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I Contain Multitudes, My First Book, Is Out In One Month

It’s nearly here! In just over a month, my first book—I Contain Multitudes—will be published in the US, with the UK edition following shortly after. It’s about the astonishing partnerships between animals and microbes. It’s a natural history book about the hidden side to humans, wasps, squid, hyenas, beetles, koalas, worms, and more. It’s like a David Attenborough series shot through a really good microscope. You can pre-order it here.

Coincidentally, the publication date of August 9th is a fairly momentous one for me. It (more or less) marks the ten year anniversary of my career as a science writer, which began when I created this blog in August 2006. Two of my very first pieces were about microbe transplants that can make mice fat, and sexually transmitted bacteria that give superpowers to aphids; both stories feature in the book. So, in many ways, I Contain Multitudes is the culmination of not just all my reporting on this topic, but of everything I’ve learned as a writer.

If you’ve enjoyed my work over the years, I hope you’ll check the book out. Any support you can give would be greatly appreciated, whether it’s leaving reviews on Amazon or Goodreads, tweeting about it, posting on Facebook, buying copies for friends and family, or anything else that takes your fancy. But above all, I hope you like reading it; I certainly loved writing it.

Early buzz has been pretty positive. Kirkus and Publisher’s Weekly both gave it starred reviews, with the former calling it “some of the finest science writing out there” and “an exceptionally informative, beautifully written book that will profoundly shift one’s sense of self”. Wired, io9, The Week, and On the Point all listed it as one of their summer picks.

Below, I’ve added a description, some early blurbs, and a list of upcoming speaking events. I’ll update the latter on my personal site as they get finalised, so check back there for more information.

As ever, thank you for reading!


Description from the book jacket

For most of human existence, microbes were hidden, visible only through the illnesses they caused. Even today, many people think of microbes as germs to be eradicated, but those that live with us—the microbiome—are invaluable parts of our lives.

I Contain Multitudes lets us peer into that world, allowing us to see how ubiquitous and vital microbes are: they sculpt our organs, defend us from disease, break down our food, educate our immune systems, guide our behavior, bombard our genomes with their genes, and grant us incredible abilities.

With humor and erudition, Ed Yong prompts us to look at ourselves and our fellow animals in a new light: less as individuals and more as the interconnected, interdependent multitudes we assuredly are. When we look at the animal kingdom through a microbial lens, even the most familiar parts of our lives take on a striking new air. We learn the secret, invisible, and wondrous biology behind the corals that construct mighty reefs, the glowing squid that can help us understand the bacteria in our own guts, the beetles that bring down forests, the disease-fighting mosquitoes engineered in Australia, and the ingredients in breast milk that evolved to nourish a baby’s first microbes. We see how humans are disrupting these partnerships and how scientists are now manipulating them to our advantage. We see, as William Blake wrote, the world in a grain of sand.

I Contain Multitudes is the story of these extraordinary partnerships, between the familiar creatures of our world and those we never knew existed. It will change both our view of nature and our sense of where we belong in it.


Early praise

“Beyond fascinating. An amazing book. It’ll change the way you think about the world. It’ll change who you think you are.” —Helen Macdonald, author of H Is for Hawk

“Ed Yong is one of our finest young explainers of science-wicked smart, broadly informed, sly, savvy, so illuminating. And this is an encyclopedia of fascinations-a teeming intellectual ecosystem, a keen book on the intricacies of the microbiome and more.” —David Quammen, author of Spillover and Song of the Dodo

“A marvelous book! Ed Yong s brilliant gift for storytelling and precise writing about science converge in I Contain Multitudes to make the invisible and tiny both visible and mighty. A unique, entertaining, and smart read.” —Jeff VanderMeer, author of the Southern Reach Trilogy

“Ed Yong has written a riveting account of the microbes that make the world work. I Contain Multitudes will change the way you look at yourself and just about everything else.” —Elizabeth Kolbert, author of The Sixth Extinction

“I Contain Multitudes changes you the way all great science writing does. You become disoriented, looking at the world around you in a new way. With vivid tales and graceful explanations, Ed Yong reveals how the living things we see around us are wildly complex collectives.” —Carl Zimmer, author of Parasite Rex

“Ed Yong has done something beautiful, and unlikely: he’s rendered the unseen world of bacteria thrilling, captivating and highly entertaining. This is a much-needed guide to the hidden kingdom that dominates life on Earth. It cuts through all the hype of microbiomes with a scientifically steady hand, but told with an infectious sense of awe.” – Adam Rutherford, author of Creation

“With a simply wonderful book, Ed Yong opens the doorway to a hidden world around and inside us. He’s smart, he’s witty, and he’s at the cutting edge. You could not get a better guide.” – Tim Harford, author of The Undercover Economist Strikes Back and Messy

“This compelling and beautifully written book will change the way people look at the world around, and within, them. Certainly among the best books in an increasingly crowded field and written with a true passion for and understanding of the microbiome.” — Rob Knight, author of Follow Your Gut and professor at University of California, San Diego

“Yong has captured the essence of this exciting field, expressing the enthusiasm and wonder that the scientific community feels when working with the microbiome.” — Jack Gilbert, professor at the University of Chicago


Speaking events (details to be confirmed) 

  • August 10th – New York, Strand Bookstore with Robert Krulwich
  • August 13th – New York, Festival of the Unknown with Maria Konnikova
  • August 16th – Washington DC, Politics and Prose bookstore
  • August 31st – London, Science Museum Lates
  • September 1st – Liverpool, Genome Science 2016 conference
  • September 1st – London, Royal Institution
  • September 7th – Oxford, Skeptics in the Pub
  • September 13th – Phoenix, Arizona State University, Tempe
  • September 18th – New York,Brooklyn Book Festival
  • September 20th – Boston, hosted by Undark
  • September 27th – New York, NYU’s Arthur L. Carter Journalism Institute
  • October 12th – London, London Literature Festival
  • October 16th – Bradford, Ilkley Literature Festival
  • October 24th – Sheffield, Off the Shelf Festival
  • November 5th – London, Intelligence Squared at the Royal Geographical Society
  • And more to be announced.




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Murder by “Blob”—the Miniature Version

It’s all so sudden.

The victim is on the left side of the screen—a single-celled little pulse of life, floating about in pond water somewhere. It’s got these little hairs called cilia. You don’t see them at first. They can turn into oars. Oars for escaping.

But it doesn’t know.

The killer comes in from the right, turning lazy circles in the water, like nothing’s going on. But that’s an act. As we’ll learn later, it is getting into position, moving close, finding an angle so it can point its … its what? I see no weapon. Does it have a weapon?

“I don’t know about this exact type of ciliate,” microbiologist Patrick Keeling wrote me, “but I know about other similar predators,” and at the very end of its snout-like appendage, it’s probably packing a bunch of “poisoned harpoons.” At nine seconds into the video, you can see it aim straight at the victim …

… There’s a shudder. The victim, which has been paddling along, suddenly gets smaller—much smaller—and stops moving. I saw no harpoon, but the water is muddy. If there is a needle, it would be very hard to see. “The poison,” Keeling figures, “causes paralysis where it hits.” But only for a beat.


