The Enteric nervous system (ENS)

There are more neurones in the ENS than there are in the spinal cord, about 10 8 ! The system is immensely complex, and until recently has been neglected. For over one hundred years we have known of the existence of peristalsis in the gut, and how control seems intrinsic --- even if all neural connections are cut, the peristaltic reflex persists! The ENS is responsible for all of the fairly complex behaviour of the bowel --- propulsive peristaltic movement, and various movements that result in mixing. Note that the ENS also regulates intestinal blood supply, and mucosal epithelial water and electrolyte transport . There is also probably complex interplay between the ENS and the immune system. It has only been recently that we've begun to tease out the various ENS components and their function. We're still very ignorant, but have begun to identify some of the basics. The two major functional components are:

  1. The myenteric plexus (of Auerbach) is large, and as the name suggests, lurks within the muscle layers of the bowel's muscularis externa. It's found throughout the gastrointestinal tract.
  2. Smaller is the submucosal plexus (of Meissner). Motor fibres from the submucosal plexus pass to epithelial crypt cells where they stimulate secretion. There are additional connections coming into the submucosal plexus from the myenteric plexus. The stomach and oesophagus lack a submucosal plexus.

There are surprising similarities between the enteric nervous system and the central nervous system, so much so that the ENS has been called the "second brain". Particularly important are glial cells associated with the ENS. Enteric glia wrap around and support entire bundles of axons originating from enteric nerves. Surprisingly , Lewy bodies are seen in the bowel of patients with Parkinson's disease, and amyloid plaques together with neurofibrillary tangles, characteristic of Alzheimer's disease, are frequently encountered in the bowel of patients with that disorder. (This raises the possibility that eventually, we might diagnose Alzheimer's using bowel biopsy)! Damage to glial cells is seen in necrotizing enterocolitis and also Crohn's disease, and may have devastating consequences.

Enteric pacemakers

The interstitial cell of Cajal (ICC) is not neural or glial, but a cell that is something in between, vitally mediating neurotransmission from nerves to bowel smooth muscle cells. (As usual, Ramón y Cajal got it right 100 years before anyone else). The ICC is however, even more important than this, as it acts as the intrinsic pacemaker (or set of pacemakers) of the bowel. We now have good models in animals where failure of appropriate developmental stimulation of the ICC results in marked bowel dysfunction.

The ICC is a temperamental little cell, whose differentiation is controlled by stimulation of a cell-surface receptor called Kit . Kit is a tyrosine kinase receptor, coded for by c-kit gene, and it's expression on ICC is so characteristic, it can be used to identify them. The ligand for Kit receptors is said to be "stem cell factor". [QV] When Kit signalling is blocked, as is seen in experimental animals (the "white spotting" and "steel" mutant mice), the ICC re-differentiates into a "smooth muscle like phenotype", which causes profound bowel hypomotility

Enteric ganglia, and neurotransmitters

Both plexuses have ganglia which are complex amalgamations of neurones which utilise a wide variety of neurotransmitters (about 30)! One of the main neurotransmitters in the ENS has been identified as serotonin. Particularly rich in serotonin are the enterochromaffin cells of the GIT mucosa. These cells appear to be mechanosensitive, and may well mediate a lot of the peristaltic reflexes of the GIT. Stimulation of 5HT3 and 5HT4 receptors initiates peristalsis and facilitates secretion in the GIT.

Of practical relevance is the importance of serotonin in emesis. Gershon well describes how stimuli such as chemo- or radio-therapy provoke serotonin release which stimulates 5HT3 receptors, mediating nausea and vomiting. This explains the potent anti-emetic worth of specific 5HT3 receptor blockers like ondansetron.

Of interest is the rapid re-uptake of serotonin at nerve terminals, limiting its action. This physiology provides a good explanation for the nausea and diarrhoea commonly seen when selective serotonin reuptake inhibitors (SSRI) are used to treat depression.

