Our Sensitive Stomach: The Enteric Nervous System

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Mankind gets some of its best thinking done while engaging the enteric nervous system. [1]

[En español] Inside every person’s gut there lies about 500,000,000 neurons. That might seem like an odd place for so many so-called “brain cells;” even odder still, the bowel’s web of nerves can function in the absence of communication to or from the brain. Its potential for independence and substantial cell count have earned the intestinal nerves a nickname – the “second brain,” – which while not entirely accurate, rolls off the tongue better than its scientific nomenclature: the enteric nervous system (or ENS).

The physical location of the enteric nervous system can spur some misunderstanding – it is not actually some seed of visceral intuition or “gut feelings.” Still, recent discoveries have suggested an interesting role for our “second brain” in regulating our mood based on the health of our guts. And while less evocative than housing a mind of its own, what we do know is that the enteric nervous system commands indispensable undertakings for the maintenance of bodily health, by ensuring food gets appropriately processed and that what goes in ultimately comes out.

     There is a lot more to the gut than will be covered here – hormone signals, the microbiome, and gut contributions to nervous system diseases will be topics for later articles. Worry not – these functions are not forgotten, but for the ease of digestion (sorry) and clarity of each topic, will be segmented into individual parts of a series exploring Our Sensitive Stomachs.

So what is the Enteric Nervous System?

     All of the 500 million neurons that make up the enteric nervous system fall into one of three categories typical of nervous structures outside the brain: sensory neurons, motor neurons, and interneurons. Most simply put, these sensory neurons detect the gut’s environment (pressure, acidity, chemical makeup), motor neurons control gut movements (moving food and waste through the intestines), and interneurons connect sensory and motor neurons (and other interneurons) together to form a neuronal network primed to both detect and initiate changes within our bowels [2]

      The second brain is less like an extra soul than a tightly woven matrix of sensation and movement. Yet with all this sensing and moving, if I asked you right now to pinpoint where and how far today’s breakfast has travelled through your intestines, I’d wager you would be unable to identify the exact location of your toast and orange juice. For while these enteric sensory and motor neurons are similar in structure and function to the more familiar ones in our hands and feet, our brain has little-to-no conscious contact with their activity.

To help illustrate how this works, let’s take a look at my favorite neural circuit – the knee jerk reflex.

Reflex Circuits

To instigate this reflexive kick, the doctor uses a small rubber mallet and taps the relaxed patellar tendon just below the knee cap (patella) which, in a healthy patient, results in an instantaneous kick from that same knee. Those of us who have had this procedure know the kick happens very quickly, and without any conscious decision to even make the kick. Physiologically, once the mallet strikes, the reflexive kick comes without consulting the brain; in fact, the kick begins before the brain is even aware of it.

      This is an example of one of the simplest neural circuits in our body. A sensory neuron detects the patellar tendon’s sudden stretch and directly alerts a spinal cord motor neuron that controls the nearby quadriceps femoris muscle, contracting it: causing a kick (that sensory neuron also contacts an interneuron that then inhibits the antagonistic hamstring muscle, relaxing the back of the leg and allowing the quad to strike the leg forward).

By hitting just below the knee, the doctor stretches the patellar tendon. This is detected by a sensory neuron that takes the information back to the spinal cord. It innervates one motor neuron in the spinal cord that then contracts the quadricep. It also contactss an interneuron, which inhibits another motor neuron to relax the antagonistic hamstring muscle.

In essence, this is how the enteric nervous system is functioning. Sensory neurons detect the status of the intestinal tract, signal to nearby interneurons, and interneurons excite or inhibit local motor neurons that control intestinal movement. And though in the case of our doctor’s office visit we do eventually recognize the hit to the knee, information about our gut’s environment is only sparsely sent to the brain, and only sparsely available for conscious consideration.

      So while not as sophisticated or diverse in function as the brain proper, tucked away in our abdomens lies an impressive neuronal computational affair, coordinating half a billion neurons and their connections behind the scenes. Evolution found this orchestration needn’t concern our stream of consciousness, freeing up our conscious mind to consider in its stead other important questions – like what to eat – without having to worry (too much) about what happens downstream. But how the ENS interacts with our affect (mood or “feelings”), on the other hand, is another question in itself that is only starting to be asked or answered.

