I Contain Multitudes: The Microbes Within Us and a Grander View of Life

by Ed Yong

Ants live in colonies that can number in their millions, but every single ant is a colony unto itself. A polar bear, trundling solo through the Arctic, with nothing but ice in all directions, is completely surrounded. Bar-headed geese carry microbes over the Himalayas, while elephant seals take them into the deepest oceans. When Neil Armstrong and Buzz Aldrin set foot on the Moon, they were also taking giant steps for microbe-kind.

Let me stress: all the visible organisms that we’re familiar with, everything that springs to mind when we think of “nature”, are latecomers to life’s story. They are part of the coda. For most of the tale, microbes were the only living things on Earth. From March to October in our imaginary calendar, they had the sole run of the planet.

During that time, they changed it irrevocably. Bacteria enrich soils and break down pollutants. They drive planetary cycles of carbon, nitrogen, sulphur and phosphorus, by converting these elements into compounds that can be used by animals and plants and then returning them to the world by decomposing organic bodies. They were the first organisms to make their own food, by harnessing the sun’s energy in a process called photosynthesis. They released oxygen as a waste product, pumping out so much of the gas that they permanently changed the atmosphere of our planet. It is thanks to them that we live in an oxygenated world. Even now, the photosynthetic bacteria in the oceans produce the oxygen in half the breaths you take, and they lock away an equal amount of carbon dioxide.

As palaeontologist Andrew Knoll once said, “Animals might be evolution’s icing, but bacteria are really the cake.”4 They have always been part of our ecology. We evolved among them. Also, we evolved from them.

For roughly the first 2.5 billion years of life on Earth, bacteria and archaea charted largely separate evolutionary courses. Then, on one fateful occasion, a bacterium somehow merged with an archaeon, losing its free-living existence and becoming entrapped forever within its new host. That is how many scientists believe eukaryotes came to be. It’s our creation story: two great domains of life merging to create a third, in the greatest symbiosis of all time. The archaeon provided the chassis of the eukaryotic cell while the bacterium eventually transformed into the mitochondria.5 All eukaryotes descend from that fateful union. It’s why our genomes contain many genes that still have an archaeal character and others that more resemble those of bacteria. It’s also is why all of us contain mitochondria in our cells.

The latest estimates suggest that we have around 30 trillion human cells and 39 trillion microbial ones – a roughly even split. Even these numbers are inexact, but that does not really matter: by any reckoning, we contain multitudes.

There are fewer than 100 species of bacteria that cause infectious diseases in humans;8 by contrast, the thousands of species in our guts are mostly harmless. At worst, they are passengers or hitchhikers. At best, they are invaluable parts of our bodies: not takers of life but its guardians.

Your cells carry between 20,000 and 25,000 genes, but it is estimated that the microbes inside you wield around 500 times more.9 This genetic wealth, combined with their rapid evolution, makes them virtuosos of biochemistry, able to adapt to any possible challenge. They help to digest our food, releasing otherwise inaccessible nutrients. They produce vitamins and minerals that are missing from our diet. They break down toxins and hazardous chemicals. They protect us from disease by crowding out more dangerous microbes or killing them directly with antimicrobial chemicals. They produce substances that affect the way we smell. They are such an inevitable presence that we have outsourced surprising aspects of our lives to them. They guide the construction of our bodies, releasing molecules and signals that steer the growth of our organs. They educate our immune system, teaching it to tell friend from foe. They affect the development of the nervous system, and perhaps even influence our behaviour. They contribute to our lives in profound and wide-ranging ways; no corner of our biology is untouched. If we ignore them, we are looking at our lives through a keyhole.

The variations that exist between body parts dwarf those that exist between people. Put simply, the bacteria on your forearm are more similar to those on my forearm than to those in your mouth.

Imagine watching a forest recently scoured by fire, or a fresh island newly risen from the sea. Both would quickly be colonised by simple plants like lichens and mosses. Grasses and small shrubs would follow. Taller trees would arrive later. Ecologists call this succession, and it applies to microbes too. It takes anywhere from one to three years for a baby’s microbiome to reach an adult state. Then, a lasting stability. The microbiome may vary from day to day, from sunrise to sunset, or even from meal to meal, but such variations are small compared to the early changes.

