Unhealthy Memories: The Effects of Early Life Experiences on the Gut-Brain Dialogue
It makes intuitive sense that growing up in a harmonious, protected family environment has a positive effect on a person’s development. Parents all over the world strive to provide such an optimal setting for their children. But ever since the advent of psychoanalysis, we know that certain repressed, adverse childhood experiences can result in psychological problems later in life. Most of the time, such childhood experiences are out of the control of the parents. In her bestselling book The Drama of the Gifted Child, psychologist Alice Miller maintained nearly forty years ago that all instances of mental illness had their developmental origin in unresolved, subconscious childhood trauma, which could be physical or psychological in nature. Even though I was fascinated when reading Miller’s book during my medical training in the early 1980s, it took me more than twenty years to realize that the connection between early adverse life events and adult health outcomes laid out in her book not only were relevant to the development of behavioral and psychological problems such as depression, anxiety, and addiction, but also might be relevant to the medical problems of my patients, in particular those with chronic gastrointestinal disorders.
Today, exploring a patient’s first eighteen years has become an essential part of any medical history I take. And it turns out it is a very simple thing to do; it doesn’t require a specialized psychoanalytical training, and it doesn’t take much time. In many patients I often get more important clues about their illness from exploring early life experiences than from asking in great length about the details of their medical symptoms. I always ask my patients the simple question, “Do you think you had a happy childhood?” What is most remarkable is the fact that asking this question, and without any additional probing, I usually get an honest account of what traumatic experiences patients remember from their first eighteen years of life. Most of the time the patient had not made a connection between such experiences and their current medical problem. Also, as I have learned over the years, their answers reveal a lot about the origin and nature of the stomach problems they experience as adults.
More than half of my patients over the years have told me of family trouble while they were growing up. One of their parents may have been ill, or there was an acrimonious divorce followed by a prolonged custody dispute, or perhaps, in more extreme cases, a close family member suffered from alcoholism or drug addiction. Some confide in me that as a child they experienced verbal, physical, or sexual abuse from a parent or stranger.
Several years ago, a thirty-five-year-old woman named Jennifer came to see me. “I’ve been suffering from belly pain all my life, but it’s gotten a lot worse this past year,” she said. To better understand the nature of her abdominal pain, I asked about her bowel movements. She said some days she had to run to the restroom all the time, while at other times she’d be constipated and couldn’t go for days. Her pain was worse on the days she had diarrhea, and her bowel movements would temporarily relieve it. As we talked, it became clear that Jennifer had been suffering emotionally as well. Since her early teens, she said, she had suffered from anxiety with accompanying panic attacks, and from recurrent bouts of depression.
Jennifer had seen several other specialists, including two gastroenterologists and a psychiatrist, and had undergone the usual battery of diagnostic tests, including endoscopies of the upper and lower digestive tract and a CT scan of her belly. None of the tests showed anything wrong. “The last two doctors I saw told me that there was nothing seriously wrong with me and implied that it was all in my head,” she said.
Jennifer’s doctors had prescribed the typical drug cocktail for such unexplainable brain-gut symptoms: the antidepressant Celexa and the acid-suppressing medication Prilosec. But they had also told her that she would have to learn to live with her symptoms, and that there was nothing more they could do for her. “I have almost completely lost my faith in the medical profession,” she told me.
Doctors generally spend much more time asking patients about the details of their bowel habits and checking blood pressure and cholesterol levels than they do exploring their risk factors related to early life experiences. Yet a recent study of close to 54,000 randomly selected Americans showed that children or teenagers who experience adverse events have a higher likelihood of suffering from poor health, a heart attack, stroke, asthma, and diabetes as adults. The risk for such negative adult health outcomes increased with the number of adverse experiences participants endured before the age eighteen. An earlier analysis of health records of a large health maintenance organization, in the Adverse Childhood Experiences (ACE) Study, had reported similar findings, including a 4–12 fold increase in the risk for alcoholism, depression, and substance abuse and a 2–4 fold reduction in self-rated health. The questionnaire used in both studies, the ACE questionnaire, asked participants about traumatic events experienced in childhood—such as sexual, physical, and emotional abuse—as well as more general household dysfunction related to the parents. The majority of these questions explored situations in which the stability in the family was disrupted and the nurturing interaction between the primary caregiver and child was compromised. Other studies have shown that the well-known association of poverty with poorer health outcomes is primarily linked to the health effects of the chronic stress that comes from living in a low socioeconomic status.
While the connection between a wide range of traumatic or unstable upbringings and negative health outcomes makes intuitive sense, it is only in the last thirty years that science has unraveled the biological mechanisms that are responsible for this connection, opening up windows for reversing the detrimental effects of this early life programming. These scientific insights are not only stunning, but have far-reaching implications for our health. If more doctors were aware of these connections and took the time to ask their patients about their childhoods, they could uncover important risk factors and possibly even devise more effective integrative treatment plans to help them.
During my consultation with Jennifer, I asked her why she had been put on the antidepressant medication Celexa several years ago. We talked about her depression and anxiety. “It has nothing to do with my stomach pain,” she insisted. I did not try to change her opinion on this sensitive subject, but I continued gently probing for factors that I suspected might underlie both her chronic digestive symptoms and her psychological symptoms.
