That anguish has paid off. With an astonishing 100 million neurons—more than in the spinal cord but a lot fewer than in the brain—arrayed over an intricately folded surface area more than a hundred times greater than that of your skin, he has found, the ENS can work all on its own, without any input from the brain, to control the movement and absorption of food throughout the intestines. No other organ can call its own tune without the baton of that conductor who stands on the pedestal above the neck.
Illustration by Guyco
But the ENS, the newest mind-body connection to be revealed—and sometimes considered a branch of the autonomic nervous system, although Gershon sees it as holding its own—does much more than control itself. It also sends signals north to the brain that directly affect feelings of sadness or stress, even influence memory, learning, and decision-making. It relies on, and in many cases manufactures, more than 30 neurotransmitters, including serotonin, that are identical to those in the brain. What's more, tinkering with the second brain in our gut has lately been shown to be a potent tool for achieving relief from major depression. Even autism, studies suggest, may be wrapped up in the neurobiology of the brain down under.
"The nervous system actually started out in the gut," says Emeran Mayer, director of the UCLA Center for Neuro-visceral Sciences and Women's Health as well as of the UCLA Center for Neurobiology of Stress. "Most of my patients have a very good understanding that there is a close connection between their emotions and their guts. But there are still very few neuroscientists who understand the complexity of this enteric nervous system and its links to the brain."
As he explained in a recent article in the journal Nature, creatures low on the evolutionary totem pole, such as helminths, a class of worms, have a single nervous system that is very much like our own ENS. "The ganglia that form the primitive brains of helminths, and eventually the brains of higher mammals, were derived from the more primitive but homologous enteric nervous circuits. Neural circuitries and transmitter systems that have evolved to assure optimal responses to the challenges presented in our internal environment may have been incorporated into the central nervous system during evolution."
It is only logical that the gut should have a nexus of sensors to gather vital information. After all, like the brain in our head, it is engaged in prolonged contact and interaction with the outside world—in this case, via the food we swallow. And it must accomplish an extraordinary feat of transformation. It is the job of the gut to take in an extensive array of external matter, break it down to its component parts, shuttle it off to various internal organs, and turn it into us.
Think of yourself as the biological equivalent of a doughnut, with the inner lining of your intestines, the doughnut hole, facing an "inner" external world—food, water, bacteria, and whatever else you swallow—just as your skin faces the "outer" external world. While your ears, eyes, and sense of touch permit you to see, hear, and feel the outer exterior of your body, the intestines employ the ENS to sense, manipulate, and respond to the inner exterior, the doughnut hole of your gut.
From humans all the way down to such primitive sea creatures as the lamprey eel and the hagfish, all vertebrates have an ENS in addition to a central nervous system (CNS). During gestation, in the first days after conception, precursor cells destined to become neurons in the gut aggregate in a transitory structure in the developing embryo called the neural crest. From there they migrate to the just-formed gut, where they grow into the network of neurons lining the intestine.
When, 50 years ago, as a fledgling physician, Gershon decided to study the ENS, only one other researcher in the world focused on it. Today there are hundreds, and they are all at the cutting edge of science. In 1998 Gershon published the manifesto of this new science, The Second Brain. In laying the foundation for much current research, it also—most improbably—led to a 2007 appearance by Gershon on The Colbert Report. "My guest, Dr. Michael Gershon, believes we have a second brain in the gut. I'll ask him where he thinks the first one is," Colbert deadpanned.
That Mac 'n' Cheese Feeling
"We all know that food can affect mood and emotions," says Giovanni Cizza, chief of the Section on Neuroendocrinology of Obesity at the National Institute of Diabetes and Digestive and Kidney Diseases. We all recognize that great class of edibles known as comfort food. But until recently, there had never been a scientific demonstration of how food affects feelings, how it brings comfort. The conventional wisdom holds that the succor provided by foods like chocolate or macaroni and cheese is purely psychological, based simply on our seeing the food and remembering Mom's cooking. A competing view is that it is based on the delicious taste or smell of the food. But neither view turns out to be correct.
In fact, specific components of the food exert a direct effect on neurohormones in the gut that then signal the brain, Belgian researchers have found. They enlisted healthy, normal-weight human volunteers who agreed to bypass all the pleasurable aspects of eating by having a nasogastric tube deliver nutrients directly to their stomach—while they underwent brain scanning. Through the tube, volunteers received either an ordinary saline solution or an infusion of fatty acids. At the same time, they listened either to neutral music or to melancholy music proven to induce sad feelings, or they were shown pictures of sad or neutral faces.
