addition to a role in classical enteric neuropathies, evidence has accumulated regarding the importance of the ENS in cancer, diabetes mellitus, neurodevelopmental disorders and neurodegenerative diseases.

  • Considering ENS-related gastrointestinal symptoms is crucial in the early detection of different diseases, for example Parkinson disease, and early targeted intervention might improve symptoms or even prevent disease.

  • More research applying state of the art tools is needed for a better understanding of ENS-related pathomechanisms.

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Fig. 1: Organization of the ENS in health and disease.
Fig. 2: Extrinsic and intrinsic factors shaping ENS structure and function.
Fig. 3: The ENS and cancer.
Fig. 4: Studying ENS in neurodegeneration/neurodevelopmental disorders.

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Authors and Affiliations

  1. Department of Human Molecular Genetics, University Hospital Heidelberg, Heidelberg, Germany

    Beate Niesler

  2. Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany

    Beate Niesler

  3. Anatomisches Institut/Neuroanatomie, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany

    Stefanie Kuerten

  4. Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany

    I. Ekin Demir

  5. SFB 1321 Modelling and Targeting Pancreatic Cancer, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany

    I. Ekin Demir

  6. Working group Enteric Nervous Systems (AGENS), University of Applied Sciences Kaiserslautern, Kaiserslautern, Germany

    Karl-Herbert Schäfer

  7. Pediatric Surgery Mannheim, University Hospital Mannheim, Mannheim, Germany

    Karl-Herbert Schäfer

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  1. Beate Niesler
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  2. Stefanie Kuerten
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  3. I. Ekin Demir
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  4. Karl-Herbert Schäfer
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B.N. and K.-H.S. developed the concept, designed, wrote, assembled input data and edited the manuscript. B.N., I.E.D. and K.-H.S. created and revised the figures. B.N., S.K., I.E.D. and K.-H.S. reviewed the literature, selected the data and wrote the manuscript, and prepared Table 1. All authors discussed the results and implications and commented on the manuscript at all stages.

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Nature Reviews Gastroenterology & Hepatology thanks P. Derkinderen, K. Nurgali and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Niesler, B., Kuerten, S., Demir, I.E. et al. Disorders of the enteric nervous system — a holistic view. Nat Rev Gastroenterol Hepatol 18, 393–410 (2021). https://doi.org/10.1038/s41575-020-00385-2

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