Gut Feelings?

      Emotional processing seems to be restricted to the brain – the whole body might contribute to overall feelings of well-being, but ultimately these signals are interpreted in the brain. But it is certainly the case that some emotions can evoke strong bodily sensations, like a “lump in the throat,” a “sinking feeling,” or “butterflies” in your stomach. 

A study asked participants to select on a computer screen where in their body they feel different emotions. A heatmap of all responses is shown above [3]. While taken from an actual interesting study, this image doesn’t actually relate to the enteric nervous system but I thought it was too cool to keep to myself.

      Sometimes these do culminate in a sort of weight or tingling just below the heart and above the belly – roughly at the stomach, which is likely the source of the phrases “gut feeling,” “gut instinct,” or “going with your gut.” Why different emotions have different bodily coordinates, and why and how these vary between people is a question still being pondered and explored experimentally, without yet yielding much in the way of concrete answers. And while an interesting question, the explanation seems likely to lie outside enteric nervous processes.    


     What recent research shows the enteric nervous system might do is perhaps the most interesting, and for the future of medicine, most important topic to discuss. So let’s revisit a point made in the introduction – the “brain-like” independence of the gut nervous system.

     While able to fulfill some functions without the brain, the central nervous system (CNS) and ENS do communicate through a specialized nerve called the vagus nerve. Unlike most nerves that interact below the neck, the vagus nerve extends directly from the base of the brain stem down through the body, without routing through the spinal cord. Where skin sensory neurons and skeletal muscle motor neurons bundle their signals through the spinal cord, the vagus nerve provides a direct conduit between the organs within the abdomen and the brain [4]

    When the vagus nerve is severed, the enteric nervous system continues to move food and waste along the many meters of intestinal tract. This is what has been ascribed ENS “independence” – without input from the brain, the reflex circuits of the ENS can continue basic digestive processes. Unfortunately, “basic digestive processes” does not include functions like actually breaking down food with pancreatic enzymes, or exerting conscious control over when and where to defecate. So, sure, then the ENS can function independently of the brain, but I think most of us would opt to keep that vagus nerve intact. Especially given some of the findings that are beginning to crop up around the gut, the vagus nerve, and our overall sense of well-being – our mood.

What Happens in Vagus

     Mood is an incredibly complex topic, and while science is still trying to figure out just what mood is and precisely how it is regulated, at this point it is almost common knowledge that mood is influenced in part by the action of different neurotransmitter circuits in the brain – most notably dopamine, serotonin, and norepinephrine. What is less known is that the enteric nervous system is one of the (if not the absolute) largest collections of dopamine-, serotonin-, and norephinephrine-responsive neurons – as many as 90% of all serotonergic neurons in a given person take residence in the gut. Furthermore, vagus nerve fibers sent to the brain from the gut act via dopamine, serotonin, and norepinephrine signals, and have been shown to directly activate reward pathways and satiety in mouse experiments [5].

     Dopamine, serotonin, and norepinephrine all belong to a class of neurotransmitters referred to as “neuromodulators” – that is, their action is often not to fully excite or fully inhibit specific neurons, like glutamate or GABA, but to broadly bias or modulate large populations of neurons to be more receptive to excitatory or inhibitory signals. If you think of a single neuron firing as a pot of water, it will take a certain amount of heat (excitation) to cause it to boil (fire). The heat required (excitatory neurotransmitter) to bring it to a boil depends on the temperature where it starts (neuronal resting potential). One way to rapidly decrease the temperature and prevent boiling would be to drop in cubes of ice (inhibitory neurotransmitter). But instead of dropping ice cubes in one pot of water, what if you just raised or lowered the temperature of the whole room that holds many pots of water? A room that sits at 95° thus has water in it sitting at 95°, and will take less additional heat energy to boil any one pot than an otherwise identical room sitting at 35°. In this analogy, dopamine, serotonin, and norepinephrine tune the temperature of different rooms (or brain regions), changing the impact of turning on the burner or dropping ice into any single pot (or neuron).

