The Mind Gut Connection: How The Hidden Conversation Within Our Bodies…

The Mind Gut Connection: How The Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices, and our overall health.

The Mind-Body Connection Is Real

When I started medical school in 1970, doctors looked at the human body as a complicated machine with a finite number of independent parts. On average, it functioned for about seventy-five years, provided you took care of it and fed it the right fuel. Like a high-quality car, it ran well, provided that it didn’t have any major accidents, and that no parts were irreversibly compromised or broken.

A few routine checkups during a lifetime were all you were expected to do to prevent any unexpected calamities. Medicine and surgery provided powerful tools to fix acute problems, such as infections, accidental injuries, or heart disease. However, over the past forty to fifty years, something fundamental has gone wrong with our health, and the old model no longer seems to be able to provide an explanation or a solution of how to fix the problems.

What’s happening can no longer be easily explained simply by a single malfunctioning organ or gene. Instead, we are beginning to realize that the complex regulatory mechanisms that help our bodies and brains adapt to our rapidly changing environment are in turn being impacted by our changing lifestyles.

These mechanisms do not operate independently, but as parts of a whole. They regulate our food intake, metabolism and body weight, our immune system, and the development and health of our brains.

In this book, I will offer a revolutionary new look at how the brain, the gut, and the trillions of microorganisms living in the gut communicate with each other. In particular, I will focus on the role these connections play in maintaining the health of our brain and our gut. I will discuss the negative consequences on the health of these two organs when their cross talk is disturbed, and propose ways of how to obtain optimal health by reestablishing and optimizing brain-gut communications.

Even in medical school, the traditional, prevailing approach did not sit quite right with me. Despite all the studying of organ systems and disease mechanisms, I was surprised that there rarely was any mention of the brain and its possible involvement in such common diseases as stomach ulcers, hypertension, or chronic pain.

In addition, I had seen a number of patients during rounds in the hospital for whom even the most thorough diagnostic investigations failed to reveal a cause of their symptoms. These symptoms mostly had to do with chronic pain experienced in different areas of the body: in the belly, the pelvic area, and the chest.

When President Richard Nixon signed into law the National Cancer Act of 1971, Western medicine acquired a new dimension and a new military metaphor. Cancer became a national enemy, and the human body became a battleground. On that battleground, physicians took a scorched-earth approach to rid the body of disease, using toxic chemicals, deadly radiation, and surgical interventions to attack cancer cells with increasing force.

Medicine was already using a similar strategy successfully to combat infectious diseases, unleashing broad-spectrum antibiotics—antibiotics that can kill or cripple many species of bacteria—to wipe out disease-causing bacteria. In both cases, as long as victory could be achieved, collateral damage became an acceptable risk. For decades, the mechanistic, militaristic disease model set the agenda for medical research: As long as you could fix the affected machine part, we thought, the problem would be solved; there was no need to understand its ultimate cause.

There is no question that some of these approaches have been remarkably successful, and for years there did not seem to be any need for the medical system and the pharmaceutical industry to change their approach; nor was there much pressure on the patient to prevent the development of the problem in the first place. In particular, there didn’t seem to be a need to consider the prominent role of the brain and the distinct signals it sends to the body during stress or negative mind states.

But today, the old mechanistic metaphors are beginning to yield. The machines of forty years ago on which the traditional disease model was based—the cars, ships, and airplanes—had none of the sophisticated computers that play a central role in today’s machines.

The traditional view of disease as a breakdown of individual parts of a complex mechanical device that can be fixed by medications or surgery has spawned a continuously growing health care industry. Since 1970, the per capita expense for health care in the United States has increased by more than 2,000 percent.

The World Health Organization, in a landmark report published in 2000, ranked the U.S. health care system as the highest in cost, it ranked it a disappointing 37th in overall performance, and 72nd by overall level of health among 191 member nations included in the study.

This data reflects the hard fact that despite the ever-increasing amount of resources spent on dealing with our nation’s health problems, we have made little progress in treating chronic pain conditions, brain-gut disorders such as irritable bowel syndrome (IBS), or mental illnesses such as clinical depression, anxiety, or neurodegenerative disorders.

Are we failing because our models for understanding the human body are outdated? There are a growing number of integrative health experts, functional medicine practitioners, and even traditional scientists who would agree with this assumption. But change is on the horizon.

The failure to deal effectively with many chronic diseases, including irritable bowel syndrome, chronic pain, and depression, is not the only shortcoming of the traditional, disease-based model of medicine. Since the 1970s, we have also been witnessing new challenges to our health, including the rapid rise of obesity and related metabolic disorders, autoimmune disorders such as inflammatory bowel diseases, asthma, and allergies, and diseases of the developing and the aging brain, such as autism, Alzheimer’s, and Parkinson’s disease.

While the increase in our longevity in the United States has paralleled that of many other countries in the developed world, we are far behind in terms of physical and mental well-being when we reach the last decades of our lives. The price we pay for an increase in the quantity of years we live is a decrease in the quality of those years.

In view of these challenges, it’s time to update our prevailing model of the human body to understand how it really works, how to keep it running optimally, and how to fix it safely and effectively when something goes wrong. We can no longer tolerate the price tag and the long-term collateral damage that our outdated model has produced.

Until now, we have largely ignored the critical role of two of the most complex and crucial systems in our bodies when it comes to maintaining our overall health: the gut (the digestive system) and the brain (the nervous system). The mind-body connection is far from a myth; it is a biological fact, and an essential link to understand when it comes to our whole body health.

