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The Second Brain, by Michael D. Gershon – Book Notes

My notes taken from the book The Second Brain, by Michael D. Gershon, which concerns the enteric nervous system and the mind-gut connection.

The brain in the gut – the second brain – plays a major role in human happiness and misery—but few people know it exists. Dr. Michael Gershon, co-founder of the neurogastroenterology field, explains why on both counts.

“We all experience situations in which our brains cause our bowels to go into overdrive. But in fact, messages departing the gut outnumber the opposing traffic on the order of about nine to one.” Michael D. Gershon, M.D.


Published in 1998, The Second Brain by Michael Gershon addresses an important and neglected subject within the field biology, and which carries especial significance to medical theory and practice. This subject is the Enteric Nervous System (ENS) – the nervous system of the bowel – and the complex role that it plays in the body. In fact, the ENS displays a complexity of functioning akin to that of the brain—hence “the second brain”.
            Throughout the book, Gershon also reveals how the second (or “lower”) brain has been overshadowed by the first (or “higher”) brain within the science and medical professions, in matters of theory, research, and medical treatment; and his book represents a most substantial effort to redress the balance. Most significantly, Gershon highlights the fact that gut problems are routinely blamed on the brain; that is, on neuroticism of one kind or another—when it has for long been scientifically established that the gut itself – which is, “with respect to intestinal difficulties, right at ground zero” – perfectly capable of causing “enteric havoc” independently of the brain. Indeed, the independent functioning of the gut is stressed throughout this work, illustrated by references to scientific experiments and biological knowledge.
         Although Gershon – who was part-founder of the new medical field called neurogastroenterology – has effectively raised the scientific and medical profile of the enteric nervous system from underserved obscurity, his work still remains both highly relevant and insightful today with regards to the personal and medical implications of a malfunctioning gut.


A Note on the Notes

The Second Brain is a highly technical book of considerable length and biological detail, one certainly not intended for popular readership. The bulk of the text (which includes numerous illustrations) concerns highly specific details that would be of interest only to neurologists and gastroenterologists. However, having recognized the rarity and significance of Gershon’s subject and thesis, I decided to read through the book selectively, scanning the text for the sections and passages that contain details and points that I find to be significant for one reason or another. Having done this, I considered that the resulting notes may be of interest to a fellow layperson who seeks to gain insight into the nature and functioning of the gut; its proper relation to the functioning of the mind; as well as to understand the historically prevalent misunderstanding on this subject.
            The notes I have produced here are formed using the author’s own words, which I have paraphrased only to the extent that was necessary in recombining the extracted sentence fragments into coherent notes. Thus, the important words are all Gershon’s and I have mostly paraphrased around them in the process of transplanting the details from his context, a technical chronicle, to that of my notes, which represents a distillation of information with an emphasis of significant points (including one two emojies! 😀 ) Thus, I have applied italics (i.e. which were not present in the original text) to emphasize key points for the purposes of my own notes, as I find it useful to state more directly certain details and points that the author had presented amidst his narrative of vast detail.
            In terms of arrangement, I have assigned note numbers to each distinct sequence of sentences, which ended at note #41. Alongside the numbers are thematic categories, which should be(come) self-explanatory and which I think will be useful for referencing. I have also emboldened parts of the text within each note, which should enable one to quickly identify the subject(s) and point(s) within that note. Finally, I have included page references to the book at the end of the corresponding passages, so that the original text can be easily referenced alongside these notes (the free digitized copy of the book is included in the links section at the bottom of this article).

Frequent Terms

ANS = Autonomic Nervous System
CNS = Central Nervous System
PNS = Peripheral Nervous System
ENS = Enteric Nervous System
IBS = Irritable Bowel Syndrome
FBD = Functional Bowel Disease
SSRI = Selective Serotonin Reuptake Inhibitor
Bowel and gut are used interchangeably, and occasionally intestine as well.

Notes from The Second Brain


The bowel is the only organ that contains an intrinsic nervous system able to mediate reflexes in complete absence of input from the brain or spinal cord, i.e. the Enteric Nervous System (ENS): Indeed, there are more nerve cells in the gut than in the remainder of the peripheral nervous system; moreover, the gut represents a vast chemical warehouse featuring every class of neurotransmitter found in the brain.
            As neurotransmitters can be thought of as ‘words’ that nerve cells use to communicate with each other and with cells under their control, the ‘language’ of the gut is therefore rich and brain-like in complexity. [page xiii]


No one is enthused when the activities of the gut rise to the level of conscious awareness: there are few things more distressing than an inefficient gut with feeling. [page xiv]

#3 [PROFESSIONAL + Symptomatic]