The narrative of disease and death still dominates our view of microbiology.

King’s choanos and Hadfield’s worms are both exquisitely tuned to the presence of microbes, and dramatically transformed by them. Without bacteria, the sociable choanos would forever be solitary, and the larval worms would forever be immature. These are beautiful examples of how thoroughly microbes can shape the bodies of animals (or animal cousins). And yet, they aren’t symbioses in the classical sense. The worms don’t actually harbour P-luteo in their bodies, and they don’t seem to interact with the bacterium after they become adults. Their relationship is transient. They are like tourists asking passers-by for directions and then moving on. But other animals form more lasting and co-dependent relationships with microbes.

We have already seen that microbes influence the development of the gut and other organs, but they can’t rest after the job is done. It takes work to keep an animal’s body going. In the words of Oliver Sacks, “Nothing is more crucial to the survival and independence of organisms – be they elephants or protozoa – than the maintenance of a constant internal environment.”19 And in maintaining such constancy, microbes are crucial. They affect the storage of fat. They help to replenish the linings of the gut and skin, replacing damaged and dying cells with new ones. They ensure the sanctity of the blood–brain barrier – a web of tightly packed cells that lets nutrients and small molecules pass from blood to brain, but bars the way to larger substances and living cells. They even influence the relentless remodelling of skeletons, in which fresh bone is deposited and old stuff is reabsorbed.20 Nowhere is this steady influence more clear than in the immune system: the cells and molecules that collectively protect our bodies from infection and other threats.

This tells us that an animal’s genome doesn’t provide everything it needs to create a mature immune system. It also needs input from a microbiome.22 Hundreds of scientific papers, on species as diverse as mice, tsetse flies and zebrafish, have shown that microbes help to shape the immune system in some way. They influence the creation of entire classes of immune cells, and the development of organs that make and store those cells. They are especially important early in life, when the immunity machine is first constructed and tunes itself to the big, bad world. And once the machine is chugging away, microbes continue to calibrate its reactions to threats.

Let’s pause to note how peculiar this all is. The traditional view of the immune system is full of military metaphors and antagonistic lingo. We see it as a defence force that discriminates self (our own cells) from non-self (microbes and everything else), and eradicates the latter. But now we see that microbes craft and tune our immune system in the first place!

Why should animals rely on microbes to make these chemical signals? Theis offers the same reason that Rawls, King, and Hadfield did: it’s inevitable. Every surface is populated by microbes, which release volatile chemicals. If those chemical cues reflect a trait that’s useful to know about – say, gender, strength, or fertility – the host animal might evolve scent organs to nourish and harbour those specific microbes. Eventually, the inadvertent cues turn into full-blown signals. So, by creating airborne messages, microbes could affect the behaviour of animals far outside their original hosts. And if that’s the case, it shouldn’t be surprising to learn that they can affect animal behaviour in more local ways.

From your perspective, choosing the right item on a menu is the difference between a good meal and a bad one. But for your gut bacteria, the choice is more important. Different microbes fare better on certain diets. Some are peerless at digesting plant fibres. Others thrive on fats. When you choose your meals, you are also choosing which bacteria get fed, and which get an advantage over their peers. But they don’t have to sit there and graciously await your decision. As we have seen, bacteria have ways of hacking into the nervous system. If they released dopamine, a chemical involved in feelings of pleasure and reward, when you ate the ‘right’ things, could they potentially train you to choose certain foods over others? Do they get a say in your menu picks?

Here is a strange but critical sentiment to introduce in a book about the benefits of living with microbes: there is no such thing as a “good microbe” or a “bad microbe”. These terms belong in children’s stories. They are ill-suited for describing the messy, fractious, contextual relationships of the natural world.6 In reality, bacteria exist along a continuum of lifestyles, between “bad” parasites and “good” mutualists. Some microbes, like Wolbachia, slide from one end of the parasite-mutualist spectrum to the other, depending on the strain, and on the host they find themselves in. But many exist at both ends of the continuum at once: the stomach bacterium Helicobacter pylori causes ulcers and stomach cancer, but also protects against oesophageal cancer – and it’s the same strains that account for both these pros and cons.7 Others can change roles in the same hosts, depending on the context. All of this means that labels like mutualist, commensal, pathogen, or parasite don’t quite work as badges of fixed identity.

