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Enteric glial biology, intercellular signalling and roles in gastrointestinal disease

Abstract

One of the most transformative developments in neurogastroenterology is the realization that many functions normally attributed to enteric neurons involve interactions with enteric glial cells: a large population of peripheral neuroglia associated with enteric neurons throughout the gastrointestinal tract. The notion that glial cells function solely as passive support cells has been refuted by compelling evidence that demonstrates that enteric glia are important homeostatic cells of the intestine. Active signalling mechanisms between enteric glia and neurons modulate gastrointestinal reflexes and, in certain circumstances, function to drive neuroinflammatory processes that lead to long-term dysfunction. Bidirectional communication between enteric glia and immune cells contributes to gastrointestinal immune homeostasis, and crosstalk between enteric glia and cancer stem cells regulates tumorigenesis. These neuromodulatory and immunomodulatory roles place enteric glia in a unique position to regulate diverse gastrointestinal disease processes. In this Review, we discuss current concepts regarding enteric glial development, heterogeneity and functional roles in gastrointestinal pathophysiology and pathophysiology, with a focus on interactions with neurons and immune cells. We also present a working model to differentiate glial states based on normal function and disease-induced dysfunctions.

Key points

  • Enteric glia are a heterogeneous population of peripheral neuroglia that regulate homeostasis in the enteric nervous system.

  • Bidirectional communication between enteric glia and neurons modulates intestinal reflexes.

  • Enteric glia are central players in neuroinflammation and contribute to neuroplasticity through interactions with neurons and immune cells.

  • Enteric glia regulate disease processes involved in tumorigenesis and extragastrointestinal diseases.

  • Therapies targeting glial mechanisms, such as gliotransmitter release or signalling pathways that promote gliosis, could substantially advance the treatment of common gastrointestinal diseases.

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Fig. 1: Main populations of enteric glia and their known physiological functions.
Fig. 2: Transcriptionally distinct glial subsets in the adult enteric nervous system.
Fig. 3: Mechanisms of bidirectional communication between enteric neurons and glia in enteric circuits.
Fig. 4: Intercellular glial signalling mechanisms that contribute to neuroplasticity during gastrointestinal inflammation.

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Acknowledgements

B.D.G. receives support from grants R01DK103723 and R01DK120862 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The content is solely the responsibility of the Authors and does not necessarily represent the official views of the National Institutes of Health.

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Seguella, L., Gulbransen, B.D. Enteric glial biology, intercellular signalling and roles in gastrointestinal disease. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00423-7

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