“Do you think you had a happy childhood?” I asked her. Almost miraculously, the question unlocked a storybook of stressful tales. When Jennifer was still in the womb, her maternal grandmother was diagnosed with breast cancer, and the crisis distressed her pregnant mother. She witnessed her parents argue and fight for years when she was a girl, and they split in a bitter divorce when she was eight. Jennifer was not the only one in her family who had struggled with symptoms of depression and gut problems. Both her mother and grandmother had suffered from depression and anxiety on and off through their lives, and she remembers that they always complained about their “stomach issues.” Jennifer’s history tipped me off about the possible roots of both her brain and GI symptoms—and gave me confidence that I’d be able to help her.
Like many patients, Jennifer had never considered that her range of physical and emotional symptoms might be connected, that they might be tied to her stressful early life experiences, or that these experiences had programmed the interactions of her brain, the gut, and its microbes in a unhealthy way. But a growing body of science suggests that it’s past time to integrate this idea into modern medical practice.
Programmed for Stress
In the spring of 2002, at a small scientific conference in Sedona, Arizona, two strong-minded physicians offered clashing views about the cause of stress-related disorders. I had co-organized the conference with Charles Nemeroff, a prominent psychiatrist then at Emory University, to explore the role of early life trauma in a range of chronic medical and psychiatric diseases. Sedona’s secluded setting amid stunning red-rock wilderness helped lure leading researchers and practitioners from across North America.
On the second day of the conference, the well-known Canadian psychoanalyst and abdominal surgeon Ghislain Devroede took to the podium. Devroede specialized in treating patients who had suffered sexual abuse as children; he used psychoanalysis to surface their repressed pain and shame. Without such treatment, he maintained, the repressed emotion is buried in the body, causing physical symptoms. Then he told stories of patients with pelvic pain and intestinal disorders like chronic constipation he had treated, whose symptoms disappeared after they underwent psychoanalysis and faced their difficult pasts.
But Nemeroff, who had made his reputation studying the biological basis of major psychiatric disorders, was having none of it. He challenged Devroede. “We’ve learned that psychoanalysis is not very effective to treat the mental and physical consequences of early life trauma.” The room grew tense. No amount of psychoanalysis would ever reverse the trace in patients’ brains of early abuse, Nemeroff claimed. Most of the participants we’d invited agreed on this point. We no longer had to wonder about murky Freudian ideas about early sexuality or neuroses to help our patients heal.
Instead, science had shifted our thinking. We now have solid evidence that stressful experiences in early life, including a compromised interaction between the primary caregiver and his or her child, can leave lasting traces on his or her offspring’s brain. We also know from extensive surveys in human populations that these changes can drive the development of stress-sensitive disorders such as depression and anxiety, and that they might also play a role in gastrointestinal pain syndromes like IBS. But questionnaire data and psychological theories are not sufficient to help affected individuals. In order to develop novel therapies aimed to reverse this early programming in patients, we needed to know how our earliest experiences alter specific neural circuits in our brains that underlie our response to a variety of stressful situations. This knowledge could only be gained from basic studies performed in animal models of early life adversity.
A breakthrough in our understanding began when psychiatry researchers in the 1980s realized that stress exerts the same biological effects on animals like rats, mice, and monkeys as it does in humans. A major focus of these animal studies was on the role of the interactions between the mother and her offspring, as such interactions were easier to model in the laboratory, compared to such uniquely human behaviors as verbal and emotional abuse, or marital discord.
For example, rodents, like people, have different temperaments: some are timid, others are social; some are intrepid explorers, others stick close to home. And some rat mothers—even genetically identical animals—are better than others at nurturing their offspring. A nurturing rat mom pampers her pups. She hovers over them with her back conspicuously arched and legs splayed outward, allowing them to switch nipples, and she spends a lot of time licking and grooming them. A more negligent rat mom lazes on her side or lies on top of her pups as they struggle to nurse. This keeps them from switching nipples or wiggling, both of which are good for infant rats.
In landmark experiments that began in the late 1980s, Michael Meaney, a neuroscientist at McGill University, in Montreal, studied how the interactions between rat moms and pups played out in the lives of the pups. His research team took genetically identical rat mothers and videotaped and analyzed their behaviors while the pups were infants. Then they let the pups grow up, and checked how the pups of nurturing rat moms fared compared with the offspring of stressed-out moms.
The pampered pups grew into adults that were more laid-back, less reactive to stress, and less prone to addictive behaviors, such as overdoing it when given a free supply of alcohol or cocaine. They were also more social with other rats, more daring, and more willing to explore new places. Pups of stressed, negligent moms grew into loners prone to the rat equivalents of anxiety, depression, and addictive behaviors. Studies of monkey moms and their infants turned up similar results. Stressed macaque infants whose moms are inconsistent, erratic, and sometimes dismissive grow up timid, submissive, fearful, less gregarious, and more prone to depression than their better-nurtured peers. These early findings were the beginning of a paradigm shift in our understanding of how experiences in childhood can affect our health and the dialogue between the gut and the brain.