The same thing probably happens to millions of people every year. We humans are also infected by pathogens that create holes in our guts; and we also get sepsis when our usual gut microbes cross into our bloodstream. As in the caterpillars, the same microbes can be good in the gut, but dangerous in the blood. They’re only mutualists by virtue of where they live. The same principles apply to so-called “opportunistic bacteria” that live in our bodies – they are normally harmless but they can cause life-threatening infections in people whose immune system is weakened.9 It is all down to context. Even symbionts as essential and long-standing as mitochondria, the energy-providing power plants that exist in all animals, cells, can wreak havoc if they end up in the wrong place. A cut or a bruise can split some of your cells apart and spill fragments of mitochondria into your blood – fragments that still keep some of their ancient bacterial character. When your immune system spots them, it mistakenly assumes that an infection is under way and mounts a strong defence. If the injury is severe, and enough mitochondria are released, the resulting body-wide inflammation can build into a lethal condition called systemic inflammatory response syndrome (SIRS).10 SIRS can be worse than the original injury. Absurdly, it’s simply the result of a human body mistakenly overreacting to microbes that have been domesticated for over two billion years. Just as a weed is a flower in the wrong place...

Why are these relationships so tenuous? Why do microbes so easily slide between pathogen and mutualist? For a start, these roles are not as contradictory as you might imagine. Think about what a ‘friendly’ gut microbe needs to set up a stable relationship with its host. It must survive in the gut, anchor itself so it doesn’t get swept away, and interact with its host’s cells. These are all things that pathogens must do, too. So both characters – mutualists and pathogens, heroes and villains – often use the same molecules for the same purposes. Some of these molecules get saddled with negative names, like “virulence factors”, because they were first discovered in the context of disease, but they are inherently neutral. They are just tools, like computers, pens, and knives: they can be used to do wonderful things and terrible things.

“We need to separate important from harmonious. The microbiome is incredibly important but it doesn’t mean that it’s harmonious,” says evolutionary biologist Toby Kiers.15 A well-functioning partnership could easily be seen as a case of reciprocal exploitation. “Both partners may benefit but there’s this inherent tension. Symbiosis is conflict – conflict that can never be totally resolved.”

The immune system’s main function is to manage our relationships with our resident microbes. It’s more about balance and good management than defence and destruction.

To allow our first microbes to colonise our newborn bodies, a special class of immune cells suppresses the rest of the body’s defensive ensemble, which is why babies are vulnerable to infections for their first six months of life.30 It’s not because their immune system is immature, as is commonly believed: it’s because it is deliberately stifled to give microbes a free-for-all window during which they can establish themselves.

By offering a wide array of nutrients we feed a wide range of microbes and stabilise our enormous, diverse communities. And those communities, in turn, make it harder for pathogens to invade. By setting the table correctly, we ensure that the right guests turn up to dinner, while gatecrashers are locked out.

Think about microbial diseases. Think about influenza, AIDS, measles, Ebola, mumps, rabies, smallpox, tuberculosis, plague, cholera, and syphilis. All of these maladies, though different from each other, fit a similar pattern. They are caused by a single microbe: a virus or bacterium that infects our cells, reproduces at our expense, and triggers a predictable panoply of symptoms. This causal agent can be identified, isolated, and studied. With luck, it can be removed, ending the affliction. Rohwer’s work with corals hints at a different type of microbial disease, one without a single obvious culprit.4 These illnesses are caused by communities of microbes, which have shifted into configurations that harm their hosts. None is a pathogen in its own right; instead, the entire community has shifted to a pathogenic state. There’s a word for such a state: dysbiosis.5 It is a term that evokes imbalance and discord in place of harmony and cooperation. It is the dark reflection of symbiosis, the antithesis of all the themes we have seen so far.

