33

Microbiome

At least half of the cells in our body are bacterial, not human. One hundred trillion bacterial cells, and they are mostly in our gut. In the individual, they are called a microbiota, and the collection of them, and the breadth of their genetic building blocks, is called the microbiome.

One review on the subject written by scholars at the University of Colorado at Boulder reported that there are 3.3 million microbial genes in the human gut, “compared to roughly 22,000 genes present in the entire human genome.” Another study estimated there were 1,000 species of bacteria in the gut with 5 million genes. The scope of the microbiome is, in a word, huge.

The paper from Boulder notes that human beings have virtually the same set of genetic material—you and I are 99.9 percent similar in our underlying genetic building blocks. But the microbiome—the underlying genetic material of the bacteria in our gut or hand—can differ by 80 to 90 percent. (Worth noting is that most bacteria are in your gut, though there are also 500 bacterial species in your mouth, and about the same number in your “airways”—the respiratory system; 300 million are on the skin; for women, about 150 million are in the genital infrastructure.)

“Everything you’re looking at is covered in microbes. You just can’t see them. They colonize the world but are invisible to us,” explained Sarkis Mazmanian, a Caltech professor who is seen as one of the field’s leading thinkers. Back when Mazmanian first got started—and “developed this love for bacteria”—he thought they were “these insidious little creatures that want to make us sick. I was wrong.”

For the longest time, there was a theory that the reason we could coexist with the bacteria in our gut was that there was a protective layer lining our gut that acted as a powerful barrier. The barrier, a mucus-like lining with the texture of Vaseline, behaves as something like a force field between the small and large intestines and the rest of the body. This lining, it was thought, kept our microbiota from getting into the rest of the body and thus away from the immune system. This theory is called immunological ignorance.

The immune cells, in effect, were thought to be ignorant of these bacteria among us.

This thinking was incomplete, if not outright incorrect. Mazmanian and others have since found that the gel that lines the gut is colonized by the microbiota, and their presence puts them very much in close proximity to cells that can trigger an immune response. On the other side of that gel-like wall is a line of cells, called epithelial cells, that is heavy with immune triggers.

This suggests the microbiota have developed with the deliberate ability to interact with and stimulate our immune system.

A salmonella bacterium (upper right) detected by epithelial cells in the digestive tract. (David Goulding/Wellcome Trust Sanger Institute)

To make sense of this, step back and think about humans in the context of the world. We exist in a literal and metaphorical sea of bacteria. We must coexist with them in the same way that we must coexist with each other. Imagine if you were at war all the time with your neighbors; you’d eventually kill each other off, as surely as the Hatfields and the McCoys. Instead we find common ground, cooperate, and maybe get some help with coexistence by setting up fences and boundaries. The relationship between humans and bacteria is even more intimate than that. We are different from one another, we can harbor antagonistic feelings at times, but for the most part we are highly supportive of each other, which is essential for protecting one another’s survival.

Still, from an evolutionary perspective and in the scale of epochs, the initial meeting of immune system and bacteria was not a friendly one.

“The first encounter was likely antagonistic—until a truce was reached,” Mazmanian says. The immune system and the bacteria felt each other out and through evolution made a mutually beneficial peace. Then they determined that they could survive only together; they could serve one another’s aim to survive. Mazmanian calls it a “partnership—both players on the same side of the net, fighting common foes.”

The shared foes are the handful of pathogens—the bacteria and viruses and parasites that would kill the human tissue. In the grand scheme, these pathogens are a tiny fraction of the bacteria in the world. For the bacteria we cooperate with, our microbiota, these pathogens become a common enemy because our body is the host where the microbiota lives. “The bacterium collaborates with the immune system to fight off an invading microorganism,” Mazmanian said. “It makes sense as a benefit to both.”

That evolutionary perspective plays out on an individual stage. Each of us develops a working relationship with our environment. It’s a social contract of sorts with the bacteria in our midst, and the contract is highly personalized and highly variable. This is underscored by one powerful piece of scientific trivia: The microbiota in the gut of an infant who is delivered vaginally differs from the microbiota of an infant delivered by cesarean section. In the early days, our business partner, the microbe, then goes from 0 to 60. It’s put nicely in an article coauthored by, among others, a Stanford geneticist:

The microbial colonization of the infant GI tract is a remarkable episode in the human lifecycle. Every time a human baby is born, a rich and dynamic ecosystem develops from a sterile environment. Within days, the microbial immigrants establish a thriving community whose population soon outnumbers that of the baby’s own cells. The evolutionarily ancient symbiosis between the human GI tract and its resident microbiota undoubtedly involves diverse reciprocal interactions between the microbiota and the host, with important consequences for human health and physiology. These interactions can have beneficial nutritional, immunological, and developmental effects, or pathogenic effects for the host.

