The thoughtful bowel

The lay public, who are not scientists, often harbour false impressions of people who make their living from science. Some, reared on fanciful stories of science fiction and fairy tales, view scientists as magicians, witches or wizards who devote much, if not all of their thoughts to subjects that could benefit from some good healthy suppression. Others regard scientists as the essence of staid, masters of the mundane, people who are constitutively incapable of thinking imaginatively. Those of us who are scientists and know the profession well realize that both of these prevailing views are wrong. It is true that scientists, who recoil at being considered individuals who do anything with magic, have such a healthy respect for evidence that they can appear to the unknowing to be aloof. Even a cursory view of the many hypotheses that scientists have put forward and tested over the years, however, makes it clear that imagination is as alive and well in the minds of scientists as in those of poets, novelists and other purveyors of ideas. The recent article, “To learn, to remember, to forget—how smart is the gut?”¹ is a beautiful example, not only of the fact that scientists can be imaginative, but also that they can write imaginatively. The article is an engaging and provocative review of the question of whether the enteric nervous system (ENS) is capable of learning and memory. Obviously, given the scientific requirement that conclusions be based on facts and evidence, this question cannot yet be definitively answered; nevertheless, the authors have used impressive imagination to formulate a rich trove of hypotheses for fellow neurogastroenterologists to test.

The authors begin with a trenchant overview of how to define learning, covering both classical (Pavlovian) and operant conditioning. They then give illustrations of the primitive organisms, with and even without nervous systems, that are capable of at least rudimentary manifestations of learning. These considerations are used to contrast strikingly with the formidable size and complexity of the mammalian ENS, which is unparalleled outside of the brain and spinal cord. The ENS also has the unique ability to control the behaviour of its organ, the gut, without input from the central nervous system. In fact, it was the independence of the ENS that originally led me to call it “The Second Brain” in my book with that title.² The authors look at the ability of the ENS to function independently and its level of complexity and take the concept to the logical, but currently not provable, next level and ask openly whether the ENS can learn, remember and forget.

Unfortunately, as the words learn, remember and forget are commonly understood, the authors cannot, on the basis of currently ascertained evidence, tell us whether or not the gut actually does those things. There is a clear implication in their writing, floating unsaid above many relevant disclaimers and calls for critical additional research, that the authors believe deep down in their own guts that the answers to all three questions are positive. The authors, however, remain true to the scientific method, and they make no attempt to be sensationalistic. This is, to be sure, a review that is designed to engage the ever-dubious impulses of their colleagues, but it does so in the most useful of ways, it challenges them to carry out studies to determine whether or not the various hypotheses the authors suggest might be correct are right or wrong. Nothing in science is better than that: assert nothing but suggest everything and put it all out for testing.

The authors present a great deal of evidence that the neuroscientific substrates of learning and adaptation are present in the ENS. There is evidence for at least relatively long-term alterations of responses of the small intestine to stretching, of the stomach to distension and, in general, of enteric reflexes to conditioning. Synaptic plasticity occurs, moreover, particularly in the context of inflammation, which alters the patterns of intestinal behaviour, often persistently, although we do not yet know whether synaptic plasticity in the ENS is responsible for the conditioning of enteric reflexes. Enteric neurons manifest long-term potentiation in the form of sustained slow postsynaptic excitation (SSPE), which is not exactly identical to hippocampal long-term potentiation, but with the exception of the frequency of impulses needed to evoke the phenomenon is pretty close to the same thing. The ENS does not segregate its neurons by function into defined nuclei like those of the CNS, which makes it hard to find defined enteric pathways to stimulate. The ENS is thus relatively resistant to easily defined experiments. Still, the substrates are there and await verification of learning and memory by clever experimentalists.

Recent publications have complicated the already difficult questions that the authors have posed. It has become clear that the old idea that enteric neurons last for a lifetime has to be modified. There is, instead, a dynamic cycle of life among enteric neurons,³ which turn over, even in adults, at a rate that has been proposed to be nothing short of astonishing.⁴ Something close to 4% of enteric neurons have been reported to be lost every day, and about 88% of the ENS may be lost every two weeks. This astounding rate of disappearance of neurons is balanced by an equivalently robust rate of replacement through neurogenesis. Enteric neurogenesis can be driven, as the authors acknowledge for neurite extension, by serotonin acting on 5-HT₄ receptors.^5–7 It can also be driven through 5-HT by the enteric microbiome.⁸ Mucosal 5-HT is essential for neuroprotection during the early phase of neurogenesis, while enteric neuronal 5-HT, again via an action on 5-HT₄ receptors, is critical for the occurrence of microbiome-stimulated neurogenesis. New neurons are generated from precursors that may be enteric glia⁹ or may be a retained population of intra-⁴ or extraganglionic⁵ neural crest-derived progenitors. The concept that there is a rapid replacement of enteric neurons seems at first glance to be hard to reconcile with the idea that the ENS has circuits that can cope with phenomena as complex as learning and memory. On the other hand, maybe the two ideas are not as disjointed as they seem. Learning, memory and forgetting require a high degree of plasticity in the ENS, and the authors cite evidence that shows that the ENS is plastic. The dynamic cycle of life in the ENS also requires that the ENS be plastic. In fact, it may be super plastic. Whatever turns out in the end to be the case, it certainly is true that the authors, who probably intended to be provocative, have succeeded in being so. More importantly, they may have been prescient.