In another animal study, neuroscientists Paul Plotsky from Emory University and Michael Meaney studied rat pups whose moms were either naturally nurturing or naturally negligent. After the pups grew up, they stressed them by restraining them for a few minutes in tiny, formfitting stalls. The better-nurtured rats had lower levels of corticosterone, the rat stress hormone. (Cortisol is the human equivalent.) They also had hormonal changes in their blood and brain that keep the body’s stress response from running wild. It turned out that pups that had been licked and cuddled released several hormones, including growth hormone, that are essential for the young brain’s development.
In the meantime, a large body of scientific evidence has accumulated that confirms the close relationship between a mother’s stress level and the way the nervous system of the child will react to stress later in life. In various laboratory situations that have been designed to stress an animal mother—and thus affect her nurturing behavior toward her young—researchers have found that the stress-induced changes in the mother’s behavior programs the offspring’s brains to become more responsive to stressful situations, and create more anxiety in adults. No matter what the initial stressor is or what kind of animal is involved, the effect is similar. The more severe the stress on the mother, the worse her behavior toward her young, turning even once-nurturing moms into negligent mothers. Stressed moms trampled their pups, didn’t give them enough time to nurse, and licked and cuddled them less. Some were so stressed out that they killed their pups and ate them!
What was even more remarkable than observing the consistent negative effects of maternal stress on their young’s behavior were the insights into the biological mechanisms underlying these behavioral changes. Studying the brains of affected mice has revealed dramatic structural and molecular changes. Whole brain circuits and connections developed differently depending on the mother’s behavior, and several neurotransmitter systems involved in these connections were altered. The neglected animals had greater production of the stress molecule CRF, and less efficient systems that can regulate the stress response, including the signaling circuit involving the neurotransmitter GABA (gamma-aminobutyric acid) and its receptors. Because of these changes, even an antianxiety drug as strong as Valium did little to ease their stress.
Largely as a consequence of my daily interaction with patients who report experiencing adverse early life events—studies suggest that such a history is reported by up to 40 percent of healthy people and up to 60 percent of IBS patients—my research during the past twenty years has focused on better understanding the link between altered brain-gut interactions and early life adversity.
Early Stress and the Hypersensitive Gut
Not long after publication of the first studies of how mothering can program the brains of young rats, I received an invitation to a conference organized by the American College of Neuropsychopharmacology that brings together biological psychiatrists from across North America. Honored by the invitation, I participated in a mini-symposium on stress mechanisms, where I met Paul Plotsky, the neuroscientist from Emory University, for the first time. Listening to his presentation about his work on stress in mother rats and how it alters the biology and behavior of their young, I immediately wondered how his findings could be applied and, more important, offer some benefit to my patients with chronic gastrointestinal disorders.
Shortly after the conference I flew to Atlanta to explore possible ways we could collaborate. It was a rainy, hot Atlanta evening, and over dinner at a restaurant and a drink at his house, Paul and I talked for hours about what his work meant not only for stress-related gut disorders, but also for mind-body science in general. I mentioned my patients’ gut disorders, pain, and other psychological symptoms. “That’s me. I have all of that,” he joked. I wondered aloud whether my patients’ symptoms could be caused by childhood programming of their brain-gut axis. And I decided to spend some time in Paul’s lab to explore this theory.
When I planned these experiments, I had IBS patients like Jennifer in mind. We knew by then that adverse childhood events predisposed adults to anxiety, panic attacks, and depression. But other than a few reports linking IBS symptoms to past sexual abuse, no one knew whether these sorts of events caused gastrointestinal pain and altered bowel habits, and we had absolutely no idea if alterations in our gut microbes were involved in these processes.
When we stressed mother rats by separating them from their pups for three hours a day during the first weeks of life, as Plotsky had, the pups later showed many IBS-like features. In IBS patients, normal gut activity can cause abdominal pain, cramping, and visible bloating of the stomach—all of which stem largely from a hypersensitive and hyperresponsive gut. The majority of patients also have elevated levels of anxiety, and a good percentage suffer from an anxiety disorder or depression. In our experiments, the rats that had experienced a less nurturing childhood presented with similar traits. The animals were more anxious, their intestines were more sensitive, and when stressed they would excrete more small stool pellets, the rat equivalent of diarrhea. Anyone who’s ever had to run to the bathroom before a big presentation or job interview knows the feeling, but IBS patients—and our rats—suffer from such stress-induced symptoms all the time.
Remarkably, a chemical that blocks the action of the chemical CRF, the master switch in the brain that we know is increased by early life stress, banished all their symptoms: their stress-related behaviors, gut hypersensitivity, and stress-induced diarrhea. Unfortunately, even though such drugs could one day treat IBS and many other stress-sensitive disorders, efforts to develop safe and effective medications targeted at the CRF signaling system in the brain-gut axis have been unsuccessful so far. Many scientists involved in this effort, including those in my own laboratory, have struggled to understand this failure. Is the story in humans more complicated than originally thought? While basic scientists are always quick to make immediate conclusions about possible novel drug treatments based on their rodent experiments, our brains are not only much larger than those of rodents, but they have circuits and regions that are either underdeveloped or don’t even exist in the brain of a mouse, such as our prefrontal cortex or the anterior insula. So I decided early on that if we wanted to determine the relevance of the groundbreaking observations made in animals for a better understanding of medical symptoms in humans, it was essential to look directly at the brain of human subjects who had experienced early adversity.