Recall that every individual animal, whether human or coral, is an ecosystem in itself. It grew up under the influence of its microbes and continues to engage them in a lively negotiation. Remember also that these partners often have competing interests and that hosts need to control their microbes, keeping them in line by offering the right food, confining them to specific tissues, or placing them under immune surveillance. Now imagine that something disrupts that control. It jostles the microbiome, changing the proportions of species within it, the genes they activate, and the chemicals they produce. This altered community still communicates with its host, but the tenor of their conversation changes. Sometimes it becomes, quite literally, inflammatory, as microbes over-stimulate the immune system or wheedle their way into tissues where they don’t belong. In other cases, microbes might start to opportunistically infect their hosts. That’s dysbiosis. It’s not about individuals failing to repel pathogens, but about breakdowns in communication between different species – host and symbiont – that live together. It is disease, recast as an ecological problem. Healthy

As in Ridaura’s work, it was the combination of poor food and the wrong microbes that mattered.

The immune system, for all its intricacy, is a lot like that dial. It works like an “immunostat”, which, rather than stabilising temperature, stabilises our relationships with our microbes.15 It manages the benign trillions that live with us, while thwarting invasions by an infectious minority. If it is set too low, it becomes relaxed, missing threats and leaving us open to infections. If it is set too high, it becomes jumpy, falsely attacking our own microbes and triggering chronic inflammation. It must tread a fine line between these extremes, balancing the cells and molecules that induce inflammation with those that repress it. It must react without overreacting. But over the last half-century, we have gradually pushed our immunostats to higher settings through a combination of sanitation, antibiotics, and modern diets. We’ve ended up with immune systems that go berserk at harmless things like dust, molecules in our food, our resident microbes, and even our own cells.

We now know that when bacteria break down fibre, they produce chemicals called short chain fatty acids (SCFAs); these trigger an influx of anti-inflammatory cells that bring a boiling immune system back down to a calm simmer. Without fibre, we dial our immunostats to higher settings, predisposing us to inflammatory disease. To make matters worse, when fibre is absent, our starving bacteria react by devouring whatever else they can find – including the mucus layer that covers the gut. As the layer disappears, bacteria get closer to the gut lining itself, where they can trigger responses from the immune cells underneath. And without the restraining influence of the SCFAs, those responses can easily build to extreme proportions.

Erica Sonnenburg, Justin’s wife and colleague, demonstrated this by putting mice on a low-fibre diet for a few months.28 The diversity in their gut microbiome crashed. It rebounded when the mice ate fibre again, but not fully; many species had gone AWOL and never returned. When these mice bred, they gave birth to pups that started off with a slightly impoverished microbiome. And if those pups ate more low-fibre food too, even more microbes fell off the radar. As the generations ticked by, more and more old friends broke contact. This could explain why Westerners carry a much lower diversity of gut microbes than rural villagers from Burkina Faso, Malawi, and Venezuela.29 We not only eat fewer plants, we also heavily process the ones we do eat. For example, the milling process that converts wheat into flour removes most of the fibre in the kernels. We are, in the words of the Sonnenburgs, “starving our microbial self”.

First, there’s a critical window in early life during which antibiotics can have particularly potent effects. Second, those effects depend on changes in the microbiome, but endure even when it largely returns to normal. The second point is important; the first is arguably old news. Farmers have been inadvertently doing the same experiment since the 1950s, by fattening their livestock with low doses of antibiotics. No matter the drug or the species, the result is always the same: the animals grow faster and end up heavier. Everyone knew that these “growth promoters” worked but no one really understood why. Blaser’s work suggests one possible explanation: the drugs disrupt the microbiome, leading to weight gain.