While medicine continues to view the digestive system as being largely independent of the brain, we now know that these two organs are intricately connected with each other, an insight reflected in the concept of a gut-brain axis. Based on this concept, our digestive system is much more delicate, complex, and powerful than we once assumed. Recent studies suggest that in close interactions with its resident microbes, the gut can influence our basic emotions, our pain sensitivity, and our social interactions, and even guide many of our decisions—and not just those about our food preferences and meal sizes.

Your gut has capabilities that surpass all your other organs and even rival your brain. It has its own nervous system, known in scientific literature as the enteric nervous system, or ENS, and often referred to in the media as the “second brain.” This second brain is made up of 50-100 million nerve cells, as many as are contained in your spinal cord. The immune cells residing in your gut make up the largest component of your body’s immune system; in other words, there are more immune cells living in the wall of your gut than circulating in the blood or residing in your bone marrow.

The gut-based immune defense system is capable of identifying and destroying a single species of dangerous bacterial invaders that makes it into our digestive system when we accidentally ingest contaminated food or water. What is even more remarkable, it accomplishes this task by recognizing the small number of potentially lethal bacteria in an ocean of a trillion other benevolent microbes living in your gut, the gut microbiota.

Accomplishing this challenging task ensures that we can live with our gut microbiota in perfect harmony. The lining of your gut is studded with a huge number of endocrine cells, specialized cells that contain up to twenty different types of hormones that can be released into the bloodstream if called upon. If you could clump all these endocrine cells together into one mass, it would be greater than all your other endocrine organs—your gonads, thyroid gland, pituitary gland, and adrenal glands—combined.

The gut is also the largest storage facility for serotonin in our body. Ninety-five percent of the body’s serotonin is stored in these warehouses. Serotonin is a signaling molecule that plays a crucial role within the gut-brain axis: It is not only essential for normal intestinal functions, such as the coordinated contractions that move food through our digestive system, but it also plays a crucial role in such vital functions as sleep, appetite, pain sensitivity, mood, and overall well-being. Because of the widespread involvement in regulation of some of these brain systems, this signaling molecule is the main target of the major class of antidepressants, the serotonin reuptake inhibitors.

The gut is connected to the brain through thick nerve cables that can transfer information in both directions and through communication channels that use the bloodstream: hormones and inflammatory signaling molecules produced by the gut signaling up to the brain, and hormones produced by the brain signaling down to the various cells in the gut, such as the smooth muscle, the nerves, and the immune cells, changing their functions.

Many of the gut signals reaching the brain will not only generate gut sensations, such as the fullness after a nice meal, nausea and discomfort, and feelings of well-being, but will also trigger responses of the brain that it sends back to the gut, generating distinct gut reactions. And the brain doesn’t forget about these feelings, either. Gut feelings are stored in vast databases in the brain, which can later be accessed when making decisions.

What we sense in our gut will ultimately affect not only the decisions we make about what to eat and drink, but also the people we choose to spend time with and the way we assess critical information as workers, jury members, and leaders.

Only 10 percent of the cells in or on a human being are actually human. Gut microbiota differ quite widely from person to person, and no two people’s gut microbiota are exactly alike in terms of the many strains and species of microbes they contain.

Some people are posing deeper, more philosophical questions about the impact of the microbiome:

Are our human bodies just a vehicle for the microbes living in it?

Do the microbes manipulate our brains to make us seek out foods that are best for them?

Should the fact that we humans are outnumbered by nonhuman cells change our concept of the human self?

According to the new science of the microbiome, we humans are truly supraorganisms, composed of closely interconnected human and microbial components, which are inseparable and dependent on each other for survival. And most concerning is the fact that the microbial components are vastly greater than our human contribution to this supraorganism.

As the microbial component is so closely connected through a shared biological communication system to all the other microbiomes in the soil, the air, the oceans, and the microbes living in symbiosis with almost all other living creatures, we are closely and inextricably tied into the earth’s web of life.

The new concept of the human microbial supraorganism clearly has profound implications for our understanding of our role on earth and for many aspects of health and disease.

When the Gut-Microbiota-Brain Axis Falls Out of Balance

The health of any ecosystem can be expressed as its stability and resilience against insults and perturbations. There is growing evidence that the mix of gut microbes falls out of its healthy stable state in several gut disorders (a state called dysbiosis).

Further confirming the importance of gut microbial diversity for gut health is the observation that the colon inflammation can be rapidly cured by reestablishing the compromised architecture of the gut microbiome.

The only currently available way to restore gut microbial diversity in these patients is the transfer of an intact microbiota from the feces of a healthy donor into the gut of the affected patient. This treatment, so-called fecal microbial transplantation, results in an almost miraculous reconstitution of the patient’s own microbial composition.

The Emerging Role of Microbes

The microbes not only inhabit the inside of your gut; many of them sit on a razor-thin layer of mucus and cells that coats the inner lining of your intestine. This location allows them to listen in as the brain signals the gut how stressed you are, or when you feel happy, anxious, or angry, even if you are not fully aware of these emotional states. But they do more than just listen.

As incredible as this may sound, your gut microbes are in a prime position to influence your emotions, by generating and modulating signals the gut sends back to the brain. Thus, what starts as an emotion in the brain influences your gut and the signals generated by your microbes, and these signals in turn communicate back to the brain, reinforcing and sometimes even prolonging the emotional state.

Is the proper balance of microbes a prerequisite for mental health?