With this goal in mind, we used the power of neuroimaging to look directly into the brain of living human subjects. Using this technology, we imaged the brains of one hundred healthy adults who before turning eighteen had experienced neglect; verbal, emotional, or physical abuse; serious parental illness or death of a parent; or divorce of their parents or other serious family strife. I was amazed to discover that even in healthy individuals who exhibited no symptoms of anxiety, depression, or gut dysfunction, their brain scans showed altered brain structures and altered neural activity in brain networks that enable us to appraise the danger of a situation or the meaning of a particular body sensation. This so-called salience system also plays an important role in predicting positive or negative outcomes of situations, and is an integral part of our gut-feeling-based decision making. These findings were remarkable in several respects. We had demonstrated for the first time in humans that our brains become rewired in response to adverse experiences early in life—and that rewiring can persist throughout our lifetime. As we saw these changes in completely healthy people, we also learned that such changes are not necessarily accompanied by a particular health problem. While such individuals are more likely to worry, to be anxious, and to be more risk-averse, they may never encounter the GI problems that Jennifer suffered from. Could it be that these altered brain networks simply put us at a higher risk of developing a wide range of stress-sensitive disorders, including IBS? Our studies have shown that IBS patients have brain network alterations that play an important role in their hyperresponsiveness to psychological stress, and to normal signals coming from the gastrointestinal tract in response to a meal.
How Stress Effects Can Be Transmitted from One Generation to the Next
One of the speakers at our Sedona conference was Rachel Yehuda, a prominent neuroscientist at New York’s Icahn School of Medicine at Mount Sinai. She talked about her groundbreaking findings that adult offspring of Holocaust survivors who had grown up without the experience of trauma themselves had a greater risk of developing psychiatric disorders such as depression, anxiety, and post-traumatic stress syndrome. Since then, several additional studies have shown similar types of “intergenerational transmission” of stress and adversity, including studies of the offspring of individuals who had to evacuate the World Trade Center on 9/11, or who had suffered through the Dutch famine during World War II. How could children raised in a safe and supportive environment by parents who had experienced the unspeakable trauma be more at risk for developing behavioral changes that are normally only seen in individuals who experience such trauma themselves?
In Meaney’s rat studies, when the daughters of stressed, neglectful rat moms became mothers themselves, they behaved no better toward their own pups. His study found that the effect could last for several generations, suggesting that the stress experienced by the mother, and the ensuing effect on her behavior toward her pups, could somehow be passed to their offspring.
The question was how. It took several years of careful laboratory detective work by Meaney and molecular biologist Moshe Szyf of McGill University to unravel the mystery, but the results revolutionized biology. They found that very specific aspects of rat mother-pup interactions (such as the arched-back nursing or licking) can chemically modify a newborn’s genes. Inside the cells of neglected rat pups, enzymes attached chemical tags called methyl groups to their DNA. This mode of inheritance is called epigenetic, since the tags sit on the DNA, and the prefix epi-, from ancient Greek, means “upon.” It differs from the conventional, genetic mode of heredity because the tagged gene still carries the same information, and makes the same protein. But when it’s tagged, it has a hard time doing so.
Here’s another way to look at the underlying biology: If the human genome—the collection of all of our genes—is the book of life, then a brain cell, liver cell, and a heart cell each reads different sections of the book. Epigenetic tags are the bookmarks and highlighting that tell a brain cell to read one passage of the book and a liver or heart cell to read another.
Poor mothering altered just a few of the bookmarks and highlights. But some of the tagged genes altered brain signaling, which made the adult daughters poor mothers themselves. This caused their own pups to tag their genes, and the cycle continued. We now know that this epigenetic editing of our genes can affect not only cells and mechanisms that determine how our brain develops, but also our germ cells or gametes, which carry the genetic information passed on to our children. The discovery of epigenetics ended a long-running debate over the degree to which nature or nurture causes stress-related diseases. Epigenetics violated everything modern biologists had believed about inheritance.
Remember that Jennifer’s mother and grandmother had suffered from symptoms very similar to her own: depression, anxiety, and belly pain. Most physicians would take this as evidence that genes for these disorders “ran” in Jennifer’s family. But a study performed of nearly twelve thousand twin pairs by Rona Levy at the University of Seattle, Washington, to determine the role of heredity in IBS symptoms questioned such a simple explanation. Not surprisingly, in genetically identical twins there was a higher likelihood that both twins suffered from IBS symptoms, compared to such concordance in dizygotic twins. This finding confirmed that genes play an important role in the development of IBS. However, Levy also found that having parents with a diagnosis with IBS was a stronger predictor of an IBS diagnosis in their children than having a twin with IBS. This means that mechanisms other than genes play a crucial role in the intergenerational transmission of clinical diagnosis. While other interpretations are possible (for example, the role of social learning), it is plausible that epigenetic mechanisms also play an important role in explaining the common family history of stress-sensitive disorders such as IBS.
Epigenetics not only called into question the prevailing dogma that an acquired trait could not be transmitted genetically; it also overturned dogma in psychiatry. For a century, psychiatrists believed that the unconscious mind contains buried feelings about early trauma, hidden desires, and unresolved dynamics between mother and child. These unresolved issues could cause psychological problems in adults, according to psychoanalytic theory, as well as stress-related diseases like IBS in patients like Jennifer.
