We have met the enemy, and he is us.
—POGO COMIC STRIP, 1971
Jeroen Raes glides onto the stage, all Dutch height and unhurried manner. Clad in a simple dark sweater but wearing confidence like an Armani suit, he glances at the overhead projection of his first slide before his gaze flits briefly in the direction of his audience. It doesn’t alight there; he’s unconcerned with eye contact.
“So you think you are human,” he begins.
Raes is giving a Brussels TED talk about his work as director of Flanders’s Vlaams Instituut voor Biotechnologie, or VIB, the Belgian research institute, and he tosses a dizzying array of numbers at us: “There are seven billion people on this planet,” he announces, and goes on to say that our bodies are home to ten times as many microbial cells as human cells. My attention begins to wander, because I’ve heard these numbers before. Except for one.
“You know how many microbes there are [on earth]? Five nonillion.”
Five nonillion? That’s a 5 followed by 30 zeros. There are, in other words, as many microbes living on this planet as there are stars in the universe—multiplied by five million.
It’s a good thing that the scientists in Paul de Kruif’s Microbe Hunters didn’t know this. Even those irrepressible twentieth-century stalwarts might have despaired of exterminating their targeted pathogens had they known the size of the army arrayed against them. Instead, to a man—and they were all men—they were confident, even arrogant in their dominance. De Kruif presents them as conquering heroes of the microbial world, and his book is studded with martial metaphors, as are others of the genre—his Hunger Fighters and Han Zinsser’s Rats, Lice and History. The warlike tone is echoed in the work of evolutionary theorists like George C. Williams, who wrote, “Natural selection, albeit stupid, is a story of unending arms races, slaughter and suffering.”1
Casting the evolutionary contest as a war to the death between humans and microbes has become a cliché, reflected in the ways we conceptualize and speak about illness. Man fights to annihilate pathogens and vanquish disease. Microbes, although versatile, often favor guerrilla warfare, invading by stealth, crippling or taking over their hosts’ immunological armies, and sapping their strength, blood, fluids, and resources before wiping them out. Patients “battle” cancer and drugs “suppress” infection in a scorched-earth arms race in which pathogens seek to eradicate their enemies by ever-harsher measures. And in this age of antibiotic-resistant organisms, we do the same to them. A type of bacterium has become drug resistant? Turn to a harsher antibiotic with a broader spectrum that will kill even more types—and render itself useless when bacteria become resistant to it too. Douse the environment, and yourself, for good measure, with the antimicrobial hand sanitizers that sprout on office walls, in restrooms, and inside handbags, although studies show that soap and water is more effective at keeping germs at bay without fostering dreaded resistant strains.
When we habitually describe contests between rival organisms as brute death matches, it helps such blunt and shortsighted approaches sound more rational and necessary than they are.
Influenced by Williams’s 1960 book Adaptation and Natural Selection, the 1976 bestseller The Selfish Gene by Richard Dawkins moved this conflict squarely into the genetic arena by proposing that it is our species’ genes, not our individual selves, that direct and profit from the battle for survival with the sole goal of propelling human genes into the next generation. We, apparently, are just along for the ride.
Dawkins’s gene-centered view of evolution recasts many instances of apparent altruism as ruthless strivings for absolute dominance. When the monkey shares his meager meal with his community, when a woman risks her life to free her trapped cousin from a burning building, when a gay man helps support and raise his niece, the altruism does not seem to improve the altruists’ fates. But, Dawkins argues, it is the gene that seeks immortality, so the more closely two individuals are genetically related, the more logical it is to behave selflessly. The fitness of the gene—that is, the extent to which it survives into the next generation—is the true measure of its evolutionary success, so saving the life of your relation, feeding your extended family from which you or your children will choose a mate, and ensuring that children who are genetically related to you survive all boost your genes’ evolutionary fitness and are therefore sound survival strategies for your genome.
But despite the sophistication of these arguments, Dawkins perpetuated the military Weltanschauung when he invested the gene with the same anthropomorphic selfishness.
The microbes within
What if this worldview is wrong, and human evolutionary survival depends on something other than killing the competition in order to usher our genes safely into the future? What if, despite the rampant sickness caused by pathogens, our myopic view of them causes us to see malevolent foreign invaders where there are none and encourages us to obliterate organisms when our future health demands a more nuanced approach?
And what if, as the Pogo epigraph above suggests, the enemy is not wholly external?
For we are mostly microbes, and this is what Raes meant by his intimation that you are not wholly human. The numbers he offered supply evidence.
One hundred trillion viruses, fungi, archaea, and protozoa—but mostly bacteria—call your intestines home, and your guests outnumber your human cells ten to one. A coat of many microbes covers your skin, eyes, genitals, and mouth, each bacterial genotype specializing in an area of the body. Microbial scientists call this the commensal microbiome, a bit of a misnomer because the adjective describes a relationship in which one organism benefits while the other is unaffected, and as we shall soon see, you and your fellow travelers affect each other in many ways, sometimes dramatically.
Staphylococci colonize the skin, Escherichia coli prefer the colon, and lactobacilli coat the vagina. And that’s just on the surface; ten thousand different species of organisms thickly populate your gut, the folded, invaginated, nine-meter expanse from your mouth through your stomach and anus. Just as our genes constitute our genomes, these creatures make up our microbiomes. But unlike genes, with their numerical constancy, the human microbiome is constantly changing in type and numbers. Its makeup varies in different sites of the body and often in different sites on the globe. It changes over a person’s lifetime and in relation to the host’s genes. And mental health changes with it.
“Half of your stool is not leftover food. It is microbial biomass,” Lita Proctor, program director of the Human Microbiome Project, told the New York Times. We are so much larger than our microbial hangers-on that they contribute only an extra five or six pounds of body weight,2 but like unemployed houseguests, you can never get rid of them.
Our wealth of internal life should not surprise us. In sheer numbers, microbes rule the world: every teaspoon of seawater contains five million bacteria and fifty million viruses,3 which are the most numerous “living” things in the sea, a summit they reached by infecting other organisms, including bacteria.
Yet size and census counts matter less to our mental health than the microbiome’s astonishing power to keep a person healthy—or ill—and guide the immune system’s development. Embedded within the walls of your gut’s microbial rain forest is a web that has a thousand times more neurons than your brain. This neural web of cells, dubbed the enteric nervous system, or ENS, weighs twice what your brain does and deploys neurotransmitters that communicate with the brain.