The researchers regard the findings as prime proof that the brain processing of bodily signals regulates emotions. "It's an important demonstration that in a nonconscious way, without knowing whether you are getting the fat or the saltwater, something you put in your stomach can change your mood," Cizza explains. With apologies to Mom's cooking, not to mention McDonald's, fat, all by itself, in the absence of any pleasant associations or free toys, has the power to lift our emotional state.Based on feelings subjects reported and on brain images the investigators observed, the fatty acids reduced both sad feelings and sensations of hunger by about half, compared with the saline. They also reduced feelings of hunger. Within minutes after the fatty acids hit the stomach, MRI scans showed that brain regions known to moderate emotions were activated, with higher levels of blood flow in the brain stem and most of the emotional parts of the brain, the limbic system. Fatty-acid infusion attenuated both the behavioral and neural responses to sad emotion induction, the researchers recently reported in The Journal of Clinical Investigation.
Illustration by Guyco
A recent study by American scientists, published in the same issue of the journal, illuminated how food influences mood and behavior. The investigators subjected mice to the equivalent of schoolyard bullying, exposing them to bigger, older, highly dominant critters who literally walked all over them. The emotional effect of such bullying is well established. Animals experience "chronic social defeat stress," and it is a model of the kind of prolonged psychosocial stress that in humans can be caused by abuse or trauma—or by being a picked-upon nerd like Peter Parker before he became Spider-Man. Not only is the experience traumatic, but it is known to give rise to psychological depression.
Previous studies had established that stressed-out mice go for high-fat, energy-dense foods. They prefer peanut butter to regular chow and gain more weight than their low-stress counterparts. The new study showed that the gut actually tells the brain what to look for in the larder when the going gets tough—which is why the mac 'n' cheese looks better than an apple at that moment.
It does this by turning on production of ghrelin, a hormone manufactured by the gut that stimulates hunger in the first brain. Ghrelin boosts the appeal of food in general, and it specifically ups the reward value of high-fat foods, probably by turning on dopamine pathways.
In their studies, the researchers created a mutant strain of mice stripped of brain receptors for ghrelin. The mutant mice ate no more high-fat food than did the low-stress mice. A penchant for peanut butter returned, however, in another strain of mice, ones that had ghrelin receptors only in regions of the brain associated with eating. Ghrelin is but one of many neurochemical messengers that traffic back and forth between the ENS and CNS to affect mood and feeding.
"The French have a phrase for it: L'appétit vient en mangeant," says Gary J. Schwartz, professor of neuroscience and endocrinology at Albert Einstein College of Medicine in New York. So do the Italians: L'appetito viene mangiando. "It means the appetite comes in the eating. And it's absolutely true: The mere taste of something fatty is enough to promote further food intake."
Not by Neurohormones Alone
Powerful as they are, neurohormones are not the only players in the gut-brain axis. There's growing evidence that its activities are mediated by another key agent—the estimated 100 trillion bacteria that live inside your intestines and apparently do much more than digest your food and make you fart.
The vast mass of gut bacteria—collectively known as the gut biome—has co-evolved over millions of years to live in symbiotic harmony with us. Most of the bacteria are beneficial. Often called probiotics, they function as auxiliary DNA, producing their own enzymes and other products that help process our food and sustain us. In fact, because of the functional importance of the gut biome to us, the Human Genome Project has added as one of its goals the doping out of the genetic makeup of this basic biological accessory.
"The gut biome is actually an interface between your diet and your genetics," says Canadian neuroscientist Jane Foster. The human diet powerfully influences the makeup of the gut flora, and the gut flora in turn influence our makeup. "Our genetics determines our predispositions, but the gut biome influences how those predispositions function on a day-to-day basis," adds Foster, associate professor of psychiatry and behavioral neurosciences at Ontario's McMaster University.
Foster and her colleagues have found that from birth on, there is constant cross talk between gut bacteria and the brain. During infancy, that communication plays a significant role in shaping how the brain is wired. It affects not only anxiety but also memory, creating changes in both the amygdala, the brain's central regulator of fear, and the hippocampus, the region deep in the brain that is essential for memory and learning.
"The cross talk between the gut biome and the brain is continual," says Foster. "That's the important take-home message. These are not two separate systems; they are two parts of a single system."
While you can just imagine the jokes yet to come, scientists now see the bowel as a new pathway for regulating behavior. In commentary accompanying Foster's report in the journal Neurogastroenterology and Motility, researchers declared, "Modulation of the enteric microbiota may be a useful strategy" for treating stress-related disorders, including depression, and for helping control such conditions as irritable bowel syndrome and inflammatory bowel disease.