Over 40% of patients who visit internists do so for gastrointestinal problems, half of which have “functional” complaints; their gut is malfunctioning, but no one knows why. If patients present themselves to doctors with problems that are insoluble, they are perceived as threatening and often dismissed as mentally unbalanced—as examples of neurotic thought processes communicating themselves to the bowel. In other words, physicians respond to such complaints as if the gut is acting up in such a way so as to defy the best that modern medicine has to offer—which in this case, is ignorance compounded by lack of compassion: of the possibility that diseases of the bowel can arise within the gut. [page xiv]


To illustrate the psychological significance of gut functioning, consider that when Descartes concluded that “I think, therefore I am”, it was only because his gut let him; meaning, the brain in the bowel – the “second brain” – must work right in order to retain the otherwise taken-for-granted luxury of thought: no one thinks straight when one’s mind is on the toilet. [page xv]


Scientists’ tendency to hubris stems from inadequate knowledge and appreciation of the past: Thus, “discoveries” are really rediscoveries—not new advances but history lessons. [p2]


The peristaltic reflex (a.k.a. “the law of the intestine”) refers to propulsive movements of a coordinated descending wave of oral contraction and anal relaxation that forces intestinal contents relentlessly and inevitably in an anal direction—and when all nerve-mediated communication between the gut and the CNS (the central nervous system) is cut, the law of the intestine still prevails, i.e. increases in intestinal pressure continue to be followed by the peristaltic reflex.
            This fact indicates the presence of a nervous mechanism of the bowel; and a similar neural apparatus does not exist in any other organ (hence all reflex activity ceases if any other organ is cut off from the CNS). Thus, the intrinsic nervous system of the gut has properties like those of the brain and spinal cord. [p4]


In the ANS (the autonomic nervous system), the autonomic pathway is always interrupted by at least one junction between nerve cells, called a synapse. The autonomic signal from the brain to an effector cell (the target of autonomic nerves) must be carried by two or more nerve cells, whereas to a skeletal muscle only one is required. Hence, the activation of autonomic effectors is infinitely more subtle than that of skeletal muscle in that there is, so to speak, room for shades of gray in the process.
            This subtlety reaches a crescendo in the bowel—which is important with regards to nerves in that it provides for instant adaptation to changing circumstances. [p11]


With regard to parasympathetic and sympathetic responses, their anatomy determines that the former tend to be faster than the latter, which are usually slower and more diffuse. Unfortunately, most people still divide the ANS into two parts, i.e. the parasympathetic and sympathetic divisions—thus ignoring the enteric division. [p13]

#9 [TECHNICAL, Professional]

The number of motor nerve fibres connecting the brain or the spinal cord to the gut is incredibly small relative to the number of nerve cells in the bowel; and most enteric nerve cells are probably not directly connected to the CNS: The ‘voice’ of the brain is certainly heard in the bowel, but not on a direct line to every member of the enteric congregation.
            The enteric differs from the sympathetic and parasympathetic nervous systems in its anatomical and functional independence from the brain and spinal cord—and this separate-but-equal classification still surprises audiences of doctors and even neuroscientists. [p15]


The CNS and PNS (the Peripheral Nervous System) are thoroughly interconnected and work together, but commands flow from the brain to the muscles and glands, and from sensory receptors back to the brain and spine via the PNS. Thus, there is a hierarchy of function and necessary linkage: the brain is at the top while the effectors and sensory receptors are at the bottom. [p16]


The ENS, however, can escape the functional hierarchy between the CNS and PNS: Technically it is part of the PNS, but by definition only, for the ENS does not necessarily follow the commands received from the brain or spinal cord, nor does it inevitably send received information back to them.—The ENS can process data autonomously and act on that basis to activate a set of effectors that it alone controls.
            Thus, the ENS is not a slave to the brain but a contrarian; an independent spirit in the nervous organization of the body—a rebel: it is the only element of the PNS that can elect not to do the bidding of the brain and spinal cord. [p17]

#12 [Technical + PROFESSIONAL]

Langley’s pioneering book The Autonomic Nervous System (1921) is cited as a reference for the binary division of the nervous system—but it specified three divisions: Thus, the work was revised – posthumously, thereby precluding the author’s objection to the revision – in deleting the ENS, which consequently faded from view. [p18]

#13 [Technical, PROFESSIONAL]

Since reflexes still occur after the gut is cut off from the CNS, the vagus and sacral nerves may be totally irrelevant to many behaviours of the bowel. Given these facts, it is not easy to explain why understanding of the ENS went into decline [Gershon goes on to discount willful ignorance of history and established biological truths as being common practise among scientists, as well as conspiracy; and essentially, he suggests that an enchantment with theory (of the binary division) combined with scientists’ characteristic over-attachment to order ensured the professional ignorance of the ENS].
            In any case, the parasympathetic and sympathetic chemical neurotransmitters came to determine all scientific thought about the ANS, which brought about a Dark Ages of enteric neurobiology: Thus, the discovery of chemical neurotransmission served initially to mask knowledge of the second brain. [p19]