The ENS influences your mind as well as your body. It first does so by globally shaping the development of the immune system, 80 percent of whose cells reside in your gut.4 By so guiding the immune system, the ENS determines your reaction to microbes’ behavior and how the interplay of the immune system and microbes affects your health, both physical and mental. But evidence from human studies suggests that the ENS is also directly connected to some specific mental disorders, including depression, autism, and possibly chronic fatigue syndrome. This explains why electrical stimulation of the vagus nerve, for example, is a treatment for depression.5 “I’m always by profession a skeptic,” Dr. Emeran Mayer, professor of medicine and psychiatry at the University of California, Los Angeles, told NPR, “But I do believe that our gut microbes affect what goes on in our brains.”6
Semantics shape conception, so in order to understand how the enteric microbes and the ENS direct the formation of our immune systems, it helps if we take off the verbal blinders. The warlike metaphors of which science is so fond distort our view and limit our ability to express what is happening, as a type of “war cam” disregards mutualism, symbiosis, and the many benefits that microbes impart. Martial language fosters a myopia that shrouds the true nature of our intimate relations with some bacteria.
Rather than mounting direct attacks on the body’s immune system and brain, as the traditional language of battling and vanquishing microbes assumes, the internal microbiome subtly shapes and directs immune responses and, therefore, health and behaviors. As I’ll soon explain, despite our big, complex brains, our single-celled passengers have a disquieting ability to manipulate us. And although this can evoke discomfort, it can also be a good thing.
Passengers is not quite the correct term. Most of the human bacterial complement has lived and evolved with our species for more than eight hundred million years,7 and some have melded so intimately with our bodies that they literally have become us.
For example, each human cell contains critically important organelles called mitochondria. They process food into energy-rich adenosine triphosphate, or ATP, molecules, whose high-energy bonds provide 90 percent of the fuel that we need to function. A mitochondrion is an endosymbiont (from the Greek words for “within,” “together,” and “living”), an organism that lives within the cell or body of another organism.
Widely accepted endosymbiotic theory holds that eons ago, these mitochondria were free-living bacteria that found it in their evolutionary interests to move into human cells permanently. As they became an essential part of us, we benefited as well, from those high-energy ATP bonds. There is plenty of evidence of mitochondria’s bacterial origins: mitochondria reproduce by dividing, as bacteria do, and they have even retained their own thirty-seven genes contained in the circular single-stranded molecule of DNA that is typical of free-living bacteria but that we now count among our human genes. More than thirteen diseases are caused by mutations in these mitochondrial genes, including forms of diabetes and deafness that are inherited through our mothers,8 but eliminating mitochondria is not an option, because we cannot survive without them.
There are many other types of relationships between us as hosts and our resident microbes that are often broadly characterized as symbiosis or commensalism, describing a relationship in which at least one of the organisms benefits. In mutualism, both organisms benefit.
We are home to other endosymbionts. We need the stomach bacteria that stimulate our immune-system development, digest our fibrous foods, and unlock nutrients like isothiocyanate, which protects against cancer and is extracted from the broccoli we eat. Microbes neutralize external pathogens, like the ingested bacteria that cause food poisoning. We need the resident microbes that make vitamins such as biotin, vitamin K,9 and vitamin D,10 and we may even need Helicobacter pylori, which causes ulcers and stomach cancers but seems to sometimes protect against obesity. Bacteria also are necessary for metabolizing drugs, and how much of some medications, like the heart drug digoxin, reaches a person’s bloodstream depends on which bacteria are in his microbiome.11
No wonder microbial scientists are wont to refer to the organisms in the microbiome as our “friends.” Jeroen Raes’s work at VIB12 includes experiments that show how anxiety behavior and exploratory behavior in mice are determined by what flora they have, and Dr. Ramnik Joseph Xavier, director of the Center for the Study of Inflammatory Bowel Disease at Harvard Medical School, agrees. Xavier points out that we rely on microbes for the folic acid that is essential to health and necessary to prevent birth defects. He warns against using probiotic supplements to do this job, because they introduce too few microbes and are not within the intestines’ carefully curated right balance: “Bacteria survive and do better when they are with their friends.”
Raes and his team divined the numbers he bandies about by using techniques unknown to the twentieth-century microbe hunters. They extracted DNA from the microbes in our internal rain forest using automated sequencing machines to determine how many and what kinds of microbes are resident in both healthy and diseased guts. They then assessed what these microbes’ genes did, because microbes other than mitochondria have genes too, a lot of them. When a European Union consortium assessed the genomes of 124 people, it found that the microbes within each individual harbor 3.3 million different genes, dwarfing the mere 25,000 in the human genome.13
What, then, does it mean to speak of the human genome when we carry millions more bacterial genes than Homo sapiens genes? And if we speak of the medical fortunes of a selfish gene, can we separate our species’ genes from those of the microbial multitudes that have evolved with us so closely and for so long that we now cannot live without them?
The wandering nerve
Human life is defined by this obligate friendship with trillions of bugs, but each of us begins life sterile and innocent of microbes within the selectively permeable space suit of the placenta. (Some question the placenta’s sterility, but a 2014 New York Times article overstated the case when it claimed, “The finding [which suggests newborns may acquire much of their gut bacteria from the placenta] overturns the conventional wisdom that the placenta is sterile.”14Overturned is premature; many microbiologists think that the placenta’s small community of bacteria is not acquired until it traverses the vagina after delivery.15)
But all agree that early in fetal development, the neural crest, a short-lived structure composed of pluripotent stem cells, differentiates into a rainbow of varied structures, including skin, muscle, heart, and fat tissue. The two poles of a person’s neurological being also spring from the neural crest: the central nervous system, or CNS, which consists of the brain and spinal cord,16 and the peripheral nervous system, including the ENS. Both contain neurons, neurotransmitters, and messenger proteins within a staggeringly complex circuitry, but they develop and function separately, with the ENS migrating to line the gut. As we will see, the CNS is the frequent target of neurotransmitters dispensed from microbes and implicated in mental disease.
As they develop, the two systems come to communicate through the vagus nerve, the tenth cranial nerve, whose long path meanders from the midbrain through the neck and chest before terminating in the peritoneal cavity. This path gives the nerve its name: vagus is Latin for “wandering.”
