Microbe-Speak: A Key Component of the Gut-Brain Dialogue
In the 1970s and 1980s, the leading research on gut-brain communication could be found at the Center for Ulcer Research and Education (CURE), on the campus of the U.S. Veterans Administration (now the U.S. Department of Veterans Affairs) in West Los Angeles. Founded by Morton I. Grossman, one of the preeminent physiologists of the digestive system, CURE was the mecca for scientists and clinical investigators worldwide who wanted to study stomach ulcers (which were a major health problem at the time) and, more generally, the fundamental mechanisms of how the digestive system operates. Books have been written and stories are still told about the center, its scientific breakthroughs, its founder and charismatic leader, and a disciple of Grossman named John Walsh.
When I arrived in Los Angeles in the early 1980s to work at CURE as a research fellow, my goal was to study the biology of communication within the gastrointestinal tract. The topic of gut-brain interactions had been completely absent from my medical school curriculum at Ludwig Maximilian University, in Munich, Germany. I had just completed my residency in internal medicine at the University of British Columbia, in Vancouver, and I couldn’t wait to start what was initially conceived as a two-year research training fellowship to pursue my scientific interest.
At the time, John Walsh was a young, brilliant investigator who made a lot of his visionary decisions and discoveries based on his gut feelings—something I only realized much later in my life. He had a career-long interest in a group of then-mysterious 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. At the time, biologists thought that these signaling molecules worked as simple chemical switches that turned on or off the stomach’s production of hydrochloric acid, or the pancreas’s secretion of digestive hormones, or the gallbladder’s ability to contract. But over the next few remarkable years in this cradle of modern gut-brain research, I would watch firsthand as our understanding of these signaling molecules evolved from simple on-off switches to 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.
Not long after the Italians reported their results, Viktor Mutt and his colleagues at the Karolinska Institute in Sweden searched for similar gut peptides in mammals. Eventually they extracted and purified these molecules on an industrial scale from cooked pig intestines, and they distributed them to interested investigators around the world. When these precious extracts were shipped in powder form to Walsh’s laboratory, we treated them with awe, considering the amount of work and time that had been invested to isolate them. Later, we headed out to a Los Angeles-area slaughterhouse in the early morning hours, returning with containers of pig intestines from which we purified the gut peptides ourselves. When we injected one of these substances, a molecule called gastrin, we observed that the animal’s stomach started ramping up its secretion of hydrochloric acid. Injecting another gut peptide—secretin—turned on secretion of digestive juices from the pancreas, while injecting the peptide somatostatin tended to turn both functions off. These gut peptides have also been called gut hormones, as they were able to reach distant targets in the body when injected into the bloodstream, just as hormones produced by the thyroid gland or the ovaries can send long-distance messages.
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.
The story took an unexpected turn in the early 1980s when a group of scientists at the National Institutes of Health, led by visionary biologists Jesse Roth and Derek LeRoith, wanted to find out if microorganisms were capable of producing the same signaling molecules that Walsh, Mutt, and Erspamer had isolated from frogs, pigs, dogs, and other animals. They grew different microorganisms in a nutrient-containing broth, separated the microorganisms from the broth, and tested them for the presence of insulin, the hormone that signals our tissues to store energy from sugar after a meal.
In both the cells and the broth, they found molecules similar to human insulin—similar enough that the molecules stimulated lab-grown fat cells from rats to sock away energy from sugar. This dramatic result suggested for the first time that insulin did not originally appear in animals, as biologists had thought, but was already present in more primitive single-celled organisms that arose about a billion years ago.
I first learned about LeRoith and Roth’s fascinating research when they sent extracts from other microbes to Walsh’s laboratory at CURE, which used the radioimmunoassay tests to identify and quantify these molecules. These studies yielded surprising results: in addition to insulin, my colleagues found molecules similar to other mammalian gut peptides. Ancient microbial versions of many gut peptides and hormones, including noradrenaline, endorphins, and serotonin and their receptors, have since been identified.
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. Several years later, I became so intrigued by this evolving science that I decided to write a speculative review article myself, in collaboration with my friend Pierre Baldi, a brilliant mathematician then working at the California Institute of Technology. Even though a prominent linguistic professor at UCLA tried to convince me that you can only talk about language in the context of human communication, we gave it the title “Are Gut Peptides the Words of a Universal Biological Language.” The article was published in the American Journal of Physiology in 1991.