We know now that many of these Freudian ideas are flawed. Science solidly supports the view that adversity experienced early in life, including poor mothering, can hardwire heightened stress sensitivity in our brains, and that this programming can be transmitted over generations, perpetuating a vulnerability for a variety of brain disorders.
DOES YOUR CHILD HAVE A STRESSED BRAIN-GUT AXIS?
If your grade school daughter is anxious, if your teenage son gets so stressed out over quizzes and finals that he smokes pot to calm himself, only to take stimulants to overcome his ADHD symptoms, or if your child suffers from IBS symptoms, is it because you failed to sufficiently nurture them when they were young? Rest assured, the answer to these questions is a definite NO. Women nurture their newborns through breastfeeding, touch, and other forms of body contact, behaviors akin to the arched-back nursing, licking, and grooming that nurture healthy brain development in young rats.
However, human brains are immensely more complex than rat brains. And there are many examples of highly successful and happy individuals, who had stressed-out single moms struggling to make a living, or who have overcome even the most severe forms of early adversity. In humans, there are many factors that can protect us from the negative effects of early life stress, ranging from genetic factors, to buffering effects during early development. Stay-at-home dads, grandparents, older siblings, nurturing nannies can all help create a supportive, stable family environment, helping children overcome the effects of early adversity. And keep in mind that the time window during which the development of the stress system is impacted by outside influences lasts up to twenty years in humans.
And even if such buffering factors are not present, as humans we have many tools at our disposal that allow us to partially reverse the programming from early stress and trauma in ways that rats and other animals cannot. For example, several mind-based therapies, including cognitive behavioral therapy, hypnosis, and meditation, have all been shown to change the way we appraise situations and body sensations. All of these therapeutic modalities are not just psychological treatments; they also have the ability to improve the cortical control over emotional and stress-generating circuits in our brains. We now know that such therapies can alter the structure and function of the brain’s networks involved in attention, emotional arousal, and salience assessment, primarily by strengthening our brain’s prefrontal cortex.
The Gut Microbiome Under Stress
Up to now, much of our discussion has focused on the programming of our brain circuits by early life experiences. There is no question that in vulnerable individuals, a disturbance of a stable, nurturing environment during the first two decades of life can change the development of the adult brain and behavior. These changes can be understood as an early programming of our nervous system in a way that reflects our first negative interactions with the world. And we shouldn’t forget that a hyperreactive stress system may provide some advantage if one is born into a dangerous environment. But what benefit is there to suffer from IBS symptoms throughout life as a “side effect” unintended by evolution? And what are the consequences of such a programmed brain-gut axis for our interactions with the trillions of microbes living in our gut?
We have made tremendous progress in understanding the relationship between early adversity, changes in the cross talk between the gut and the brain, and the role of the gut microbiome in these interactions. It is becoming clear that early life stress not only affects the brain and the gut, but also has a profound effect on the gut microbiome as well.
Studies have shown that when adolescent rhesus monkeys leave their mothers for the first time, they develop separation anxiety and diarrhea—just like many teenagers do when they leave home for college. Diarrhea develops because stress causes the gut to contract more forcefully and propel ingested food faster throughout its length. In addition, stress increases the secretion of various digestive juices into the gut. These stress-induced changes in gut function have dramatic effects on the living conditions for gut microbes. In response, fecal bacteria numbers drop significantly, and the ranks of lactobacilli, a genus of protective bacteria, thin the most. Pathogenic microbes such as Shigella or E. coli are emboldened, opening the door to gut infections. The stress hormone norepinephrine also makes such invaders more aggressive and more persistent. In the monkey experiments, though, the stress effects were temporary. By the end of the first week, when the young monkeys adapted to their newfound independence, their gut lactobacilli levels returned to normal levels. Since the effect on the gut microbiota was transient, does it matter? Do these transient microbial changes have any effect on our brains?
In a recent study by Premysl Bercik’s group at McMaster University, in Hamilton, Ontario, the investigators confirmed our earlier findings in the same animal model that poor mothering was responsible for the increased responsiveness of the gut to stress, consistent with alterations in the brain’s stress circuits. But remember that animals with compromised maternal care also showed other changes, such as anxiety and depression-like behaviors. Bercik’s group identified for the first time the special role of the gut microbiota in the development of these behavioral changes. It was only these “psychological” consequences of compromised maternal behavior that were dependent on the alterations in the gut microbiota and their metabolites, whereas the changes in gut reactivity were related to the increased stress responsiveness in animals. If these remarkable findings can be confirmed in human studies, it would have profound implications not only for our full understanding of the role of the gut microbiota in stress-related psychiatric disorders, but also for the treatment of patients like Jennifer and others with stress-sensitive disorders and a history of early adversity. Modulating the gut microbiota with dietary interventions and with pre- and probiotics, thereby reversing some of the effects of the altered gut microbes on the brain, could become an important tool in the integrative treatment plan.
Stress in the Womb
It has long been known that if you’re pregnant, your stress level can jeopardize your baby’s future health. Babies born to highly stressed mothers develop more slowly, weigh less at birth, and are more vulnerable to infections. However, until very recently little has been known about the potentially detrimental effects of maternal stress on the behavior and brain development of the offspring.
