Verified by Gut-Brain Axis
The gut brain axis is the collective term for all the channels of direct and indirect communication now known to exist between the brain and the intestinal tract, providing a pathway for thoughts and feelings to influence the operations of the intestinal system and for the state of the viscera to affect all the ways the brain works. Over the past few decades, researchers have discovered that the brain and the gut communicate in many more ways than once thought and they talk about many things, from hunger to happiness to how much power your brain cells need to generate your thoughts.
In addition to direct nerve pathways through which the brain and the gut message each other, there are many biologically active substances produced in the gut through processes of digestion that enter the bloodstream or, through other means, affect the operations of the brain. What’s more, it has become clear that the actions in the gut are strongly influenced by the billions of bacteria that normally live in the intestines, collectively referred to as the microbiome.
For several decades, it has been known that the gut produces hormones such as ghrelin and leptin that send signals of hunger and satiety, respectively, to the brain. But only more recently have researchers discovered that there are many more things the gut and the brain talk to each other about and many more ways of doing so.
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The gut-brain axis links the cognitive and emotional activity of the brain with the activity of the intestinal system, enabling talk between the two systems. Through the bidirectional communication network, the brain can influence the activities of the gut, and the activities of the gut, including the products of digestion, have an impact on all the ways the brain works.
The gut-brain axis is a channel by which the food we eat, after it is broken down by digestive enzymes and acted upon by the trillions of bacteria living in the gut, shapes our moods, our cognitive function, our reactivity to stress, our memory operations, how the brain ages, and much more. It’s also a pathway through which emotional experience can change the physiology of the body and affect how the intestinal system works.
Knowledge of the gut-brain axis opens a whole new channel not simply for understanding mental disorders but for treating them, too. Diet is becoming a necessary instrument of mental health and psychiatric treatment.
Psychiatrists have known for years that 60 to 70 percent of depressed and anxious people, for example, have gastrointestinal problems, such as irritable bowel syndrome (IBS). Approximately 84 percent of patients with IBS also have a depressive disorder and 44 percent have an anxiety disorder. Moreover, 45 percent of patients with anxiety and 30 percent of those with a depressive disorder develop IBS.
It was commonly assumed that the gut problems were peripheral to the mental disorders. But there is mounting evidence that they are related. Studies show that disruption in the gut bacteria—the result of a poor diet, a prolonged course of antibiotics, or chronic stress—affects the substances they produce, and many of those substances “speak” to the nervous system and brain. Many animals and human studies are now underway to better understand the connection.
In addition, the gut-brain axis engages in constant crosstalk with other major systems of the body, including the immune system and the neuroendocrine system, which plays a prominent role in the stress response. As a result, the microbiome is increasingly linked to immune function and immune disorders and a range of metabolic disorders as well as to mental health and psychiatric conditions.
The world is full of microbes, and there are far more of them than of us. Over the millions of years of evolution, we have made a truce with many of them and live not just peaceably among them but actually have devised ways to be useful to each other—what’s known as symbiosis. The microbiome refers the trillions of microorganisms, including bacteria, that normally live in and on humans and which perform important functions for us.
There are bacteria and other microorganisms living on the skin and on mucous membranes, but microbes are most concentrated—said to number about 100 trillion and weigh about a kilogram—in the gut, primarily in the large intestines, or colon. There they help us digest the complex sugars in milk and break down dietary fiber to get some important substances out of them. But the bacteria in the gut don’t just influence digestion and energy production. Over the past several years, researchers have discovered that they are key regulators of overall health. Among many other functions, they play a major role in metabolism and in immune function throughout the body, and they directly and indirectly affect nervous system function, including susceptibility to stress and responsiveness to negative stimuli.
The gut microbiome, the name for the trillions of biologically active microorganisms living in the intestines, is emerging as a key modulator of the human nervous system (and other systems of the body). Gut bacteria produce substances that are neurally active. For example, The action of gut bacteria on fiber-rich foods results in the production of short-chain fatty acids, important as regulators of the integrity of the intestinal wall, as signaling molecules in the nervous system, and as regulators of stress reactivity.
Gut microbes also produce or cause to be produced neurotransmitters including serotonin, affecting brain functions such as sleep, mood, and cognition. Studies—most conducted on animals—show that gut bacteria influence development of the brain, particularly in early life and at adolescence; they stimulate the growth of new neurons in the brain and new neural connections throughout life. They play a role in memory, social behavior, stress reactivity, and more.
The microbes that live in the gut represent thousands of different species of bacteria, and that is a good thing. Diversity of the gut microbiome is strongly linked to both mental and physical health. Lack of bacterial diversity changes the way the microbiome functions and is a distinctive feature in many disorders, among them Alzheimer’s disease, anxiety, vascular disease, and type-2 diabetes. The composition of the gut microbiome is also thought to influence a person’s response to medication. The diversity of the gut microbiome is heavily dependent on what you eat.
There are thought to be somewhere between 1,000 and 1,500 distinct species of bacteria residing in the gut. The composition of the microbiome varies somewhat from person to person but in each individual is relatively stable. Nevertheless, it changes in response to what we do, where we are, and, especially, what we eat.
The most abundant bacteria in a healthy gut belong to a phylum called Firmicutes; they have been shown make up about 80 percent of a well-balanced microbiome. Another prominent phylum of bugs in the microbiome is Bacteroidetes, constituting about 15 percent of a balanced microbiome. They are known for the many metabolic tasks they perform on our behalf, such as breaking down complex carbohydrates, or polysaccharides, from fiber-rich plants. In contrast to Bacteroidetes, Firmicutes have a negative influence on glucose and fat metabolism.