When I showed the manuscript to Walsh, he jokingly said: “You’re lucky this speculative paper was accepted for publication. These ideas are about thirty years ahead of their time.” (As usual with his visionary statements, his prediction wasn’t very far off.) 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.
Unfortunately, the time was not yet ripe for the rest of the scientific world to realize the impact of these early discoveries. As Walsh predicted, it would take nearly three decades of research into brain-gut interactions for gut microbes to again take center stage.
The Downside of Early Gut Cleansing
Dahlia walked into my clinic in black clothing and dark sunglasses, as if she were on her way to a funeral. Having seen many such patients, I wasn’t surprised by her appearance. The dark glasses may have been due to an extreme sensitivity to light, which is often associated with migraines. Or perhaps her outfit was a cloak that Dahlia, a forty-five-year-old woman, was wearing to try to hide her feelings of chagrin.
Dahlia had made the appointment to get help with her intractable constipation, but her medical problems were not limited to her bowel movements. Other symptoms included chronic pain all over her body, fatigue, and migraine headaches. During my conversations with her, it became clear that Dahlia was also chronically depressed, a situation that she attributed solely to her gastrointestinal issues. She told me that her difficulties with regular bowel movements dated back to infancy, when her mother gave her regular enemas—a common practice that many mothers of the era employed to ensure daily bowel movements in their children.
Regrettably, the only way Dahlia could guarantee regular bowel movements was by taking daily enemas and by receiving high colonics (a more extensive enema in which warm water is injected into the upper colon) on a weekly basis. Without the daily enemas, she said, she was unable to have any spontaneous bowel movements for up to several weeks at a time. Dahlia insisted that her colon was “dead” and was no longer able to transport any of its contents, and she was terrified that she would experience unbearable discomfort if she didn’t induce a daily bowel movement. These facts, combined with her fear of discomfort from constipation, had fostered a strong belief that she would never be able to stop this enema regimen.
Dahlia had tried many previous therapeutic approaches, which had all failed, and treating her depression with various drugs only had a transient effect on her constipation. It seemed as if some unknown mechanism forced her gut-brain axis always back to its disturbed mode of communication. I ordered a series of diagnostic evaluations, none of which revealed anything that could explain her constipation. Most interesting was the fact that, based on a specialized test called a colonic transit study, the time it took for digestive waste to move through her colon was completely normal.
Dahlia was also convinced that her symptoms of anxiety, depression, fatigue, and chronic pain were caused by fermenting toxic waste products in her intestinal tract, and that her inability to rid herself of these waste products was having a major effect on her overall well-being. Many physicians upon encountering such a patient, with her constellation of symptoms and her bizarre-sounding stories, would perform a colonoscopy, and provide a prescription for the newest laxative and a referral to a psychiatrist. Today we know that such a strategy would ignore some important biological factors in the patient’s symptoms. It is likely that the enemas Dahlia received as a young child interfered with the development of a normal gut microbial composition during her first years of life, resulting in long-lasting changes in the way her gut microbes communicated with her nervous system. Even though we still don’t have the science to know exactly what these early gut microbial changes are that lead to symptoms like Dahlia’s, her story strongly suggests that changes in the normal development of a healthy gut microbiome can put patients at risk of developing psychiatric symptoms as well as a lifelong miscommunication between the gut and the brain. I am convinced that in the future we will have therapeutic strategies to reverse such early programming errors of the gut-brain axis. Until then, a holistic treatment approach including a combination of pharmacologic and behavioral treatments to deal with her psychiatric symptoms, establishing a greater diversity of gut microbes through probiotic ingestion and a diet high in plant-based fiber, and the administration of herbal laxatives to stimulate fluid secretion in the colon is likely to be beneficial. Such an approach will also help to validate the patient’s suffering and her unique story. In the case of Dahlia, this approach was able not only to gradually improve her gastrointestinal symptoms, but also to reduce her symptoms of anxiety and depression.
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. Medical students are not taught how to diagnose such patients, so it would be easy for even an experienced gastroenterologist to pass off Dahlia’s misguided assumptions as a psychological aberration with specifics unique to her. But I suspect that in addition to the altered development of the gut microbiota-brain communication, her routine was in part a remnant of the ancient and all-too-enduring belief that toxic waste products accumulating in the colon play a role in all kinds of diseases and ailments, both physical and psychological, and that cleansing the colon is the essential remedy for this. This belief, called intestinal putrefaction or autointoxication, is nearly as old as papyrus, and its treatment was part of ancient healing traditions in every corner of the world.