Nicotine potently stimulates both sympathetic and parasympathetic post-ganglionic nerve cells. In fact, Langley used nicotine to map out the ANS. [p24]


Receptors can be thought of as ears for chemical words: they are the molecules expressed on cell surfaces that enable cells to respond to signalling substances in their environment; they are present in the membrane of responding cells, and signalling cells bind to them. After they have bound a signalling molecule, the receptors go on to initiate the Rube Goldberg-like “transduction machinery” that converts the binding of the signalling molecule into a physiological event. Drugs and toxins are able to take over the molecular switches that activate cells by mimicking natural signalling molecules and binding to receptors. [p25]


Products are advertised as “all natural” as if that property somehow confers a special blessing upon them—yet some of the deadliest toxins to humankind are “all natural”. [p31]


It is hubris in scientific exploration to criticize works in benefit of hindsight: at least half of what is taught in academia will eventually be proven to have been wrong—and neither teachers nor scientists know which half it will be. Yet, a herd instinct often grips the imaginations of scientists: they are prone to charge off a cliff when a large enough pack of them moves in the right direction (like lemmings), i.e. a theory becomes accepted because it becomes dogma rather than because a good case has been made for it. [p34]

#18 [Technical + PROFESSIONAL]

The serotonin theory – i.e. that the substance plays a critical role in the creation of happiness, or more specifically, that its malfunctioning as a neurotransmitter in the brain causes depression – is still in vogue.
            The scientific suggestion [Gershon’s] that serotonin is an enteric neurotransmitter was based on the following facts: (i) Serotonin is manufactured and stored in the bowel. (ii) Serotonin is preferentially located in enteric nerves (following its biosynthesis from its immediate precursor). (iii) These nerves release serotonin when they are stimulated. (iv) Serotonin exerts the same effect on the bowel as does the stimulation of enteric nerves (as others have previously shown).
            My suggestion that serotonin might be a neurotransmitter in the gut was viewed as outrageous in the scientific world: it contradicted the scientific gospel prevalent at the time, and was considered not just wrong but perverse and immoral. Scientists, you see, admire order more than most people—and the established order left no room for another neurotransmitter: Hence, I was perceived as a heretic for disputing the concept of a ‘beautiful’ duality of the ANS—and I was treated accordingly. [p38, p41]

#19 [TECHNICAL + Therapeutic]

Interneurons are cells that add layers of complexity and sophistication that distinguish the CNS and ENS from the banal peripheral ganglia found outside the bowel. The nerves of the gut do not just slavishly pass signals from sensory receptors to muscles, glands or blood vessels: the ENS can modulate and process the information it receives; and serotonin – as a neurotransmitter of an interneuron – enables the bowel to function as an independent information processing centre.
            Drugs designed to modify the actions of serotonin may be great tools for treating patients whose bowel is malfunctioning: This would be far more therapeutically effective than trying to affect either the sensory nerve cells that initiate critical reflexes, or the motor nerve cells that activate muscle glands—because interference with the ability of the ENS to either receive information or send signals would likely paralyze the gut. [p45]


Success in science comes not just from excelling, but from excelling in such a way that important colleagues know of one’s excellence. [p46]

#21 [PROFESSIONAL + Technical]

By 1981, virtually everyone in the scientific community assumed that serotonin was a very important neurotransmitter in the brain; and the whole scientific world was transfixed by the possibilities that the understanding of it was thought would open up for manipulating mood and treating psychiatric illness. Even then, the gut was known to manufacture nearly all the body’s serotonin; and since only 1% of it is made in the brain, the brain’s output of serotonin can be thought of as a minor supplement.
            Despite these known facts, the brain’s serotonin was the source of tremendous excitement—whereas there was no interest in the massive concentration of serotonin in the bowel. [p48]


The body’s lumen is the open tube that begins with the mouth and ends with the anus—and the space enclosed within the wall of the bowel is part of the outside world: Paradoxical as it may seem, the gut is a tunnel that permits the exterior to run right through us; for whatever is inside the lumen of the gut is actually outside of our bodies (no matter how counterintuitive that seems). In other words, the body proper stops at the wall of the gut: nothing is truly in us until it crosses that boundary and is absorbed.
            Conversely, anything that moves across the intestinal wall in the reverse direction – i.e. into the lumen – is gone—hence a fatal haemorrhage can occur without a drop of blood being externally visible; and even water moving from the body proper into the lumen of the gut can be lethally dehydrating (cholera is a fatal disease for the same reason). [p84]