Two lines of evidence pinned some of these stress effects to changes in our microbial companions. First, monkey experiments showed that maternal stress alters our gut microbiota. Neurobiologist Chris Coe, of the University of Wisconsin-Madison, exposed pregnant rhesus monkeys to alarming noises on and off for ten minutes every weekday for six weeks. This stressed the monkey moms about as much as traffic, noise, or working until a few days before delivery stresses a pregnant mom in a big city. Surprisingly, newborns of the stressed-out monkey moms had much fewer good gut bacteria—lactobacilli and bifidobacteria—than newborns of monkey moms who’d been left in peace.
At first it was unclear how maternal stress could alter the newborn’s gut microbiota, since the unborn baby’s gut is largely devoid of microbes. But now we know that stress can alter the mother’s vaginal microbiota, which in turn has a major influence on the newborn’s gut microbes. Neuroscientist Tracy Bale, of the University of Pennsylvania, and her team stressed out pregnant mice by exposing them to a series of uncomfortable situations, including the lingering odor of a fox. Bale’s laboratory had previously shown that the same prenatal stress paradigm resulted in major neurodevelopmental changes in male pups in emotion- and stress-regulating brain networks.
In addition to what we already know about the effects of stress on an animal’s gut microbiota, the investigators found major changes in the vaginal microbiome of the stressed moms, in particular a reduction in lactobacilli. It had long been known that stress-induced reductions in vaginal lactobacilli can change the acidity of the vaginal environment and predispose women to vaginal infections. But why on earth would these stress effects on the vaginal microbiome be so important for the young animal’s brain development and behavior?
Because the mother’s vaginal microbes first seed the baby’s gut microbiota, these mice gave birth to babies with fewer lactobacilli in their guts, just as the stressed monkey moms had babies with reduced lactobacilli in their intestines. This stress effect is particularly concerning as it occurs at a crucial time, when the complex architectures of both the baby’s gut microbiome and its brain circuits are being programmed for a lifetime.
But the mouse mom’s stress didn’t just affect her pups’ gut microbes—it affected their brains as well! Bale’s team analyzed the mix of molecules produced by the baby mice’s microbiota. They found changes in molecules that supply the animals with energy, which the infant’s brain consumes voraciously, and a short supply of amino acids, which help the fast-developing brain grow and form new connections between certain brain regions.
What are the implications of these laboratory studies for women experiencing pregnancy and motherhood today? Many adult brain disorders, including anxiety, depression, schizophrenia, autism, and most likely IBS, are now considered neurodevelopmental disorders, meaning that the basic brain changes start very early in life, many of them already in utero. As we have learned, stress is a major factor that influences these neurodevelopment changes, and there are at least two major pathways by which early adversity can affect the brain-gut axis: one is by epigenetic modification of the stress response system and the brain-gut axis; the other one is through stress-induced changes in the gut microbiota and their products, which can further affect the brain. This means if we really want to have a major and long-lasting impact on the development and trajectory of these devastating diseases, interventions will have to start very early in life. Once the adult patient comes to the clinic with the full-blown syndrome, most treatments will be largely symptomatic and transient, while it is more challenging to get long-lasting therapeutic success. But as we will see in the case of Jennifer, the new understanding made possible by recent science opens up more effective treatment options for the adult patient as well.
Microbes for a Healthy Start
Years before I began my research career, I witnessed an astounding event that even today sways my thinking about our microbial companions. On a winter break from college, I had been lucky enough to join a documentary filmmaker on an expedition to film the Yanomami people, who live on the upper Orinoco River, deep in the rain forest of Brazil and Venezuela. One moonlit night, I lay in my hammock near my host Yanomami family, listening to the sounds of the jungle and unable to sleep. I stood up, heard a noise nearby, and walked a few steps into the surrounding forest. There I saw a fifteen-year-old native woman alone, squatting over a large banana leaf on the ground, giving birth to her child in nearly complete silence. After delivering the baby, she severed the umbilical cord with a sharp object.
Here was a child being born naturally, without any help or medical intervention, and so quietly that no one else in the entire village seemed to notice. The circumstances of this childbirth were a world away from our modern hospital deliveries, which I had experienced during my medical training: no sterile hospital environment, no ob-gyns to treat the mother’s vagina with antiseptics to “cleanse” it of microbes. Instead the newest Yanomami had been exposed not only to the mother’s vaginal microbiome but also to all the microbes on her (unwashed and unsanitized) hands, on the banana leaf and in the soil. Yet over the next weeks, the baby cuddled by both parents seemed perfectly healthy.
In the Western world, childbirth goes a lot differently, of course, and the roots of our own practices run deep. At the turn of the twentieth century, French pediatrician Henry Tissier proposed that human infants develop within a sterile environment, and that our first contact with microorganisms occurs when we are exposed to the vaginal microbiota during birth. This view has remained dogma for more than one hundred years, but today there’s good reason to doubt it.
