by Rob Dunn
One of the first hints at the larger problem came from, of all places, termites. In the dead wood of Earth exists an empire of termites, trillions of individual animals, each of them dedicated to living off what no other animals want. Picture all of the wood and leaves that have ever fallen. Imagine them piling up, rising around you. Most pieces of wood that have ever fallen on the earth have been consumed by termites. By the time of the first mammals, the world was already thick with their nearly transparent bodies and their long, thin, noodlelike guts.
Termites survive by eating what few animals are able to digest, the nutrients in dead wood and leaves, particularly those locked up in two hard-to-break-down compounds, lignin and cellulose. Lignin in particular is a stingy, rotten food. It was long unclear exactly how termites did this good and necessary work. Then, in the early 1900s, Joseph Leidy—forefather of both modern American microbiology and dinosaur paleontology—cracked open the gut of a termite. Who knows what he expected to see, perhaps their food? What he found was a swirling tumult of life, multitudes that looked to Leidy like people pushing shoulder to shoulder out of a crowded meetinghouse. This crowd included bacteria, but also other creatures—protists, fungi, and harder to characterize beasts. These inhabitants of termite guts evolved over a hundred million years traits and behaviors that allow them to be passed from one termite to the next and, in doing so, to get a free ride to wood and leaves. The termites, for their part, evolved guts to help their denizens. In fact, the variation from one termite species to the next tends to be in the shape and chemistry of their guts. This variation favors different microbes in different termite species and, with them, different abilities to digest food. Some termites have microbes that are better able to eat soil, others leaves, still others wood. Some termites, by dint of their microbes, can actually extract nitrogen from the air around them, equally able, in effect, to eat twigs and air.
Just as with guinea pigs, one of the first questions for termites was whether their microbes were necessary. Sure, the microbes seemed to need the termites, or at least most of them did, but did the termites need their microbes? With termites, testing such a question was easier than with guinea pigs. The termites could be warmed or frozen. Freezing killed the microbes, but left the animals themselves otherwise alive. You can put termites in an ice cube tray for a short while and bring them out. They thaw slowly and then look around as if they have been born again. (In fact, in a way they have. They lose all memory of smells when chilled, and so come out unable to recognize their own queen or king.) It is an experiment you can repeat at home, so long as you live where termites live and have an ice cube tray. When this experiment was first performed, there was a surprise, at least in the context of Reyniers’s work. When termites are cooled or warmed and their microbes killed, the termites die. They continue to feed for a while, but the food they eat passes through them undigested. They starve even if surrounded by wood. They starve because without their microbes, they are unable to digest their preferred, but difficult, diet.
No one studying germ-free vertebrates (rats, guinea pigs, chickens, and the like) considered this work on termites. In order to do so, they would have had to talk to termite people. Termite people do their own thing. They converse with ant and bee people only begrudgingly, and with people who study people even less. There are a few hundred of them and they are, largely, happy to focus exclusively on termites for the rest of their lives. Nor were vertebrate biologists particularly concerned about termites. Each group went its own way and ignored the fact that the two bodies of research had come to exactly opposing conclusions—one at the cost of tens of years of work and lots of metal, and the other at the cost of an ice cube tray.
The difference in the results between experiments on termite and guinea pig guts is relevant to all of humanity. It explains what Reyniers got wrong in the context of Pasteur’s question. It is not that Reyniers made some big mistake, some folly of hubris.13 He failed in the same way that much of modern medicine does; he failed to put his question in context, whether of our origins or of our modern lives. He wanted to make the germ-free guinea pigs useful by making them survive, which he did. But in the process, he accidentally rigged the competition between germless and germy guinea pigs in such a way that it was nearly impossible for his germ-free guinea pigs to die.
You might pause here to think about the difference between the termite experiment and the guinea pig experiment. The answers are food, disease, and chance. The story of the food is one of plenty, a bounty of last suppers. The termites, when they were cleansed of the species living on and in their bodies, had been given the food they actually encounter in the wild. Without microbes, this food was indigestible. Cellulose requires cellulase and lignin lignase to be broken down into usable nutrients. Termites produce very little or none of these enzymes and so the food they consumed sat in their guts, where any simple sugars were digested, but most of the wood and leaves passed out the other side, smaller but otherwise unchanged. The guinea pigs, on the other hand, had been given as much food as they might ever want. That food was supplemented with every conceivable nutrient until the guinea pigs were nearly assured enough of each and every nutrient. When one diet did not work (which is to say when the guinea pigs died, which happened, it turns out, many, many times), another was tried. The competition between germy and germless guinea pigs had occurred under rules guaranteed to benefit the germless pigs. To Reyniers, the animals were machines to be raced on the best fuel possible. They were like stock cars or steam engines that needed simply to be fueled with whatever they might need. But the guinea pigs, like us, were not machines. The competition that they evolved to compete in, that of natural selection, occurred on a diet of wild foods, not optimal foods, and it occurred in the context of disease.