Digestion is a term for a variety of means by which the complex and often very large molecules in food are converted to simpler and smaller molecules that can be moved from the lumen of the gut into the body. Absorption is a term for the transmission of the products of digestion across the lining of the bowel to reach blood and lymph vessels in the wall of the intestine, which carry away the absorbed nutrients and distribute them to all the cells of the body. [p84]
            Digestion and absorption are thus essential for life—just as essential, in fact, as the beating of the heart and the drawing of breath: for when either digestion or absorption fails, starvation looms. This is why the intestinal lining cannot be constructed like the skin, i.e. as a tough an impenetrable barrier; instead, it must permit nutrients to go right through it, many of which have to be helped across the surface by the cells that line the gut, which work very hard and overcome serious obstacles to get these substances absorbed. Thus, the bowel displays a cleverness in carrying out its basic functions that is not shown by the skin. [p85]


The CNS is needed for swallowing; but once food is in the stomach, its further movement can occur even in individuals who are brain dead: For from the time food is swallowed to the moment it reaches the anus, the gut can regulate events all by itself (i.e. until the point of defecation, for which the requirement of the CNS is resumed). [p87]


In the relationship between the nervous system and acid production, even the contemplation of steak (or tofu for a vegetarian 😀 ) can make the lumen in the stomach turn acid: this is the cephalic, or ‘head phase’, of digestion and is evidence of the brain in action. Consciousness or even the imminence of food is enough to cause the parietal cells to secrete acid; alternatively, if one swallows something without thinking or even knowing, the stomach will sense the presence of food in the belly and the parietal cells will produce acid: this is the ENS at work. [p104]

#26 [Symptomatic + Technical + PROFESSIONAL]

Anxiety can also make the stomach more acidic: the head phase of digestion can be co-opted by a neurotic brain. It can also make the stomach and bowel churn: the excited bowel sends return messages to the brain that result in perceptions that range from butterflies and queasiness in the belly to cramping and frank abdominal pain.
            The link between gastric acidity and anxiety led people to believe that ulcer disease was a psychosomatic illness, i.e. that ulcer disease was the result of excessive acid produced by aberrant signals sent from a misguided brain. Thus, it was concluded that ulcers come from neurotic thoughts, even though the conclusion was wrong. [p105]
            Few people were willing to challenge the idea that ulcers are always due to excessive gastric acid caused by stress: generations of medical students and thousands of unhappy businessmen were told that ulcers of the stomach were the prototype of a psychosomatic illness.
            Although almost everyone thought that ulcers came from anxiety, ironclad proof was never obtained. For example, this particular “psychosomatic” disease was extremely resistant to cure by psychotherapy: Tranquilizers were found to be far more likely to put patients to sleep than cure their ulcers; and epidemiological confirmation was not forthcoming.
            In fact, the evidence suggested the opposite to the psychosomatic theory: that anxiety might be a consequence rather than a cause of the majority of ulcers. Patients with ulcers were often anxious—but concerning the derivation of ulcers, the psychosomatic theory required that the anxiety precede the ulcer. [p107]

#27 [Technical + PROFESSIONAL]

Pathologists kept finding bacteria in people’s ulcers lesions that they tended to ignore; but once they were fist studied carefully (by B.J. Marshall in 1984), bacteria in the stomachs and intestines of patients with ulcers almost always seemed to be Helicobacter pylori. Following this discovery, it did not take long to establish that this bacteria is not a bystander taking advantage of a psychosomatic illness: on the contrary, the bacteria is the major culprit of an illness that was supposedly psychosomatic—a peculiar organism that manages to avoid getting killed by the stomach’s hydrochloric acid. [p107-8]


The medical problem of ulcer disease is serious because it causes discomfort and pain that can be intolerable. Even worse, it can bleed into the gut causing severe and often unrecognized blood loss; and it can actually burrow right through the bowel and perforate it—a situation which is a medical emergency: if it is not repaired quickly and successfully, it is likely to be a lethal event; and because of infection, it can be fatal even if it is repaired quickly and successfully.
            Therefore, ulcers cannot be ignored and must be treated once diagnosed. Ulcers are also widespread, occurring in millions every year—hence they attract and are responsible for a great deal of utilization of the health care system. [p108]

#29 [Professional + SOCIO-PSYCHOLOGICAL]

Certain personality disorders have for many years been associated with the effort devoted to learning to bring the anal sphincter under socially acceptable control. For example, “anal retentive” or “obsessive personality” has long ago passed from the annals of medicine to popular literature and common usage.—People are thus accustomed to believe that thought, conscious or otherwise, can affect behaviours that they associate with the gut. The notion that thinking can alter what goes on in the bowel leads easily and comfortably to the belief that neurotic or psychotic thoughts in the head can raise enteric havoc. For this reason, psychosomatic disease of the gut is a concept that has never encountered much difficulty in gaining acceptance. [p176]
            Personal experience is another factor that enhanced the idea that the CNS can be the cause of intestinal malfunction. For example, butterflies in the belly and diarrhoea are frequent accompaniments to anxiety—thus the enteric consequences of strong emotions are sensed by most people, which is a factor in making the brain seem as an obvious perpetrator of intestinal grief. However, when behaviours of the bowel that are essentially under enteric control are disturbed, it is by no means clear that the output of the ENS is aberrant because the brain has made it so: although conceivable, there is nothing to prevent the ENS from giving rise to enteric misbehaviour independently of any influence the second brain received from the first. [p177]