The relative proportion of Bacteroidetes to Firmicutes is thought to drive gut bacterial diversity. An increase in the ratio of Firmicutes to Bacteroidetes has been linked to weight gain, gut inflammation, and an increase in pro-inflammatory cells circulating in the body.
The lack of a diverse array of bacteria in the gut has a name—dysbiosis. The condition is negatively associated with body weight, body mass index, triglyceride and LDL (bad) cholesterol levels, insulin-resistance, and blood pressure.
Dysbiosis is increasingly viewed as a marker for many health disorders. Dysbiosis of the gut microbiome causes dysfunction in the intestine leading to inflammatory, immune, metabolic, and infectious diseases in the intestines; but its effects extend was beyond through metabolic, inflammatory and hormonal pathways as well as the gut-brain axis.
Researchers have detected shifts in the balance of gut bacteria in a number of psychiatric disorders, suggesting that gut bacteria help mold the brain. For example, those with major depression seem to have a decrease in the number of Firmicutes and an increase in Bacteroidetes. Patients with autism spectrum disorder, compared to control subjects, have been shown to have increased levels of Clostridia, Desulfovibrio, Sutterella, and Bacteroides species, and decreased levels of Firmicutes, Prevotella, and Bifidobacteria, but researchers are not sure whether the microbial changes in autism spectrum disorder are causes or effects of the condition.
There is not one single microbiome profile that is healthy. It’s best to think of the gut as a whole ecosystem unique to an individual. Many species of gut bacteria have overlapping functions allowing different bacteria to take on the same role in different people. As a result, a “healthy gut” can encompass differing sets of beneficial bacteria. Two unrelated people typically share only 40 percent of their microbial species, researchers find.
Because the microbiome is sensitive to where we are, what we do, and what we eat, engaging in physical activity can alter the composition of the microbiome, in positive ways. Stress disturbs the balance of bacteria in the gut. Taking medications, especially antibiotics, and especially during childhood, kills off many beneficial bacteria in the gut. But everyone who eats a high-sugar, high-fat diet will shift the composition of the gut microbiome by increasing the proportion of several classes of bacteria relative to others that produce health-enhancing substances.
Most bugs in our gut come from the environment we live in. In fact, infant guts are first colonized by bacteria on the way down the birth canal. In addition to conventional nutrients, breastfeeding supplies many important substances stimulating the development of a healthy gut microbiome.
The foods we eat are major representatives of the environment we live in. At every stage of life, the composition of the gut biome and the diversity of bacteria in it are heavily dependent on diet. Studies show, for example, that it takes less than two weeks for a switch from a good plant-rich diet to an American-type diet— characterized most notably by high-fat red meats and industrially processed foods—to induce changes in microbiome. Some animal studies find changes beginning in as little as a day.
Almost every component of diet, including common nonnutritive additives used in commercial food production, has been shown to have an effect on the microbiome. Even if the additives supply no calories or nutrients, they can destroy bacteria in the gut—one more reason the typical American diet, loaded with highly processed and additive-heavy foods, is bad for the microbiome. Among them are artificial sweeteners, thickeners, emulsifiers, food colorants, and preservatives.
The gut talks to the brain constantly and rapidly. There are direct connections between the gut and the brain, the major one being the vagus nerve. The gut also produces neurotransmitters that relay messages to the brain. There are many indirect ties, such as short-chain fatty acids, substances produced by bacterial action in the gut that act on nerve pathways or circulate to the brain or stimulate processes that affect the brain. These activities are currently under intensive research, because they suggest new ways of approaching treatment of both psychiatric conditions and gastrointestinal problems.
Vagus means wandering, and the vagus nerve, the longest in the body—reaching from the brainstem to the abdomen, with branches to all the visceral organs—is a prominent component of the gut-brain axis. The vagus nerve oversees many body functions—heartbeat, for one—but as the main highway connecting brain and gastrointestinal tract, it sends information about the state of the gut to the brain, delivering it to important information about, say, hunger, or the need for specific nutrients.
In the course of digesting food, the bacteria of the microbiome produce many substances that act on the nervous system. Chief among them are neurotransmitters—including serotonin and GABA—known to be involved in many psychiatric disorders. There are many other neurally active substances produced in the gut as well, and they send signals to the brain via the vagus nerve or are directly transported to the brain by the vagus nerve. In addition, the vagus nerve brings to the brain news of the body’s inner sensations, an awareness known as interoception. Because it is a two-way road, the vagus nerve is also a pathway by which thoughts and feelings affect the operation of the intestinal tract.
The therapeutic implications of this understanding are huge. The vagus nerve can be used as a channel for improving disordered brain function; manipulation of the microbiome by diet is one significant way. It is also possible to directly target the vagus nerve as treatment for both psychiatric disorders and such somatic conditions as irritable bowel syndrome and inflammatory bowel disease.
Short-chain fatty acids (SCFAs) are an important class of biologically active substances produced in the gut, specifically by the action of gut bacteria on plant-derived foods containing fiber that is otherwise resistant to digestion, such as artichokes and legumes. SCFAs are emerging as important contributor to metabolism, immunity, and mental health. But exactly what those roles are is very much a developing story. It is safe to say that the more scientists discover, the more important SCFA’s are becoming to general and mental health.