Gut Suspicions
In ancient Egypt and Mesopotamia, people believed that rotting food in the intestines forms toxins, which then move through the body via the circulatory system and cause fevers, resulting in disease. To heal such ills, the Ebers Papyrus, an Egyptian medical text from the fourteenth century B.C., provides directions for using an enema to treat more than twenty different stomach and intestinal issues by “driving out excrements.” Ancient Egyptians claimed that the god Thot had taught them about autointoxication and about purifying the gut to avoid disease. This led the pharaoh to name an appointee known as “keeper of the rectum,” whose job was to manage the royal enemas—one of history’s first truly rough gigs.
Across the Red Sea in ancient Mesopotamia, Sumerians, members of the oldest known human civilization, also applied enemas to expel disease. So did ancient Babylonians and Assyrians, whose tablets from as early as 600 B.C. mention the use of enemas. Over in India, Susruta, the father of Indian surgery, was specific in his recommendations, describing in Sanskrit medical texts how to use syringes, bougies, and a rectal speculum. The tradition continued with Ayurvedic practitioners: the most important of the five detoxifying and cleansing Ayurvedic therapies was enemas to clear the lower GI tract. Ayurvedic healers also commonly used niruha basti, a type of medicated enema, to treat a variety of ailments, including arthritis, backache, constipation, irritable bowel syndrome, neurological disorders, and obesity. And in East Asia, Chinese and Korean healers were also concerned with the dangers of an unclean bowel. They prescribed enemas and colonic irrigation to manage the dangers of “internal dampness,” which they believed could cause myriad problems, including high cholesterol, chronic fatigue syndrome, fibromyalgia, allergies, and cancer.
The founders of Western medicine had other ideas about how autointoxication affected the body, but they agreed that it was definitely not good. The classical Greek physician Hippocrates, for whom the Hippocratic Oath is named, documented using enemas to treat fevers and other bodily disorders. Hippocrates is also credited with the profound statement that all diseases start in the gut. Ancient Greeks adopted the Egyptian idea that rotting food inside us leads to disease-causing toxins, which brought about the idea of the four humors that had to be balanced to maintain health—an idea that held throughout the Middle Ages.
Why have humans been so obsessed for so long with the dangers lurking inside our guts? Many patients from different ethnic, educational, and socioeconomic backgrounds whom I see in my clinic strongly believe in this idea as well. 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. The fact that they still come to my clinic with unabated digestive problems makes me wonder if any of the treatments they’ve tried have really done any good, or if they have at most simply relieved the patients’ anxieties.
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 work published in 2000 by Manuel Berdoy and his research group at Oxford University. That study showed that T. gondii has its own agenda of survival and reproduction, which it pursues in a remarkably cunning and egotistical fashion.
While toxoplasma can reproduce in one place only—the gastrointestinal tract of infected cats—the parasite can actually infiltrate the brain of any mammal (including humans), by outsmarting the blood-brain barrier, which functions as a firewall to isolate and protect the brain from any unwanted influences. Once cats are infected, they then dispel this microorganism in their excrement. Thus gynecologists recommend that pregnant women keep cats and their litter boxes out of the house, and refrain from gardening in areas where cats may bury their feces in the ground. In toxoplasma’s ideal world, cats excrete the parasite, and rodents subsequently ingest it. The parasite then forms round cysts throughout the rodent’s body, and, in particular, in its brain. A cat in turn eats the infected rodent. The ingested cysts reproduce in the cat’s gastrointestinal tract, the cat sheds newly hatched parasites in its feces, and the cycle of life continues.
Here is where the plot takes a fascinating turn, attesting to the remarkable cleverness of this microbe. Under normal circumstances, a pathogen from an infected rat would be very unlikely to wind up back in a cat because rodents instinctively avoid cats. But 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.