Very quickly, the victim bounces back, gets larger, sticks out its cilia and begins paddling furiously, trying to get away. It’s beating so fast, its oars become a blur on its exposed side—but then comes the second blow.

This happens 15 seconds in; when I looked close, there’s a second snout, inside the killer’s body that grabs onto the victim, pulls, and fires. Is there a second dart? A bite? (It has no teeth, so it can’t bite.) But the victim now goes all quiet. The cilia disappear. This is a big catch. It would be like you or me eating an entire goat. “They eat by phagocytosis,” Keeling says. These small bits of pond life have cell walls, but those walls (if you’ve seen the 1956 horror pic The Blob, you know how this goes) can suck in and extend at the same time. The killer slowly surrounds, then pulls in its victim, like this:

GIF by Robert Krulwich
Phagocyte surface receptors lock and pull their prey in. GIF by Robert Krulwich

Can it stuff everything in? Won’t it gag? No, biologist David Caron wrote me. “Our (human) perception is that food particles have to be a small fraction of our own size. Not necessarily true to many single-celled organisms which can expand their membranes quite a bit to accommodate large prey items.” (Really large. This victim is roughly half the size of its killer.)

Well, at least it’s still. I wouldn’t want one of those things jiggling inside me. But here’s the thing: The victim, now stitched into a sack of its own, called a vacuole, may not be dead. That other yellowish package, already floating in there, both biologists say, is a previous victim, now awaiting “further breakdown.”

Still Alive?

“The prey is indeed alive when it gets eaten,” Keeling wrote. Does it stay alive?

“When a cell ‘dies’ is a hard question,” he says, “Some cells stay alive inside others for a long time, even after partially being digested.” There are single-celled creatures that feed on algae but leave the parts that turn sunshine into food—the chloroplast—alive and working for long periods.

So at the end of the video, neither Keeling nor Caron could say if the victim is dead. “Every food vacuole has its own processes … and its own timing,” Caron writes. It will die eventually, dissolved by acids, the unused bits flushed out. “Yes, essentially, they defecate,” Caron says, but how long that takes, we don’t know.

The victim, of course, has no questions. One moment it’s free, paddling about, then, in a flash, it’s shot, grabbed, swallowed, walled-in, and stuck. “What just happened?” it should wonder. But it can’t. Single celled creatures don’t wonder. At least I presume they don’t.

We do. Being three trillion cells bigger, we have the machinery to call experts, email videos, figure out motive, cause, possible weapon—and even, if you’re me, feel bad for the victim. This takes a lot of cells.

Not to brag, but when it comes to murders, this is an advantage we humans have over pond scum. It’s just better to be multicellular. (Unless you’re the victim. Dead humans and dead protozoa are pretty much the same—dead.) But alive, it’s people, not protozoa, who can enjoy a good murder mystery. That’s why my audience, small as it is, is (like you, I presume) entirely multicellular.

Thanks to the University of British Columbia’s Professor Patrick Keeling, who argued with me about my headline. He doesn’t think “murder” is the right word for what happened here. “I don’t think of it as murder,” he wrote me; it’s “more like hunting. I see it as being like the Serengeti on a small stage, where the lions and zebras all have their roles to play and there is no moral message in any of it.” I suppose that’s fair, but when I saw Wim van Egmond’s gorgeous video, what got me fascinated was how the killer killed. I couldn’t figure out how it did it. Having a very Agatha Christie reaction, I chose very Agatha Christie language. That, alas, is my excuse.

Thanks also to Professor David Caron at the University of Southern California, who on Christmas Eve watched the video and answered my questions so promptly, and to Elio Schaechter of the Small Things Considered blog, who told me who to call. And most of all, a pop of flashbulbs to Wim van Egmond, one of the world’s great microbiology photographers, who won first prize in 2015’s Nikon Small World video competition for this video of a single-celled Campanella ciliate being swallowed by a Trachelius predator. Apparently, he had scooped some pond water from a local pond, thinking he would show someone how to look through a microscope. When he leaned in and saw one protist swirling suspiciously close to its neighbor, he thought, “Eh, something’s up. I’m going to shoot this.” And he did. And he was so right.

Oh, and one last thing. Sometimes ciliates get inside their food AND GET OUT! This is Win van Egmond’s true-life video of two ciliates feasting on a baby copepod, and they both wiggle out—through a tiny hole …

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Why Sea Monkeys Love Salt: A Fable on the Cost of Symbiosis

Time and again, microbes have opened doors for animals, allowing them to exploit niches that would have otherwise been denied to them by their basic animal-ness. By providing nutrients that are missing from the sap of plants, bacteria have allowed bugs to subsist on a diet of nothing else, turning them into the bane of greenery and greenhouses worldwide. By breaking down the tough and typically indigestible carbohydrates in plant matter, bacteria allowed mammals to become extreme grazers and gave rise to the thundering herds of Africa’s plains. By providing a source of energy that isn’t tied to sunlight, bacteria allowed worms, clams, and hundreds of other creatures to colonise the abyssal oceans, and lose their mouths and guts in the process.

These examples inform the common view that symbioses (partnerships) between animals and microbes lead to mutual benefit and expanding opportunities. But symbiosis also comes with costs and constraints. Microbes can bar animals from valuable opportunities, restrict their options, and place burdens upon them—all without causing infections or disease.

Odrade Nougué and Thomas Lenormand from the University of Montpellier have found a great example of such constraints in an animal that will be familiar to anyone who grew up in the 70s and 80s: the sea monkey.

These little creatures are more formally known as brine shrimp, or Artemia. As their name suggests, they live in salty water, but they evolved from freshwater ancestors. They cope with salt by efficiently pumping it out of their own bloodstreams. The saltier the water, the harder they have to work and the more energy they burn.

So you’d expect that Artemia does best in mildly salty water. In fact, they can’t tolerate the stuff. At more than 40 grams of salt per litre, they’re fine. Below that threshold, they’re less likely to survive. Bizarre! Surely, it should be the other way round?

Nougué discovered that Artemia’s gut microbes are behind this weird paradox. When Nougué raised Artemia larvae in sterile cultures, so they grew up without their usual coterie of microbes, these germ-free shrimp did better in low-salt water. Likewise, when she fed them a diet of yeast instead of their usual meals of algae, they also did better with less salt. Their usual preference for high-salt water only exists when they eat algae and carry microbes. Why?

These bacteria help to break down the carbohydrates in the algae, as well as detoxifying the many poisons in those mouthfuls. Without them, the shrimp wouldn’t be able to survive on their usual meals. And here’s the rub: the bacteria like salt. They grow less well at low salinities. So Artemia, to provide these partners-in-digestion with the ideal living conditions, is forced to live in water that’s saltier than it would naturally prefer, and is effectively barred from mildly salty places.