And when these connections between the mind and gut are altered, can they raise a person’s risk of developing chronic diseases of the brain?

Gut microbiota have also been linked to depression, which is the second leading cause of disability in the United States. The drugs used most often to treat depression are the so-called selective serotonin reuptake inhibitors such as Prozac, Paxil, and Celexa.

These drugs boost the activity of the serotonin signaling system, which psychiatry had long thought is exclusively located in the brain. However, we know today that 95 percent of the body’s serotonin is actually contained in specialized cells in the gut, and these serotonin-containing cells are influenced by what we eat, by chemicals released from certain species of gut microbes, and by signals that the brain sends to them, informing them about our emotional state.

As we know from animal experiments, an absence of gut microbes is compatible with life, including the digestion and absorption of nutrients, that is, as long as you live in an environment free of pathogens.

However, we now know that such germ-free animals—mice, rats, and even horses—have significant alterations in the development of their brains, in particular in brain regions involved in emotion regulation. Growing up in such a germ-free environment takes a serious toll on the development of your brain.

The well-being of your gut microbes depends on the food you eat, and they are more or less programmed in their food preferences during the first few years in life. However, regardless of their original programming, they can digest virtually everything you feed them, regardless of whether you’re an omnivore or a pescatarian.

No matter what you feed them, they will use their enormous amount of information stored in their millions of genes to transform partially digested food into hundreds of thousands of metabolites.

A particularly important role of microbe-produced molecules is their ability to induce a state of low-grade inflammation in their target organs, which has been implicated in obesity, heart disease, chronic pain, and degenerative diseases of the brain. These inflammatory molecules and their effect on certain brain regions may well be a major clue to our understanding of many human brain disorders.

What Does This New Science Mean for Your Health?

Who would have ever believed that simply transferring fecal pellets containing gut microbiota from an “extrovert” mouse could change the behavior of a “timid” mouse, making it behave more like the gregarious donor mouse? Or that doing a similar experiment transplanting stool and its microbes from an obese mouse with a voracious appetite would turn a lean mouse into the same overeating animal? Or that the ingestion of a probiotic-enriched yogurt for four weeks in healthy human females could reduce their brains’ response to negative emotional stimuli?

This new understanding will require us to demand more from our health care system. We’ll need it to move away from dominant yet outmoded ideas of the body as a complex machine with separate parts, and toward the idea of a highly interconnected ecological system that creates stability and resilience against disturbances through its diversity.

The time has come to empower ourselves to become the engineers of our own internal ecosystem, and our bodies and minds. To become your own ecosystem engineer, you will first need to understand how your brain communicates with your gut, how your gut communicates with your brain, and how your gut microbes influence both of these interactions.

Chapter 2

How the Mind Communicates with the Gut

Emotions are closely reflected in a person’s facial expressions. A similar expression of our emotions occurs in the different regions of the gastrointestinal tract, which is influenced by nerve signals generated in the limbic system. Signals to the upper and lower GI tract can be synchronous or go in opposite directions.

The activity of these brain circuits affects other organs as well, creating a coordinated response to every emotion you feel. When you’re stressed, for example, your heartbeat speeds and your neck and shoulder muscles tighten, and the reverse happens when you’re relaxed. But the brain is tied to the gut like no other organ, with far more extensive, hardwired connections.

Because people have always felt emotion in their gut, our language is rich with expressions that reflect this. Every time your stomach was tied up in knots, you had a gut-wrenching experience, or you felt butterflies in your stomach, it was the emotion-generating circuits of your brain that were responsible. Your emotions, brain, and gut are uniquely connected.

Nearly 15 percent of the U.S. population suffers from a range of aberrant gut reactions, including irritable bowel syndrome, chronic constipation, indigestion, and functional heartburn, which all fall into the category of brain-gut disorders. They suffer from symptoms that range from queasiness, gurgling, and bloating all the way to unbearable pain. Amazingly, the majority of patients suffering from abnormal gut reactions have no idea that their gut problems reflect their emotional state.

In patients with cyclical vomiting syndrome, stressful life events generally spark the attacks. A wide range of seemingly unrelated stimuli including strenuous exercise, menstruation, exposure to high altitudes, or simple prolonged psychological stress can cause enough of an imbalance in the body to trigger an attack. When the brain (not necessarily our conscious brain) perceives such a threat, it signals the hypothalamus, an important brain region coordinating all our vital functions, to crank up release of a critical stress molecule called corticotropin-releasing factor, or CRF for short, which functions as a master switch that sends the brain (and the body) into stress-response mode.

Patients with this disorder may be completely symptom-free for several months or even years, even though their CRF system is primed all the time. But when they experience additional stress, a recurrence of symptoms is triggered. When CRF levels rise high enough, it switches every organ and cell in your body, including the gut, into stress mode. In a series of elegant animal experiments, my UCLA colleague Yvette Tache, who’s one of the world’s experts in stress-induced brain-gut interactions, revealed the many shifts in the body that CRF induces.

You don’t have to suffer from the crippling symptoms of cyclical vomiting syndrome to experience the limited knowledge that many physicians have about gut reactions gone wrong, and the resulting lack of effective therapies. Nearly 3 in 20 people in the United States suffer from symptoms or syndromes caused by problems from altered brain-gut interactions, including irritable bowel syndrome, functional heartburn, or functional dyspepsia.

However, those of you who are not bothered by nasty and unpleasant gut sensations should be aware that you don’t have to have any of these disorders for gut reactions to occur.