After the fetus has developed for nine months, powerful uterine muscles propel the baby through his mother’s birth canal, where he acquires her vaginal, fecal, and skin germs to emerge veiled in the microbial life that will determine his medical fate. Everything from the refinement of the skin and blood vessels to the development of the immune system is directed by such microbial anointings.17
As some microorganisms flourish and others die out, your gut becomes an evolutionary chessboard, courtesy of your developing immune system and your environmental exposures—including the diet that your mother chooses for you. Breast-fed babies acquire a distinctive microbial world that is far richer and populated with different species than the bottle-fed babies’. Breast-fed children benefit from exposure to the mother’s immune defenses, while formula-swillers miss out on Mom’s gastric lactobacilli and borrowed immunity.
During those first months and years of life, a person’s exposure to antibiotics is fraught with lingering consequences. In mice, as in humans, antibiotics kill off some microbes while leaving others to thrive, and this changes the nature of the microbial community. If the antibiotics’ collateral damage decimates the “wrong” bacteria, say H. pylori, which causes 90 percent of ulcers, the mouse will grow obese. If the antibiotics kill off a different set of bugs, the baby becomes more likely to develop allergies or asthma.18
Your enteric microbiome—the population of bacteria, viruses, and fungi in your gut and elsewhere—mutates constantly as a result of complex interactions that scientists are still unraveling. Meanwhile, the versatile vagus nerve, which connects the CNS and ENS, comes to manage many disparate functions such as heart rate, sweating, speaking, breathing, and coughing. It is even involved with the inner ear, which is why some people cough when the ear is tickled. The hardworking vagus also governs digestive functions such as peristalsis, the involuntary movements of the intestine that shepherd food along the gut.
It was through peristalsis that English physiologists William M. Bayliss and Ernest H. Starling first showed how the ENS functions independently of the brain. In 1899, the University College duo described how hormones were regulated in the gut. They discovered that applying pressure within the abdominal cavity of dogs triggered the “peristaltic reflex”—contractions followed by a propulsive wave that moves food through the stomach. In humans as well as dogs, these movements are necessary for digestion, but were they controlled by the ENS, or did the brain dictate them via the abdominal nerves? To find out, Bayliss and Starling boldly cut the Gordian knot, severing all the nerves connecting the brain and ENS. The peristalsis continued, demonstrating that the ENS governs it independently of the brain.
But rather than place the ENS on equal footing with the brain, scientists simply subsumed the enteric nerves under the heading “parasympathetic nervous system” as brain studies focused on how neurotransmitters dictate mood and behavior. Not until 1967 did the ENS studies of Michael Gershon, now chairman of anatomy and cell biology at Columbia Presbyterian Medical Center, reveal the existence of the neurotransmitter serotonin in the ENS as well as in the brain.
In Aldous Huxley’s Brave New World, the drug Soma provides contentment and euphoria. Such instant utopia seems chimerical and ethically questionable, but if there were a happiness drug, serotonin would be it. Neuroscientists think that it elevates mood and is crucial for emotional health and balance. Besides bolstering feelings of well-being, serotonin eases the function of the digestive system. And 90 percent of the body’s serotonin emanates from the ENS, not the brain. Serotonin’s usual target? The central nervous system. The neurotransmitters dopamine, glutamate, norepinephrine, and nitric oxide are also deployed by the gut, and 90 percent of vagal fibers carry information from the gut to the brain, not the other way around.19 ENS pioneer Gershon, author of The Second Brain, followed his discovery with innovative research into how the ENS uses infectious agents to produce mood disorders and mental illness. Because the antidepressant medications called selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels, it’s little wonder that meds meant to cause chemical changes in the mind often provoke GI issues as a side effect. Irritable bowel syndrome—which afflicts more than two million Americans—also may arise in part from too much serotonin in our entrails and could perhaps be regarded as a casualty of the second brain.
Microbes affect the brain by activating the gut endocrine system, which produces neurotransmitters and related signaling molecules called neuropeptides. These chemicals are involved in social behaviors and in learning, memory, pain relief, reward, and food intake.
Gut feelings
Researchers must create animal models of disease that mirror human ailments or behaviors so the animals can stand in as test subjects when studies are too unwieldy or unethical to attempt in humans, and research laws and ethics generally require that animal studies precede similar testing in humans. Creating animal models of disease can be challenging, but mimicking human emotions and behaviors presents an even greater hurdle. How, for example, can you duplicate human anxiety, panic attacks, or hopelessness in mice?
Well, you could buy the emotions. Mice are bred and sold with inherited temperaments; for example, there are high-anxiety and low-anxiety stocks.
Or you could make your mice go swimming. Persistent anxiety and depression are often modeled and measured by a forced-swimming test called the behavioral despair test or Porsolt forced-swimming test.
Any neophyte swimmer who’s sought to conquer a fear of the deep end can appreciate this classic model of murine anxiety and depression. A mouse is placed in a water-filled transparent acrylic swimming chamber from which it cannot escape and left there for fifteen minutes. It’s then fished out, and after twenty-four hours, the mouse is subjected to another swimming test of five minutes. The time that it spends in this chamber without moving, called immobility time, is considered a measure of hopelessness.
This model seems far from perfect. Some consider applying the concept of despair to a mouse a troubling bit of anthropomorphism, and others question whether the period of immobility may represent not hopelessness but an attempt to conserve resources after the mouse learns that escape is impossible. However, mice that are given antidepressants swim for longer periods and more vigorously than controls, and scientists (and the makers of antidepressants) have chosen to accept this as a measure of alleviated depression and despair. So have immunologists who wish to learn how commensal microbes regulate complex behaviors like anxiety, learning, memory, and appetite.