#30 [PROFESSIONAL + Medical]

The theory that the brain must be responsible for almost any malfunction of the bowel that cannot be explained by any anatomical lesion in the gut has attracted enthusiastic support. The alternative possibility – that an abnormality of the gut’s own nervous system might be the cause of intestinal grief – has long not been seriously entertained. The reluctance of the medical community to accept the ENS as a cause of intestinal disease is in part due to the fact that many physicians consider it unreasonable to blame enteric troubles that they cannot diagnose on the out-of-sight-out-of-mind ENS—despite the fact of its location which is, with respect to intestinal difficulties, right at ground zero.
            In medical science, the brain is an éminence. Thus, where primitive peoples use a variety of gods to explain the inexplicable, modern humans use psychiatric illness: when all else fails, invoke psychoneurosis. [p177]
            Since the hypotheses involving the psychosomatic cause of disease are hard to test, it is easy to attribute aberrant enteric functions to unconscious thought processes. For example, unvented anger has often been invoked as a cause of intestinal malfunction: according to this view, intolerable feelings that cannot be expressed, or even consciously thought, become internalized and find expression in enteric havoc. [p178]


That pain and/or discomfort a patient reports as coming from his/her abdomen may actually be the result of real pain and real discomfort triggered by undetected physical or chemical abnormalities in the patient’s gut is a concept that seems less than revolutionary to me—but I have discovered that it is very revolutionary to others. Physicians tend to believe that gastroenterology is a field that attracts the most flagrant of psychoneurotic people; and to assume (as many do) that a patient’s pain is minor and psychogenic in origin in the absence of evidence to the contrary is both unjustified and unhelpful.
            In dealing with other organs as the heart, doctors believe patients when they report that they feel pain—and it is not clear to me why the gut should be treated differently: If a lesion in the gut is obvious, doctors become sympathetic, grant a patient the right to be in pain, and seek to alleviate the problem. If, however, no lesion can be detected, enteric pain tends to be belittled and blamed on neurotic thought processes. The fact that doctors do not always know why pain from the gut occurs is no reason to dismiss its severity or to attribute the pain to what substitutes in the modern world for a supernatural cause: psychoneurosis.
            Thus, many physicians still have yet to learn the lesson Hippocrates (c. 460 – c. 370 BC) drew from epilepsy: He had no idea why patients had fits—but that made no difference to him, for he was certain that the cause would eventually become known. In the meantime, however, it was useless to attribute the condition to supernatural origin. [p178]


At any given time, about 20% of the American population is partially disabled, or at least made miserably by, Functional Bowel Disease (FBD): It is a disturbing and intractable medical problem that physicians still cannot properly define, let alone cure. The most common variants are non-ulcer dyspepsia and, especially, Irritable Bowel Syndrome (IBS).
            It is very rare for anyone to be diagnosed for the first time with IBS after the age of sixty: old people with IBS get it whilst they are young, keep it for years, and carry it with them into old age. IBS accounts for about 25% of all patients that gastroenterologists see; and only about 10% of people with IBS present themselves to doctors for medical care—either because they are embarrassed, they are not greeted warmly by the medical profession, or they have had it for so long that they are unaware it is not present in everyone. [p179]

#33 [PROFESSIONAL + Medical]

The layers of medical enigma that surround FBD are so thick that international conferences have to be held to establish criteria by which it can be recognized: Almost as soon as the various criteria are published, they are inevitably found wanting by at least some “experts” in the field—and the criteria instead of the illness become objects of research and contention.
            What the lack of definitional clarity illustrates very well is that even today, no one actually knows what functional bowel disease is: In fact, whether it is one disease or many has yet to be determined.
            FBD is diagnosed by the presence in a patient of a set of symptoms that may themselves be self-contradictory and do not all have to be noted simultaneously. Clinicians who operate in the real world – where they encounter three-dimensional people instead of idealized representations – see many patients who do not meet the official criteria but who they nevertheless know to have FBD. Thus as a result, the next iteration of the established criteria is awaited to fine-tune the diagnostics. [p181]

#34 [PROFESSIONAL + Technical]