Here, then, is a case where microbes expand an animal’s ecological opportunities (by allowing it to eat an otherwise inaccessible source of food) but also constrain it (by forcing it out of low-salt environments). They provide a valuable service, but they inadvertently issue demands in return. These aren’t mild demands, either. Salinity is the single biggest factor that defines where Artemia lives, more so than temperature or predators or parasites.

There are other examples of such constraints. Insect symbionts, of the kind that allow bugs to suck on sap, tend to be more sensitive to high temperatures than their hosts, so their numbers plummet in hot weather. (What happens to those partnerships in a warming world, you might ask?) And in some cases, hosts and microbes could become so dependent on each other that they risk both becoming extinct—consider the case of the 13-year-cicada and its ridiculously degenerate bacteria.

Reference: Nougué, Gallet, Chevin & Lenormand. 2015. Niche Limits of Symbiotic Gut Microbiota Constrain the Salinity Tolerance of Brine Shrimp. American Naturalist. http://www.jstor.org/stable/10.1086/682370

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Bug Stops Food Halfway Down Its Gut to Make Room for Microbes

Your gut is a long continuous tube. Food goes in one end, gets digested and stripped of nutrients, and is shunted out the other end. That’s the case in ants and elephants, lions and sea lions, hawks and hawk moths. But not in stinkbugs. In the guts of these sap-sucking, shield-shaped insects, food goes in one end, gets digested and stripped of nutrients… and then stops. It never flows into the back half of the gut. That end of the organ has been transformed from a site of digestion, into an apartment complex for microbes.

Our guts are full of bacteria and other microbes too, but they live among the currents of food and help us to digest our meals. The stinkbugs have a very different arrangement. Their guts consist of several chambers in a row. The first three (M1, M2, and M3 in the diagram) are for storing and digesting food, and absorbing nutrients. The fourth (M4 and M4B) consists of many branching sacs and crypts, all densely filled with symbiotic bacteria.

Stinkbug gut. Credit: Ohbayashi et al, 2015. PNAS
Stinkbug gut. Credit: Ohbayashi et al, 2015. PNAS

Now, Tsubasa Ohbayashi and Yoshitomo Kikuchi from Hokkaido University in Japan have discovered that this separation is enforced by a special organ—an extremely narrow corridor (CR in the diagram) that separates the third and fourth chambers. It’s  thin and inconspicuous, which is why no one had noticed it before.  But it plays a vital role: it allows certain bacteria to colonise the back half of the gut, while keeping food and other microbes in the front half.

This discovery speaks to two of the most important sides to the wide-ranging partnerships between animals and microbes. The first is conflict. Even beneficial bacteria aren’t an inherent good. They have their own evolutionary interests and can cause severe problems for their hosts if they get into the wrong body parts. So, they need to be contained and controlled. We do so with a wall of mucus that coats our guts, and with immune cells that patrol that wall. Other animals have special compartments, in which they house their bacteria. The back half of a stinkbug’s gut is one example of such specialised living quarters.

That brings us to the second issue: selectivity. The microbes that live in animal bodies aren’t just the same ones the surrounding environment. Only some species have the abilities to thrive in an animal host, and only some are allowed to do so. In stinkbugs, just one bacterium called Burkholderia can colonise the gut. (It’s not entirely clear what Burkholderia does for its host, but we know that it’s important because bugs that don’t encounter it can’t reach their full size and die early.)

The stinkbugs’ newly discovered corridor is responsible for this extreme selectivity. It’s a symbiont sorter. Last year, Kikuchi’s team fed young bean bugs with Burkholderia that had been labelled with a glowing green molecule. They saw that the bacteria formed a queue at the entrance of the narrow corridor and, over several hours, slowly squeezed through. Only Burkholderia does this. Other bacteria can’t make the same journey.  

Neither can food or liquid. More recently, the team fed young bedbugs with water that had been stained red with food colouring. The wave of red dye slowly made its way through the gut, and then completely stopped at the narrow corridor. Whatever the organ was, it was impervious to food and liquid, as well as to most microbes.

By studying it under a microscope, the team discovered its secret. For a start, it is impossibly thin: just a few millionths of a metre wide. It is also filled with mucus, which acts as a physical plug. Only Burkholderia can power its way through, partly because it’s a strong swimmer. It propels itself with a powerful whip-like tail, called a flagellum. When Kikuchi’s team engineered mutant Burkholderia that couldn’t assemble a proper flagellum, these strains also couldn’t pass through the corridor.

Then again, other bacteria like E.coli and B.subtilis have their own flagella, and they can’t pass, either. There must be something else that bars their way, and no one knows what that might be. It’s possible that Burkholderia alone can make enzymes that break down the mucus, so that it tunnels as well as swims. Alternatively, Burkholderia might uniquely resist a battery of digestive enzymes and antibacterial chemicals that the bug releases to restrain other microbes.

It’s likely that both the bug and the bacteria have their roles to play in ensuring the fidelity of their partnership. The same is true in other natural alliances. The dinky Hawaiian bobtail squid is colonised by a single species of glowing bacterium called Vibrio fishceri, which it houses in crypts within its body. Despite the legions of bacteria that swarm in the surrounding seas, only V.fischeri can enter and colonise the squid’s crypts. And as I have written about previously, this selectivity depends on both the squid and the microbe.

The squid and the bug have another thing in common: they both have to get their microbes from the environment with each new generation. So, selectivity is really important to them. They need precise ways of yanking the right partners out of the surrounding milieu. The same is true for most species of stinkbugs, which is why the corridor organ seems to exist throughout the family’s 40,000 or so members.

The only exceptions also prove the rule. Some stinkbugs have evolved very specific ways of handing down the right beneficial microbes to their babies. Some lay capsules full of microbes next to their eggs. Others slather their clutches in a bacteria-rich mucus. Either way, the young bugs are guaranteed to find the appropriate microbes, so the symbiont-sorting corridors in their guts are less useful. So, as is often the way in evolution, they have vanished. When these bugs grow up, their corridor withers into a thread-like strand, and the two halves of the gut essentially become disconnected.

How, then, do these insects excrete waste? Kikuchi’s experiment with the red food colouring revealed the answer. Food gets absorbed in the front half of the gut, channelled to the insect equivalent of kidneys, and then sent back into the very end of the gut to be excreted in faeces. Perhaps that’s as clear a sign as any that these microbes matter. To accommodate them, the bugs have re-routed the entire flow of food in their bodies, bypassing the fourth chamber of their guts, where their bacteria reside.

Reference: Ohbayashia, Takeshita, Kitagawa, Nikoh, Koga, Meng, Tago, Hori, Hayatsu, Asano, Kamagata, Lee, Fukatsu & Kikuchi. 2015. Insect’s intestinal organ for symbiont sorting. PNAS http://dx.doi.org/10.1073/pnas.1511454112

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Look Up! There’s an Invisible Zombie Highway Right Above You

Step outside on a clear day this summer and look up.