Some microbes directly produce neuroactive molecules that affect brain function and have been used to treat autism symptoms in mice. Researchers raised mice that had no microbiomes, then seeded these germ-free mice with colonies of whatever organism they wished to study. When scientists gave such sterile mice the bacteria Lactobacillus rhamnosus, the mice showed fewer depressive behaviors in the swimming test. However, when they gave the L. rhamnosus and then severed the vagus nerve (and thus the ENS’s connection to the brain), the mice were not soothed by the lactobacilli in the gut, so scientists concluded that L. rhamnosus helped govern depression and depressive behavior by activating the vagus nerve. Other bacteria produce natural antianxiety agents, such as an endogenous form of Valium, a benzodiazepine. In his book Missing Microbes, Martin J. Blaser points out that people who are dying of liver cancer often become comatose, but if they are given a drug that stops the action of this natural Valium, they awaken. This is because healthy livers can break down the natural benzodiazepines and prevent them from affecting mood and consciousness, but nonfunctioning livers cannot, and the endogenous benzodiazepines go directly to the brain, where they rob the patient of consciousness.20
Yet another type of bacterium was shown to protect against a murine version of multiple sclerosis. Mice that were infused with Bacteroides fragilis by Caltech neuroscientists became more resistant to multiple sclerosis, but only if a certain regulatory T cell, CD25, was active. If the action of CD25 was blocked, Bacteroides fragilis could not protect the mouse against MS.
But the most curious results, for our purposes, came when the bacterium B. fragilis was injected into so-called autistic mice.
A burgeoning of disease and distrust
In 1994, Joseph, my nephew, was five years old, a beautiful little boy with a warm, gentle demeanor and a distracted air.21 But he didn’t yet speak, and my brother and his wife had sought answers for this since he’d turned two. At that time, his hearing had been extensively tested and his intelligence called into question, but the source of his silence remained unclear. Now, three years later, they were left hanging with such airy platitudes as “Oh, he’ll probably grow out of it.”
This wasn’t nearly good enough, and my brother began taking his son to see specialists, paying a small fortune for out-of-network consultations that quickly deteriorated. He and his wife were questioned extensively about their home environment in a manner that annoyed me, if not my brother. He was vigorously pursuing an answer in the face of medical indifference; the fact that he also had to suffer implications that he was somehow to blame seemed profoundly unjust.
In 1996, we learned that autism was what was wrong, and our family struggled to deal with the shock. The disease is characterized by atypical communication and language development, avoidance of eye contact, and sensory experiences that differ from the norm, which explained Joe’s acute dislike of certain foods and textures. Aside from this, the disease was highly variable. We learned just enough to worry about Joe’s future, but my brother, as is his wont, saw the bright side. “Now that he has the diagnosis, he’ll qualify for medical treatment, special education, and services. Now I know I’ll be able to care for my son.”
Today my brother, who has divorced and remarried, is the primary caregiver for Joe, a friendly, happy, and industrious high-school graduate in his twenties.
Around 1911, Swiss psychiatrist Eugen Bleuler coined the word autistic to describe what he called the “morbid self-admiration” shown by children with what was then regarded as a type of schizophrenia.22From the Latin autismus, meaning “self,” the word reflects the inward focus of autistics. The term made its first appearance in the Diagnostic and Statistical Manual of Mental Disorders in 1980 as a type of schizophrenia, but by 2013 it occupied its own disease category, as autism spectrum disorder, or ASD, with conditions such as Asperger’s subsumed. Autistic children were once hidden away, but today medicine recognizes that the right combination of support can give affected people a good quality of life. However, autism’s frequency has exploded in a disturbing manner and the disorder has assumed center stage as people debate whether we are in an autism epidemic, and if so, why? According to the CDC, one of every sixty-eight U.S. children is diagnosed with ASD, a mushrooming of 30 percent since 2012,23and it is twenty times more common now than it was in the 1940s. The surge is not confined to the United States; Norway diagnoses six cases for every thousand children, a tenfold increase since the 1980s.24This increase in diagnosis is easily explained by a wider awareness of the disorder and better diagnostic tools, coupled with incentives such as the medical, educational, and financial support a child’s diagnosis offers parents like my brother. Still, the dramatic increase in autism provides a case study in twenty-first-century medical anxiety. When it comes to the state of autism research, perhaps Professor Jeremy Nicholson of Imperial College London said it best: “We know a lot about autism, but we don’t understand much.” But an escalating number of cases abroad as well as in the United States feeds a sense of urgency.
The disease has spawned seemingly endless controversy, beginning with the question of whether, despite its medical approbation, it is even a disease at all. In his revelatory book Dread: How Fear and Fantasy Have Fueled Epidemics from the Black Death to Avian Flu, epidemiologist Philip Alcabes dissects autism in the light of fears of modernity and observes that the furor over whether it is caused by immunizations obscures the possibility that we may not be dealing with a disease at all but rather a disquieting but normative human type.
There are precedents for creating a disease from a human outlier. Philosopher Ian Hacking notes early in his essay “Making Up People”25 that “statistical analysis of classes of people is a fundamental engine. We constantly try to medicalise.” And in “The Looping Effects of Human Kinds,”26 he writes, “We engage in ways of classifying [people] that became possible only in industrial bureaucracies.”
Some categories of people did not exist until society created them. Adolescents, perverts, people suffering from multiple personality disorder—these are kinds of people that did not inhabit preindustrial societies, at least not as any recognizable group. Since the nineteenth century, the human penchant for compartmentalization to deal with the stresses of modernity has impelled us to categorize people, partly to help them fit in.
We cannot be sure that autism has truly earned its disease label. But Alcabes, professor of public health at Adelphi University, makes a direct and practical observation in Dread that can hardly be refuted: debate over autism’s cause deflects attention from the question of whether people who exhibit autism’s symptoms are truly diseased. “The controversy over causes,” he writes, “makes autism seem less like a broad spectrum of normative mental-emotional states and more like an illness…. The dialogue about the nature and origin of the epidemic helps create the epidemic.”27
However, in a 2015 e-mail, Alcabes added that when writing Dread he was “uncertain whether there had really been a biological shift leading to more children who were quirky and unable to multitask, or if the epidemic was really just perceptual. I wrote the chapter in hopes of arguing for a more benign, de-pathologizing, way of looking at autism…. I’m more sure now that something really has changed biologically.”
If some autism is caused by infection, this helps validate its disease status. Are there any microbial causes? Perhaps.
I earlier mentioned that B. fragilis protects against a type of multiple sclerosis in mice under certain conditions. The bacteria also address the communication deficits that are central to autism in mice. As revealed in chapter 2, the children of mothers who contract severe viral infections while pregnant have a higher risk of autism. Paul Patterson of Caltech created mice with autism using a viral mimic that evoked an immune response in the mouse mothers similar to the one you would see in real viral infections. The offspring of these mice displayed the basic behaviors associated with autism.