One of the major difficulties that has precluded any effective investigation of the cause or causes of the complex of symptoms that occur in FBD is the inadequacy of commonly used techniques for examining the human ENS: Neuropathologists are very competent when they work with the brain, or spinal cord, or ordinary peripheral nerves; but most, however, do not have a clue how to examine the ENS—and the gross examination of the gut reveals nothing.
            In short, the immense strides that have been made in understanding the composition of the ENS by basic scientists have yet to make any impact on the neuropathological investigation of the bowel. Worse still is that even if they knew what they were doing, pathologists would only rarely be able to obtain the tissue they need for the investigation of the ENS in FBD; for while the mucosa of the bowel is easily biopsied (by way of a flexible tube illuminated by fibre optics), mucosal biopsies do not include the full thickness of the wall of the gut.
            However troubling it may be, FBD is not often fatal (despite being very disturbing). Autopsies of patients who die while in the throes of FBD are rare to say the least; and the hypothesis that the ENS is defective with FBD has never been adequately tested by a proper search for associated defects in enteric nerve cells. [p182]


Years ago, a young neuropathologist (Michael Schuffler from the University of Washington in in Seattle) recognized the inadequacy of existing neuropathology and set out to do something about it: Armed with an approach that for the nervous system as a whole seemed primitive, but which for the ENS was so novel as to be revolutionary, he began to bring order out of the chaos of enteric nervous disease—but he was able only to begin his job, for his research funding dried up and the resulting shortage of money stopped him in his tracks.
            It is not really clear why this happened to him, but a contributing factor appeared to be the lack of support he received from an unappreciative scientific community: Many scientists looked down at what he was doing because they thought that his methods were not sufficiently “molecular”. There is a tendency among some biologists to consider that the value of any scientific discovery is directly proportional to its closeness to the expression of genes: they consider that work which identifies the genes responsible for a given disease is far more worthwhile than work that simply describes what is wrong in anatomical, chemical, or even functional terms.
            Another institutional problem for Schuffler was that his work was descriptive: he did not frame hypotheses and test them with functional experiments—the approach that stirs the blood of grant reviewers; and this kind of investigation, however necessary it may have been, lacked either the electricity of molecular biology or the suspense of a test of a high-flying hypothesis: In fact, in many scientific circles – particularly those that comprise the peer review panels that control the funds disbursed by the National Institute of Health (NIH) – the word “descriptive” is, when applied to the critique of a grant, a kiss of death. Even today, the effect of judging a work to be descriptive has the same effect on continued research funding that the thumbs-down sign given by a crowd in the Colosseum of Rome had on the continued life and good health of a defeated gladiator. [p183-4]
            The vacuum created by the stifling of Schuffler’s promise has created a void that still exists; and the nature of his fate has discouraged anyone else from stepping into his particular breach: Hence, there is no clear categorization of the ENS and – to my knowledge – no one is now trying to provide one. [p185]


An experiment with a guinea pig terminal colon – which would seem to be the right part of the gut to study for interest in an irritable colon – revealed the reliability with which artificial faecal pellets were transported down the isolated gut: they moved at an absolutely constant rate that stayed the same through repeated trials for hours and hours—A “Clockwork Colon”, you could say. This transport was found to be nerve-mediated, and thus stopped immediately when the nerves of the gut were paralyzed (chemically).
            On the basis of these and other experiments, it was concluded that an artificial pellet moved down the bowel because it exerted pressure on the lining of the gut; the pressure applied by the pellet on the EC cells* released serotonin, which stimulated receptors on intrinsic sensory nerves and which in turn triggered the peristaltic reflex that transported the artificial faecal pellet. [p219-20]

*Enterochromaffin (EC) cells (also known as Kulchitsky cells) are a type of enteroendocrine cell, and neuroendocrine cell. They reside alongside the epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal regulation, particularly intestinal motility and secretion. –Wikipedia

#37 [Technical, MEDICAL + Symptomatic]

Serotonin is an important signalling molecule in the intestinal mucosa that initiates enteric reflexes and sends messages up to the brain; and once it has done its job, serotonin in the ENS and CNS is turned off via reuptake by the serotonin-containing nerves that release it. However, this mechanism can be blocked: longterm treatment with an SSRI (Selective Serotonin Reuptake Inhibitor) causes some serotonin receptors to desensitize and fail to respond anymore, while others simply become less sensitive to stimulation by serotonin. In addition, nerve cells in individuals treated with an SSRI may make less serotonin.
            Because of all these complications, which can be grouped as various kinds of down-regulation, no one yet knows exactly why SSRIs, including Prozac, relieve depression. Thus, how they accomplish this is hard to say and very confusing; but nevertheless, their effectiveness is unchallenged.
            While their effects on mood can be uplifting and wonderful, the effect of SSRIs on the gut can be a real downer: When a person first begins taking them, they are very likely to cause nausea and even vomiting; then, the SSRI-induced intestinal disturbance can progress on to diarrhoea and finally to constipation. It seems as if SSRIs cause the poor bowel to writhe, churn, and finally freeze up.
            Many people find it difficult to get beyond the gastrointestinal “side-effects” of the SSRIs, which are a depressing denouement to taking anti-depressants: their untoward “side-effects” are not rare and may interrupt, limit, or delay treatment in up to 25% of the patients who take them. The frequent occurrence of these “side-effects” suggested to me that they could be a misnomer: there might be nothing “side” about the gastrointestinal effects of SSRIs. [p222-3]