Even in healthy pregnancies, maternal gut bacteria—most of them beneficial—have turned up in umbilical cord blood, amniotic fluid, meconium, and on the placenta, according to recent work. As the time of delivery nears, the vaginal microbiota changes a great deal. The diversity of microbial species decreases, and a lactobacillus species normally found in the small intestine becomes more prevalent. During birth, a baby born naturally is exposed to the mother’s vaginal microbiota, including this lactobacillus species, providing the key source of microbes to colonize the infant’s gut. In this way, your mother’s distinct set of vaginal microbes formed the basis for your own distinct pattern of gut microbes, and will for the rest of your life. The mother’s microbes also supply our newborns with a key piece of its metabolic machinery, giving the baby the ability to digest the milk sugars and special carbohydrates in breast milk.
Since vaginal microbes can get your newborn’s intestinal tract off to a healthy start, scientists are now studying whether cesarean delivery jeopardizes a newborn’s future brain health. It is amazing that in such countries as Brazil and Italy the rates of C-section delivered babies surpass those who come into this world in the natural way, even though we have no clue about the long-term consequences of “bypassing” the normal vaginally mediated gut microbiome programming on brain development. So far we know that the intestines of cesarean-born infants are colonized not by the mother’s vaginal microbes, but by microbes from the mother’s skin, from midwives, physicians, and nurses, and from other newborns in the maternity ward, and that important beneficial bacteria such as bifidobacteria take longer to colonize their guts than they do the guts of babies born vaginally. We know the dangerous gut microbe Clostridium difficile is more likely to overgrow in the gut and harm C-section babies, and that C-section babies are more likely to become obese as they get older. Scientists suspect that C-section birth may also make a child more vulnerable to brain-gut changes and serious brain disorders, including autism, and several studies are under way to find out for sure. And finally, we know from a landmark study by M. Blazer’s group in mice that the transient disturbances of the gut microbiota in early life by low doses of antibiotics can have long-lasting effects on the vulnerability of adults to the detrimental results of a high-fat diet on obesity.
Adapted for Survival
Survival of the species is one of the dogmas of evolution, and nature has programmed every species to deliver it. That’s how we and our animal forebears have survived for millions of years. In this chapter, I’ve described several mechanisms by which early life stress can influence brain and behavior of animals and humans, and have focused on our growing understanding of how stressful environments and stressed mothers imbue long-lasting changes in their baby’s brain. Using different biological pathways and mechanisms, these changes program his or her stress-response system for a dangerous world. By interacting with her child, a mother modifies the salience system in her infant’s brain so that the baby’s gut feelings are biased in a way to be prepared for a potentially dangerous world when he or she has grown up. She alters the microbes in her vagina, changing her infant’s gut microbiome. She tags key stress-response genes with chemicals called methyl groups, providing epigenetic changes that can last for several generations.
Why would evolution have developed a system that makes us unhealthy and unhappy? If nature, in its wisdom, devised several strategies toward a single end, and if those strategies can be seen in many species, including us humans, they must be there for a good reason.
The science all points in one direction. When the mother perceives danger, these strategies inculcate into her baby a heightened fight-or-flight response, plus more careful, less aggressive, and less outgoing behaviors. Even without her knowledge, she’s preparing her baby for a world she perceives as dangerous.
This system may have helped us when we had to flee attacking lions or vanquish a competitor in a fistfight, as our ancient ancestors did. Even though no scientific data is available to prove this hypothesis, it may even make millions of people today who are unfortunate enough to have to face battles, famines, and natural disasters, or who grow up in rough neighborhoods, more resilient and better adapted to deal with their hostile living conditions.
But those of us in relatively safe, industrialized societies pay a high price for these ancient and inborn biological programs. As we’ve seen, an overactive fight-or-flight system with constantly elevated stress hormones circulating through our bodies can lead to serious mental illness, including anxiety disorders, panic disorders, and depression. It can also cause a nasty assortment of stress-sensitive physical disorders, including obesity, metabolic syndrome, heart attacks, and strokes. And finally, the hyperresponsiveness of the brain-gut axis associated with this programming can cause chronic gut disorders like irritable bowel syndrome and chronic abdominal pain.
We don’t yet know whether a pregnant woman should worry if she deals with commuter traffic, project deadlines, and financial worries, and works until a few days before she’s due. And we don’t yet know the degree to which practices that alter the vaginal microbiome, such as antimicrobials before and during delivery, birth by cesarean section, or a young mother’s diet and stress, jeopardize a child’s health. We also don’t know whether the huge changes we’ve made to our babies’ early lives help explain the meteoric rise of autism, obesity, and other diseases over the last half century. However, it is clear that certain types of stress during pregnancy, and familial distress during the time when our children grow up, are harmful for their brain development and carry a high risk of permanently altering the architecture of their brain-gut-microbiome axis. I feel strongly that any interference with the normal programming of the infant’s gut microbiome through avoidable stress, nonvaginal delivery, unnecessary use of antibiotics, and unhealthy dietary habits during the pre- and postnatal periods can lay the groundwork for brain-gut disorders. And the changes to the child’s brain-gut axis may not be noticeable until later in life, when it may be too late to reverse them. Becoming aware of these connections and understanding the basic biological mechanisms is the first step. Implementing strategies to minimize these unhealthy influences is often more difficult. However, adhering to a healthy diet, practicing simple stress-reduction techniques during pregnancy, and being vigilant to avoid unnecessary antibiotic exposure are all options most mothers are able to consider.