However, when B. fragilis was added to the gut of an autistic mouse, the microbes produced neuroactive molecules that are known to enhance social behavior, and the mouse’s social interactions were enriched.28 How did these beneficial bacteria get from the gut to the central nervous system in order to change behavior? In their 2013 Cell paper,29 the investigators explain that the guts of the autistic mice were more permeable—“leaky”—which allowed neuroactive molecules to pass through the intestines into the bloodstream. Once there, they circulated to the brain and caused behavior changes.
Autism’s clinical picture is quite variable and the disorder probably has many causes, but this leaky gut is more than a feature of autism; it can sometimes be the cause. Michael Gershon has discovered that the same genes involved in the formation of synapses (infinitesimal spaces between neurons where communication by neurotransmitters takes place) in the brain are also involved in the formation of ENS synapses. “If these genes are affected in autism,” he says, “it could explain why so many kids with autism have GI motor abnormalities” as well as elevated levels of serotonin.30
It’s not completely surprising that interactions between the gut and immune system affect our thinking, feelings, and behavior; our language suggests that we’ve long sensed this. At my college and many others, students jubilantly recommended easy, intuitive courses to each other as “gut” courses, implying that little toil was needed because visceral wisdom would get you through without much studying. John Wilce, Ohio State coach, physician, and university professor, coined the phrase intestinal fortitude around 1915. It means “courage, willpower, guts, stamina, and determination.”31 Who has not endured loss of appetite, stomach cramps, or butterflies when facing a confrontation, an important test, or—quelle horreur—public speaking? Our instincts tell us that knowledge, fear, and courage emanate from the gut. But until recently, determining precisely how was difficult, because most gut microbes could not be cultured and studied in the laboratory.
We’ve long known that stress and fear produce gastrointestinal pyrotechnics, but in 1933 neuropathologist Armando Ferraro and clinical psychiatrist Joseph E. Kilman turned the equation on its head when they posited in Psychiatric Quarterly “the existence of cases of mental disorders which have as a basic etiological factor a toxic condition arising in the gastrointestinal tract.”32
The duo, based at the New York Psychiatric Institute, theorized that some mental illnesses arose from differences or changes in the permeability of the gut that permitted potentially harmful chemicals to leak from it. Sometimes these chemicals combined in a fearful synergy. They then made their way to the CNS, where they were much more toxic at relatively low levels than they were in the gut. Once in the CNS, they caused serious destruction. Researchers called this effect autointoxication genera.33
The results, proposed Ferraro and Kilman, were legion: levels of inflammatory cytokines increased, and microbes produced more or fewer neurotransmitters, causing levels to rise or fall alarmingly, all of which could lead to depressed or anxious moods. This situation was worsened by the fact that intestinal microbiota would normally attempt to counteract the surges of neurotransmitters by releasing cytokines that added to the witches’ brew from the leaky gut.
A person’s behavior can be transformed by levels of cytokines that are too low to detect by conventional tools, which makes identifying the responsible microbes very difficult.34
Autism’s leaky origins
Normally the tubes and pouches of the digestive system are surrounded by an impermeable wall of cells that protect the abdominal cavity from the stomach’s sea of gastric acid, and the neurons of the central nervous system from the microbes of the gut and their psychoactive products. But when a medical condition or other event causes a break or weakening of this wall, dangerous substances, including pathogens, can leak through it and enter the bloodstream. The breach may be caused by something as ominous as HIV infection or alcohol abuse, or it can be the product of inflammatory bowel disease (IBD) or autoimmune disorders. It may occur after radiation therapy, stress, exhaustion, or severe allergic reactions to food. Regular use of seemingly innocuous medications like OTC painkillers and antibiotics can also compromise the intestinal walls and cause a leaky gut. What’s more, reverse causation is a possibility, because a leaky gut can also cause some cases of IBD and autoimmune disorders. And some researchers think that the atypical, late-onset form of autism may be due to the leaky-gut syndrome, theorizing that mental diseases such as depression, like autism, are sometimes caused by microbes, psychoactive molecules, and toxic substances that slip from the viscera and migrate to the brain. In a study of depressed people that appeared in the May 2013 issue of Acta Psychiatrica Scandinavica, 35 percent of subjects showed serological evidence of leaky gut.35 This condition is currently being successfully treated with a combination of glutamine, N-acetylcysteine, and zinc—all believed to have anti-inflammatory properties—in the relatively few cases that are diagnosed. The diagnosis is gaining traction in the wake of such research, but we cannot yet be sure of the causal connection.
The science and ethics of vaccination in the context of autism fears have been exhaustively debated elsewhere, most recently in Eula Biss’s fine 2014 book On Immunity: An Inoculation, and I must forgo adding much to the discussion because it ranges almost completely outside the scope of this book, which focuses on infectious triggers of mental disorders.
Almost completely—there is an exception. In June 2010, Jeremy Nicholson of Imperial College London undertook human studies of the microbiome’s role in autism. He investigated the intestinal “forests” of thirty-nine children with autism and found that, unlike their twenty-eight nonautistic siblings and a control group of thirty-four unrelated children without autism, those with autism showed changes in their gut bacteria,36 suggesting that in some cases, autism may result from such changes.
The symptoms of autism usually appear during infancy or early childhood, although they are not always recognized as such until later, as in the case of my nephew. A 2010 study37 found that a group of six-month-olds displayed similar behavior when it came to gazing at faces, sharing smiles, and vocalizations, but by the time the children were a year old, those who went on to develop autism had largely lost these behaviors.
Other parents report that their autistic children seemed to develop normally until later, about age three, at which point the features of autism suddenly appeared. Parents of children who have what’s called “regressive-onset” autism often report that symptoms began after their child was given antibiotics that were followed by persistent diarrhea.
Proponents of the regressive-onset theory suggest that the antibiotics selectively kill some microbes, and as the community of microbes in the bowels of these children changes, it becomes colonized by bacteria that produce toxins that harm neurons, bringing on the symptoms of autism.