What do you see? Blue. Nothing more. Or so you think.

But surprise! In July and August, an enormous herd of animals is passing directly over our heads. There are so many creatures up there, creatures that are so busy, so athletic, so tiny, so invisible. I’m talking about three to six billion of them every month soaring through the air directly above us. You should meet them. They are insects. High-flying insects. When I read about them in a science paper five years ago (I was at NPR at the time), I made this video, which provides a short introduction:

And now for the update.

It turns out, as you just saw, that the highest flying insect made it to 19,000 feet above sea level. That’s almost the height of Mount McKinley in Alaska. But more recently scientists have found another, even higher zone that’s also home to live critters that soar way, way up—miles higher, to the upper edge of the Earth’s atmosphere.

They are Earthlings that spend days, even weeks, practically in outer space.

What Are They?

According to David J. Smith and his team at the University of Washington and Kostas Konstantinidis and his team at Georgia Tech, there are thousands of species of very small, simple Earth life—bacteria, fungi, viruses—that get swept up by storms and make it to where there’s hardly any oxygen, where the temperatures are fiercely cold, and where they’re no longer protected from solar radiation by the Earth’s ozone layer.

And yet, write Peter Ward and Joe Kirschvink in their new book A New History of Life, most of these microbes will eventually come back down to Earth no worse for wear. They’re teeny. You can’t see them without a microscope. Typically, it would take almost 40,000 of them laid end to end to make it around your thumb.

Drawing by Robert Krulwich
Drawing by Robert Krulwich
Drawing by Robert Krulwich

But there are lots of them up there, so many that Ward and Kirschvink say this zone is becoming “the most newly discovered ecosystem on Earth,” a vast territory (many, many times greater than our oceans) where microbes routinely spend time dancing in the air.

Drawing by Robert Krulwich
Drawing by Robert Krulwich
Drawing by Robert Krulwich

Some bacteria have been in this high zone so regularly or for so long that they’ve adapted to life in the sky. Some species develop pigments that mimic sunscreen; some, says the New York Times, feed only on cloud water; and some can reproduce within clouds.

Drawing by Robert Krulwich
Drawing by Robert Krulwich
Drawing by Robert Krulwich

Scientists call this new family of creatures-in-the-sky “high life,” and it is a biological zone with its own rules. Up there is not like down here.

How Do They Survive Up There?

For one thing, scientists differ about how microbes at the upper end of the zone stay alive. When deoxygenated and freezing, do they slow way, way down like a hibernating bear? Or do they go dormant and essentially suspend their lives until they return? Or, as Ward and Kirschvink suggest, do they spend a brief period being dead?


This is one of the most provocative passages in Ward and Kirschvink’s book. “Most of us would agree,” they write, “that for mammals, and perhaps all animals, dead is dead.” You don’t come back from “dead.” But then they go on:

“… in simpler life, such is not the case. It turns out that there is a vast new place to be explored between our traditional understanding of what is alive and what is not.”

What if, in this new airy realm high above the planet, there could be “a place in between,” where bacteria might take wing, arrive in that freezing, irradiated zone, lose their life-giving machinery, and then, somehow, on the trip back down, build it back again?

Ward and Kirschvink are both well-respected senior scientists. Ward studies mass extinctions, Kirschvink magnetofossils. Neither is given to overstatement, which is why when I hit this line in their book, I put down my copy, stared out the window and thought, What?

How can anything be undead?

In the chapter I was reading, Ward and Kirschvink explore how life came to be four billion years ago. They suggest that instead of a single Genesis-like event (a bag of inert chemicals suddenly sparks into living chemistry), maybe “in the beginning,” chemistry switched back and forth, sometimes alive (on), sometimes not (off), and maybe, just maybe, in the simplest creatures, this may still be a habit—in fact, it may be happening to this day. Very simple creatures high in the sky, they say, might be alive, then not, then alive again, or as they put it:

“Life, simple life at least, is not always alive.”

Woah! This is a new idea to me. I tried to talk more with Peter Ward, but he’s in Papua New Guinea doing ocean research in a dugout canoe and doesn’t have a good internet connection, and Kirschvink is not answering email at Caltech, where he teaches. But I’m curious: Have any of you readers bumped into this notion? Life de-animating, then reanimating? It seems wonderfully preposterous—and very intriguing.

Let me know …

Peter Ward and Joe Kirschvinck’s new book “A New History of Life: The Radical New Discoveries About the Origins and Evolution of Life on Earth” goes after the hardest questions in life’s history, how did we begin, how simple life grew more complex, the origin of sex; they attack these puzzles carefully, feasting on the latest and especially the wildest research, so if you want an up-to-date primer guaranteed to keep your inner-college-sophomore up all night arguing, binging on ideas, going “no way”—this is a pretty good book. I also relied on David Montgomery and Anne Bikle’s “The Hidden Half of Nature, The Microbial Roots of Life and Health,” to get my head around itty bitty bits of life, the fungi, the bacteria, the archaea, the viruses, the protists. Their book took me into intestines, soil, and, yes, to the sky. It comes out in November. Also, my artist for the video, Benjamin Arthur, is about the most elegant, sly, multi-talented illustrator around; give him a tale, he’ll give you a perfect look to tell it with. Each of our ventures has a completely different visual style. Check out Why Can’t We Walk Straight? Last year he even turned in a piece (not with me, alas) on microbes. You can find it here.

Editor’s Note: This post has been updated to correctly reflect the spelling of Anne Bikle’s name.

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How To Make Better Health Predictions From Our Gut Microbes

We all know people who act very differently depending on the company they find themselves in. They can be delightful in some circles, and obnoxious in others. The same principles apply to the microbes in our bodies—our microbiome. They have important roles in digestion, immunity, and health, but none of them is inherently good. They can be helpful in one part of the body and harmful in another, beneficial when paired with certain partners and detrimental when teamed up with others.

This means that, as I’ve written before, there’s no such thing as a “healthy microbiome”. Context matters. And contrary to what some companies might tell you, we’re still not very good at looking predicting what any particular community of microbes means for our health. One common approach is to compare microbiomes in people with or without a disease, single out species that distinguish the two groups, and use their presence or absence to make predictions. But those same bugs might have the opposite effect, or none at all, in another setting.

Alyxandria Schubert from the University of Michigan used a less reductionist approach—one that embraces the complexity of the microbiome rather than shoving it aside.

She studied Clostridium difficile: a weedy bacterium, known colloquially as C-diff, which can cause debilitating bouts of diarrhoea. A thriving community of gut microbes can hold C-diff at bay, but when those communities are cleared by antibiotics, the weed can bloom freely. That’s why C-diff is the single biggest cause of hospital-acquired infections in the USA.