Fibrous foods pass through the stomach and small intestine intact but meet a special group of bacteria in the lower intestines, or colon, that work them over by fermenting them— releasing energy, gases, and SCFAs, the most common of which are acetate, propionate, and butyrate.
Acetate, produced by Bifidobacteria, Lactobacilli, Akkermansia, and species of Prevotella and Ruminococcus, regulates the acidity of the gut, which keeps pathogenic bacteria under control. It also boosts gut diversity by nourishing other bacteria in the gut, and, through actions on cells lining the gut, helps regulate appetite.
Butyrate, produced by members of the Firmicutes family (such as Faecalbacteria and Roseburia), is a local source of energy powering cells lining the colon. But it does much more. It is critical for maintaining the integrity of the intestinal barrier and preventing a condition known as “leaky gut,” implicated as a source of inflammation of many organs, including the brain. Butyrate is especially important for mental health. It is active as a neurosignaling agent in the gut-brain axis, and it activates the vagus nerve. Studies show that butyrate crosses the blood-brain barrier and stimulates neuroplasticity in the brain. Animals studies show it raises levels of BDNF, brain-derived neurotrophic factor, crucial to learning and memory. By its chemical nature, butyrate is an anti-inflammatory molecule, extinguishing inflammatory processes wherever they occur, including the brain.
Propionate, produced both by Bacteroidetes and Firmicutes, is also ani-inflammatory, and it helps regulates appetite.
SCFAs are one of the many ways the gut communicates with the brain. They serve as signaling molecules throughout the body—mobilizing hormones and activating nerve pathways and many types of cells to regulate appetite, energy balance, body weight, immunity, brain function, and mood states. Butyrate also helps protect the brain, shielding it from toxins and infectious agents by maintaining the integrity of the blood-brain barrier. In addition, SCFAs are essential to liver function, regulate the activity of immune cells, and stimulate the sympathetic nervous system.
There’s evidence that lack of SCFAs is a hidden force behind rising rates of obesity, diabetes, and such psychological ills as anxiety and depression. Studies show that depressed people have far less diversity of the microbiome than do people who are not depressed. When the diversity of the microbiome is narrowed, there’s a failure to produce molecules that have become essential to normal brain function, including the response to stress and the processing of emotional information.
One distinguishing feature of the Mediterranean diet is the predominance of such foods, and the production of SCFAs is believed to account for many of the mental and physical health benefits of the Mediterranean diet. It is closer than the highly processed American diet to what our ancestors ate for most of human history—a hardscrabble diet in which nuggets of nutrients came bundled in indigestible plant material. The human gut was adapted to a diet of more than 100 grams per day of fiber from foraged food—compared with the fewer than 15 grams of fiber a day supplied by the typical Western diet of highly processed, energy-dense foods.
Recent research has demonstrated that neurotransmitters are not confined to regulating activities within the brain; they play a large role, for example, in the gut. Both bacteria in the gut and the cells lining the intestines produce neurotransmitters, among them GABA, serotonin, dopamine, and acetylcholine. The gut produces 90 percent of the body’s total serotonin, which helps regulate gut peristalsis, the contractions that move food through the digestive tract.
Exactly how the neurotransmitters produced in the gut influence the brain is not clear, but it is the object of intense research. There is a nerve mesh that surrounds the intestines—it is called the enteric nervous system—and it communicates both with gut bacteria and, through the vagus nerve, the brain. It is thought that the neurotransmitters produced by the gut act on the brain via the enteric nervous system.
Studies show that it is possible to “transplant” psychiatric disorders, including some features of schizophrenia, simply by transplanting the microbiome. When the microbiome (read: the poop) of depressed people is transplanted into the intestines of germ-free animals, those animals display many of the behaviors of depression—they lose interest in pleasurable activities, they stop exploring and socializing, and they display signs of anxiety. The researchers transferred the blues.
In other studies, researchers removed fecal matter from human subjects suffering from schizophrenia and transplanted it into mice. The mice developed many schizophrenia-like behavioral abnormalities. There is evidence that, in both cases, a lack of diversity of gut bacteria disrupted the conversion of tryptophan, a component of food, into serotonin.
The intestinal walls serve as an important barrier, separating the contents within from the rest of the body. The intestines have specific mechanisms for transporting contents, such as nutrients, from within to the other organs for everyday functioning and for growth and repair. As understanding of the gut microbiome increases, it is becoming clear that under some conditions, the intestinal walls lose their integrity; they become permeable, creating a condition known as “leaky gut.”
Under these circumstances, whole microbes, their byproducts, other bacterial materials, and poorly digested proteins and fats can inappropriately find their way out of the gut and into to the general circulation and distant tissues, creating inflammation and injury. Bacteria that are normally not pathogenic within the environment of the gut set off pathologic processes in other organ systems. While the processes are not yet fully understood, leaky gut is increasingly associated with a number of conditions, including metabolic and psychologic disorders. Chronic inflammation stemming from leaky gut processes may set off depression, for example, and it may also explain the link between heart disease and depression. It is also thought to play a role in autism.
The composition of the gut microbiome is believed to directly affect the permeability of the intestinal barrier. Various diet components are also known to have effects on intestinal permeability. For example, proteins such as casein and other nutrients such as vitamin D and the mineral zinc have a beneficial effect on intestinal permeability, while alcohol increases gut permeability. Meat proteins, in the course of digestion, release substances that impair the intestinal barrier integrity. By contrast, short-chain fatty acids, produced by microbes acting on resistant carbohydrates in the colon, play an important role in maintaining the integrity of the intestinal barrier.