ICCs – the interstitial cells of Cajal (named after the discovering scientist Ramon y Cajal) – refer to the cells in the interstices of the bowel. More than just the pacemakers for muscle, ICCs also seem to receive messages from nerves and transmit them to muscle. In fact, when it comes to the inhibitory neurotransmitter that gets muscle to relax, ICCs appear to act as amplifiers, not only relaying the message from nerves but making it stronger.
            One of the most important molecules that nerves use to get muscle to relax is the gas nitric oxide: Released around the smooth muscle, as well as electrical signals the ICCs pass on to the muscle cells, nitric oxide helps to bring the mass of muscle under inhibitory control.
            To help understand how smooth muscle of the gut is controlled, a good model is a flock of sheep: Like sheep, layers of smooth muscle stay together, but they can also move about on their own; however, for the good of the whole, their movements are better directed by a benevolent controlling force that makes decisions for them.
            For sheep, this controlling force is provided by a shepherd. If the flock is a large one, a single shepherd needs help to keep all the sheep in order. It is possible to use a number of shepherds for this purpose, but it is more economical to use sheepdogs instead: The shepherd issues orders to the dogs, which pass the message on to the sheep and keep them in order. The effect of the message from the shepherd is both transmitted to the sheep and amplified as the dogs spread the word.
            In the gut, the smooth muscle cells play the role of sheep; the nerve cells as the shepherds; and the ICCs as the sheepdog: The nerve cells make the big decisions that determine what the layers of intestinal muscle will ultimately do; the ICCs get the message and amplify it, helping to keep the mass of muscle under control.
            Thus biologically, it seems more economical for an intermediary cell – which can multiply and be replaced – to play the role of an enteric sheepdog than to increase the size or number or nerve cells, which are irreplaceable. [p230; 233-4]


The ENS of a newborn baby is still not fully mature: the post-natal acquisition of new enteric nerve cells means that an infant’s nervous system is still plastic and developing. It is therefore possible that the early experiences of a young bowel can affect the “personality” of the second brain that matures within it. [p270]
            Neurotransmitters are released by nerve cells that are stimulated; and since a neurotransmitter, serotonin, may well affect the development of enteric nerve cells, it follows that whatever activates the serotonin-containing nerve cells (or other developmentally active neurotransmitters) in the immature bowel is likely to exert effects, for better or worse, on the development of the ENS: The experience of the infant’s bowel determines how active various enteric nerve cells become, and when those cells are turned on or off.
            By thus regulating the activity of enteric nerve cells and the release of developmentally active neurotransmitters, like serotonin, experience may alter the course of ENS development. It follows that it would be wise to treat an immature gut well—unfortunately, no one knows what the immature ENS considers to be good treatment. [p272-3]

#40 [Medical + PROFESSONAL, Technical]

When a cause for gastrointestinal malfunction is not obvious, there is a tendency (of physicians) to deny that the problem is real; or if denial becomes untenable (as it may in the face of visible difficulties), to attribute the problems of the gut to bad thoughts emanating from the brain: This attribution again provides a rationale for blaming the thinker. [p310]
            The nervous system works so closely with the immune system in defending the gut that a developmental interaction between the nervous and immune systems, each of which secretes chemicals that affect the other, should be anticipated. For example, there are more nerve cells in segments gut affected by inflammatory bowel disease: since nerve cells do not proliferate, how can this happen? Are those additional nerve cells the products of precursors that are retained in the ENS of adults, or were they pre-existing? Could it be that too many nerve cells in particular regions of the gut is a cause of inflammatory bowel disease? I cannot answer these questions—but the discovery of the second brain carries hope for making the lives of people with troubled bowels so much better. [p311]


I have never observed moral consistency in animal rights crusaders: Those who oppose animal research should forgo the use of the products and techniques that come from it—which, for example, includes antibiotics, cancer therapy, painkillers, vaccines, and heart surgery; and for which activists should announce and carry out personal boycotts of. If anyone has done this, I have yet to hear of it. If an animal rights person were to renounce the benefits of animal experimentation, I would regard such a person as incredibly stupid—but I would consider them as living a truly righteous and consistent life. [p313]

The Enteric Nervous System: A Second Brain, by Michael D. Gershon – Article Extracts

Below are a few direct quotations, followed by a diagram, taken from Gershon’s follow-up article that essentially summarises his book; and which I have selected to complement the above book notes.

Structurally and neurochemically, the enteric nervous system (ENS) is a brain unto itself. Within those yards of tubing lies a complex web of microcircuitry driven by more neurotransmitters and neuromodulators than can be found anywhere else in the peripheral nervous system. These allow the ENS to perform many of its tasks in the absence of central nervous system (CNS) control.