Is Kimchi the New Prozac?
Studies are already under way to determine which gut flora do what for our mental health and to turn those findings into treatments. At the Alimentary Pharmabiotic Centre at University College Cork in Ireland, John Cryan is working with a strain of lactobacillus, a common and generally safe bacterium found in the gut.
Lactobacillus is also a component of yogurt and cheese, as well as of many fermented foods, including sauerkraut and kimchi. In the long history of the human species before the advent of refrigeration, fermented foods played a significant role in our diet. Now, if they are consumed at all, they are occasional condiments, typically added in minuscule amounts. Cryan has found that the specific lactobacillus strain he is working with alters the expression of brain-cell receptors for a key neurotransmitter, GABA, and reduces anxious behaviors in mice.
"The possibility that distinct patterns of gut flora have an influence on aspects of our emotional processing is intriguing," says UCLA's Emeran Mayer. Although he is cautious about interpreting the latest findings, he is among the first to bring rigorous scientific scrutiny to the cognitive effects of probiotics in humans.
"We're just writing up the results of a study in 40 patients," he confides. "But it's going to be pretty revolutionary. Half took a placebo, and half took a probiotic for three weeks. We took a brain scan before and after. We were surprised to find that we could indeed detect a change in brain function in those who took the probiotic compared to those who received the placebo."
As for probiotic products already on the market, no one has yet proved scientifically that any of them affect mental or physical well-being. So far, it seems to be a case of very specific strains of bacteria having very specific effects.
But it is also possible that changes in the American diet over the past century have shifted the composition of the gut flora in ways that render us susceptible to such physical ailments as diabetes, irritable bowel disease, and immune disorders and to such mental conditions as depression and anxiety. The incidence of these conditions has skyrocketed as our diet has turned more to highly processed foods devoid of the kinds of bacteria our bodies and brains have unwittingly relied on for eons.
The Autism Connection
Autism has long been linked with disorders of the gut, most commonly chronic constipation, abdominal pain, and encopresis. In January 2010, Gershon coauthored a consensus report for the American Academy of Pediatrics on the gastrointestinal ills that are often seen in people with autism spectrum disorders.
"The take-home message is that autism is a genetic disease, and there are small abnormalities, probably in the synapses, that affect both the central nervous system and the enteric nervous system," he says. "People with autism have trouble with both systems."
Why that is remains a mystery. Perhaps, says Gershon, the autistic brain causes disorders in the gut. Or it may be that abnormalities in the gut somehow trigger autism in the brain or worsen its symptoms. Some parents and researchers believe that a diet free of gluten and the milk protein casein lessens the symptoms of autism, although evidence from randomized trials is limited. Gershon suspects that some combination of genes and environment causes both the autism and the GI troubles. Despite much searching, however, so far no study has conclusively established which way the causal arrow travels.
The ENS Versus the CNS
Researchers are also now unraveling the neurobiology of gut feelings, those intuitions on which so many of us base personal and professional decisions. They actually originate not in the gut but in the brain, when a decision is in the offing. A sensation of "butterflies" in the stomach arises because the brain sends a message of anxiety to the gut, which sends messages back to the brain that it is unhappy.
What to do with that exchange of information? It's best not to overrely on it. As much as he respects the powers of the ENS, Gershon does not believe the second brain is conscious or that it has the capacity for complex emotions or reasoning. "Sometimes emotions trigger a primitive response and the gut contracts a little bit," says Gershon. "It adds an exclamation point that you notice. That might help you decide something, but the gut as far as we know is not doing any reasoning. Religion and philosophy and poetry are for the brain in the head." Better to use that gut feeling to review the situation with the first brain.
Although he only tested skin, he believes signals emanating from the gut, too, can provide useful clues to the brain when we face tough choices. "I would agree that the ENS helps us to make decisions," he says.French neuroscientist Wim De Neys recently found that when people "intuitively" guess wrongly on questions of logic, their skin gets sweaty, suggesting that they actually realize an answer is wrong. "The presence of a clear autonomic conflict response during reasoning lends credence to the idea that reasoners have a gut feeling signaling that their intuitive response is not logically warranted," says De Neys.
Illustrations by Guyco
Decision-making may be firmly monopolized by the executive center of the brain located above the neck. But that doesn't minimize the contributions to our mental life now being discovered in our gut. Unfortunately, the gut's reputation fails to rise to the occasion. "The gut is a reptilian, disgusting organ, and we're told to forget about it," Gershon says. "The head is a serious organ; the heart is a serious organ."
But, like Rodney Dangerfield, the gut may finally be getting some respect.