Because the gut-brain axis is a two-way channel, it provides a pathway for the gut and its operations to influence the brain and its activities and for brain states to influence the gut. Just as disturbances of the gut microbiome can undermine mental health, and disturbances in thinking can throw gut operations into disarray, so can the influence be positive. Growing understanding of the gut-brain axis not only puts a new emphasis on the role of diet and the composition of the microbiome in health and disease but is expected to provide new ways of intervening in disorders of both mental function and gut function.
Stress and the gut are intimately connected, and the gut microbiome is a major influence on adaptation to stress. Stress negatively affects the diversity and complexity of the microbiome. But in a cruel twist of fate, the very reactivity to stress is affected by the composition of the microbiome. The relationship between stress and the gut takes on special importance as stress susceptibility plays an outsize role in common psychiatric conditions such as anxiety, depression, and PTSD. And it is thought to influence the waxing and waning of symptoms in many other conditions, including bipolar disorder and schizophrenia.
At the simplest level, stress can promote consumption of highly palatable comfort foods, loaded with simple carbohydrates, and directly influence which gut bacteria thrive. In addition, stress can reshape the composition of the gut bacteria through the actions of the hormone cortisol, released by the brain's hypothalamic-pituitary-adrenal axis in response to the perception of threat to prepare the body to meet a challenge or flee from it. An array of changes occurs quickly, including alteration in the diversity and function of the gut bacteria. Studies show, for example, that gut bacteria have the ability to sense cortisol in their environment and change their gene expression in response to it.
Researchers have found that specific strains of gut bacteria influence fear learning and extinction, processes at the heart of anxiety conditions such as PTSD. In studies of one strain of beneficial gut bug, Bifidobacterium longum 1714, fed to healthy men for a month, the subjects displayed reduced levels of stress measured psychologically and physiologically after being subjected to a challenge; researchers recorded a blunted hormonal response to stress.
Studies suggest that there are specific times during development when the threshold of stress responsiveness is set by the composition of the gut microbiome—just before and after birth, and again at adolescence, all periods when there is rapid growth of connectivity between brain cells. Preclinical studies indicate that shifts in the normal composition of the microbiome early in life—through Caesarean birth, lack of breastfeeding, antibiotic exposure, infection, or significant stress exposure—can enduringly influence stress physiology and influence the risk for depression and many other psychiatric disorders.
But there’s more. An increase in levels of cortisol, the physiologic hallmark of stress, increases the permeability of the gut. That, in turn, allows the leakage of bacterial substances that set off inflammatory processes throughout the body, including the brain, activating yet another pathway of disorder.
Evidence that the makeup of the microbiome plays a major role in depression took a giant leap forward when, in 2016, researchers transplanted into healthy, germ-free rats the poop of people suffering from depression. The animals lost interest in pleasurable activities, they stopped exploring and socializing, and they displayed signs of anxiety—the classic behavioral abnormalities seen in depression.
There are many ways the composition of the gut microbiome and the activity of the gut-brain axis can lead to depression. Multiple studies have established that the microbiome of depressed people lacks bacterial diversity. The lack of diversity of gut bacteria can lay the groundwork for depression by rendering people overreactive to stress. A lack of bacterial diversity can diminish the conversion of tryptophan, a component of food, into the neurotransmitter serotonin. It can also undersupply microbes known to stimulate the vagus nerve connecting brain and gut. For example, researchers have found deficits in bacteria, specifically those in the Prevotella family, known to produced short-chain fatty acids.
Studies show that the imbalance of gut microbes linked to depression is characterized by over-representation of bacterial species that promote inflammation. An unbalanced microbiome also alters the permeability of the gut, allowing the slow leakage into the bloodstream of substances that can set off systemic inflammation and ignite inflammatory processes in the brain.
Microbes and mood are linked in yet other ways. The slow burn of inflammation can activate the hypothalamic-pituitary-adrenal axis to release the stress hormone cortisol, altering the way emotional stimuli are processed and biasing the brain toward negativity. At the same time, people who experience depression have fewer microbes that produce short-chain fatty acids. All are pathways to depression. There’s additionally some evidence that depression can be caused by shifts in gut bacteria active in the metabolism of amino acids.
While understanding of the pathways is still in its early stages, knowledge of the gut-brain axis opens up new possibilities for the prevention and treatment of depression—with a diet and lifestyle that ensure a healthy balance of bugs in the microbiome. Important foods include fiber-rich fruits and vegetables that lead to production of short-chain fatty acids (SCFAs), essential to brain health and immune health. Researchers have found that highly fibrous foods function like antidepressants. Equally important is exercise and activity, which not only promote the growth or new nerve connections in the brain but also promote the growth of healthy bacteria in the gut.
Depression and anxiety are overlapping disorders, often coexisting, characterized, among other features, by overactivation of the hypothalamic-pituitary-adrenal axis that orchestrates the stress response and by disproportionate attention to negative stimuli. Many of the same changes to the gut microbiome seen in depression have also been found in patients suffering from anxiety—a lack of bacterial diversity, fewer bacteria producing short-chain fatty acids, an abundance of bacteria that stimulate inflammatory processes.
While the two disorders are often clinically indistinguishable, there’s some evidence that what sets them apart are different patterns of change to individual bacterial species in the microbiome. For example, depression may result from the presence of bacteria that specifically affect thyroid hormone, decreasing its production, while anxiety does not.