But not everyone who takes antibiotics gets infected. What separates them from those who succumb? Is it just luck? Is it the specific drugs they take? And can you look at someone’s microbiome after they take antibiotics, and accurately predict their risk of contracting C-diff? To find out, Schubert put mice on seven different antibiotics, and then exposed them with C-diff. Each drug changed the rodents’ gut bacteria in different ways, giving some species a boost while repressing others.

None of these changes could consistently account for an animal’s susceptibility to C-diff. For example, mice with a particular Bacteroides species were more likely to be colonised by C-diff if they had taken streptomycin, but a lower risk if they had taken cefoperazone.

Akkermansia, a microbe that seems to protect against both obesity and malnutrition, also failed to show a clean pattern. “If you picked the right antibiotic, you’d say Akkermansia is protective. Pick another one, and you’d see mice with just as much Akkermansia and high levels of C-diff,” says Pat Schloss, who led the study. “This is a bug that’s being used in probiotic trials, but we find it associated with inflammation and other stuff. It’s a pretty strong example of context-dependency.”

It’s not the actions of any one microbe that protects a gut from C-diff incursions, but the interactions between them. So, rather than trying to identify a particular protective species, we need to study the community as a whole.

To do that, Schubert turned to a technique called random forest machine-learning. She fed her data from the various post-antibiotic microbiomes into a computer program, and asked it to pick features that could predict the level of C-diff colonisation. The program then built a “decision tree” based on those features—imagine a game of Twenty Questions. Does the community have lots of Bacterium A but little of B? Lots of C and D? Neither E nor F? Any one tree might be wrong a lot of the time, so the program generated a lot of them—an entire “forest”. It could then run any new microbiome through all of the trees, aggregate their responses, and make a prediction.

When Schubert it to predict the degree of C-diff colonisation, it explained 77 percent of the variation from the antibiotic experiment. When she gave it the simpler task of just predicting whether C-diff would colonise or not—yes or no—it got the right answer 90 percent of the time.

This is encouraging. Still, the team needs to test their program on a different data set than the one they used to build it. And although they measured how accurate it is, they need to show that it’s both sensitive (it rarely misses when a person is at risk) and specific (it doesn’t sound a false alarm when the risk is low). And obviously, they need to test it on people, rather than mice.

Still, it’s the right sort of approach. When humans look at complicated data sets, we try to pare things back to manageable simplicities: this bacterium is protective and this one isn’t. Machine-learning avoids this problem, and grapples with all the complexities hidden in the data. “You’re not just looking at one organism but the whole collection,” says Schloss.

Other teams are doing the same. Last year, Sathish Subramanian and Jeff Gordon built a mathematical model that could work out if a baby’s microbiome was maturing at the right pace—if its microbiological age matched its biological one. And Schloss is using the same method to try and predict a person’s risk of colon cancer from their gut microbiome. “Maybe you’d go into the intensive care unit and we’d put you on antibiotics, we could predict your risk of C-diff or colon cancer or any number of diseases,” he says.

If the predictive models work, they could also be used to personalise treatments—another future goal for microbiome research. Rather than just offering everyone the same probiotics, or giving them a faecal transplant (yes—that’s a thing), doctors might be able to tailor a prescription of microbes to a person’s existing community. Given what they’ve got now, what do they need to make them healthier?

“One of my fears with microbiome research is that we’re finding all these associations and not doing anything with it. We have no deliverables,” Schloss says. “My hope is that we could translate this into humans.”

Reference: Schubert, Sinani & Schloss. 2015. Antibiotic-Induced Alterations of the Murine Gut Microbiota and Subsequent Effects on Colonization Resistance against Clostridium difficile. mBio. http://dx.doi.org//10.1128/mBio.00974-15

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This Beetle is Ruining Your Coffee With the Help of Bacteria

I am writing a book about partnerships between animals and microbes. In the process, I have consumed a frankly obscene amount of coffee, to the extent that the dedication might just read “To coffee, with thanks”. So, it is with mixed emotions that I now write this post, about an animal that is ruining coffee with the help of bacteria.

The coffee berry borer is a small, black beetle, just a few millimetres long. The females bore holes into coffee berries and then lay their eggs in the seeds within—the bits that we know as “coffee beans”. The larvae devour the seeds when they hatch, destroying them. In Brazil alone, its antics lead to some 300 million dollars worth of losses, and it has spread to coffee-making nations all over the world. This tiny pest is the single greatest threat to your cup of blissful java.

Coffee berry borer beetle. Credit: L. Shyamal (CC BY-SA 3.0)
Coffee berry borer beetle. Credit: L. Shyamal (CC BY-SA 3.0)

The beetle is the only animal that can feed solely on coffee beans. Others might occasionally nibble the seeds or other parts of the coffee plant, but they don’t dedicate themselves to the task. There’s a reason for that: caffeine. This stimulant draws many of us to coffee, but it effectively deters plant-eating animals. Not only does it taste bitter, but at the doses found in coffee seeds, it can poison and paralyse any wayward insect. Any insect, that is, except for the coffee berry borer. As a larva, it’s practically bathed in caffeine, and yet it survives. Even the most caffeine-rich beans fail to deter it.

Javier Ceja-Navarro from the Lawrence Berkeley National Laboratory has discovered its secret: it has bacteria in its guts that can detoxify caffeine.

When he fed the beetles with coffee beans and analysed their faeces for traces of caffeine, he couldn’t find any. None. Something in their gut had completely destroyed the would-be poison. Bacteria seemed like the obvious candidates, so Ceja-Navarro fed the beetles with antibiotics. This time, when they ate coffee beans, their poo was laden with caffeine. And when they got a chance to breed, they utterly failed. Most of their eggs and larvae died outright, and none of the survivors made it to adulthood. Without their microbes, they couldn’t handle their caffeine.

Ceja-Navarro’s team, led by Eoin Brodie, found that the bacteria in the coffee berry borer’s gut vary from country to country, but some species turn up everywhere. At least a dozen of these can grow on caffeine and nothing else, and one—Pseudomonas fulva—was especially good at it. It’s was the only microbe with a gene called ndmA, which starts the process of metabolising caffeine.

When Ceja-Navarro fed P.fulva to the antibiotic-treated beetles, he restored their ability to metabolise caffeine. Then again, the insects still couldn’t reproduce, which suggests that other bacteria also affect its health, and perhaps its ability to withstand its toxic meals.

Whether this discovery will help coffee farmers is not clear. It would be a truly terrible idea to start spraying coffee plants with antibiotics, but perhaps there might be subtler ways of breaking the alliances between the beetles and their detoxifying microbes.

Detoxification is only one part of the coffee berry borer’s success. There’s also digestion. Coffee berries are 60 percent carbohydrates, and since the beetle larvae eat nothing else, they need some way of breaking down these large, tough molecules.