Before antibiotics, alarming numbers of people died from simple scratches, bites, bouts of pneumonia, or childbirth. After antibiotics, these potentially life-threatening events became controllable. Everyday life became safer. And medical procedures that would have carried a lethal risk of infection became feasible or common: plastic surgery; C-sections; surgery of any kind that involves bacteria-rich organs like the gut; treatment that suppresses the immune system, like cancer chemotherapy and organ transplants; anything involving catheters, stents, or implants, such as kidney dialysis, cardiac bypasses, or hip replacements. Much of modern medicine is built upon the foundations that antibiotics provide, and those foundations are now crumbling. We have used these drugs so indiscriminately that many bacteria have evolved to resist them, and some nigh-invincible strains can now shrug off every medicine we throw at them.36 At the same time, we have utterly failed to develop new drugs to replace the ones that are becoming obsolete. We are heading into a terrifying post-antibiotic era.

When you move away from the one-microbe-one-disease model and into the messy, multifaceted world of dysbiosis, the lines of cause and effect become much harder to untangle.

The microbiome is not a constant entity. It is a teeming collection of thousands of species, all constantly competing with one another, negotiating with their host, evolving, changing. It wavers and pulses over a 24-hour cycle, so that some species are more common in the day while others rise at night. Your genome is almost certainly the same as it was last year, but your microbiome has shifted since your last meal or sunrise.

It would be easier if there was a single “healthy” microbiome that we could aim for, or if there were clear ways of classifying particular communities as healthy or unhealthy. But there aren’t. Ecosystems are complex, varied, ever-changing and context-dependent – qualities that are the enemies of easy categorisation.

It’s likely that many symbioses started this way, with random environmental microbes – some parasitic and others more benign – that somehow sneaked into animal hosts. Such incursions are common and inevitable. The ubiquity of bacteria means that almost everything we do brings us into contact with new species.

The newly arrived microbes might stick around if they are capable parasites, but some guarantee their residency by providing a benefit. They don’t even need any special adaptations. The world is full of microbes that are preadapted to symbiosis by dint of what they naturally do. If a plant-eater ingested microbes that could break down complex fibres in plants and in doing so release otherwise inaccessible chemical by-products that their cells can burn for energy, the microbes would fit in immediately. By getting on with their usual activities, in a purely selfish way, they incidentally benefit their hosts.

Think of it this way: an animal’s genes are like set designers in a theatre – they create the stage upon which specific microbes can perform.20 Our environment – friends and footsteps, dirt and diet – then affects the actors that take the stage. And random chance lords over the whole production, which is why even genetically identical mice that live in the same cage end up with slightly different microbiomes. The composition of our microbiome is a bit like height, intelligence, temperament, or risk of cancer: a complex trait that is controlled by the collective action of hundreds of genes, and by even more environmental factors. The big difference is that our genes don’t directly create the microbiome as they do our height or the size of our brains. They set conditions which, in turn, select for certain species over others.

All of these things – dams, nests, and books – are what Dawkins calls extended phenotypes. They are products of a creature’s genes that extend beyond its body. In a way, that’s what our microbiomes are. They too are shaped by animal genes, which create environments that encourage specific microbes to grow. Although they lie inside their owners, they are just as much an extended phenotype as a beaver dam.

But even this comparison doesn’t entirely work because microbes – unlike the dam or this book – are themselves alive. They have their own genes, some of which are important or essential to their hosts. They aren’t just extensions of a host’s genome, any more than the host is an extension of the microbes’ genomes! So, argue some scientists, maybe it makes no sense to conceptually separate them. If animals are picky about their microbes, and microbes are picky about their hosts, and both are locked in partnerships that endure through generations, maybe it makes more sense to think of them as unified entities. Maybe we should think of them as one.

An animal doesn’t just depend on its own genes but also on those of its microbes, which are often many times more numerous. Likewise, the microbes depend on the genes of their hosts to build the bodies that will carry them into future generations. To Rosenberg, it made no sense to think of these collections of DNA separately. He believed that they work as a single entity – a hologenome, which “should be considered as the unit of natural selection in evolution”.