Because the reflex persisted even after all of the extrinsic nerves to the gut had been severed, Bayliss and Starling deduced—correctly—that the ENS was a self-contained hub of neuronal activity that operated largely independent of CNS input. Eighteen years later, the German scientist Paul Trendelenburg confirmed these findings by demonstrating that the peristaltic reflex could be elicited in vitro in the isolated gut of a guinea pig, without participation of the brain, spinal cord, dorsal root, or cranial ganglia.

Trendelenburg knew this finding was unique; no other peripheral organ had such a highly developed intrinsic neural apparatus. Cut the connection linking the bladder or the skeletal muscles to the CNS, and all motor activity ceases. Cut the connection to the gut, however, and function persists. Trendelenburg’s results were published in 1917.

Discovery of the ENS

The ENS is remarkably brainlike, both structurally and functionally. Its neuronal elements are not supported by collagen and Schwann cells, like those in the rest of the peripheral nervous system, but by glia that resemble the astrocytes of the CNS. […] The ENS is also vulnerable to what are generally thought of as brain lesions: Both the Lewy bodies associated with Parkinson’s disease and the amyloid plaques and neurofibrillary tangles identified with Alzheimer’s disease have been found in the bowels of patients with these conditions.

The Anatomy of the ENS

Clinical Implications. Obviously, these data have important implications for
physicians who regularly prescribe mood-altering drugs. Because the
neurotransmitters and neuromodulators present in the brain are nearly always present in the bowel as well, drugs designed to act at central synapses are likely to have enteric effects.

The Serotonin Model

Provided that the vagus nerve is intact, a steady stream of messages flows back and forth between the brain and the gut. We all experience situations in which our brains cause our bowels to go into overdrive. But in fact, messages departing the gut outnumber the opposing traffic on the order of about nine to one. Satiety, nausea, the urge to vomit, abdominal pain–all are the gut’s way of warning the brain of danger from ingested food or infectious pathogens. And while the brain normally responds with appropriate signals, the ENS can take over when necessary, as for example when vagal input has been surgically severed.

Correlation or Causation? Whatever the exact connection, the relationship between the cerebral and enteric brains is so close that it is easy to become confused about which is doing the talking. Until peptic ulcer was found to be an infectious disease, for example, physicians regarded anxiety as the chief cause. Now that we recognize Helicobacter pylori as the cause, it seems clear that the physical sensation of burning epigastric pain is generally responsible for the emotional symptoms, rather than the other way around. But because most ulcer patients, if questioned, will admit to feeling anxious, the misunderstanding persisted for decades. Another illustration is ulcerative colitis, which was considered the prototypic psychosomatic disease when I was in medical school. There were even lectures on the “ulcerative colitis personality.” The ulcerative colitis personality, if indeed there is one, is a consequence of living with a disabling autoimmune disease that prevents patients from feeling relaxed and comfortable in social situations. It is altogether possible that with passage of time, many of the ailments currently labeled as functional bowel diseases will prove to have similarly identifiable physiologic causes.

More About the Brain-Gut Connection

The Enteric Nervous System (Diagram)

An illustration of the Enteric Nervous System, taken from the article The Enteric Nervous System: A Second Brain, by Michael Gershon (1999)


The Second Brain, by Michael Gershon (1998 Book)Digitized copy at the Internet Archive
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The Enteric Nervous System: A Second Brain, by Michael D. Gershon (1999 Article, PDF)
An article which provides an introduction to the key information of the book.

Complex and Hidden Brain in Gut Makes Stomachaches and Butterflies, by Sandra Blakeslee, The New York Times, Jan. 23, 1996
Essentially, this long-form article is a journalist’s summary of Gershon’s findings prior to the release of his book, very much tailored for the lay reader and is thus a good introduction to the subject.

Rasaesthetics, by Richard Schechner, TDR / The Drama Review Sept. 2001 (22pg Article, PDF)
This is the article from which I learned of all Gershon’s work. This article explores the ancient Indian Sanskrit treatise on dance/theatre, The Natya Shastra by Bharata Muni, and its impact on Western performance theory. A major theme of the article is the psychobiological phenomenon of “gut feelings”, concerning which the author cites Gershon’s work and even shares a correspondence with him.

The Mind-Gut Connection: How the Astonishing Dialogue Taking Place in Our Bodies Impacts Health, Weight, and Mood, by Emeran Mayer (2016 Book)
This book seems to be the closest thing to a follow up of Gershon’s book written for the mass market, with the intent of providing practical advice with regards to matters of the gut. I have not read the book, but I have noticed that Michael Gershon himself features among the author endorsements on the back cover of the book.

Author: Simon Kanzen

I value reading substantial literature, enjoy thought-provoking entertainment, and above all, I think every day. With Stepping Stones, I develop my thoughts in writing and share references to relevant media, intending for other readers and thinkers to find these writings useful.

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