These troublemaking bacteria wear coats of lipopolysaccharides, or LPS, a tongue-twisting name for molecules that contain antigens and that elicit strong immune responses in animals. These LPS produce endotoxins, poisons that bacteria normally retain within their cell walls.38
The endotoxin-covered bacteria have evolved to be adept at crypsis; that is, the ability to escape detection by other organisms. In this case, the bacteria avoid destruction by the immune system by adopting a wily camouflage. On their surface, they present portions of their endotoxins that chemically resemble molecules on human cells, masking their true identity and fooling the immune system into thinking that LPS are a nonthreatening part of the host’s self. This strategy is called molecular mimicry. In this theory of the origin of autism, the LPS-clad bacteria proceed to exude their poisons, the affected neurons become impaired or die, and the symptoms of autism emerge.
Finding an animal whose reaction to the LPS-veiled bacteria resembles that of humans would seem the logical next step for testing this theory, but rodents make dodgy models for studying the effects of endotoxins because humans are far more sensitive to them. Ingesting one microgram—that’s one millionth of a gram—for every kilogram of body weight will send a person into shock, but mice tolerate a thousand times that dose without ill effects.
Happily, human studies have been conducted to test the theory. When the stools of children were analyzed, those of children with regressive-onset autism had much greater numbers of clostridium bacteria, which thrive when antibiotics kill other species in the bowel. In addition, compared to controls, a greater-than-usual diversity of clostridium proliferated.39
There are many infamously toxic strains of clostridium, from C. difficile, which causes diarrhea and sometimes colitis in the aftermath of antibiotics, to C. botulinum, which causes fatal food poisoning but has been tamed for cosmetic use as Botox, to C. tetani, which causes the equally fatal tetanus. Another member of the genus, C. perfringens, causes gas gangrene. What all these species of clostridium have in common is that they produce a dizzying assortment of toxins that attack neurons, and by doing so, they encourage madness as well as death.
In another study of children with regressive-onset autism following antibiotics and chronic diarrhea, ten children were given the antibiotic vancomycin by mouth.40 If this routed the clostridium and cured the symptoms of autism, the recovery would serve as evidence that the clostridium levels were associated with the autism. Before and after the children were given the vancomycin, their skills and behaviors were evaluated in several ways, including by clinical psychologists who viewed videotapes of children but did not know who had been treated.
The scores revealed that eight of ten children demonstrated improvement after being on vancomycin. Although the response was not long-lasting, this points to a new treatment direction.
It’s important to note that this study did not suggest that the initial use of antibiotics caused autistic symptoms, only that these symptoms were correlated with changes in the gut. It’s possible that parents’ belief in antibiotic-triggered symptoms is a result of recall bias. Or parents may unwittingly exaggerate the proximity of antibiotic administration and symptoms.
And not everyone agrees that regressive-onset autism even exists. Some insist that these children had not developed normally, but that their deficits and missed milestones had gone unnoticed until the other symptoms of autism emerged.
Even if larger future studies validate the finding that microbial changes are causally related to some types of autism, this is not an argument against using antibiotic therapy, which is often necessary and lifesaving, during childhood. Before such treatment was available, diseases killed and incapacitated children in numbers far greater than those who may risk late-onset autism. It may, however, be yet another argument for using more specific antibiotics to avoid changing the incredibly complex microbiome more than is necessary, as chapter 7 discusses.
Microbial frenemy
Helicobacter pylori, found in 90 percent of people with ulcers and stomach cancers, wreaks even greater havoc when it escapes from the gut. According to a report in Psychosomatic Medicine, errant H. pylorialso contributes to the cognitive impairment of Alzheimer’s disease. People who are infected with H. pylori perform significantly worse on cognitive tests than those who are uninfected, writes the study’s coauthor May Baydoun. Her laboratory found that H. pylori cells travel from the gut to the brain, where the bacterial cells aggregate with the characteristic amyloid proteins of Alzheimer’s and trigger the buildup of plaque. Baydoun, a scientist at the National Institute on Aging, estimates that about 20 percent of people younger than forty and half of adults older than sixty are infected with H. pylori.41
Worse, the bacteria’s effects may not be limited to aging brains; children infected with this ulcer-causing bacteria performed more poorly than controls on IQ tests in a study that suggests a broader link between H. pylori infection and cognitive impairment. H. pylori can be eliminated with antibiotics, which might conceivably lower the incidence or severity of Alzheimer’s, but this is a move to ponder carefully, because the pathogen has beneficial effects as well. The bacteria’s decline coincides with the epidemic of obesity and diabetes in developed countries. Josep Bassaganya-Riera conducted H. pyloristudies that suggested this maligned catalyst of ulcers, stomach cancer, and cognitive erosion acted as bacterial armor against obesity. His laboratory at Virginia Tech’s Center for Modeling Immunity to Enteric Pathogens is where, he says, “we demonstrated for the first time that gastric colonization with H. pylori exerts beneficial effects in mouse models of obesity and diabetes.”
Other constituents of the microbiome have positive effects on mood and mental health. Lactobacillus, for example, seems to bestow serenity. Healthy human volunteers who consumed a mix of Lactobacillus helveticus and Bifidobacterium longum exhibited less anxiety and depression, while students’ stools contained fewer lactobacilli during a high-stress exam period than during a less stressful period. These findings suggest an inverse link between stress and lactobacilli that will need to be more fully investigated.
Preparations containing lactobacilli and other probiotic microbes are often touted and sold as health supplements that can improve everything from mood to digestion, but scientists like Ramnik Xavier advise caution. Some of the commercial claims are unproven, warns Xavier, and the microbes may not be helpful when isolated from their companion organisms or when taken by people who do not suffer from leaky-gut syndrome.
One group of investigators scrutinized probiotics to see which, if any, might exploit the benefits of the ENS rather than the credulousness of consumers, and their 2007 report on preliminary human studies, published in the European Journal of Clinical Nutrition, demonstrated that consuming some probiotic strains can improve cognition and mental outlook via the psychotropic influence of lactobacillus and bifidobacterium. In an intriguing grace note, their work mentions why honey is so soothing: kynurenic acid,42 which is produced by intestinal microbiota but also found in honey, is easily absorbed from the intestines and is an anxiolytic, defusing anxiety by damping the activity of excitatory amino acid receptors. Certain vegetables contain kynurenic acid too, but tubers and greens stirred into that comforting cup of tea sounds far less inviting.43
Know thyself: The Human Microbiome Project
Our bacterial genes outnumber our human genes by an order of magnitude,44 and bacterial cells outnumber our human ones ten to one. After beginning life wholly human, we soon become 90 percent microbial. What picture of our health, including our mental health, can emerge without knowing something of the microbes within?