That dense but highly informative passage refers to bacterial colonization of the baby’s digestive tract. The colonists are “microbial immigrants”—another indication of the essential balance and blurring of self. Who are we and what is other? What is alien? To survive, how essential is it that we cooperate with other and not shun or destroy?

The paper makes several other powerful scientific points. One of them is about the role that our environment plays in the formation of our microbiota. In mice, babies who live in the same cage with their mothers have microbiota more similar to their mothers than do babies of the same mother who are caged elsewhere. As the paper notes: “The bacterial population that develops in the initial stages is to a significant extent determined by the specific bacteria to which a baby happens to be exposed.”

To explain why these bacteria are so crucial, I will briefly reprise a pioneer from the 1970s, Susumu Tonegawa. Tonegawa helped discover that the underlying genetics of the human immune system can be so diverse because genes rearrange at random during development and infection so that each of us comes equipped with an immune system with a great ability to recognize and then “bind” to a wide range of potential threats. We have developed a nearly infinite array of antibodies; to many, this was the key to how we could survive.

However, despite the profound and extensive nature of the tool kit, it is not sufficient to ensure our survival. Here is where the microbiome comes in. “The human genome is not sufficient to confer all the benefits of health. We require input from the microbiome. We need this second genome. So we actually harbor two genomes, our own and our microbiome,” Mazmanian told me.

The incredible cooperation between human and microbe has led to a new terminology to describe us. We are superorganisms. Yes, that’s the scientific term. You should feel good about yourself. You are superpowered, a human being strengthened by the power of bacteria.

But what specifically does the microbiome help with?

Digestion, nutrition, obesity—broadly, how much energy we take from foods and how effectively we squeeze nutrients from them—but also anxiety and mood, and significantly in this context, how we defend ourselves against pathogens and defend against ourselves.

It helps to see the idea in practice.

One of the many variations of T cells, we now know, is called a T regulatory cell, or Treg. It is a powerful subset of our T cells that has been shown, among its other roles, to help suppress the immune system. In the big picture, this makes sense; it is part of a defense network that is primed to destroy party crashers without being so overzealous that they ruin the party.

In that respect, Treg cells are not so unusual. What makes them worthy of note here is that there is a decent chance they wouldn’t exist without the presence of the microbiome in the gut. What Mazmanian discovered, using experiments in mice, is that Treg cells don’t get developed when certain gut bacteria are missing. In other words, when the microbiome of the mouse is incomplete, so is the immune system.

Mazmanian and his fellow researchers also discovered that the bacteria had a signaling mechanism that stimulated the development of the Treg cells. The way this works, simplistically, is that the gut bacteria send a message that is passed via the immune cells that line the gut and then is received by cells in the bone marrow or thymus that are awaiting the command to take on the Treg identity.

Mazmanian described the upshot to me in fairly stark terms. “There are entire cell types in the body that don’t exist because the DNA doesn’t have all the information to tell that cell to develop,” he said. It’s not just Treg cells, but natural killer cells and other killer immune cells that appear to be triggered by the bacteria.

Broadly, Mazmanian’s work also shows that the microbiome plays a key role in dampening the immune system, in addition to helping it to attack foreign invaders. This is because—as I hope has become abundantly clear—the immune system is as dangerous to us as it can be to invaders. The microbiome can’t afford to have the host hurt by its own immune system, by an overzealous police state. It is in the microbiome’s self-interest to keep the body from attacking itself, so the bacteria contribute to helping keep the immune system in check.

“The immune system is a loaded gun, and when it fires and is uncontrolled, then you get allergies, then you get autoimmunity, then you get inflammation,” Mazmanian says.

There is a powerful punch line to Mazmanian’s work: The way we relate to bacteria in the world dictates our health. If the relationship gets out of whack, our immune system becomes unbalanced too. “What we are discussing here,” Mazmanian says, “is the modern interpretation of the hygiene hypothesis.”

The hygiene hypothesis stated that our environment has become so clean that it has left our immune system insufficiently trained. Mazmanian and others believe that the microbiome lies at the heart of the challenges faced by the immune system in modern times.