Other studies suggest that exposure to antibiotics such as ampicillin can cause anxiety. Antibiotics don’t kill just the bacteria involved in infections; they decimate populations of beneficial bacteria as well, leading to dysbiosis. By disproportionately elevating populations of bacteria belong to the Proteobacteria family, antibiotic treatment may set off gastrointestinal inflammation that activates neuroinflammation, resulting in anxiety.
There’s evidence that stress, too, can lead to anxiety through neuroinflammation that has its origins in the microbiome. Stress activates the hypothalamic-pituitary-adrenal axis, setting off a cascade of hormones that can, among many other actions, increase the permeability of the gut lining. Toxins may then leak from the intestines into the bloodstream, triggering an inflammatory response. Inflammatory substances can travel to the brain via nerve pathways connecting brain and gut.
Until recently, anorexia has been considered a purely psychiatric condition. But that view is shifting as researchers turn up evidence that there are profound differences in the makeup of the microbiome between anorexics and healthy people. Overall, Bacteroidetes prospers at the expense of Firmicutes. One result is a deficit of short-chain fatty acids; another is a tilting of the system toward inflammation. But the changes in microbiome composition leave almost no bacterial class unaffected, researchers find.
Reduced microbial diversity and significant shifts in proportions of specific bacteria populations implicate the microbiome through effects on appetite, energy metabolism, increased intestinal permeability, immune function, anxiety, and repetitive and compulsive behaviors. Moreover, gut dysbiosis may be responsible for the high rate of relapse of the disorder, as neither standard renourishment protocols nor psychotherapy addresses the makeup of the microbiome.
As is the case with other mental disorders, the bacterial makeup of the gut in people with schizophrenia distinctly differs from that in healthy people. There is both diminished diversity of bacterial types and disturbances of microbial composition, or dysbiosis. And the dysbiosis of schizophrenia is distinct from that seen in patients with major depression. One distinctive feature researchers have observed is disruption in levels of the neurotransmitters glutamate and GABA. Another is alterations in amino acid and lipid metabolism. What’s more, the specific microbial markers of schizophrenia have been found to correlate strongly with symptom severity.
Do the gut changes have anything to do with the mental states? Researchers believe the answer is a strong yes. When one team of scientists transplanted fecal matter from the colon of schizophrenic people—some of whom had been medicated and some of whom had not— into mice that had been raised to be germ-free, the animals developed symptoms analogous to those of schizophrenia in people, such as hyperactivity, decreased anxiety- and depressive-like behaviors, and increased startle responses.
Autism is a neurodevelopmental disorder that is poorly understood, but a variety of evidence implicates the infant microbiome, perhaps through inflammatory processes affecting the developing brain. Animal studies, for example, suggest a complex relationship between a dysbiotic gut inclined toward inflammation—possibly the consequence of early-life antibiotic treatment of a bacterial infection—and viral exposure, possibly in utero. What is known is that, in addition to the sensory processing, language, and social difficulties children with autism experience, and the anxiety they typically display, they also suffer from digestive and gut problems at an unusually high rate.
Studies in animals and humans show:
• Children with autism consistently show reduced levels of specific gut bacteria, notably Bifidobacteria and Prevotella.
• Among the beneficial gut bacteria lacking are those that lead to production of the neurotransmitter serotonin.
• Gut microbes appear to play a significant role in orchestrating normal social behavior, and animals that are bred to be germ-free show social deficits similar to those seen in autistic children—they avoid others, they shun new social situations, and they engage in repetitive behaviors such as grooming themselves obsessively.
As with other psychiatric disorders, researchers have transplanted fecal matter from autistic children into germ-free animals. The animals wound up lacking bacterial metabolites that stimulate activity of the neurotransmitter GABA, known to be involved in sensory processing and motor control. That’s significant because abnormalities in the GABA system are common in children with autism. When the mice were given doses of the missing metabolites, social behavior improved and repetitive behaviors diminished. Suggestive—but not definitive evidence.
More suggestive are studies of autistic children given gut microbes of people without autism. Their gastrointestinal symptoms abated and their autism symptoms were markedly reduced, even two years after treatment. In addition, they had thriving numbers of such specific microbe strains as Bifidobacteria and Prevotella.
But no one is sure how the dysbiosis in autism arises. There is some evidence that, rather than causing autism, gut microbial disarray is the result of the idiosyncratic dietary preferences of autistic children. Moreover, no firm explanation has yet emerged about how gut dysfunction produces autistic symptoms. It may be that multiple pathways are involved. But studies in which autistic children were fed microbial mixes of Bifidobacteria and Lactobacilli have shown reduction in autistic behavior.
The gut-brain axis now appears to be the route by which Parkinson’s disease takes hold in the brain and disrupts movement and cognition. Various lines of research indicate that, at least in a large proportion of patients, Parkinson’s begins in the gut, with the production of a toxic neuron-killing protein (alpha-synuclein) that travels to the brain via the vagus nerve and accumulates in an area of the brain that produces dopamine. The loss of dopamine-producing neurons accounts for the disordered movements (dyskinesia) characteristic of Parkinson’s.
Gut disturbances have long been linked with Parkinson’s. One of the earliest symptoms of the condition—years before the disordered movements occur— is constipation. Dysbiosis appears to be a trigger—if not the trigger. Exactly how alpha-synuclein accumulates in the gut is the subject of intense study, but evidence indicates it may be the product of pathogenic bacteria that gain advantage in the disordered microbiome. At the same time, the dysbiosis increases intestinal permeability, gastrointestinal inflammation, and, through a leaky gut, dispersal of alpha-synuclein. Ongoing research suggests that nutrition-based treatment, including the use of probiotics, might be able to interrupt the development of Parkinson’s very early in the disease.