Ligand-gated ion channels feature prominently. Examples are: nicotinic acetylcholine receptors (nAChRs), P2X receptors, 5-hydroxytryptamine3 (5-HT3) receptors, gamma-aminobutyric acid (GABAA) receptors, N-methyl-d-aspartate (NMDA) receptors,alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and glycine receptors. P2X (ligand is ATP), 5HT3 and nAChRs all participate in fast synaptic transmission ("S-type neurones").

Adenosine A1, 2 and 3 receptors may all be important at various points in the ENS. Neurotrophin-3 may affect motility through its effects on potassium channels (IK1). Oh, and don't forget the mu receptor, important because of the constipating effects of opiates!


Enteric connections

A wide variety of connecting fibres link the ENS and the rest of the nervous system. Vagal connections provide a massive sensory link for "physiological information", while sympathetic unmyelinated C fibres provide sensations of visceral pain. Vagal intramuscular arrays are mechanoreceptors that are intimately associated with the interstitial cells of Cajal.

In addition, vagal motor fibres may modify bowel function through connections to the myenteric plexus, affecting both serotonergic and VIPergic neurones.

Development of the ENS

It's important to understand the embryology of the ENS if one is to begin to understand its function in the adult. ENS neurones come from the neural crest. Precursors migrate from very specific rostral and caudal neural crest sites, starting at the oral and anal ends, and then colonising (heh) their way along.

There are several important regulators of precursor migration:

  • Mash-1 is a transcription regulator which defines the precursors of all serotonergic neurones in the bowel [QV].
  • Peptidergic neurones (e.g. those using CGRP) are independent of Mash-1.
  • The RET receptor is crucial in differentiation of most bowel neurones. Glial cells stimulate these receptors by producing GDNF (glial-cell derived neurotrophin factor). In Hirschsprung's disease (HD), ENS neurones are absent from a section of the bowel, usually the sigmoid colon and rectum, but longer and shorter variants are well-characterised. The disorder is common, occurring once in about 5000 live births, and about half of the cases of Hirschsprung's are thought to be related to abnormalities of RET signalling.
    RET signalling requires co-receptors to work, the GFR-alpha family of receptors, but they do not seem to be very important in HD. It's fascinating that distinct mutations in the RET gene result in not only HD, but also in multiple endocrine neoplasia type II
  • Other gene abnormalities also result in HD. Absence of expression of endothelin-3 (ET3) is another cause Hirschsprung's. Lack of this peptide results in precursor cells of enteric nerves prematurely differentiating before they manage to spread distally to the colon! The ET3 receptor is called ET B .
  • Knock-out of other genes (such as laminin-1) too, may result in Hirschsprung's.
  • A variety of other molecules (such as netrins and semaphorins) may guide migrating nerve cell precursors through the developing bowel.

Clinical conditions affecting the ENS

All diseases with an `autonomic component' may alter function in the ENS. In addition, as already mentioned, "central nervous system" diseases such as Parkinson's and Alzheimers also affect the bowel. Of particular importance are:

  1. Diabetic autonomic neuropathy, which results in profound gastroparesis ("autovagotomy") as well as colonic movement disorders (notably nocturnal diarrhoea).
  2. Infectious diarrhoea!
  3. Scleroderma
... but a variety of other disorders may have ENS dysfunction as a component. These include:
  • amyloidosis;
  • porphyria;
  • mitochondrial cytopathies;
  • Chagas disease;
  • "intestinal pseudo-obstruction";
  • Post-infectious irritable bowel syndrome (with e.g. Campylobacter infection);
  • Domoic acid (seafood) poisoning

Bibliography and Further Reading

(Many references are contained as a subtext within the HTML of the above article)

  1. The Enteric Nervous System: A Second Brain MICHAEL D. GERSHON Columbia University


  3. Pediatric and Developmental Pathology 5, 224–247, 2002 Enteric Nervous System: Development and Developmental Disturbances—Part 1 NEWGREEN D, and YOUNG HM. (PDF)

  4. Check out:

  5. N Engl J Med. 1996 Apr 25;334(17):1106-15