The evolutionary intelligence behind these strategies is remarkable. Pharmaceutical companies have spent billions of dollars to develop medications designed to perform the same tasks that toxoplasma accomplishes with such ease. Most of these investments have failed. For example, compounds developed to attenuate the fear response in anxiety disorders and to block the action of CRF, a molecule involved in the stress response, and compounds designed to boost libido in women with hypoactive sexual desire disorder have proven marginally effective, and they come with potentially serious side effects.
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. While the toxoplasma parasite and the rabies virus stand out in terms of the highly specialized knowledge of their host animals’ nervous system, many other disease-causing microbes, including bacteria, protozoa, and viruses, have developed surprising and clever ways to manipulate the behavior of their host animals.
If a hacker had manipulated a company’s computer system the way the toxoplasma parasite and the rabies virus manipulate the brain, we’d suspect that the infiltrator was a skilled hacker with in-depth knowledge of the system’s code, and that he had perpetrated an inside job. Toxoplasma and rabies have evolved to understand the ins and outs of the mammalian brain-gut axis, and they have a detailed knowledge of mammalian emotional operating systems—and can manipulate them to achieve their goals.
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.
We knew about many of the ways the gut keeps tabs on digestion and on our environment: how it 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. It seemed clear that 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. This new knowledge explained why our digestive system functions perfectly and without our awareness most of the time, why the gut reacts the way it does to a tainted meal, and why we feel good after a delicious meal.
We also knew that in managing digestion, 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 had learned that when we experience emotions, specialized emotional operating programs in the brain 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 clinicians among us were satisfied with our new knowledge that the disturbed communication between brain and gut plays a prominent role in functional gut disorders such as irritable bowel syndrome. And contrary to the view of the great majority of psychiatrists and most of my gastroenterology colleagues, I suspected early on that modifications in this communication system might even be involved in such nondigestive disorders as anxiety, depression, and autism.
Still, as happens often in science, our initial confidence turned out to be premature. Though we had uncovered much about bidirectional communications between the gut and the brain, it was becoming apparent that our bodies actually organize gut reactions and gut feelings in the form of an elaborate brain-gut circuitry that includes the gut microbiota as an essential component. We had come to our earlier conclusions and made our predictions without taking into account this crucial role of the gut microbiota.
As it turns out, our emotionally triggered gut reactions do not remain tied up in the twists and spasms of our gut. They also 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. And we have realized only in the last few years—to the surprise of scientists around the world—that our gut microbes play an integral role in this interaction between gut reactions and sensations.
As we now understand it, 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. These metabolites are the result of the microbes’ peculiar eating habits and are produced when they feed on the indigestible leftovers of what we consume, on bile acids secreted by the liver into the gut, or on the mucus layer covering your intestine. In fact, in the conversation between the gut and the brain, your gut microbiota engage in an extensive running dialogue, using a sophisticated biochemical language I’ll call “microbe-speak.”
Why do our gut microbes and our brains need such a sophisticated communication system? How did microbe-speak develop? To answer these questions, I need to take you back in time—far back, to the earth’s primeval, microbe-rich oceans.
The Dawn of Microbe-Speak
Approximately four billion years ago, life first appeared on earth in the form of single-celled microorganisms, the archaea. 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.
Over this vast stretch of time, through the trial and error of natural selection, these microbes gradually perfected the ability to communicate with each other. To accomplish this, 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. And this signaling actually triggers a transient or persistent change in behavior in the receiving microbe. As Jesse Roth and Derek LeRoith discovered, many of these signaling molecules closely resemble the hormones and neurotransmitters that your gut uses today to communicate with your enteric nervous system and brain. Together you can think of these molecules as an ancient and relatively simple language—just like the various biological signaling dialects that different organ systems in your body use today.
About 500 million years ago, the first primitive multicellular marine animals began to evolve in the ocean, and some marine microbes took up residence inside their digestive systems. One of those tiny marine animals—the hydra—can still be found today in bodies of fresh water. This creature is little more than a floating digestive tract. It’s a tube a few millimeters long, with a mouth at one end, a digestive system filled with microbes running down its length, and an adhesive disk at the other end to anchor the animal to a rock or underwater plant.
Gradually, the animals and microbes developed a symbiotic relationship, and the microbes found ways to transfer vital genetic information to their host animals. This information provided the host animals with a range of molecules that they were lacking, but which the microbes had learned to manufacture during billions of years of trial and error. Some of these molecules became the neurotransmitters, hormones, gut peptides, cytokines, and other types of signaling molecules our bodies use today.