The other major neurodegenerative disease, Alzheimer’s, has eluded understanding for decades. While there are distinctive brain signatures of the disorder, such as the accumulation a beta-amyloid protein between nerve cells in the brain, the cause of the disorder has been difficult to pinpoint, and treatments targeting amyloid accumulation and clumping have been notable flops. Recent evidence suggests that Alzheimer’s is more a lifestyle disease, the result of decades of nutritional and lifestyle choices that slowly erode the energy processes powering brain cells, leading, eventually, to cognitive impairment.
It may be that diet is the instigator—the standard American diet undermines healthy metabolism in a number of ways—and the microbiome is the mediator of those processes. For example, the Western diet, loaded with sugar and fat, promotes insulin resistance, and evidence suggests that impairs the brain’s use of glucose to power its activities.
As with other mental health disorders, Alzheimer’s disease is marked by diminished diversity of bacterial species in the gut. Notably there is a shift in the relative populations of Bacteroidetes and Firmicutes, with increased levels of the former and decreases in the latter. The microbial shifts in the gut, some evidence suggests, incline it towards production of inflammatory compounds that set off inflammation in the brain—another way the microbiome is involved.
What you eat is a primary determinant of which bacteria get to thrive in your gut and, as a result, of how the gut-brain axis functions. Eating a largely plant-based diet, for example, supplies an abundance of digestion-resistant fiber, which in fact supports the growth of the very bacteria that are capable of breaking it down in the colon and releasing substances important to mental health, such as short-chain fatty acids.
Manipulation of the microbiome by diet and by diet supplementation is emerging as a promising pathway for the treatment of many disorders, including mood and other psychiatric disorders. It’s not clear yet what a stress-proof or depression-proof or anxiety-proof microbiome looks like, but the day may not be far off when mental distress is cured in the kitchen.
The so-called standard American diet is an industrial triumph but, it is becoming increasingly clear, a biological disaster. Highly processed, laced with stabilizers and emulsifiers and other additives to give foods appealing texture and a long shelf life, it is loaded with fats and with simple carbohydrates, particularly sugar, which can be highly palatable but bias the gut microbiome in favor of bugs that make a cheap living off glucose and, especially, fructose.
At the same time, the standard American diet supplies little plant-based fiber—fewer than 15 grams a day, far less than the human body requires for optimal functioning. Lacking digestion-resistant complex carbohydrates, such a diet cannot sustain the bacteria in the colon that produce short-chain fatty acids, important for mental and physical health. The bacterial composition supported by such a diet contributes to leaky gut, inflammation, and is associated with disorders ranging from diabetes to schizophrenia.
In addition, the American diet contains a disproportionate amount of meat relative to fruits, vegetables, and other plant sources of food. A diet weighted toward animal proteins and fats disrupts the diversity of the microbiome in still other ways. For example, red meat is rich in the amino acid derivative L-carnitine. Eating red meat encourages the growth of the gut bacteria that are capable of metabolizing L-carnitine—but those very gut bacteria produce a substance, TMAO (trimethylamine N-oxide), known to contribute to atherosclerosis.
Then there are all the food additives in commercially produced foods, from breads and spreads to chocolate milk, ice cream, soups, and sauces. Most additives have no nutritional value, add no calories, and are eliminated in the feces unchanged. That turns out to be deceptive. Studies show that they nevertheless interact with bacteria in the gut in largely detrimental ways.
Even in healthy people food additives such as emulsifiers affect gut bacteria and create dysbiosis, altering both the composition of the microbiome and the way it functions. For example, common emulsifiers such as carboxymethylcellulose and polysorbate-80, used in baked goods, margarine, processed meats, chocolates, and other foods, have been found to wipe out healthy populations of gut microbes in ways that promote chronic gut inflammation, lead to inflammatory bowel conditions and metabolic disease, as well as to anxiety and disrupted mood states. Recent studies of many other food emulsifiers and stabilizers used in soups and sauces show that that the vast majority destabilize the gut, typically decreasing such beneficial bacteria as Akkermansia.
The standard American diet is saturated with simple refined sugar, that is, sugar stripped of its natural context of complex carbohydrates such as fiber. Americans consume an average of 77 grams of sugar daily—the recommended ceiling is 25 grams for women, 36 for men. While some of the sugar Americans consume comes from obvious sources such soft drinks, much of it enters the body surreptitiously; 68 percent of all packaged foods and beverages—from chicken nuggets to ketchup to salad dressings—contain added sugar.
Studies in healthy animals show that sugar consumption shifts the bacterial composition of the gut. Specifically, it promotes the growth of directly pathogenic bacterial species such as E. coli, and it feeds a species of bacteria that erodes the protective lining of the gut and strips it of its mucus coating. Lacking a protective layer, the intestines develop inflammation from direct exposure to bacterial products.
But that’s not all that happens. The overall ratio of Bacteroidetes to Firmicutes shifts, and the entire body is set on a pro-inflammatory course. There are major metabolic consequences. Fructose—the primary sugar in fruit juices and sugar-sweetened beverages—specifically undermines populations of bugs that produce the short-chain fatty acid butyrate as well as those involved in lipid metabolism. In addition, the composition of the microbiome shifts in such a way that it is unable to do its share in regulating blood sugar levels, paving the way for diabetes.