In 2012, Ricardo Acuña from Cenicafé, a Colombian coffee research centre, discovered its trick by analysing the genes that are switched on in its guts. One of them – HhMAN1 – stood out for two reasons. First, it creates a protein called mannanase that breaks down galactomannan, one of the major carbohydrates in coffee beans. Second, insects aren’t meant to have mannanases.

Acuña found that the beetle’s version of HhMAN1 is most closely related to genes from bacteria. He checked to make sure that he hadn’t sequenced some contaminating microbe, and indeed he hadn’t: HhMAN1 was surrounded by other typical insect genes and was clearly a bona fide part of the beetle genome.

So, at some point in their history, these beetles stole a gene from bacteria, perhaps the same ones that live in its gut. That gene now lives permanently in their genome and allows them to digest the signature carbohydrates found in coffee beans.

Bacteria, then, have helped the beetle in two ways—by donating a digestive gene at some point in the distant past, and by donating their detoxifying powers in the present. Boosted by microbial power, the beetle has become a worldwide pest, and a royal pain-in-the-espresso.

Reference: Ceja-Navarro, Vega, Karaoz, Hao, Jenkins, Lim, Kosina, Infante, Northern & Brodie. 2015. Gut microbiota mediate caffeine detoxification in the primary insect pest of coffee. Nature Communications http://dx.doi.org/10.1038/ncomms8618


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How to Program One of the Gut’s Most Common Microbes

Last month, I wrote a feature for New Scientist about smart probiotics—bacteria that have been genetically programmed to patrol our bodies, report on what they find, and improve our health. Here’s how the piece began:

“[There’s a] growing club of scientists who are tweaking our microbiome—the microbes that live in or on our bodies—in pursuit of better health. They are stuffing bacteria with circuitry composed of new combinations of genes, turning them into precision-targeted micro-drones designed to detect and fix specific problems.

Some lie in wait for pathogens like P. aeruginosa or the cholera bacterium Vibrio cholerae, releasing lethal payloads when they have the enemy in sight. Some use the same tactics to attack cancer cells. Others can sense signs of inflammation and release chemicals that could help to treat chronic conditions like inflammatory bowel disease. And these tricks aren’t just confined to the lab. In the next 18 months, at least one start-up is expected to put its newly created synthetic bugs into clinical trials with real people. Welcome to the age of smart probiotics, where specially designed bacterial rangers patrol the gut, reporting on the state of the environment, eliminating weedy species, and putting out fires.”

This work is part of the growing field of synthetic biology, which brings the principles of engineering to the messy world of living things. Synthetic biologists treat genes as “parts”, which they can pick from a registry, combine into “circuits” or “modules”, and stuff into a living “chassis”. Rather than modestly modifying one or two genes, they remix large networks, to produce yeast that can brew antimalarial drugs instead of beer,  cells that self-destruct if they turn cancerous, or microbes that can sense and quench inflammation in the gut.

Initially, these microbiome engineers started by modifying the obvious laboratory darlings, like Escherichia coli, or species used in probiotic yoghurts, like Lactobacillus. These bacteria have been studied for a long time and are easy to manipulate. But they are actually relatively rare in our guts. They also lack staying power, which is why the current generation of probiotics don’t colonise the people who swallow them, and rarely deliver on their fabled health promises.

If you want to turn a microbe into a gut ranger, you’re better off starting with a species that’s well-adapted there. And there are few better choices than Bacteroides thetaiotamicron—B-theta to its friends. Collectively, the Bacteroides genus makes up between 30 and 50 per cent of the microbes in a Western person’s gut. They’re exquisitely attuned to that environment and they’re excellent colonisers. And B-theta is arguably the best-studied of them. It was an early star of the microbiome craze: by working on this microbe back in the 1990s, pioneers like Jeff Gordon began to understand how important gut bacteria are to our lives.

Now, Mark Mimee and Alex Tucker from MIT have hacked B-theta, creating a small library of biological parts that can be used to programme it.

They started by building circuits that can permanently activate a given gene, and then tune its activity to a specific level within a 10,000-fold range. They tested these circuits by hooking them up to a gene that makes a glowing enzyme, and showed that they could precisely set the brightness of the glow.

Next, they created inducible circuits, which would activate a target gene only when they receive some kind of external trigger, like a drug or a dietary nutrient. When the trigger arrives, the circuit produces an enzyme that cuts out a particular piece of DNA, flips it around, and glues it back into place. A microbe that carries this circuit has memory—by inverting its DNA, it permanently records its encounter with the triggering substance. Mimee and Tucker could then tell if the trigger was present by sequencing the right region and looking for the inversion. They had effectively turned B-theta into a journalist that could sense and report on the events in a gut.

Finally, the team created circuits that can inactivate specific genes in B-theta. They used a powerful new technique called CRISPR interference, in which an enzyme called Cas9 is guided to a specific stretch of DNA. Cas9 normally acts like a pair of scissors that cuts whatever DNA it encounters. But in CRISPR interference, the scissors have been blunted. Rather than cutting a target gene, Cas9 just sits there, stopping other enzymes from activating it.

Mimee and Tucker connected Cas9 to genes that sense external triggers, so they could unleash it when they wanted. Then, they used different guide molecules to target Cas9 to specific genes. Now, they could inactivate those genes whenever they wanted, by delivering the right trigger. “It’s a flexible strategy for turning off any gene you want,” says Timothy Lu, who led the study.

A cynic might say that these circuits already existed, and the team just repurposed them for use in B-theta. But that was not easy. Unlike E.coli, which grows with ridiculous ease, B-theta is exquisitely sensitive to oxygen. To work with it, the team had to exclude the omnipresent gas by buying an anaerobic chamber. They also had to develop new ways of introducing foreign DNA into the bacterium—something that’s easy to do in E.coli, but harder in several other species.

Synthetic biology projects have often advanced to this point and then face-planted. Circuits that look good on paper and work in a dish will then fail when they’re incorporated into an actual cell or, in the case of gut microbes, when those cells are loaded into an animal. Pamela Silver from Harvard Medical School achieved one of the first successes last year by programming E.coli with a memory switch, and testing it in mice Lu’s team have now done the same. When they gave their programmed microbes to mice, everything worked. The inducible memory switches turned on when the mice ate the right triggers, as did the Cas9 suppressors. “We were surprised at how well they did,” says Lu.

“This is a beautiful, elegant piece of work that shows the power of synthetic biology to make a previously challenging organism immediately accessible to the scientific community,” says Michael Fischbach from the University of California, San Francisco, who is also programming his own microbes. “Bacteroides is an ideal ‘chassis’: a friendly bacterium that colonizes the gut professionally.”

“This study provides a nice proof of concept that portable components can be combined and function in this gut commensal,” agrees Justin Sonnenburg from Stanford University, who has been working with B-theta for decades and is also engineering it. This rapidly expanding direction for gut microbiota research will eventually give us new insight into microbiota-host interaction and medically useful microbes.”