      This neuromodulatory activity is so strong that vagus nerve stimulation (VNS) has been used for decades to treat epilepsy, where direct electrical stimulation of the vagus nerve adjusts aberrant brain signals sufficiently to markedly reduce the occurrence of seizures in epileptic patients. Researchers suspected the same action might modulate mood – that broadly releasing dopamine, serotonin, and/or norepinephrine from the vagus nerve into the brain might alter feelings of anxiety or depression. A wealth of VNS experiments have been conducted in rodents, repeatedly showing therapeutic reduction of readouts for anxiety and depression. In humans, a clinical trial was run on patients diagnosed as currently being in a Major Depressive Episode (MDE), where it was found that 30-37% of patients who received VNS demonstrated decreased depressive symptoms after 8 weeks of daily stimulation [6]. Evidence like this and others for vagus contributions to mood are now accepted to the extent that VNS has actually been FDA approved [7] for use in patients with treatment-resistant depression, but used sparingly due to some of its side effects.

A young Dr. Frankenstein uses Vagus Nerve Stimulation (VNS) in an attempt to cure his monster of the existential dread endemic to the human condition.

 To Be Continued…

     Research has therefore drawn a clear link between electrical stimulation of the nerve fiber that connects the central and enteric nervous systems – the vagus nerve – and mood. But what, under normal circumstances, might the ENS detect that is worth influencing our sense of well-being? How strong is this effect, and how might it be impacted by diet? And can we impact this circuitry to effect mood without the side effects of VNS (or, do we already target the ENS with mood medications? Selective serotonin-reuptake inhibitors (SSRIs) are a major class of antidepressant that act directly on serotonergic neurons, and ~90% of serotonergic neurons are in the gut!)? The link between digestive health and mood is still an ongoing field of research, with promising findings coming especially from investigations into the gut microbiome – a topic to be discussed in a later Neuwrite SD article.

      For now, we have built a foundational understanding of what the enteric nervous system is, what it is not, and what it might be. It has a clear, pivotal role in digestion; no discernible role in “gut instincts;” and an exciting but thus far elusive role in modulating mood. We, or at least I, may be convinced “second brain” is not the greatest (or even an accurate) nickname, despite the still impressive tasks within the ENS’s domain. While it is not one of the hottest topics in neuroscience, I personally find the enteric nervous system fascinating, and look forward to a deeper dive into the inner workings of our guts in future Neuwrite articles!


[1] Image By Mgmoscatello – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=33597049

[2] Furness JB, Callaghan BP, Rivera LR, Cho H-J. The Enteric Nervous System and Gastrointestinal Innervation: Integrated Local and Central Control. In: Advances in Experimental Medicine and Biology. Vol 817. ; 2014:39-71. doi:10.1007/978-1-4939-0897-4_3

[3] Nummenmaa L, Glerean E, Hari R, Hietanen JK. Bodily maps of emotions. Proc Natl Acad Sci U S A. 2014;111(2):646-651. doi:10.1073/pnas.1321664111

[4] Breit S, Kupferberg A, Rogler G, Hasler G. Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders. Front Psychiatry. 2018;9:44. doi:10.3389/fpsyt.2018.00044

[5] Han W, Tellez LA, Perkins MH, et al. A Neural Circuit for Gut-Induced Reward. Cell. 2018;175(3):665-678.e23. doi:10.1016/j.cell.2018.08.049

[6] Sackeim HA, Rush AJ, George MS, et al. Vagus Nerve Stimulation (VNSTM) for Treatment-Resistant Depression: Efficacy, Side Effects, and Predictors of Outcome. Neuropsychopharmacology. 2001;25(5):713-728. doi:10.1016/S0893-133X(01)00271-8

[7] O’Reardon JP, Cristancho P, Peshek AD. Vagus Nerve Stimulation (VNS) and Treatment of Depression: To the Brainstem and Beyond. Psychiatry (Edgmont). 2006;3(5):54-63. http://www.ncbi.nlm.nih.gov/pubmed/21103178.

[8] Furness J. Enteric nervous system. Scholarpedia. 2007;2(10):4064. doi:10.4249/scholarpedia.4064

[9] Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305-312. doi:10.1016/J.TINS.2013.01.005

[10] Rao M, Gershon MD. The bowel and beyond: the enteric nervous system in neurological disorders. Nat Rev Gastroenterol Hepatol. 2016;13(9):517-528. doi:10.1038/nrgastro.2016.107