The enteric nervous system (ENS)—also called “our second brain”—is an autonomous part of the nervous system consisting of in the myenteric and submucosal plexus within the wall of the gastrointestinal tract. Comprising primary afferent neurons, interneurons and motor neurons, alongside intestinal cells involved in immune responses and endocrine and paracrine functions, it is involved in the sensory-motor control of the gut, local blood flow, cell proliferation, mucosal transport and modulation of immune and endocrine functions.

A new review article, led by Dr. Michael Schemann from the Technical University of Munich in collaboration with Dr. Thomas Frieling from Helios Clinic Krefeld, Germany, and myself, updates learning and memory processes that take place in the gut. The paper is accompanied by an editorial from Michael Gershon from Columbia University, New York.

Both the belly brain and the head brain involve complex neural networks. However, when considering the case of Hydra, for instance, which only has enteric neurons and no central nervous system, it can be implied that the belly brain came first, with the head brain developing later.

In general, however, the enteric and central nervous systems constantly interact and, apart from the gastrointestinal tract, other simpler biological systems are also able to learn and remember under environmental stimulus. These include plants and monocellular organisms such as slime mould.

In the review, we discussed evidence of the gut’s ability to learn behaviors, which implies that the ENS acts like a little brain in the gut. Evidence that supports the existence of implicit learning in the ENS includes:

  • Synaptic plasticity and structural changes: habituation, dishabituation and sensitization related to decreased neurotransmitter release and enhanced synaptic strength reported in Aplysia—a species of sea slug often used for exploring molecular mechanisms in neuroscience research—also apply to the ENS. Furthermore, the enhanced gut response to repeated stimulus shows that gut reflexes may be conditioned at least in the short term, which can be explained either by synaptic plasticity or the involvement of sensitized sensors.
  • Altered neuronal sensitivity: a sustained slow postsynaptic excitation in specific neurons from the ENS may explain how our second brain adapts in the context of physiological digestive needs or pathological conditions.
  • Long-term memory in the gut after an inflammatory insult or extra-intestinal stress stimulus: an inflammatory insult (e.g. chemical-induced colitis) or extra-intestinal stress can drive motor gut dysfunctions that persist in the long term, even when the intestinal segments remain isolated after stimulus application.

Altogether, these findings show that synaptic plasticity in the ENS network of sensory neurons, interneurons and motor neurons exists and can be maintained over time even after the original stimulus is removed.

Although simple ways of learning occur in the gut, however, there is no evidence for explicit learning in this area.

The possibility of memory formation and alterations in the gut open up new ways of exploring altered gut behavior under pathological conditions. For instance, in the last part of the review, we discussed how an altered memory in the ENS might explain the onset of certain gut disorders. This is the case of gut motility disorders such as post-infectious irritable bowel syndrome or functional dyspepsia, which can have their roots in an altered postsynaptic sensitization and desensitization or hyporesponsiveness to synaptic activation.

In conclusion, our hypothesis that the ENS within the gastrointestinal tract is able to learn behaviors is plausible. Scientific evidence that supports this includes synaptic plasticity and structural changes in response to conditioned stimulus, altered neuronal sensitivity under physiological needs or pathological conditions and long-term memory in the gut after an inflammatory insult or extra-intestinal stress stimulus.

Studies are urgently needed to explore whether the gut’s ability to learn behaviors as described persists in the long term and to what extent we can re-program the way the ENS processes information to better manage disorders involving the head and/or belly brain that we do not currently know how to cure.

 

References:

Schemann M, Frieling T, Enck P. To learn, to remember, to forget—How smart is the gut? Acta Physiol (Oxf). 2019; e13296. doi: 10.1111/apha.13296.

Gershon MD. The thoughtful bowel. Acta Physiol (Oxf). 2019; e13331. doi: 10.1111/apha.13331.

Paul Enck
Paul Enck
Prof. Dr. Paul Enck, Director of Research, Dept. of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Germany. His main interests are gut functions in health and disease, including functional and inflammatory bowel disorders, the role of the gut microbiota, regulation of eating and food intake and its disorders, of nausea, vomiting and motion sickness, and the psychophysiology and neurobiology of the placebo response, with specific emphasis on age and gender contributions. He has published more than 170 original data paper in scientific, peer-reviewed journals, and more than 250 book chapters and review articles. He is board member/treasurer of the European Society of Neurogastroenterology and Motility and of the German Society of Neurogastroenterology and Motility, and has served as reviewer for many international journals and grant agencies.