Researchers believe that the effects of sugar on the microbiome explain the rising incidence of inflammatory bowel disease in countries with a Western-type diet, fatty-liver disease and other metabolic disorders, mood disorders, and cognitive decline. In addition, changes to the gut lining disrupt the integrity of the intestinal barrier, making the gut permeable and setting the stage for persistent low-grade inflammation of other organs that, over time, is a significant contributor to many types of illness. Inflammation triggers a threat response that biases the brain to negative expectations, a primary feature of both anxiety and depression.
Establishing a balanced microbiome or resetting the balance of the microbiome is not only possible but likely to improve many aspects of health, including mental health, throughout the lifespan. Backing away from the overprocessed, fat- and sugar-rich standard American diet is likely to have the most far-reaching effects. Minimizing exposure to antibiotic drugs takes on a new importance for maintaining a healthy microbiome.
Then there are dietary actions to take on the positive side of the ledger to foster gut health and mental health. Eating foods that encourage the growth of specific groups of bacteria known to perform important functions, such as those that produce short-chain fatty acids, is well supported by data. In addition to their neural, metabolic, and immune importance, SCFAs help maintain the acidity of the gut, which in turn limits the growth of harmful bacteria. And there’s some evidence that consuming supplements with specific populations of beneficial bacteria is generally helpful and sometimes, such as following a course of antibiotic treatment, specifically warranted.
Nature supplies an abundance of foods that promote a healthy gut. Generally speaking, that equates to a diet tilted toward plants, and then in as close to their whole form as possible. Whole grains rather than refined flours. Whole fruit rather than juices.
Foods containing digestion-resistant fiber, composed of complex carbohydrates known as polysaccharides, are particularly beneficial to the gut. Because they nourish and prompt the proliferation and activity of beneficial bacteria that metabolize them (and release important bioactive substances from them), they are sometimes called prebiotics. All prebiotics are fiber, but not all fiber is prebiotic (some fiber resists even fermentation in the colon). Some prebiotics, such as pectin, abundant in citrus peels and apples, and inulin, found in oats, are soluble; often added to commercial foods as a thickener and stabilizer, pectin is one of the few food additives that has beneficial effects on gut bacteria.
A diet rich in fiber has long been associated with health. Consumption of dietary fiber is linked to reduced rates of all-cause mortality. Fiber is known not only to promote good bowel function but to prevent cardiovascular disease, for example. It also protects against diabetes, colon cancer, and obesity—diseases associated with the Western, or American-type, diet. The presence of fiber in foods slows down the release of sugar from the digestive tract, stabilizing blood sugar levels after meals. But it may be that the most far-reaching benefits of fiber are achieved through effects on the microbiome.
Probiotics is a term denoting microorganisms that confer health benefits to people. The term is also widely applied to foods that naturally contain live beneficial microbes—many kinds of yogurt and kefir, for example, and naturally fermented foods. But perhaps most often the term is used to refer to supplements containing various species of live bacteria that are beneficial to health.
Studies show that probiotics influence mental health as well as physical health. Overall, they maintain a healthy balance of bacteria in the gut microbiome. They exert an expanding portfolio of effects in many direct and indirect ways. They produce substances that maintain the integrity of the gut, preventing the leakage of material that is directly toxic or that can stimulate inflammatory processes in the body, including the brain. They produce neurotransmitters and many other substances, such as SCFAs, biologically important to the nervous system. They activate the vagus nerve. And more.
Two species of bacteria stand out for their role in maintaining a healthy balance of bacteria in the git and for safeguarding the integrity of the gut barrier. Not coincidentally, studies show that they also improve mood. They are Bifidobacteria longum and Lactobacillus rhamnosis.
As the science of the microbiome advances, there’s growing understanding that particular families and individual strains of bacteria may be involved in the onset and/or the advancement of specific disorders. Because the influence of the microbiome is extensive and complex, and the science is still in its infancy, it’s too early to expect prescriptions of specific probiotics in specific amounts for any disorder. Nevertheless, the day may not be far off when it’s possible to treat many conditions by manipulating bacteria in the gut. It is an area of intensive study.
Currently, there are many preparations of bacteria being marketed as probiotics. Researchers are wary of most. They point out that, even if anyone had any idea about what the right dose of bacteria might be (they don’t), most concoctions of bacteria do not survive the highly acidic environment of the stomach to make it to the colon, where they do the most good. So far, the most reliable way of maintaining health and preventing disease is by balancing the biome though diet.
Psychobiotics are the types of gut bacteria known to be psychoactive and to have a positive effect on mental health. In limited studies, some have been shown to actually relieve psychiatric disorders. Among the best-studied bugs that benefit mental health are species of Bifidobacterium and Lactobacillus, and some studies suggest that when given to depressed patients, they alleviate symptoms. Psychobiotics are of considerable research interest for possible role in treatment of depression, anxiety, autism, and neurodegenerative disorders.
Many people take probiotic supplements routinely to maintain gut health. Global sales of probiotic supplements reached $5 billion in 2021 and are expected to climb to $7.1 billion by 2027.
While most experts believe that the best way to maintain a balanced microbiome is through diet, they point to several situations where probiotic supplements may be helpful:
• replenishing bacteria after antibiotic use
• rebalancing the microbiome after a bout of diarrhea
• to fight anxiety. Studies show that probiotics containing Bifidobacterium longum and Lactobacillus helveticus can decrease anxiety; beefing up populations of both types of bugs, research shows, increases production of short-chain fatty acids such as butyrate.
