Enteric Neurons

The enteric nervous system (ENS) consists of interconnected networks of neurons and glia organised into ganglia within distinct plexuses. The myenteric (Auerbach’s) plexus lies between the longitudinal and circular muscle layers. The submucosal plexus, located in the submucosa, can be further subdivided into outer (Meissner’s) and inner (Henle’s) submucosal plexuses in humans, with Henle’s plexus situated most closely to the mucosa.

Enteric neurons are a diverse population that are as complex as those found in central nervous system (CNS) regions. However, unlike the clear spatial segregation of functional classes of neurons in the CNS, enteric neuronal subtypes within the ENS exhibit a mixed functional organisation along the intestinal length, with multiple different subtypes often found within a single enteric ganglion. Broadly, 10–15 myenteric and 4–5 submucosal neuronal classes have been described across species, based upon their combined morphology, electrophysiology, connectivity, and neurochemical coding (Furness et al., 2026).

Morphologically, neurons are classically divided into Dogiel types I–III. Dogiel type I neurons are mono-axonal, stellate cells and include motor neurons and interneurons. Dogiel type II neurons are larger, multi-axonal neurons corresponding to intrinsic primary afferent neurons (IPANs, that are also described as intrinsic sensory neurons), while Dogiel type III neurons exhibit filamentous morphologies with short dendrites confined to the ganglion (Furness, 2007). Additional morphologies (e.g. Dogiel type IV) have also been described, and these include secretomotor and secretomotor/vasodilator submucosal neurons.

Electrophysiologically, enteric neurons are broadly classified as S-type (fast excitatory post-synaptic potentials and monophasic action potentials) or AH-type (prolonged after-hyperpolarisation, AH). S-type behaviour is associated with Dogiel I/III neurons, while AH-type neurons correspond to Dogiel II/IPANs (Furness, 2007).

Neurochemically, enteric neurons are now defined by combinatorial patterns of neurotransmitter(s) or their cognate synthetic enzyme expression.  Predominantly they group into two major classes: cholinergic (ChAT⁺; ~70%, primarily excitatory neurons) and nitrergic (nNOS⁺; ~29%, primarily inhibitory neurons) (Qu et al., 2008). Co-expression of neuropeptides (e.g. VIP, neurokinins, CGRP, NPY) further refines the subtype identity, although a primary neurotransmitter typically determines predominant functional output (Sharkey and Mawe, 2023).

On the basis of the combination of the morphological, electrophysiological and neurochemical characteristics, enteric neurons have been grouped into five major functional classes:

• Motor neurons (excitatory cholinergic or inhibitory nitrergic) that regulate smooth muscle contraction/relaxation.
• IPANs (Dogiel II, AH-type) that act as chemo- and mechanosensors of luminal contents and paracrine agents e.g. 5-HT released from enterochromaffin cells.
• Interneurons (ascending or descending) that coordinate reflex circuits, enabling peristalsis.
• Intestinofugal neurons that project to sympathetic paravertebral ganglia, mediating long-range reflexes that regulate the passage of the intestinal contents in a proximal to distal direction.
• Secretomotor/vasodilator neurons that regulate epithelial secretion and blood flow.

Recent single-cell transcriptomic studies (Zeisel et al., 2018; Drokhlyansky et al., 2020; Morarach et al., 2020; Elmentaite et al., 2021; Fawkner-Corbett et al., 2021; May-Zhang et al., 2021; Wright et al., 2021) have profiled enteric neurons based on their molecular signatures, in different species, developmental stages and gut regions, revealing a conserved subtype-specific transcription factor code that arises during development, and includes cholinergic-associated (Bnc2, Casz1) and nitrergic-associated (Etv1, Ebf1) programmes. While this core transcriptional signature is conserved in humans, there are notable differences in gene co-expression that indicate species-specific specialisation within the ENS (e.g. LEPR and TPH2 expression in human, but not mouse, mouse IPANs are Nmu+ Klhl1+, but human IPANs are NMU+ only) (Drokhlyansky et al., 2020; May-Zhang et al., 2021).

Additionally, enteric neuronal composition varies along the gastrointestinal tract length. While major functional classes are conserved, their proportions, connectivity, and neurochemical coding differ between regions (e.g. stomach vs small intestine vs colon) (Karaosmanoglu et al., 1996; Sang and Young, 1996, 1998). Transcriptomic studies further reveal region-specific gene expression signatures that are conserved across species (colon-restricted expression of Pou3f3) (Obata et al., 2020; May-Zhang et al., 2021; Wright et al., 2021), suggesting molecular specialisations that may underlie segment-specific functions and differential susceptibility to disorders such as achalasia or colonic dysmotility. Other regional differences include the enrichment of Cckar in duodenal neurons (May-Zhang et al., 2021), and the enrichment of glutamate receptor in ileal neurons (Drokhlyansky et al., 2020). However, linking transcriptional identity to the precise functional circuitry remains a key current challenge in the field.

Text authored by Maryam Rahim¹, Fränze Progatzky², Helen Cox³

¹ Hong lab, UKDRI at UCL, ² The Kennedy Institute of Rheumatology, University of Oxford, ³ Wolfson Sensory Pain and Regeneration Centre (SPaRC), King’s College London

References

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