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. The nerve networks in these creatures used some of the genetic instructions they received from the microbes to produce signaling chemicals, which allowed neurons to pass messages to each other and instruct muscle cells to contract. These were the precursors of our human neurotransmitters.
Amazingly, these simple nerve networks and their signaling molecules enabled the primitive animals of millions of years ago to respond to ingested food in a similar, programmed way as our guts do today. When they consumed food, they engaged in stereotypic movements equivalent to those of the human digestive tract: a series of reflexes that propelled ingested food from the esophagus through the stomach and upper intestine, and that helped to excrete unwanted intestinal contents. When these animals consumed toxins, they were able to expel them from either or both ends of their GI tract, the human equivalent of the vomiting and diarrhea associated with food poisoning. These early marine animals also contained cells that could secrete certain chemicals to help trigger their digestive reflex. These secretory cells may well be the ancestors of our enteroendocrine cells, the specialized cells in the gut that produce most of the body’s serotonin and the gut hormones that make you feel hungry or full.
The new symbiosis between the tiny marine creatures and their resident microbes led to many benefits for both of them. The animals gained the ability to digest certain foods, obtain vitamins that they couldn’t synthesize themselves, and evade or expel toxins and other dangers in their environment. The microbes in their digestive systems gained a contained, convenient environment in which they could thrive, and free transport from one location to another. That collection of microbes can be viewed as the earliest version of the gut microbiota in your intestines.
This symbiotic relationship between gut microbes and their hosts turned out to be so beneficial for both partners that it has been conserved in virtually every living multicellular animal on earth today, from ants, termites, and bees to cows, elephants, and humans. The fact that these basic digestive activities have persisted through hundreds of millions of years attests to the remarkable evolutionary intelligence that has been programmed into your gut and its enteric nervous system. It also makes it understandable why there is such an intricate relationship between our microbes, the gut, and the brain.
As more complex types of animals evolved, primitive nervous systems grew into a more elaborate network of nerves outside the digestive system. This network was separate from—yet still intimately connected with—the enteric nervous system, and it retained most of the signaling mechanisms. The elaborate new nerve network eventually developed into a central nervous system, which established its headquarters inside the cranium.
Gradually, central nervous systems took over management of behaviors related to the outside world that had originally been handled exclusively by the enteric nervous system, including the ability to approach or withdraw from other animals as circumstances warranted. These functions were eventually transferred to emotion-regulating regions of the brain, while the enteric nervous system itself was left in charge of the basic digestive functions, a division of labor that has persisted in our own gut-brain axis.
It’s been hundreds of millions of years since a handful of microbes made initial contact with the primitive gut of a simple marine animal. But the long evolutionary journey that we’ve taken since then helps explain why today your own gut, including its enteric nervous system and its microbiome, continues to have such a powerful influence on your emotions and your overall well-being.
An Ancient Binding Contract
Take a moment now to ponder the wonders of your gut microbiota. This collection of some one thousand species of microbes comprises 1,000 times more cells than exist in your brain and spinal cord, and ten times more than the number of human cells in your entire body. Together, the gut microbiota weigh about as much as your liver, and more than your brain or your heart. This has led some people to refer to the gut microbiota as a newly discovered organ, one that rivals the complexity of your brain.
The vast majority of gut microbes are not only harmless, but are in fact beneficial for our health and well-being; these are referred to by scientists as symbionts or commensals. The symbionts obtain nutrients from their hosts, and in exchange they help keep the gut in balance and defend against intruders. But there is a small number of potentially harmful microbes, called pathobionts, that reside in your gut as well. Under certain conditions, these untrustworthy microbes can turn their weapons against us. Pathobionts have molecular tools that serve as artillery for attacking your gut lining, causing inflammation of the lining or ulcers. This change of loyalty can be a consequence of changes in diet, antibiotic treatment, or severe stress, and it results in the abnormal accumulation or increased virulence of certain populations of bacteria, thereby transforming former symbionts into pathobionts.
Yet human gut microbes rarely resort to such aggressive tactics. Instead, they usually live in harmony with us, minding their own affairs, which include digestion, growth, and reproduction. Nor does our immune system turn its formidable weapons on gut microbiota. The simple reason is that the costs to both sides greatly outweigh the benefits. Instead, both sides provide services for the other. It’s an ancient binding contract that functions as both a peace treaty and a trade agreement, ensuring substantial reciprocal benefits to all involved.