Our efforts to scrub our environment of bacteria, while well intended, have wound up limiting the number of bacteria that colonize and populate our gut. Mazmanian jokes that the toilet is a mixed blessing, compared to pooping in the woods: half burying the bacteria, half washing our hands. Instead of that, “We’re flushing the good guys away.”

Does he mean it when he says we’d be better off with fewer modern amenities?

Well, it is true that people in less developed countries, say some parts of Africa, have much more complex microbiomes than we do. When Mazmanian first got to Caltech in 2006, an idealistic part of him thought that these complex microbiomes and the environment that fostered them are superior to those of the Western world.

“Trust me,” a colleague told him, “you don’t want a microbiome full of tropical virus and parasites.”

There are also lots of examples where exposure to dangerous pathogens at a young age can lead to illness later, or to autoimmunity. So it’s not that we want to do away with many modern amenities and be surrounded by bacteria. But it is true, Mazmanian says he has since learned, that the result of overly cleansing our environment and using antimicrobial soaps and wipes is to limit the microbiota we pass back and forth among us. This is the essential point. As a species, we have all kinds of beneficial bacteria. Some of us are colonized with certain types of bacteria while others of us carry different ones. Throughout human history, we have passed these back and forth, shared them, creating a vast trading network through handshakes, hugs, and cheek pats, shared use of stair banisters or countertops, and on and on. Now we kill our microbiome instead of sharing it.

“We’ve distanced ourselves from infectious agents, but also distanced ourselves from microbes that confer benefits,” Mazmanian said. “I will likely have a less complex microbiome than my mother, and that of my kids will be less complex than mine. Every generation may just be less diverse.”

We relied on these microbes to fill out our defense, including the signals that dampen our immune system. This appears to be one key reason allergies and autoimmunity have risen. We aren’t getting the signals that say: Slow down. Don’t react to the pollen. Don’t attack yourself.

These ideas, the hygiene hypothesis and the microbiome, impact the health of the population at large, the broader environment surrounding our immune systems.

We have reached an inflection point at which our relationship with bacteria is fundamentally shifting. Bacteria are organisms we share this planet with, and with which we have coexisted for millennia. The relationship is changing because we as a species are fighting to survive and bacteria are fighting to survive. That relationship has always been in flux, but the pressures on the relationship have intensified because of human technology, like antimicrobial soaps, antibiotics, and nonorganic foodstuffs. These advances, wonderful in certain respects, hallmarks of human innovation, are so powerful that they have sharply thrown off the tenuous balance between bacteria and us. This is similar in key respects to other technological advances that have had unintended consequences. The birth of the automobile allowed fast transportation and led immediately to thousands of road deaths; processed food allowed widespread preservation and transport of calories but led to junk food and a deadly obesity epidemic; cell phones changed communications overnight and have also threatened focus and attention, led to distracted driving and compulsive computer use; and so forth.

There is one key difference between those situations and those we confront with bacteria. In all those other cases, we have ultimate control. We can change how we behave or modify the technology. But in the case of our relationship to bacteria, we control only half the equation. We can try to take steps to put less pressure on bacteria, but we can’t ultimately dictate how these powerful organisms will react.

So what does this add up to? First, simply, we must have an awareness that we are sharing the earth with these distant cousins. Second, we will need societal policies to address things like the resistance of bacteria to antibiotics. We can at least try to use our technology more judiciously.

On an individual level, there is less we can do. But it is possible to be less neurotic about the use of products that can have a counterproductive impact on our own bodies and on bacteria as a whole. We can choose to eat foods not raised with antibiotics. We can decide to pick up a piece of food dropped from the floor, rinse it, and eat it.

I concede that it’s a tough balance to strike at times. After all, the rise of resistant bacteria makes it hard to think about eating food off a hospital floor (where bacteria are rampant) or eating meat without caution while traveling in a developing country when those meats might well have been raised without antibiotics and could be undercooked, allowing them to transfer resistant bacteria.

In the end, another major collective step we can take is to support science. It has yielded terrific answers and likely holds the key to helping us right the balance with our bacteria.

Meanwhile, on an individual level, there are other areas of life where we can take concrete steps to keep our immune systems in balance. These are central to health, not just autoimmunity, and they are under our control. In fact, if you pick only two chapters in this book to read and apply to your life, these are the ones. They focus on stress and sleep and the science of how they impact your immune system.