Your emotional brain can mess up just about every one of those seemingly automatic functions. If your dinner conversation takes a wrong turn and you get into an argument with your friend, your stomach’s wonderful meat-grinding activity is quickly turned off and instead goes into spastic contractions that no longer allow it to empty properly.

Half of a tasty steak you ate will remain in your stomach without further digestion. Long after you have left the restaurant, your stomach will still be in spasms as you lie awake. Because there is still food in your stomach, the nocturnal migrating contractions won’t happen, preventing the usual overnight cleansing of your gut.

In patients who have a hyperactive brain-gut axis to start out with, stress-related or emotional triggers that won’t cause much harm to a healthy individual will forcefully inhibit stomach peristalsis and even reverse it, while at the same time creating spastic contractions in his colon. It is as if the set points on the warning system in these brains are off, triggering frequent false alarms, with devastating consequences for well-being.

Your enteric nervous system can handle all routine challenges related to digestion. However, when you perceive a threat and feel afraid or angry, the emotional brain center does not send individual instructions to every single cell in the gastrointestinal tract. Instead, the brain’s emotional circuits signal the enteric nervous system to divert from its daily routine. The digestive system switches back to local control once the emotion has passed.

For some people, the plays performed in the gut include more thrillers and horror stories than romantic comedies. Gut cells in a chronically angry or anxious person, using a script that dates back to childhood, may play out dark plots day after day. Many gut cells in these people over time adapt to accommodate the stage directions: nerve connections in the enteric nervous system change, the sensors in the gut become more sensitive, the gut’s serotonin-producing machinery shifts into higher gear, and even gut microbes become more aggressive.

It’s no surprise that when scientists study the gut in patients with functional GI disorders, anxiety disorders, depression, or autism, they find changes in the makeup and behavior of many of these gut players, and the scientific literature is filled with such observations. However, developing therapies targeted at such gut changes has generally failed to provide symptomatic relief for patients with these disorders. On the other hand, one would expect that changing the playbook of the brain to more positive stories, with the goal of altering the gut reactions and thereby reversing the cellular changes in the gut, is more promising.

Studies are currently under way to determine if gut microbial changes are associated with positive mind-based interventions, such as hypnosis and meditation, and if these changes lead to symptom improvements in such disorders as irritable bowel syndrome.

How the Brain Programs the Gut’s Emotional Responses

Today, we know a great deal about how emotion affects our bodies, including our GI tract. To understand how it works, you first need to know about the limbic system, a primitive brain system that we share with other warm-blooded animals and that plays a major role generating your emotions.

Deep in your gray matter, emotion-specific circuits within the limbic system get activated when you’re angry, scared, feel sexually attracted, or hurt—and also when you feel hungry or thirsty. Like a miniature supercomputer, these circuits aim to adjust our bodies to respond optimally to changes both inside and outside our bodies.

When we face a life-threatening situation, it can turn on a dime, quickly rearranging thousands of messages to individual cells and organs throughout the body, which shift their behavior just as quickly. We’re all familiar with what happens next. The emotion-related brain circuits send signals to the stomach and intestine to rid themselves of contents that might otherwise drain energy required for action, which is why you might need to head to the bathroom before your big presentation.

Jaak Panksepp, a neuroscientist at Washington State University who has made important contributions to the field of affective neuroscience (which applies neuroscience to the study of emotion), has concluded from his experiments on animals that our brains have at least seven emotional operating programs that direct the body’s response to fear, anger, sorrow, play, lust, love, and maternal nurturance.

They execute the appropriate set of bodily responses quickly and automatically—even when you don’t know you’re feeling a particular emotion. They make your face flush when you feel embarrassed, give you goose bumps when you watch a scary movie, make your heart beat faster when you’re scared, and make your gut more sensitive when you are worried.

Our emotional operating programs are written in our genes. This genetic coding is, in part, inherited from our parents, and it is also influenced by events we experience early in life. For example, you may have inherited genes that predispose your fear or anger program to overreact to stressful situations. If you also experienced emotional trauma as a child, your body added chemical tags to these key stress-response genes. The net result is that as an adult, you will most likely experience exaggerated gut reactions to stress.

When the Gut Gets Stressed

Of all of our emotional operating programs, the one engaged by stressful events is among the best studied. When you feel anxious or fearful, your stress response is at work, trying to maintain a state of homeostasis, or internal balance, in the face of internal or external threats. When we talk about stress, we usually talk about stress from daily living pressures, or larger stressors such as trauma or natural disasters. But your brain also perceives many bodily events as stressful, including infections, surgeries, accidents, food poisoning, sleep deficits, attempts to stop smoking, or even something as natural as a woman’s menstrual period.

These stress-induced changes in your digestive system may not sound like the ideal way to enjoy a meal, and they’re not. The next time you’re in the midst of a particularly stressful day, just remember that you might not want to eat a large lunch. Even if you eat when you’re more relaxed, there’s still a chance you could experience an unpleasant gut reaction to your meal.

Once an emotional motor program has been triggered, its effects may linger for hours—or sometimes for years. Our thoughts, memories of past events, and expectations of the future can influence the activities within our brain-gut axis, and the consequences can sometimes be painful.

For example, if you return to the restaurant where you argued with your spouse over dinner, your memories may trigger your anger operating program, despite a friendly dinner conversation this time around. If that restaurant was an Italian restaurant, any Italian restaurant or even the mere thought of risotto di mare may trigger the anger program.