The symbiosis between the microbes and their hosts that developed in its simplest form millions of years ago continues in our bodies today. Microbes gain by being able to live a privileged life in our intestines, which comes with a constant supply of food, moderate temperatures, and unlimited free travel. They also gain a free connection to our internal Internet traffic—the constant flow of information transmitted by hormones, gut peptides, nerve impulses, and other chemical signals. This information allows them to keep track of our emotional states, our stress levels, whether we are asleep or awake, and which environmental conditions we are exposed to. Having access to this private information helps the microbes to adjust production of their metabolites not only to ensure optimal living conditions for themselves, but also to stay in harmony with our gut environment.
In exchange, the microbes provide us with essential vitamins, metabolize digestive compounds, called bile acids, that are produced by the liver, and detoxify foreign chemicals that our bodies have never experienced—so-called xenobiotics. Most important, they digest dietary fiber and complex sugar molecules that our digestive system can’t break down or absorb on its own, and thus provide us with a substantial number of additional calories that we would otherwise lose in our stool. In prehistoric times, when people were more concerned with hunting and gathering enough food to eat than fitting into their skinny jeans, the extra calories that gut microbiota extracted from food helped them survive. But today, as we’re awash in excess food and obesity is epidemic, the extra calories that gut microbes provide have become a liability.
Respecting the key points of this ancient binding contract has produced a remarkably peaceful and mutually beneficial coexistence between microbes and hosts that has persisted for millions of years. It is an astonishing accomplishment—we humans are light-years away from such a track record of harmony.
Microbe-Speak and Your Internal Internet
Your gut microbes are engaged in ongoing conversations with your GI tract, your immune system, your enteric nervous system, and your brain—and as with any cooperative relationship, healthy communication is essential. Recent research reveals that the disturbance of these conversations can lead to GI diseases, including inflammatory bowel disease and antibiotic-associated diarrhea, and obesity, with all its deleterious consequences, and may be involved in the development of many serious brain diseases, including depression, Alzheimer’s disease, and autism.
The communication with the brain occurs in several parallel “channels” that use different modes of transmission. This includes molecules that can communicate with the brain as inflammatory signals, travel through the blood like hormones, or reach the brain in the form of nerve signals. Communication through these channels does not occur in isolation; as we will see, there is extensive cross talk between them. Your gut microbes can listen in on your brain’s ongoing conversation and vice versa, and information flow through the biological channels that your gut microbes use to communicate with your brain is highly dynamic.
The amount of information that is allowed to travel through this system depends in large part on the thickness and integrity of the thin mucus layer lining the gut surface, the permeability of your gut wall (its leakiness), and the blood-brain barrier. Normally, these barriers are relatively tight, and the flow of information from gut microbes to the brain is restricted. But stress, inflammation, a high-fat diet, and certain food additives can make these natural barriers leakier.
To fully grasp what your microbes are doing inside you, for the moment consider the various microbial communication channels together as a conduit of information akin to the fiber optic line or cable that supplies your home with Internet service. The amount of information being transmitted through this conduit varies. At some moments, the microbes will be uploading relatively small “text documents,” and the amount of transmitted information will be small; but at other moments, they’ll be uploading a series of huge, information-dense video clips.
However, there are ways that this communication system works differently from your home broadband service. The service contract with your Internet provider caps the amount of information you can upload or download per second. In other words, you have a fixed bandwidth, depending on whether you signed up for the cheaper economy plan or the more expensive deluxe plan. The Internet connection between your gut microbes and your brain, in contrast, is highly dynamic, as if you had the economy plan for most of the time, but quickly switch to the deluxe plan when you are stressed—say, after you had dinner in a French restaurant that included an appetizer of foie gras and a filet of sole sautéed in lots of butter.
As we turn to the communication channels of microbe-speak, let’s start by looking at the role of the immune system in the gut microbial signaling to the brain. There are several ways by which this microbe-immune system-brain dialogue can take place, and the consequences of altered interactions between the gut microbe and immune system have received a lot of attention recently, as disturbances in this complex dialogue have been implicated in many brain diseases.