When Reyniers’s experiments are repeated today, in much smaller chambers typically made of plastic, the germ-free animals continue to do relatively well. But there is a caveat. They have to be fed extra food to gain the same amount of weight as the germy guinea pigs, and they have to be fed food that is richer in nutrients than is the food fed to normal animals. The microbes in the guinea pigs’ guts, just like those in the termites’ guts and, it turns out, in our guts, provide enzymes that their hosts lack, enzymes that allow their hosts to use a larger proportion of the nutrients in their food, particularly those nutrients trapped in the complex carbohydrates one finds in plant material, so-called fiber. The bacterium Bacteroides thetaiotaomicron, for example, which is common in human guts, produces more than 400 enzymes related to breaking down plant material, enzymes that you and I lack. When food is limited, the microbes make it less so. The microbes in the guinea pigs’ guts and, we now know, in our guts, produce up to 30 percent more calories from food than the hosts can produce on their own. For each food you eat today, this is likely still true. Your microbes help you to get more out of it, more nutrients but also more calories, whether you want them or not.
The second reason that the germless guinea pigs die is that they end up lacking specific vitamins, in particular, vitamin K but also some B vitamins. Without microbes, vertebrates (guinea pigs and humans included) are not able to synthesize enough vitamin B or any vitamin K. Vitamin K works in vertebrate bodies, including yours, to coagulate blood (the “K” is actually for “coagulate,” or at least the German version thereof ). As adults, we store up the vitamin K that we gain both from eating plants and from our microbes. As newborns, though, we have little vitamin K and, at least at the moment of birth, no microbes. Nor does breast milk fill the void (it is low in vitamin K). Historically, babies relied on quick colonization by microbes for their vitamin K. When newborns do not acquire microbes in their guts quickly enough, they are at risk for developing a disease called, with little in the way of euphemism, hemorrhagic disease of the newborn. Newborns with this disease lack the ability to clot blood and are at a high risk of bleeding to death. As a precaution against this disease, all newborns in the United States and the United Kingdom are n
ow given vitamin K shots at birth. In countries where children do not uniformly receive such shots, hemorrhagic disease is more common in babies that are born by C-section (and hence have less exposure to the mother’s microbes during birth) and appears to be increasing in incidence. And just as babies that have not yet been colonized by microbes are at risk of blood coagulation diseases, so too are children or adults who are given antibiotics that deplete their microbes and in turn their ability to produce vitamin K.14
If we reorient ourselves a little and think not about guinea pigs and modern infants but instead about early hominids, whether Ardi or her descendants, we can revisit just what it is our microbes once did and whether they were pathogens (as Reyniers thought) or mutualists. They provided vitamin K where it was once scarce, but just as importantly, they allowed us to extract extra calories from our food, up to 30 percent extra. More of those calories would, in turn, have been converted to fat on our bodies, which, for most of our history, was a good thing. In other words, they were our mutualist partners. Most years, but particularly the lean years, their offerings would be the difference between life and death. Most years in our history, we would have survived by dint of our microbes. If one had to spend ten hours a day gathering food without microbes, the gathering day was shortened to seven or even just six hours with microbes. Microbes helped our ancestors to get more from their food, as they had done for their ancestors and so on, going back tens of millions of years. Nor was this even the only big difference between having and not having microbes. There were still the issues of chance and disease, and to understand them, we need to go back to Nita Salzman, Amy Croswell, and their mice.
Amy Croswell and Nita Salzman, you recall, varied the antibiotics that the mice in their lab received. They also, though I did not mention it before, subjected some mice but not others to the pathogen that causes salmonella. Croswell and Salzman wondered whether the native microbes in the mice’s guts might help to prevent infection by salmonella, act, in other words, as a kind of living defense system. The native microbes, after all, would have nearly as many reasons to defend the gut as the mice themselves. It was their bread and butter (or, in this case, their mashed-up mouse pellet). The mice treated with the pathogen and antibiotics became sick, but the mice given the pathogen but no antibiotics did not. When antibiotics were given, the salmonella was more likely to invade their body cavity through the gut. In addition, guts were more likely to be inflamed. But when the native microbes of these mice were allowed to reestablish, the salmonella no longer found its way into the body cavity. It was repelled, apparently by the native microbes that compete with the salmonella and in doing so prevent the salmonella from establishing itself. Antibiotics, in other words, kill the existing microbes in guts (be they ours or those of mice), but make it easier for whoever shows up next to move in. If, by chance, that happens to be a deadly pathogen, the result is dead mice or, in our case, humans.
Perhaps the closest ecological analogy for what Croswell and Salzman observed is the use of pesticides to control fire ants. Fire ants (Solenopsis invicta) were introduced accidentally to the United States (and subsequently much of the world) from Argentina early in the twentieth century. When these ants were first noticed in Mobile, Alabama, and observed to be spreading, a decision was made to spray massive quantities of pesticides in the affected regions. In the short term pesticides succeeded in killing the fire ants, but also killed native ants. In the long term, the killing of the native ants appears to have been the more significant consequence. In those areas in which both the fire ants and native ants were killed, the native ants were slow to rebound; not so the fire ants, which appear to have spread faster rather than slower in areas where pesticides had been applied. So it is too that we might expect the invading armies of microbes to advance one antibiotic-treated gut at a time.