In 2007 the federal government sought to help microbiologists untangle the complexity of the microbial biome when it committed $115 million to the Human Microbiome Project, or HMP,45 which is to culminate in 2015.46 In a parallel to the Human Genome Project, two hundred scientists at eighty institutions are sequencing the genetic material from bacteria taken from nearly two hundred and fifty healthy people in order to unravel the relationship of our microbial “self” to our health, and they are seeking to perfect tools that will allow them to evaluate significant findings. There are many similar institutional efforts, but this federal HMP is the largest, best funded, and most coherent.
The first phase, which ended in 2012, sought to characterize the diversity and genetics of microbial life hiding within the nasal passages, oral cavity, skin, gastrointestinal tract, and urogenital tract. The current phase peers at human groups to collect data detailing both the microbiome’s biological properties and microbiome-associated disease.47
Genome technology has provided tools that allow researchers to obtain DNA directly from samples and sequence it. For instance, the HMP is cataloging these bacteria indirectly by searching for DNA with 16S rRNA, a gene that serves as a bacterial marker. Thanks to these studies, we now know that by your third birthday, a delicate balance of environmental and developmental forces has cast your own distinctive microbial identity. Each person’s microbiome is unique and each varies greatly, so two healthy people can have completely different microbiomes. And yet, knowing the composition of a person’s gut allows scientists to profile the demographics of his mouth’s microbes, although different organisms inhabit each site. Some researchers say they can determine whether a person was breast-fed; some even claim they can divine someone’s probable education level from his microbial fingerprint, a statement that sounds rather… optimistic. Still, scientists hope all this will one day be useful in tailoring therapies to individuals.48
Although your microbiome will continue to change somewhat throughout your life in response to the same pressures that forged it—diet, stress, medications, age, and genetics—it remains as recognizable a biological signature as your blood type, for those who are able to read it.
Three bacterial groups rule our colons: Firmicutes, Bacteroidetes, and, to lesser extent, Proteobacteria. Fungi, protozoa, and viruses constitute minority populations.49 Most human guts fall into one of three groups, or enterotypes, based on which bacteria is dominant. Enterotypes play a key role in disease susceptibility.
Jeroen Raes likens these enterotypes to forests. There are tropical forests, temperate forests, and bamboo forests. They’re all forests, but they feature different species living together and functioning as a unit. He also points out that the environment of the gut is the food that you eat. People who eat high-fat diets have different microbial populations than those who eat more protein or those who eat mostly carbohydrates. That’s important, he says, because more and more diseases are linked to a disturbance of gut flora—chronic diarrhea, obesity, irritable bowel syndrome (IBS), and, as you’ve read, “even autism, all have been associated with disturbed gut flora.”
The connection is causal, not a mere association, says Raes. “Bad” gut flora actually cause disease. “If you take the flora of an obese mouse and you put it into a germ-free mouse, that germ-free mouse becomes obese…. We’re moving toward diagnosing people on the lifelong monitoring of your gut flora from feces.”
Moreover, the environment these bacteria live in determines the variations in enterotypes, and the genetic signature of microbes helps explain why some people are susceptible to certain diseases while others enjoy immunity as well as why individuals react differently to various drugs and foods.50
Americans may find that overindulging in sushi carries dire gastronomic consequences. Japanese who live on a diet of seafood have evolved gut bacteria that can break down algae, apparently due to genes transferred from a marine bacterium called Zobellia galactanivorans, explains Ramnik Xavier. This allows them to digest sushi in quantities that those in the United States cannot, because the microbes are absent in North American populations.
Fat and Firmicutes
Speaking of food, rodent and human studies demonstrate the paradoxical role microbiomes play in obesity and overweight. The histrionics over the “obesity epidemic” are widely overstated; many fears promulgated by the weight-control industry and public-health leaders are not backed up by the facts. But there is no question that obesity is a serious medical issue in the United States, where more than one in three citizens are obese. That’s 78.6 million people. The fact that Americans are growing fatter at younger ages raises the U.S. rate of metabolic syndrome, a connection between excess weight, insulin insensitivity, and high blood pressure that leads to diabetes, heart disease, and stroke—a dread trifecta. Obesity also encourages depression.
The Diagnostic and Statistical Manual of Mental Disorders 5 pleads insufficient evidence to declare obesity a full-blown disorder. It speaks instead of binge-eating disorder, which, without purging,51“portends a greater risk of weight gain,”52 leading in many cases to obesity. But anyone wondering whether obesity falls within the province of psychiatry need only attend an American Psychiatric Association meeting, as I did in New Orleans, and observe the wealth of workshops, panels, discussions, and lectures—to say nothing of the pharmaceutical advertisements—devoted to treating obesity. Or peruse the American Journal of Psychiatry, wherein obesity is discussed as a psychiatric condition requiring medication, counseling, and behavioral therapy in addition to bariatric surgery, candidates for which have a higher number of mental disorders than the general population. There is also research literature linking obesity to trauma; for example, to sexual abuse in young women. All this leaves little doubt that obesity falls within the purview of mental health.
But if we all live in the same country where cars replace walking, escalators replace steps, and commercials relentlessly tempt us with cheap, high-calorie, high-fat foods, why do only some of us become overweight or obese? An obvious answer is that some people eat better and exercise more than others. But this is unlikely to be the only answer, because in groups of people who have similar habits of eating and exercising, some still gain more weight than others. No one knows why.
Jeffrey Gordon and other researchers at the Washington University School of Medicine offered an answer when they discovered a large microbial contribution to obesity. Remember the three enterotypes mentioned earlier? One of them, Firmicutes, may be running the obesity show.
Some microbes, such as those in the clostridia and bacilli genera, are very efficient hoarders, extracting every bit of nutrition from foods. Moreover, these hoarder microbes also regulate gene function, encouraging their hosts to preserve more of this nutrition in fat. This helped our ancestors to survive when food was scarce and they had to work hard for each mouthful, but in today’s world of drive-through triple-bacon cheeseburgers, ice cream trucks, and delivered pizzas, the hoarders’ blessing has become a curse called obesity.
Gordon’s team reported in Nature that the microbiomes of the obese, which differ from those of the lean, have especially high proportions of these hoarder microbes. When the researchers sequenced bacterial DNA from fecal samples, they found that the obese had a higher proportion of Firmicutes than did lean people.