Prebiotics are food nutrients —specifically difficult to digest complex carbohydrates known as polysaccharides—that enhance the growth or activity of beneficial bacterial in the gut. They are concentrated in fiber-rich foods like leeks, onions, bananas, artichokes, cabbage, and asparagus, but they are also sometimes extracted from foods and made available as supplements. Chemically, they carry such names as fructo-oligosaccharides (FOS, found in fruits and vegetables) and galacto-oligosaccharides (GOS, found in cow’s milk and legumes) , and inulin (found especially in chicory root, Jerusalem artichokes, unripe bananas, garlic, globe artichokes, and oats).
Prebiotics resist digestion until they reach the colon, the end of the digestive line, where they are fermented by specific populations of bacteria—serving as a kind of inner dinner. While their digestion in the colon does not provide the human system with much caloric energy, it has many other health benefits. It yields important substances, such as short-chain fatty acids (SCFAs), that are critical to brain health, immune health, gut health, and metabolic health.
All three prebiotics, researchers have discovered, curb secretion of the stress hormone cortisol and influence emotional processing in the brain—they keep it from dwelling on negative stimuli, studies, show. They also activate a channel of biochemical signaling between the gastrointestinal tract and the brain, and they increase levels of BDNF, or brain-derived neurotrophic factor, which promotes mental flexibility by stimulating the growth of new neurons. That is likely why animals fed a prebiotic-enriched diet for 10 weeks resisted the animal equivalent of behavioral despair when subjected to specific kinds of stress. The researchers conclude that prebiotics function like an antidepressant.
In addition, fermentation of oligosaccharides shifts the composition of the microbiome, specifically increasing such bugs as Bifidobacteria and Lactobacilli while decreasing known pathogens such as E. coli. As a result of oligosaccharide consumption, the microbiome of older animals resembles that of young animals and displays souped-up metabolic efficiency. Unfortunately, the microbiome of people consuming an American-type diet is depleted of fiber-degrading microbes.
Human breast milk is rich in its own array of oligosaccharides. Because oligosaccharides suppress the growth of pathogenic bacteria in the gut, they help confer on breast-fed infants the well-established benefit of protection against infection. In addition, oligosaccharides are thought to help stimulate the development of a balanced microbiome in human infants. Human milk oligosaccharides, for example, are known to stimulate the grown of Bifidobacteria in the colon. As a result, commercial manufacturers have recently begun adding oligosaccharides to infant formula.
While a prebiotic-rich diet is advisable, there are no dietary guidelines establishing how much should be consumed. Experts point to data showing how little fiber most Americans consume (15 grams per day) and recommend “more.” Large-scale analyses of fiber consumption show that the higher the intake of fiber, the greater the protection against death. While intake of 25 to 29 grams of fiber per day produced the greatest incremental risk reduction, researchers conclude that even higher intakes of fiber “could confer even greater benefit to protect against cardiovascular diseases, type-2 diabetes, and colorectal and breast cancer.”
But adding prebiotic foods to the diet is best approached gradually by those not used to such foods. They can generate gas and abdominal discomfort until large enough bacterial populations are built up..
Because life doesn’t always sort itself into simple categories. there are in fact some prebiotics that are not fiber at all—but nevertheless act as prebiotics, stimulating the growth and activity and beneficial bacteria in the gut. One large group of them is polyphenols, colorful chemical compounds found in plants (berries are especially rich in them) that help protect the plants against environmental insults—and do the same for the human body. They often act as antioxidants and anti-inflammatory agents in the human body and can be found especially in green tea, red wine, dark chocolate, and olive oil as well as colorful fruits and vegetables.
Studies show that polyphenols increase the abundance of Bifidobacteria, Lactobacilli, and various species of Akkermansia, Roseburia, and Faecalibacteria in the colon. Further, they stimulate the production of short-chain fatty acids, including butyrate. (It is not clear precisely how polyphenols increase the production of SCFAs.) At the same time, they reduce production of proinflammatory cytokines. The most prebiotically active polyphenols are:
• catechins, found especially in apples, blackberries, broad beans, cocoa, green and black tea, raspberries, red wine.
• anthocyanins, found especially in blackberries, blueberries, red cabbage, cranberries, cherries, red radishes.
• proanthocyanidins, found especially in barley, chocolate, cinnamon, plums, pecans, red wine.
Sauerkraut, kimchi, miso, tempeh, kefir, kombucha—all are actively fermenting foods that promote a healthy, diverse microbiome and reduce markers of inflammation circulating throughout the body. Fermentation is a process in which live microorganisms—yeast and bacteria—enzymatically convert the carbohydrates in food to produce alcohol and organic acids (such as lactic and citric acids). In metabolizing food, the live bacteria also often produce vitamins and reduce anti-nutrients in food.
The fermentation process confers on foods a distinctive tangy taste. The alcohol and organic acids, in turn, become fodder to support the growth of diverse gut bacteria.
All fermented foods are, potentially, rich sources of probiotics. Some fermented foods, such as sauerkraut and kimchi, both made from cabbage, are both probiotic, containing live beneficial bacteria, and prebiotic, rich in digestion-resistant fiber. There are lots of foods that are made by fermentation, including wine, beer, and sourdough bread, but fermented foods are probiotics only when they are not baked, pasteurized, or otherwise processed after fermentation and the bacteria remain live and active.