By that, he means that programmed gut microbes could tell us a lot more about the gut than we currently know. The organ is still a bit of a black box.Food goes in and, some 8.5 metres later, waste comes out. Yes, we roughly understand what happens in the middle, but the details are still elusive. When Sonnenburg applied for his position at Stanford, an interviewer asked him: “What a single cell has experienced while transiting the digestive tract? If there’s a little inflammation, has it experienced that? Does it stick around eating plant polysaccharides? How could you tell?” Those are the kinds of questions that he, Lu, and others hope to address with their microbial reporters.

They also want to connect detection circuits to therapeutic ones, so that microbes can not only spot early signs of infections and chronic diseases, but also correct them. You could imagine handing out these sentinel microbes to people in the midst of epidemics, like the cholera outbreak that is still raging in Haiti. Alternatively, soldiers and tourists could take them before travelling abroad to regions with a high risk of diarrhoeal diseases. The possibilities are vast.

Reference: Mimee, Tucker, Voigt & Lu. 2015. Programming a Human Commensal Bacterium, Bacteroides thetaiotaomicron, to Sense and Respond to Stimuli in the Murine Gut Microbiota. Cell Systems http://dx.doi.org/10.1016/j.cels.2015.06.001

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The Slow-Motion Symbiotic Train Wreck of the 13-Year Cicada

Round about now, in various US states, a vast swarm of cicadas will start crawling out of the ground. These black-bodied, red-eyed insects have stayed underground for 13 or 17 years, drinking from plant roots. When they greet daylight for the first time, they devote themselves to weeks of frenzied sex and cacophonous song, before dying en masse. They’ll be picked off by birds, snagged by squirrels, and crunched under shoes and tyres, but none of that will dent their astronomical numbers—which is perhaps the point of their lengthy underground stints, and their synchronous emergence.

But the cicada’s weird lifestyles have also left them with a different legacy. It involves the bacteria that live in their bodies, and it’s so weird that when John McCutcheon first discovered it, he thought he had made a technical error.

Many insects carry bacteria inside their cells. These ‘endosymbionts’ are especially common among sap-sucking bugs, like cicadas, and help their hosts to make nutrients that they can’t get through their food. They almost always have exceptionally tiny genomes. Once they get inside insect cells, they become isolated from other bacteria and restricted to small populations. This deprives them of opportunities for shuffling or acquiring genes, and allows harmful mutations to build up in their DNA. One by one, their genes break and disappear, leaving them with shrivelled minimalist genomes.

McCutcheon is one of a small cadre of scientists who, over the past 15 years, have deciphered the weird genomes of many insect symbionts. When he started his own lab at the University of Montana, he decided to look at Magicicada tredicim—one of the periodical 13-year species. He did the usual thing: he dissected out the organs where the bacteria live, pulled out their DNA, cut it into fragments, sequenced the pieces, and used a computer to assemble those portions into a coherent whole.

Except, it didn’t work. The sequences just wouldn’t assemble neatly. It was as if someone had taken several similar but incomplete jigsaw puzzles, and jumbled all the pieces together. “It was just such a mess,” he says. “I thought it was something technically wrong but I couldn’t figure out what.”

Perplexed, he moved on to a different cicada—a South American species called Tettigades undata. There, he found yet more weirdness. It contained a bacterium called Hodgkinia, which had somehow split into two distinct species inside its insect host. As I wrote last year, these daughter species are like two halves of their ancestor. They’ve each lost different genes so that individually, each is a pale shadow of the original Hodgkinia, but collectively, they complement each other perfectly.

When McCutcheon worked out what was going on in T.undata, he suddenly realised what was happening in the 13-year cicada. It also contained Hodgkinia symbionts that had split into separate lineages—and not just two.

Graduate students Matthew Campbell and James Van Leuven eventually showed that the DNA from this cicada’s symbionts form at least 17 distinct circles. It’s not clear if each of these represents a Hodgkinia chromosome, or an entire Hodgkinia genome on its own, but at least four of them are found in distinct cells You can see this in the images below, where the blue, green, purple, and orange dots all represent cells that have just one of the 17 circles.

Hodgkinia cells in cicada tissue. Credit: Campbell et al, 2015. PNAS.
Hodgkinia cells in cicada tissue. Credit: Campbell et al, 2015. PNAS.

As in the earlier discovery, these circles complement each other; they share sets of genes for making nutrients that matter to the host, but none of them has the full complement. They’re also found in other species of periodical cicadas. And they might just be the tip of the iceberg: the team could confidently identify 17 circles, but the insects likely harbour many more. “If I had to guess, I’d say there’s between 20 and 50,” says McCutcheon. “It’s incredible. It’s a mess.”

From Hodgkinia’s point of view, one lineage has clearly split into several, and irreversibly so. “That’s the baseline definition of speciation,” says McCutcheon. “It’s happening in an asexual population, but the lineage has fractured and it’s not going back.” But if you take the cicada’s perspective, the collective symbionts are still doing the same thing as the original. And while they parcelled their genes into separate cells, the total amount of bacterial DNA has increased. Each part became smaller, but collectively, their genome got bigger.

So are the Hodgkinia circles different species or lineages? Is the Hodgkinia genome the total of the circles in a single cicada, or does each distinct lineage have its own genome? It’s really hard to say. “The problem is that when we write a paper, we have to use words, and words mean something,” says McCutcheon. “It is very hard to put labels on this stuff, and I will not just give this a new name willy-nilly, because I don’t think we understand it well enough.”

There are other mysteries too. The cicada also has another bacterial symbiont called Sulcia, which shows no sign of this ridiculous fragmentation. There’s just one Sulcia and it’s the same in all cicada cells. Why has this microbe stayed whole, while its neighbour rent itself asunder? No one knows. A reasonable guess is that Hodgkinia evolves much faster than Sulcia, and more quickly builds up mutations that disable its genes.

Also, why has Hodgkinia fractured into many lineages within cicadas, when other insect symbionts have not in their respective hosts? McCutcheon thinks the answer lies in the insects’ long lives. Most sap-sucking bugs are lucky to make it past their first birthday. They lead short, fast lives, and if their symbionts developed detrimental mutations, they and their hosts would be weeded out by natural selection. Cicadas, by contrast, can live for 2 to 19 years, and for most of that time, they’re barely moving or growing. During those slow years, their symbionts aren’t that important, and are free to build up detrimental mutations without affecting their hosts or falling foul of natural selection—at least, not in the short term.

The long-term outlook may not be that rosy. Partnerships with microbes often furnish animals with incredible and valuable skills—in this case, the ability to drink plant sap without becoming deficient in important nutrients. But with great opportunity comes great risk. Once host and bacterium become dependent on each other, they can enter into a kind of symbiotic trap—or, as Nancy Moran puts it, they could jointly “spiral down the symbiosis rabbit hole”.

Take Hodgkinia. If it continues to fragment and degenerate, it—they?—may eventually be unable to sustain the cicada. “It just looks like it’s going off the rails,” says McCutcheon. “It’s like watching a train wreck or a slow-motion extinction event. It makes me think differently about symbiosis.”