One means of communication involves specialized immune cells known as dendritic cells, located just under the inner lining of the gut. Dendritic cells have “tentacles” that extend into the gut’s interior, where they can communicate directly with the group of gut microbes that live near the gut wall. These immune cell sensors are a first line of detection. Under normal conditions, receptors on these cell parts—so-called pattern recognition or toll-like receptors (TLRs)—recognize various signals from benign microbes, assuring the immune system that all is well and that no defensive response is necessary. Our immune cells have learned to correctly interpret these peace signals from interactions with a large variety of gut microbes early in life. In contrast, when harmful or potentially dangerous bacteria are detected through these mechanisms, they trigger an innate immune response—a cascade of inflammatory reactions in the gut wall—to keep the pathogens in check.
Recent studies have shown that the mucus protecting the gut surface is produced by specialized cells in the gut wall and is organized into two layers: a thin, inner layer that firmly sticks to the cells of the gut wall and an outer, thicker, and nonattached layer. Together these two transparent layers are nearly invisible to the human eye, measuring only 150 microns across, or about one and a half times the thickness of a human hair. The inner mucus layer is dense and does not allow bacteria to penetrate, thus keeping the epithelial cell surface free from bacteria. In contrast, the outer layer is home to the majority of your gut microbes as well as complex sugar molecules called mucins, which serve as an important source of nutrients for the microbes, especially when you fast or you have less fiber in your diet.
When microbes penetrate the protective mucus layer that covers the lining of the gut, the molecules of their cell walls trigger the activation of immune cells beneath the gut lining, which then tailor the immune response depending on whether, or to what degree, the microbe poses a danger. One such molecule—lipopolysaccharide, or LPS—is of particular importance in this microbe-immune system dialogue. LPS, a component of the cell wall of certain microbes called gram-negative organisms, is able to increase the leakiness of the gut, thereby facilitating the transfer of microbes to the immune system.
In contrast to common belief, no gut infection with a nasty bacterium or virus is required to trigger such responses of the immune system. However, as scientists recently found out, several other mechanisms related to our diet and the resulting alterations in the composition of our gut microbia come into play. First, people eating a high animal fat diet have an increase in the relative abundance of such gram-negative bacteria in their gut, or Firmicutes and Proteobacteria, and are therefore more likely to chronically engage this immune activation mechanism. Secondly, a diet low in plant-based fiber reduces the abundance of a particular microorganism called Akkermansia muciniphilia inside of our gut. Under normal conditions, this organism plays an important role in regulating the quality and thickness of the mucus layer that is part of the barrier separating the inside of our gut from our immune system (the other part of the barrier is the intestinal wall itself). The bacterium does this by stimulating the mucus production by cells lining our intestines. The thinner the mucus layer, the closer the intestinal microbes get to the cells lining the gut, the leakier the gut becomes and the easier it is for the gut microbes to activate the gut’s immune system. Thus when excessive dietary fat and greatly reduced dietary fiber intake—the hallmarks of the modern North American diet—has compromised the two natural intestinal barriers (the mucus layer and the gut lining) that keep us separated from the trillions of microorganisms in our gut lumen, the gut microbes or their signaling molecules can cross the gut lining in greater numbers, causing even greater engagement of the gut-based immune system, an inflammatory process that can spread throughout the body. This process has been referred to as metabolic toxemia.
No matter how the gut’s immune system detects microbes, it responds by producing a number of molecules called cytokines. Under certain circumstances, these cytokines can cause local full-blown inflammation of the gut, as happens in inflammatory bowel disease or in acute gastroenteritis. But once the cytokines are generated in the gut, these signals can also be sent to the brain. For example, they can bind to receptors on sensory nerve terminals of the vagus nerve, the gut-brain information highway, and send long-distance messages into vital regions in the brain that can reduce your energy level, increase feelings of fatigue and pain sensitivity, and even make you feel depressed. And with milder degrees of vagal inflammation, the sensitivity of vagal nerve terminals to satiety signals decreases, compromising the normal mechanism that stops you from eating after a full meal. Interference with this mechanism is often a problem for patients with high dietary fat consumption.
Alternatively, cytokines may spill into the bloodstream, travel to the brain like a hormone, transverse the blood-brain barrier, and activate immune cells—called microglial cells—inside the brain. As the majority of cells in our brains are microglial cells, which respond to cytokines, this makes the brain a receptive target of gut-microbial-immune system signaling. Such long-distance immune signaling from the gut to the brain has been implicated in the development of neurodegenerative diseases such as Alzheimer’s.