I often explain this scenario to my patients, who are quick to blame certain foods for causing digestive distress. I ask them to explore whether it’s the food or in fact a recollection of an earlier event that’s responsible for their symptoms. When they start paying attention to the circumstances that trigger their symptoms, they often realize the incredible power of the brain-gut connection.

After years of suffering and enduring humiliating comments from emergency room physicians, patients are excited to finally be able to rebuild their lives. Other cyclical vomiting patients I’ve seen have required additional treatments to recover, including cognitive behavioral therapy and hypnosis.

Normal gut reactions, such as worrying about a job interview, or transient upsets from being stuck in traffic or running late to an appointment are never a major problem. However, we should be mindful of the detrimental effects of such emotions on our gut and its many residents when they occur chronically, in the form of anger, sorrow, or recurrent fear.

It is of greater concern when we recall that emotions always have a mirror image in our gut, and speculate about the detrimental effects that chronic anger, sorrow, or fear may exert not only on our digestive health but on our overall well-being.

Chapter 3

How Your Gut Talks to Your Brain

We remain blissfully unaware of most gut sensations until we experience some gastro-calamity such as a stomachache, heartburn, nausea, a persistent sense of bloating, or, worse, a bout of food poisoning or a viral gastroenteritis. Or we may just feel we ate too much and feel awful, even after eating a normal-sized meal. Suddenly the sensory information from our gut becomes quite relevant—and usually for good reasons. These unpleasant sensations drive us to seek help, and they help us avoid whatever caused our distress in the future by making sure we never forget.

More than 90 percent of the sensory information collected by your gut never reaches conscious awareness. For most of us it’s easy to ignore the daily sensations from our belly; yet the enteric nervous system is monitoring them very carefully.

More than 90 percent of the sensory information collected by your gut never reaches conscious awareness. For most of us it’s easy to ignore the daily sensations from our belly; yet the enteric nervous system is monitoring them very carefully.

Through a complex system of sensory mechanisms, many of your gut sensations are quietly directed to the little brain in your gut, providing it with vital information to ensure optimal functioning of your digestive system twenty-four hours a day. But a huge flow of gut sensations is also directed upward, to the brain.

Ninety percent of the signals conveyed through the vagus nerve travel from the gut to the brain, while just 10 percent of the traffic runs in the opposite direction, from the brain to the gut. In fact, the gut can handle most of its activities without any interference from the brain, while the brain seems to depend greatly on vital information from the gut.

While this information is vital to ensure proper functioning of the digestive tract, the enteric nervous system has no ability to produce conscious sensations. When Gershon’s book, The Second Brain, came out, it sparked much speculation about the abilities of the enteric nervous system.

Some even wondered if the second brain not only is capable of perception, but may also be the seat of our emotions and our unconscious mind. However, we can almost certainly say that these speculations were false. The sensory information from the gut is also sent to the brain in your head, and if you pay attention to these sensations you will be able to feel them. Twenty-four hours a day, seven days a week, our GI tract, enteric nervous system, and brain are in constant communication. And this communication network may be more important for your overall health and well-being than you ever could have imagined.

It would hardly make sense for this high-performance data collection system to be immersed in the messy world of partially digested food and corrosive chemicals moving through the gut. In fact, it’s not: the neurons themselves sit inside the gut lining, out of direct contact with the gut’s contents, and rely on specialized gut-lining cells that do face the inside of the gut to sense events there.

Those cells signal to intermediaries in the gut wall, in particular the various endocrine cells that in turn signal to nearby sensory neurons, in particular the vagus nerve. To date, a large number of different sensory neurons have been identified that are each specialized for a specific aspect of gut sensations and respond to a particular molecule released by the gut’s endocrine cells.

Each of these nerves will send signals to the enteric nervous system or to the brain. The gut’s endocrine cells are so abundant and so deft at signaling our nervous system that they play crucial roles in our health and well-being.

For example, when your stomach is empty, specialized cells in the stomach wall produce a hormone called ghrelin, which travels via your bloodstream or signals via the vagus nerve to your brain, where it triggers a strong urge to eat.

On the other hand, when you’re satiated and your small intestine is busy digesting your food, cells there release “satiety” hormones that tell your brain that you’re full and it’s time to call a halt to further eating.

The immune cells living in our gut are preferentially located in clusters in the small intestine known as Peyer’s patches, and are also found in our appendix and scattered throughout the wall of the small and large intestine. The gut-based immune cells are separated by a tiny layer of cells from the space inside the gut, and some of them, the so-called dendritic cells, even extend through the gut layer, where they can interact with our gut microbes and with potential harmful pathogens.

Most important, cytokines released from these cells can cross the gut lining, enter the systemic circulation, and ultimately reach the brain. Alternatively, the signaling molecules released from hormone-containing gut cells signal to the brain via the vagus nerve. With so many mechanisms involved in informing our nervous system about aspects of the foods we ingest, it is becoming clear that our gut is designed to do far more than just absorb nutrients.

The gut’s elaborate sensory systems are the National Security Agency of the human body, gathering information from all areas of the digestive system, including the esophagus, stomach, and intestine, ignoring the great majority of signals, but triggering alarm when something looks suspicious or goes wrong. As it turns out, it’s one of the most complex sensory organs of the body.

Total Gut Awareness

Whenever you consume food or drink, reports from your intestinal data collection system provide a variety of vital information to both the little brain in your gut (your enteric nervous system) and the brain in your head. Your big and little brains are both interested in obtaining these reports whenever you consume food or drink, but they’re interested in different aspects of this information.

