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.

Fig. 1 |. Main populations of enteric glia and their known physiological functions.

Local subpopulations of glia are defined based on their morphology, anatomical location throughout the intestinal wall, and localization either within or outside of enteric ganglia. Based on these criteria, at least six main types of enteric glia are identified in any given region of the intestine: intraganglionic glia, including glia associated with neuronal cell bodies in the myenteric and submucosal plexuses (myenteric glia or Type-I_MP and submucosal glia or Type-I_SMP, on the top right and left, respectively); interganglionic glia, located within nerve fibre bundles connecting myenteric ganglia (Type-II); extraganglionic glia, including glia associated with nerve fibres at the myenteric and submucosal plexus but outside the ganglia (Type-III_MP/SMP) and in the intestinal mucosa (mucosal glia or Type-III_mucosa, bottom left); and glia associated with nerve fibres in the circular and longitudinal muscle layers (intramuscular glia or Type-IV, bottom right). Known functions of each subtype are listed beside each representative image.

Fig. 2 |. Transcriptionally distinct glial subsets in the adult enteric nervous system.

Distinct subsets of enteric glia display unique transcriptional profiles in the enteric nervous system. Data from single-cell sequencing experiments indicate the presence of distinct glial populations that vary according to location along the gastrointestinal tract and species. The mouse ileum exhibits seven glial populations according to data from Zeisel et al. (part a) and two glial subpopulations according to data from Drokhlyansky et al. (part b). The mouse colon displays three glial subsets according to data from Drokhlyansky et al. (part c) and the human colon displays six glial subsets (part d; also data from Drokhlyansky et al.). tSNE, t-distributed stochastic neighbour embedding. Part a was adapted from REF., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Parts b–d were adapted with permission from REF., Elsevier.

Fig. 3 |. Mechanisms of bidirectional communication between enteric neurons and glia in enteric circuits.

a | Enteric glia surround neurons in the myenteric and submucosal plexuses and are associated with nerve fibres in the mucosa. b | Glial Ca²⁺ responses are evoked in the myenteric plexus by neurotransmitters such as acetylcholine (ACh) and ATP, which, in turn, induce the release of gliotransmitters such as ATP and GABA through membrane channels composed of connexin 43 (Cx43) and/or through the reversal of neurotransmitter transporters (such as GABA transporter 2 or GAT2). These gliotransmitters act on receptors expressed by excitatory and inhibitory neurons to exert reciprocal effects on enteric neural circuits that control the intestinal motility. EEC, enteroendocrine cells; eNTPDase, ectonucleoside triphosphate diphosphohydrolase 2; NO, nitric oxide; SP, substance P; VIP, vasoactive intestinal peptide.

Fig. 4 |. Intercellular glial signalling mechanisms that contribute to neuroplasticity during gastrointestinal inflammation.

a | Reactive enteric gliosis is a protective response to potentially harmful stimuli. Reactive enteric glia contribute to functional abnormalities that underlie both functional and organic gastrointestinal disorders by promoting neuronal plasticity. b | Enteric glial signalling mechanisms active during acute inflammatory responses. Enteric reactive gliosis may be driven by adenosine triphosphate (ATP) release via pannexin 1 channels from enteric neurons intensively stimulated by neuronal mediators, such as neurokinin A (NKA), substance P (SP) or ATP. A self-perpetuating process derives from the activation of P2Y1Rs in the surrounding glial cells and their release of ATP through connexin 43 (Cx43) hemichannels. ATP released by glia drives P2X7R-mediated neuroinflammation and nociceptive neuron activation, likely via P2X3Rs. Glial activation also mediates the Cx43-dependent release of macrophage colony-stimulating factor (M-CSF) and other mediators that potentially regulate the activation of muscularis macrophages and visceral sensitivity in intestinal inflammation. Pro-inflammatory signals, such as S100β, IL-1β and bacterial products, increase the release of nitric oxide (NO) and other inflammatory signals via NF-κB that directly or indirectly affect the normal glia–neuron purinergic signalling and/or neuronal sensitivity through actions on local immune responses. eNTPDase, ectonucleoside triphosphate diphosphohydrolase 2; GDNF, glial cell-derived neurotrophic factor; LPS, lipopolysaccharide.