In addition to their elaborate ways of communicating with our immune system, microbes also use their metabolites to communicate with your brain in ways that are less dramatic, yet equally vital. Gut microbes are highly diverse and numerous—there are 360 microbial genes in the gut for every human gene—and can digest substances that we cannot. This produces several hundred thousand different metabolites, many that our digestive system doesn’t produce itself. A large number of these microbial metabolites make it into the bloodstream, where they account for nearly 40 percent of all circulating molecules. Many are considered neuroactive, which means they can interact with our nervous system. The large intestine absorbs some of these metabolites, transferring them into the bloodstream, and more make it into the bloodstream if you have a leaky gut. Once in the circulation, the metabolites can then travel to many organs in your body, including the brain, as a hormone does.
Another important way microbial metabolites signal the brain is via the serotonin-packed enterochromaffin cells in your gut wall. These cells are studded with receptors that detect a variety of microbial metabolites, including bile-acid metabolites, and short-chain fatty acids, such as butyrate, that come from whole-grain cereal, asparagus, or your favorite vegetable dish. Some of these metabolites can increase the production of serotonin in enterochromaffin cells, making more of this molecule available for signaling to the brain via the vagus nerve. They can also alter your sleep, pain sensitivity, and overall well-being. In animal experiments, they were shown to influence the development of anxiety-like and social behaviors. And they may play a role in how good you feel after a healthy meal rich in fruits, whole grains, and vegetables, or how bad you feel after eating too many greasy potato chips or a basket of deep-fried chicken.
Millions of Conversations Within
What makes the role of the gut microbiota so intriguing and far-reaching is the fact that this mass of microbes is sitting right at the interface that separates our gut reactions and our gut sensations. Depending on the type of meal you just ate, or whether your gut is completely empty, the enteric nervous system alters the gut environment and manages digestion by controlling the acidity, fluidity, secretions of digestive fluids, and mechanical contractions of your GI tract. Thus gut microbes constantly adapt to regional shifts in acidity, secretion of vital digestive fluids, available nutrients, and how much time they have to digest them before they’re excreted. Likewise, when stress or high anxiety causes the brain’s emotional operating programs to create dramatic plots that play out in our guts, it alters gut contractions, rates of transit from the stomach to the large intestine, and blood flow. This can dramatically alter living conditions for microbes in the small and large intestine, and is probably one of the reasons why the composition of your gut microbes is altered during stress. In contrast, when you feel depressed and everything in your gut slows down, microbes sense these changes and activate genes that help them adapt to those shifting conditions.
Meanwhile, the digestive, immune, and nervous tissues are busy communicating with each other, using signaling molecules that include gut peptides, cytokines, and neurotransmitters. Crucially, all of these substances are elements of biochemical languages that, thanks to our long, shared evolutionary history, are actually distant dialects of “microbe-speak.”
As we scientists got over our initial surprise at the pivotal role of gut microbes in brain-gut communication, and as we investigated this relationship further over the last few years, it became ever clearer that the brain, the gut, and the microbiome are all in constant, close communication. We began thinking of the brain, the gut, and the microbiome as parts of a single integrated system, with plenty of cross talk and feedback from one part to another. I refer to this system throughout the book as the brain-gut-microbiome axis.
For the entire twentieth century, scientists could not see our microbial partners because the great majority of them could not be grown in the laboratory. Until the advent of automated gene-sequencing techniques to identify classes of microbes and supercomputers to process the massive microbial data, we had no way of conducting extensive surveys to determine which microbes were there, which genes they collectively possessed, and which metabolites they produced. More specifically, we had only limited understanding of how the various players in the brain-gut-microbiome axis communicate with each other.
It’s now clear that our gut microbes have more than just a privileged role in our body. As the prominent microbiome expert David Relman, of Stanford University, expressed it, “The human microbiota is a fundamental component of what it means to be human.” In addition to their indispensable role in helping us digest large parts of our diet, it is becoming clear that gut microbes have an extensive and wholly unexpected influence on the appetite-control systems and emotional operating systems in our brain, on our behavior, and even on our minds. These invisible creatures in our digestive system have a word to say when it comes to how we feel, how we make our gut-based decisions, and how our brain develops and ages.