Your little brain needs vital information from the gut to generate optimal digestive responses and, when necessary, to eliminate toxins by expelling the intestinal content from either end of the GI tract by vomiting or diarrhea.

These reports cover the size of the meal, the contents that are entering the gut (including chemical information such as fat, protein, and carbohydrate content, as well as concentrations, consistencies, and particle sizes).

They also include intelligence revealing any signs of hostile intruders such as bacteria, viruses, or other toxins from contaminated food.

When it obtains information about the high fat content of a rich dessert entering your stomach, it will slow the rate of gastric emptying and intestinal transit.

When it obtains information about the low caloric density of a meal, it will speed up its emptying from the stomach to deliver enough calories for absorption.

And when it obtains information about potentially harmful intruders, it will stimulate water secretion, change the direction of peristalsis to empty the stomach from its content, and accelerate the transit throughout the small and large intestine to expel the offending agent.

Your brain, on the other hand, is more concerned with your overall health and well-being and as such it monitors different cues from your gut and integrates them with a variety of signals from other parts of your body as well as information about your environment.

It monitors what is going on in the enteric nervous system, but in addition is closely interested in your gut reactions, the state of the gut reflecting your emotions, the wrenching contractions of your stomach and colon when you are angry, and the absence of intestinal activity when you are depressed.

In other words, the brain watches its own theater being played out on the stage of the gut. The brain almost certainly also receives information generated by the trillions of microbes living in the gut, an aspect of gut-brain signaling that only came into focus during the past few years.

While the brain constantly monitors all sensory information coming from the gut, it delegates the day-to-day responsibilities to local agencies, in our case the enteric nervous system. The brain only gets directly involved in the action if an action is required by you, or if the situation poses a significant threat that warrants a brain response.

Through these various sensory mechanisms, your gut informs your brain every millisecond of the day, whether you’re awake or asleep, about everything taking place deep inside you. It’s not the only organ providing ongoing feedback to the central nervous system: Your brain continually receives sensory information from every cell and organ in your body.

Your lungs and diaphragm transmit mechanical signals to the brain every time you inhale and exhale, your heart generates mechanical signals with each heartbeat, your artery walls send signals about blood pressure, and your muscles transmit information about their tone or tightness.

Scientists call these ongoing reports about the state of the body “interoceptive” information—information that the brain then uses to keep the body’s systems balanced and functioning smoothly.

Although interoceptive information comes from every single cell of the body, the messages the gut and its sensory mechanisms send to our brain are unique in their sheer number, variety, and complexity.

Start with the fact your gut’s sensory network is distributed over the gut’s entire surface area, which is two hundred times larger than the surface area of your skin—about the size of a basketball court.

Now imagine a basketball court with millions of tiny mechanical sensors that collect information about the movement of the players, their weight, their acceleration and deceleration, and about every jump and landing.

Since the gut’s signals also include chemical, nutritional, and other information, this metaphor only begins to describe the vast amount of information encoded as gut sensations.

The Information Highway for Gut-Brain Traffic

The vagus nerve plays a particularly important role in communicating gut sensations to the brain. The great majority of gut cells and receptors that encode gut sensations are closely linked to the brain via the vagus nerve. And much of the signaling of our gut microbiota to the brain relies on this pathway as well.

In the majority of rodent studies on the effects of gut microbial changes on emotional behaviors, the effects were no longer seen after the vagus nerve was cut. But the vagus nerve is more than a one-way communication channel:

This nerve is a six-lane freeway, allowing rush hour traffic in both directions, though 90 percent of this traffic flows from gut to brain.

The vagus nerve carries so much traffic because it’s one of the most important regulators of our viscera, linking the brain not just to the GI tract but to all other organs as well.

Today we know about the complexity of gut sensations and the crucial role the vagus nerve plays in transmitting these signals to brain regions like the hypothalamus and limbic brain regions, which in turn influence a wide range of vital functions such as pain, appetite, mood, and even cognitive function.

Electrical or pharmacological vagal stimulation has been evaluated as a novel way to simulate gut sensations, and as therapy to treat a range of brain disorders, including depression, epilepsy, chronic pain, obesity, and even various chronic inflammatory diseases such as arthritis.

These new findings further confirm the importance of vagal-gut-brain communication to people’s health and well-being.

The Role of Serotonin

Serotonin is the ultimate gut-brain signaling molecule. Serotonin-containing cells are intricately connected to both our little brain in the gut and to our big brain. This gut-based serotonin-signaling system plays a key role in linking events in the gut related to food, intestinal microbes, and certain medications to the activity of our digestive system, and to the way we feel.

When secreted under normal conditions, serotonin helps the digestive process proceed in regular fashion. It is released by subtle mechanical shearing forces exerted when the gut’s contents slide along the GI tract and rub against what are known as enterochromaffin cells.

Just like the other hormones contained in the endocrine cells of the gut, the released serotonin activates sensory nerve endings in the vagus nerve and the enteric nervous system (ENS), which in turn keep the ENS informed about what is moving down the intestinal tract, enabling it to trigger the all-important peristaltic reflex.

A more concentrated serotonin release, such as occurs with food poisoning or in response to the chemotherapeutic agent cisplatin, on the other hand, will lead to vomiting, intensive bowel movements, or both.

The small amount of serotonin contained in nerves in the gut and in the brain plays crucial roles as well: serotonin-containing nerves in the gut play a key role in regulating the peristaltic reflex, while clusters of nerve cells in the brain send their signals to most regions of the brain, exerting an influence over a wide range of vital functions, including appetite, pain sensitivity, and mood.