Nor is Croswell and Salzman’s work the end of the story. In addition to the hundreds or thousands of microbes in our guts, we, of course, have microbes all over our skin, in our hair, and in our mouths. We are covered in many kinds of life. There are fungi even in our lungs. These life-forms are as yet poorly studied, but it remains conceivable that they too help to protect us, or at least that some of them do. That is even more of a problem today inasmuch as we seem committed to using antibiotic wipes on our hands. Recent studies are unable to find any benefit to antibiotics in hand sanitizers, soaps, or other household products in terms of preventing disease. But such products do have disadvantages. They can lead to antibiotic resistance and may also be killing good bacteria and in doing so making room for the bad, which, especially if they are resistant to antibiotics, are all too happy to move in.
What does all this mean for your gut in the modern world? Ironically, and in no small part thanks to Reyniers, we are now more like Reyniers’s guinea pigs or a lab rat than was our potential ancestor, Ardi. At least in developed countries, most of us have ample food, and we have attempted, although only partially and fitfully, to make our environment “germ-free.” One key difference, though, other than the fact that we, unlike germ-free rodents, remain covered in microbes, is that whereas the food of guinea pigs and rats has been optimized for their health, the same cannot be said of our own diets. In developed countries, the additional calories from our microbes may actually add insult to injury. Worse yet, obese individuals tend to have more efficient, rather than less efficient, microbes, both in humans and in mice, rats, and pigs.15 In particular, they tend to have microbes that are better at breaking down complex sugars and fats. Scientists have transplanted the microbes from fat mice into skinny mice and in doing so made the skinny mice fat. All of these features of microbes that are efficient at using sugar and fats have become bad now that we have enough food. But, on the other hand, in countries where many (or in some cases even most) people go hungry, which is to say most countries on Earth, the effect of these efficient microbes and microbes in general on harvesting nutrients is likely to still be very beneficial. If you happen to get microbes that are very efficient at harvesting and providing energy from your food and you are hungry, they will save you. If you get those same microbes and feed them chips, cheese, and white bread daily, they are more likely to make you fat. The difference between our modern lives and the lives we once lived has changed the effect our microbes have on us. Once they made us fitter, but now they may make us fatter, though still, it appears, less prone to disease from other microbes.
Living in a bubble without germs is fine, so long as you are alone and someone gives you everything you need, but a leaky bubble and a crappy diet, well, that is another thing entirely. The boy who lived in the bubble, with time, grew terrified of the possibility of a leak in the bubble through which germs might sneak. We have become similarly terrified about germs around us, germs that might leak through the barriers of our antibiotics. But the problem is not the potential of leaks—the problem is our idea that we might create a bubble for ourselves in the first place. Our microbes are largely good for us. Pasteur was right; without their microbes, our ancestors would have died of hunger and disease. Without our microbes today we might be thinner, but we would be missing key nutrients, and we would be at a much higher risk of disease. It seems likely that in the coming years, our frequent use of antibiotics will progressively make each bite of our food less nutritious and give each pathogen to which we are exposed a better chance of taking over our body, one inch of colon, intestine, and stomach at a time. With time, we may learn to better manage for particular kinds of microbes (those that help with vitamin K, but not those that help to make us fat, for example), but that time is not yet here. Nor is this the end of the story. For that it is useful to first go back to other, apparently more sophisticated societies, those of termites and ants and then from them to the human appendix, which (despite its name) is central to who we are.
It would be fair to ask how as scientists and as a society we missed the value of many of our microbes, missed their value and instead of figuring out how to help the g
ood microbes, focused on killing them all. Part of the answer is that there was a time when we were so threatened by microbial diseases that killing them all was not a terrible idea. Reyniers himself may also, in his fervor, be partially to blame. But the big reason, I will argue, has to do with Babel. A central premise in ecology, and of this book, is that nature repeats itself with variations on a few main themes. If one understands how an individual ecological system, for example deep-sea vents, works, the lessons learned in that system can be applied to others. The crashes and peaks of lynx populations feeding on hares are very similar to those of predatory mites feeding on dust mites in your pillow. By that token, lessons that would apply to our guts can be garnered from the many ecological studies of mutualisms between animals and microbes. Until very recently, researchers studying the human body have missed such lessons, whether they come from termites, ants, tardigrades, at our collective expense, though the problem is not their lack of vision or insight. It may have to do with broader changes that have occurred in science in the last fifty years, changes that find their own best model in Babylon. History, like ecology, repeats. This is why Reyniers missed the real significance of his results for Pasteur’s question. It is also why we continue to miss just where it is that we fit in the writhing universe of living things.