New Therapies for Brain-Gut Disorders
We now know that from the time a fetus is in the womb, the stress level experienced by her mom can alter her susceptibility to stress, gut diseases, anxiety disorders, and depression. And this early life programming is not limited to maternal behaviors. We also know that any event that’s a major threat to a child’s well-being can alter susceptibility to the same conditions.
All of these findings can help us to understand the roots of Jennifer’s health problems. Recall that when she was still in her mother’s womb, her maternal grandmother was diagnosed with breast cancer, precipitating great grief and anxiety in her pregnant mother. When Jennifer was a young child and needed a nurturing family environment, her parents fought bitterly. When Jennifer was eight, her parents divorced. A large number of patients with IBS report early life stress, and Jennifer had it in spades. Such stress most likely upped her odds of developing anxiety, depression, and GI symptoms as an adult. The fact that both her mother and grandmother suffered stress-sensitive syndromes similar to hers further increased her vulnerability to develop those symptoms as well, presumably through genetic or epigenetic mechanisms or both.
These days, when I meet a patient like Jennifer who has chronic stress-related symptoms, including anxiety or IBS, I base my advice on the evolving science of brain-gut interactions as discussed in this chapter. “Your early experiences almost certainly played a role in the development of your symptoms,” I say, “both in terms of your gut symptoms, as well as your anxiety and depression.” I want to make sure that the patient understands the biological nature of her symptoms—that it’s not just “in their head,” as other doctors might have said. “But if it has all been hardwired during my first years of life, and if my family history further increases the odds that I will suffer from these symptoms, does that mean I have to live with this pain for the rest of my life?” Jennifer asked me, somewhat distressed. I told her that the bad news is that her brain-gut axis had been programmed for life, but the good news is that humans have a very unique part of the brain, the prefrontal cortex, which gives us the ability to override the function of altered brain circuits and learn new behaviors.
There are several therapies that help us to learn these new behaviors, much as adding some new code—a patch—to an existing computer program can override the flaws in the program. Such therapies include a short course of cognitive behavioral therapy, hypnosis, or another mind-body intervention such as mindfulness-based stress reduction. Not only do these strategies ease brain-gut symptoms, such as those of irritable bowel syndrome, but they also often help treat associated symptoms of depression and anxiety. And there’s more good news from recent research. These approaches can actually change the wiring of our brains, thereby helping the prefrontal cortex exert some control on an overactive emotional brain network. They can also help to reset the brain salience system, improving the way we appraise potentially threatening situations. Sometimes these mind-based approaches require a little help from the often-maligned psychotropic medications, in particular different types of antidepressants that have shown beneficial effects in mouse models of early life stress. My initial treatment plan almost always includes very low doses of tricyclic antidepressants like Elavil or similar drugs that help calm the firestorm in their limbic system in early stages of therapy. The same drugs can reduce abdominal pain with minimal side effects, and without any effects on mood or mental state. And, if appropriate for the patient, full doses of modern antidepressants, including SSRIs, can ease anxiety and depression and stabilize mood. These drugs by themselves provide significant benefit in about 30 percent of patients, but the success rate is much higher when combined with other, nonpharmacological treatments.
Based on our new scientific insights into the role of gut microbiota in the altered brain-gut interactions, I also told Jennifer to increase her intake of probiotics. Beneficial microbes such as lactobacilli and bifidobacteria delivered via fermented foods, yogurts, or in probiotic capsules may improve the diversity of the gut microbial ecosystem. In addition to naturally occurring probiotics in fermented foods, I recommend a trial of a small number of probiotics that have proven beneficial in clinical trials.
In the end, Jennifer agreed to the integrative therapy approach I recommended to her, which included a short course of cognitive behavioral therapy, including instructions in self-relaxation and self-hypnosis. She switched to a diet high in fermented foods and supplementary probiotics, and added the low dose of the antidepressant Elavil to her long-term Celexa intake. I emphasized to her that she’d probably need both the medications and nonpharmacological therapies to get better, but if she followed the treatment plan there was a good chance that she could ease off the drugs within a year.
Jennifer’s symptoms didn’t disappear completely. But several months later, when she returned to my clinic for a follow-up visit, she reported a 50 percent improvement of her quality of life and overall well-being, and much less frequent abdominal pain, long periods of nearly normal bowel movements, and far less anxiety. Before leaving my office, she shook my hand and with tears in her eyes said, “I wish someone had explained to me all of these connections much earlier, in particular the fact that my rough early life set me up for anxiety, depression, and IBS.” Jennifer is not the only patient who has left my office telling me that.
In a sense, people like Jennifer have adapted perfectly to the stressful world of their youth, with their brains, guts, and even their gut microbes programmed in multiple ways for danger. If more doctors knew this, they’d help, rather than frustrate, patients with IBS and many other stress-related disorders. And if more patients knew this, they would find help faster and have more peace of mind.
But early life programming affects us all. Our mothers instinctively and biologically programmed us for survival, beginning when we were still in the womb. Later, our families did the best they could to steer us through a complex world. All this leaves us with a lasting trace on our basic emotional makeup, and influences how we cope, how we make decisions, and possibly our personality. By understanding how this natural programming operates, and by learning how to patch any maladapted software, we can avoid overreactions that no longer serve us, if they ever did.