Given the gut’s enormous serotonin stores, located close to vagal nerve pathways that link directly to the brain’s affective control centers, it’s certainly conceivable that a constant stream of low-level, serotonin-related gut signals are being sent to our brain’s emotional centers, in response to intestinal contents rubbing against the serotonin-packed cells, or in response to gut microbial metabolites.

Even if these serotonin-encoded signals don’t enter our conscious awareness, this low-level serotonin release could affect our background emotions and influence how we feel, exerting a positive “tone” on our mood—which in turn could explain why so many people experience a sense of contentment and well-being around the ingestion of an enjoyable meal.

Food as Information

Why does the gut need its specialized sensory apparatus?

The simple and scientifically supported answer is that these sensing mechanisms are essential to the smooth operation and coordination of basic gut functions such as gastric emptying, movement of food through the intestines, and the secretion of acid and digestive enzymes; to body functions related to food intake, such as appetite and satiation; and to our basic metabolism, including blood sugar control.

The massive amount of gut-related information being sent to the brain, which includes a barrage of messages from the trillions of microbes living in our gut, gives the gut-brain axis a unique and unexpected role in modulating our health and well-being, our feelings, and even the decisions we make.

When we consider the scientific complexities of the various gut sensors and the vagus nerve, together with their functions in the digestive process, and place them into the overall context of gut sensations, a revolutionary picture of our eating habits emerges:

-Our digestive tract able to absorb most of the nutrients and calories contained in a meal (with our intestinal microbes taking care of the leftovers that our gut cannot digest)

-The gut’s sophisticated surveillance system can actually analyze food’s nutritional content and, at the same time, extract the information needed for its optimal digestion.

-The dense distribution and vast area that the gut’s sensory receptors occupy on the lining of our gut wall. Your gut is transmitting immense amounts of information to the brain at any given moment.

-Your gut with its nervous system and its microbial residents is actually an amazing information-processing machine that greatly surpasses our brains in terms of the number of cells involved and rivals some of the brain’s capabilities.

In other words, food comes with its own instructions for how to optimally digest it, and with a lot of fine print that until recently we didn’t even know about, and are still trying to figure out the meaning of. This is true whether you are a vegan, pescatarian, omnivore, meat-meister, fast-food junkie, serial dieter, episodic faster—or even if you recently picked up a gut infection while traveling in Mexico.

Chapter 4

Microbe-Speak: A Key Component of the Gut-Brain Dialogue

Signaling molecules called “gut hormones” or “gut peptides,” which had first been isolated from the skin of exotic frogs and later from the guts and the brains of mammals are a complex universal biological language that the trillions of microbes in our intestines use to communicate with our digestive system and even our brain.

A group of Italian biologists under the leadership of Vittorio Erspamer had discovered some of the first gut peptides in the skin of exotic frogs, where their role seemed to be to help deter predators.

When an inexperienced young bird ingested such a frog, these molecules would be released in its GI tract, triggering a bad gut reaction that spoiled the meal and caused the bird to regurgitate the frog.

This taught the young bird not to touch that type of frog in the future. And since the frog produced a peptide to which the bird’s tissues reacted, the results proved that frogs and birds shared a chemical communication system.


It didn’t take long for scientists to discover that gut peptides were present not only in the intestine’s hormone-containing cells, but also in the nerve cells of the enteric nervous system, which used them to fine-tune peristalsis, fluid absorption, and secretion.

And when neuroscientists started looking in the brain, they found identical substances. There the peptides functioned as important chemical switches that could turn on and off various behaviors and motor programs involved in hunger, anger, fear, and anxiety.

Roth and LeRoith summarized their findings in a 1982 review article in the New England Journal of Medicine, writing that the signaling molecules that our endocrine system and brain use to communicate probably originated in microbes.

(Insert MAAPs Work on mental health and the role of psilocybin on depression and the Big 5)

Several years later, I became so intrigued by this evolving science that I decided to write a speculative review article myself.

“Are Gut Peptides the Words of a Universal Biological Language.” The article was published in the American Journal of Physiology in 1991.

In the article, we proposed that these signaling molecules represent the words of a universal biological language used not only by the gut, but also by the nervous system, including the little brain and the big brain, and by the immune system. Humans were not the only organisms using this cellular communication system: science had demonstrated that frogs, plants, and even microbes living inside our intestines used it as well.

By applying a mathematical approach called information theory to the biological data, we even speculated about the amount of information that different types of signaling molecules—from hormones to neurotransmitters—were able to send between different cells and organs.

Over the years I’ve seen many patients with complex, seemingly unexplainable symptoms, and one of the important lessons I’ve learned is to listen to their stories in an unbiased way—no matter how odd they may sound, and no matter how poorly they fit into current scientific dogma.

Many patients from different ethnic, educational, and socioeconomic backgrounds whom I see in my clinic strongly believe in the dangers lurking inside our guts. They come convinced that some ill-defined and largely scientifically unsubstantiated processes in their GI tract are responsible for various digestive and other health problems.

Over the years, such suspected processes have included candida yeast infections of the intestine, allergies and hypersensitivities to all kinds of dietary components, leakiness of the gut, and most recently, a perceived imbalance of their gut microbiota. Many of these individuals have embarked on often costly and cumbersome routines to combat these suspected ailments, including highly restrictive diets, supplements, and even antibiotics.