To understand what that means, remember that evolution by natural selection depends on just three things: individuals must vary; those variations must be heritable; and those variations must have the potential to affect their fitness – that is, their ability to survive and reproduce. Variation, inheritance, fitness: if all three boxes are ticked, the engine of evolution whirrs into action, pumping out generations that are successively better adapted to their environment. An animal’s genes certainly meet this trinity of criteria. But Rosenberg noted that an animal’s microbes do, too. Different individuals can carry different communities, species, or strains of microbes – so, there’s variation. As we have seen, there are many ways in which animals can pass microbes down to their offspring – so, there’s inheritance. And as we shall see, the microbes bestow important abilities that influence the success of their host – so, they can affect fitness. Tick, tick, tick, and the engine starts up. Over time, the holobionts that can best meet life’s challenges will pass their hologenomes – the total of their genes plus those of their microbes – to the next generation. The animals and their microbes evolve as one. It’s a more holistic take on evolution, one that redefines what it means to be an individual and emphasises the indivisibility of microbes from animal life.

he isn’t very keen on the hologenome idea. It has a somewhat hokey vibe, he feels, in which hosts and microbes harmoniously skip into a brighter future together. Evolution doesn’t work like that. As we know, even the most harmonious of symbioses are tinged with antagonism. Rohwer feels that Rosenberg, by positioning the hologenome as the fundamental unit of selection, is glossing over those conflicts.

The hologenome idea isn’t necessarily about togetherness and cooperation, as its critics (and some of its proponents) suggest. It merely says that microbes and their genes are part of the picture. They affect their hosts in ways that matter to natural selection, and in ways we can’t ignore when thinking about animal evolution.

the brutal contract of natural selection ensures that if one partner is unnecessary, it gets dumped. This diktat applies to genes too, and explains why hemipterans landed themselves in a nutritionally precarious predicament in the first place. They are animals, and all animals evolved from single-celled predators that ate other things. Their food gave them many of the nutrients they needed, so they lost the genes for making these nutrients for themselves. We – that is, aphids, pangolins, humans, and the rest – are saddled with their legacy. None of us can make those ten essential amino acids, and we eat to fill the gap. And if we want to eat a specialised and impoverished diet like phloem sap, we need help. Enter bacteria. They have repeatedly allowed hemipterans to overcome a limitation that restrains the entire animal kingdom, and feast on a food that little else could exploit.

The bacteria oxidise these chemicals and use the liberated energy to fix carbon. This is chemosynthesis: making your own food using chemical energy instead of light or solar energy. And rather than producing oxygen as a waste product, as photosynthetic plants do, these chemosynthesising bacteria churn out pure sulphur. Hence the yellow crystals in Riftia’s trophosome.

Chemosynthesis explains why the worms are gutless and mouthless: their symbionts provide them with all the food they need. Unlike aphids or sharpshooters, which rely on bacteria for amino acids, these worms rely on their symbionts for everything. Scientists soon found similar symbioses throughout the deep oceans. It turns out that a huge variety of animals play host to chemosynthetic bacteria, which use either sulphides or methane to fix carbon.

Life on Earth originated at deep-sea vents, and first took the form of chemosynthetic microbes. (Fittingly, one of the sites at the Galapagos Rift is called the Garden of Eden.) These ancestral microbes eventually evolved into endless forms most beautiful and most wonderful, spreading out of the depths and into the shallows. Some gave rise to more complex forms of life, like animals. And some of these, by partnering with chemosynthetic bacteria, managed to descend back into the abyss, to a world that would otherwise be too low in nutrients to support them. All the animals that live at hydrothermal vents today, Riftia included, evolved from shallow-water species that became hosts for deep-sea microbes. By internalising those bacteria, the animals gained a ticket to the Hadean depths from which all life emerged.

The plant-eating herbivores typically had the highest diversity of bacteria. The meat-eating carnivores had the lowest. The omnivores, with their broad diets, were in the middle. There were exceptions: the gut microbes of red and giant pandas are more like those of their carnivorous relatives – bears, cats, and dogs – than the herbivores they surely are.15 Still, the general pattern held, and it has both a simple explanation and a profound implication.

First, the explanation. Plants are by far the most abundant source of food on land, but it takes more enzymatic power to digest them. Compared to animal flesh, plant tissues contain more complex carbohydrates, such as cellulose, hemicellulose, lignin, and resistant starches. Vertebrates don’t have the molecular chops for breaking these apart. Bacteria do.