So did fat mice. The types of Firmicutes in obese animals are more efficient at converting complex polysaccharides (carbohydrates that mammals need microbial help to digest) into simple sugars. Using this knowledge, Gordon took mice that had no microbiomes because they had been raised in a sterile environment and successfully manipulated their microbiomes to make them fatter or thinner by seeding their guts with microbes from either obese or lean mice.
Turning to humans, he put some overweight people on different diets and noted that regardless of whether the subjects were on low-fat or low-carbohydrate diets, their microbiomes shifted to the composition of slim people’s as they lost weight. This would suggest that one’s microbial population is a product of one’s weight, not the other way around.
But another of his experiments, reported in the Proceedings of the National Academy of Sciences, adds a twist. When Gordon fed both the normal mice and the germ-free mice a high-fat, high-sugar diet, the normal mice gained weight, but the germ-free mice stayed lean.
The normal mice had microbes that, like a milder version of the hoarding microbes discussed above, made sugar more available to their bodies. And when researchers compared the two types of mice, they found that gut microbes in the normal mice regulated their hosts’ metabolisms through two mechanisms. First, they suppressed fasting-induced adipose factor, a substance that encouraged mice to store fat. Second, they reduced the levels of the enzyme adenosine monophosphate–activated protein kinase, an enzyme that made it harder for mice to burn fat they already had. All this means that gut microbes release energy from food and encourage bodies to store that energy as fat while also making it difficult to get rid of the fat once it’s stored.
Studies of obese people who undergo stomach stapling have found that their levels of Firmicutes change with weight loss, and their diabetes resolves too quickly to be attributed to the weight loss. Could microbes be responsible? Research is under way to find out.
Obesity is a complex problem born of both physical and psychological factors, and even within the ENS, many more factors are likely to emerge. Everything from genetics to childhood sexual abuse to the diet one’s mother ate has been implicated, and the solution to the problem will not be as simple as going germ-free. But knowing that microbial balance plays a role enables us to look in a direction that could provide safer, more fruitful, and more permanent answers than the fat-busting pills of yore.
The measles, mumps, and rubella, or MMR, vaccine has been noisily demonized, leading distrustful groups and fearful parents to shun the vaccinations. Predictably, measles outbreaks have risen, and by late February 2015 a single outbreak that began at Disneyland sickened 123 children; most were unvaccinated. The first five months of 2014 saw more measles cases than comparable time periods in any year since 1994; the CDC reported that 90 percent of those cases were among people who hadn’t been vaccinated.53
This rise in cases is a potential disaster, because measles is one of the most deadly and the most contagious of childhood diseases. In his landmark study of measles, Danish pathologist Peter Panum established this when he determined that of the 7,864 people living in the Faroe Islands in 1846, 6,100 of those who were exposed to the infection fell ill, an infection rate of 99.5 percent, and 23 of every 1,000 infected people died.54
Measles’s carnage is not relegated to the past. In sub-Saharan Africa, measles still kills half a million children every year. But when I was a child and measles was ubiquitous, no one feared it. In spite of the deaths, pneumonia, and encephalitis it trailed, it was regarded as a mildly irritating rite of passage for mothers who had whining sick children underfoot. A familiar disease often breeds this sort of contempt, according to nineteenth-century Scottish health minister William Simpson, who noted the “peculiar fact, that the most dreaded diseases are the least fatal, and the least dreaded diseases are the most fatal… the disease that comes unexpectedly, and passes over quickly, is looked upon with greater feelings of terror than the disease which may be more fatal, but more common.”55
If we need another reason to fear the measles virus, here it is: measles joins the growing number of microbes known to precipitate mental disease. Approximately one of every thousand children with measles develops encephalitis, a potentially dangerous irritation and swelling of the brain. There’s also a severe long-term complication, subacute sclerosing panencephalitis (SSPE), a very rare fatal disease of the nervous system that occurs when children, usually younger than two, contract measles; their inability to produce certain proteins can allow the virus to survive indefinitely without evoking an immune response.56
Encephalitis symptoms appear within two weeks of infection; the disease kills 15 percent of affected children outright and leaves one in every four with permanent brain damage. SSPE symptoms begin months to years after the infection and lead to personality changes in the child—he or she becomes more irritable and argumentative and behaves erratically. Seizures and a stumbling gait follow, along with sensitivity to light and spastic movements, including involuntary jerking of the arms and legs. Cognitive skills begin to decline, resulting in memory loss, and the child becomes unable to walk. Speech is first impaired, then silenced. The child cannot swallow, goes blind, and is racked by seizures before falling into a final coma. Globally, only 5 percent of those with SSPE survive, but in the United States, lifelong treatment with interferon and inosine pranobex saves half of affected children.
In many cases of SSPE, the virus that is retrieved from the brain is abnormal and cannot be grown in culture. Scientists theorize that the virus mutated during the long years after the measles infection and before the viral destruction of the brain began.57 Measles is not alone among childhood disorders in triggering mental illness; whooping cough causes ten times as many cases of brain damage.
Unfortunately, children whose cases of measles are routine and uncomplicated by encephalitis are not safe from mental disease. As many as ten years after they developed the skin rash, their personalities may begin to change, and irritability and erratic behavior signal a mental deterioration. How well they do depends on the particulars of their infection, but this scenario is not one that is considered by those who urge parents not to vaccinate their children.
The U.S. story is not the only one. Measles complications that threaten mental health are as common in the Middle East and regions of Asia as they are here, and there is no cure. The measles vaccine, however, has slashed the number of global cases.58
Fecal future?
We need to embrace novel therapies that don’t involve decimating helpful bacteria or encouraging antibiotic resistance. Michael Pollan writes of one of these: “Fecal transplants, which involve installing a healthy person’s microbiota into a sick person’s gut, have been shown to effectively treat an antibiotic-resistant intestinal pathogen named C. difficile, which kills 14,000 Americans each year.”59 Today the transplants are done by colonoscopy or by a tube that runs through the nose into the stomach, but a 2014 study published in JAMA predicts that pills may soon be available, a more pleasant, safer, and cheaper technique.60
But as scientists decide which strategies to endorse, there is a further dimension of infection to consider that can dictate our collective, not just our individual, mental health. We must consider how the infinite variety of pathogens can distort the very nature of societies.