Humans have used all kinds of nonscientific explanations and rituals to reduce their fear and anxiety over health threats outside their control. Dietary cleansing rituals have been particularly popular, including juicing and special diets aimed to achieve a clean gut, a contradiction in itself.

Today, these basic anxieties have been whipped up dramatically by the endless stream of stories from popular authors in popular publications—stories that make shifting claims about the ever-present dangers contained in what we eat. On the other hand, we now know from scientific studies that there is some validity to the fear of microbes in our gut and of the many substances they can produce.

Just as there are criminals, scammers, and computer hackers in human society, there are microbes that don’t play by the rules. Some of these transient microorganisms, in particular parasites and viruses, have their own agenda (usually procreation), and they ignore or even sabotage our health and wellness as they pursue it. They have learned to hack into our most sophisticated computer system, the brain, to use its emotional operating programs for their own selfish benefits. To demonstrate how sophisticated these microbes can be, let me share a fascinating story that I first heard some fifteen years ago at a meeting of psychiatrists in San Francisco.

There, Robert Sapolsky, a leading expert on the ill effects of chronic stress on our brain, gave an inspiring talk about an evil but clever microorganism named Toxoplasma gondii. In the talk he described a study showed that T. gondii has its own agenda of survival and reproduction, which it pursues in a remarkably cunning and egotistical fashion.

Toxoplasma-infected rodents not only lose their instinctive fear of cats—they also begin to prefer areas that smell like cat urine. To make this happen, the parasite’s tiny cysts home into a specific region of the rat’s brain with the accuracy of a cruise missile, and with minimal collateral damage. The target is the emotional operating system responsible for triggering the fear-and-flight response.

This emotional and motor program normally causes the rats to flee at the first whiff of a nearby cat, but the parasite specifically eliminates rats’ fear of cats. Infected rats continue to exhibit their normal defensive behaviors toward predators other than cats, and they perform normally on laboratory tests of memory, anxiety, fear, and social behavior. But when it comes to cats, the cysts don’t stop there.

They also boost activity in nearby brain circuits that control sexual attraction, causing toxoplasma-infected rats that smell cats to become sexually attracted to them. This clever hijacking of the rat brain’s operating systems overwhelms the innate fear response by causing a sexual attraction to cat odor. In other words, the infected rats develop a fatal attraction to cats.

There are many other microbes that have developed astonishingly sophisticated ways of manipulating the host animal’s behavior. When the rabies virus causes its host—such as a dog, fox, or bat—to become aggressive, it does so by infiltrating a specific brain circuit responsible for anger and aggression. This increases the chance of the infected animal attacking and biting another animal (or human), thereby transferring the virus contained in its saliva into the wounds of the victim.

However, parasites and viruses are not the only microbes with a remarkable ability to influence our brain. Over the last decade, researchers have found that some of the microbes living peacefully in our gut have equally impressive skills, though they don’t use these skills against us. But still, their effects on the brain-gut axis are profound.

Do Microbes Mediate Gut-Brain Communication?

Just a few years ago, many of us studying brain-gut interactions thought we had identified all the essential components that contributed to bidirectional brain-gut-brain communication.

-How the gut senses heat, cold, pain, stretch, acidity, nutrients in food, and other characteristics—so many, in fact, that our intestinal surface is arguably the largest and most sophisticated sensory system in our bodies.

-Those gut sensations were relayed to our little brain and big brain through the action of hormones, signaling molecules of immune cells, and sensory nerves, especially the vagus nerve.

-The enteric nervous system—the little brain in your gut—acts as a local regulatory agency that stays in constant close contact with the federal authority, your brain, in case of emergencies.

-We experience specialized emotional operating programs in the brain that create distinct dramatic plots that play out in our guts, causing a characteristic pattern of gut contractions, blood flow, and the secretion of vital digestive fluids for each emotion.

-The disturbed communication between brain and gut plays a prominent role in functional gut disorders such as irritable bowel syndrome and involved in such nondigestive disorders as anxiety, depression, and autism.

-Our bodies actually organize gut reactions and gut feelings in the form of an elaborate brain-gut circuitry that includes the gut microbiota.

-Our emotionally triggered gut reactions trigger a myriad of gut sensations which then travel back to our brain, where they can modulate or create gut feelings, and where they are stored as emotional memories of a particular experience.

-This mass of invisible life can communicate constantly with our brains through a variety of signals, including hormones, neurotransmitters, and myriad small compounds called metabolites.

-In the conversation between the gut and the brain, your gut microbiota engage in an extensive running dialogue, using a sophisticated biochemical language called “microbe-speak.”

The Dawn of Microbe-Speak

For the first three billion years of their existence, microbes were the sole living inhabitants of the planet. And there were trillions of them, more numerous than the stars in our galaxy. They floated in a silent but massive marine-based universe, packed with close to a billion different species of invisible microbes of different shapes, colors, and behaviors.

These microbes gradually perfected the ability to communicate with each other. They manufactured signaling molecules to send signals, along with receptor molecules to serve as specific decoding mechanisms for these signals. In this way, signaling molecules released by one microbe could be decoded by another one nearby. These signaling molecules closely resemble the hormones and neurotransmitters that your gut uses today to communicate with your enteric nervous system and brain.

Over millions of years, as primitive marine animals evolved into more complex creatures, they developed simple nervous systems in the form of nerve networks surrounding their primitive guts, not very different from the networks of the enteric nervous system that surround our guts today.

This makes it understandable why there is such an intricate relationship between our microbes, the gut, and the brain.