Reference: Campbell, Van Leuven, Meister, Carey, Simon, and McCutcheon. 2015. Genome expansion via lineage splitting and genome reduction in the cicada endosymbiont Hodgkinia. PNAS http://dx.doi.org/10.1073/pnas.1421386112

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Can The Microbes You Leave Behind Be Used to Identify You?

When you touch a surface, you leave behind fingerprints—distinctive swirling patterns of oils that reveal your identity. You might also deposit traces of DNA, which can also be used to identify you. And you leave microbes. You are constantly bleeding microbes into your surroundings, and whenever you touch something, bacteria hop across from your skin.

It’s increasingly clear that everyone has a unique community of microbes—or microbiome—living on their bodies. We share species and strains but the exact roll call varies from person to person. “If you take a collection of people, their microbes will look very different but their genomes will look mostly the same,” says Curtis Huttenhower from the Harvard School of Public Health. So, could the DNA of these tiny variable residents also reveal our identity, just like fingerprints or our own DNA?

A few studies have suggested so. In 2010, Noah Fierer from the University of Colorado found that bacteria swabbed from keyboards and mice matched those on their owners’ skins more closely than those from other people. (The match wasn’t quite accurate enough for forensic use, although that didn’t stop CSI Miami from running with it.) And last year, Simon Lax and Jack Gilbert from the University of Chicago managed to identify people, from a pool of 18 volunteers, based on the microbes they left behind in their homes.

More recently, Lax and fellow student Sean Gibbons spent two days swabbing their mobile phones, the soles of their shoes, and the floor around them, on an hourly basis, to many strange looks. They found that the shoes and phones retained traces of their owners, so that an algorithm could accurately identify whose items any given sample came from. The objects were also heavily influenced by their environment; the shoes, in particular, quickly picked up microbes from the floors they walked over, suggesting that it might be possible to track a person’s movements from the microbes on their belongings.

But what would happen if you scaled these studies up to larger populations? Could you still accurately pinpoint a person using their microbes, without false alarms? Would the results be consistent? And while fingerprints and genomes are largely constant, microbiomes change a lot—so will a person’s abandoned microbes still identify them weeks or months later?

To answer these questions, Eric Franzosa and other members of Huttenhower’s team worked with data from the Human Microbiome Project, which collected microbes from the guts, skin, and other body sites of 120 people, at several points in time. They used an algorithm that took data from each volunteer’s first visit, extracted features like the presence of certain species, strains, or genes, and combined the most distinctive ones into a “code” that was unique to each individual, but also consistent over time. They then compared these codes to samples collected several months later to see if they could still identify the right owners.

They only managed to recognise a third of their volunteers in this way. That’s nothing to sniff at, but it certainly doesn’t match the forensic utility of the human genome, or even fingerprints. The results were more promising when the team focused on gut microbes, which proved to be exceptionally stable; gut-based codes identified 86 percent of the volunteers.

“That’s a floor. The accuracy can only go up if we have more sequencing data and better algorithms,” says Huttenhower. He also notes that “since the microbiome changes over time, we wanted to get as few things wrong as possible, so we biased the algorithm in favour of false negatives.” That is, the program might fail to identify people based on their microbes, but it will almost never identify the wrong person.

Their results reflect our growing understanding of the human microbiome. Our bodies—and our guts, in particular—are colonised by a surprisingly stable set of bacterial strains. Their levels might fluctuate, but the same coterie persists for decades. Perhaps our genes or our immune systems determine who gets to stay. Perhaps there’s a “first-mover advantage”, where the first strains to set up shop then dictate which others get to immigrate. Either way, as Huttenhower says, “Not only are we robots for microbes, but each of us is a robot for a specific set of clones or strains that ride around with us for a long period of time.”

He doubts that these results are important for forensic science. “If you deposit your microbes, you’re probably depositing your DNA too and DNA forensics is so well developed,” he says. But he adds that microbiome researchers need to be wary of these issues to protect the privacy of study volunteers. The data from such studies is always anonymised, but if people have unique and consistent signatures, there’s a risk that information from different data sets could be compared in ways that break anonymity.

Consider what happened with Netflix. In 2007, the online media company released movie rankings from 500,000 of its customers, so that others could help to improve its recommendation algorithms. Even though the data were anonymised, researchers still managed to identify some of the individuals by comparing their rankings to non-anonymous profiles from IMDB, another movie site. And unlike movie rankings, our microbiome could reveal potentially sensitive information about what we eat, and whether we suffer from health problems.

“This isn’t an issue now and it’s not a high-risk issue, but it’s still important for us to consider,” says Huttenhower. “No one study has any danger of releasing private information but due to uniqueness, the ability to link across studies becomes a possibility.”

Reference: Franzosa, Huang, Meadow, Gevers, Lemon, Bohannan & Huttenhower. 2015. Identifying personal microbiomes using metagenomic codes. PNAS http://dx.doi.org/10.1073/pnas.1423854112

Lax, Hampton-Marcell, Gibbons, Colares, Smith, Eisen & Gilbert. 2015. Forensic analysis of the microbiome of phones and shoes. http://dx.doi.org/10.1186/s40168-015-0082-9


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Could Mothers’ Milk Nourish Mind-Manipulating Microbes?

Breast milk seems like a simple nutritious cocktail for feeding babies, but it is so much more than that. It also contains nutrients that feed the beneficial bacteria in a baby’s gut, and it contains substances that can change a baby’s behaviour. So, when a mother breastfeeds her child, she isn’t just feeding it. She is also building a world inside it and simultaneously manipulating it.

To Katie Hinde, an evolutionary biologist at Harvard University who specialises in milk, these acts are all connected. She suspects that substances in milk, by shaping the community of microbes in a baby’s gut, can affect its behaviour in ways that ultimately benefit the mother.

It’s a thought-provoking and thus far untested hypothesis, but it’s not far-fetched. Together with graduate student Cary Allen-Blevins and David Sela, a food scientist at the University of Massachussetts, Hinde has laid out her ideas in a paper that fuses neuroscience, evolutionary biology, and microbiology.

It begins by talking about the many ingredients in breast milk, including complex sugars called oligosaccharides. All mammals make them but humans have an exceptional variety. More than 200 HMOs (human milk oligosaccharides) have been identified, and they are the third most common part of human milk after lactose and fat.

Babies can’t digest them. Instead, the HMOs are food for bacteria, particularly the Bifidobacteria and Bacteroides groups. One strain in particular—Bifidobacterium longum infantis—can outcompete the others because it wields a unique genetic cutlery set that allows it to digest HMOs with incredible efficiency.

Why would mothers bother producing these sugars? Making milk is a costly process—mums quite literally liquefy their own bodies to churn out this fluid. Obviously, it feeds a growing infant, but why not spend all of one’s energy on filling milk with baby-friendly nutrients? Why feed the microbes too? “To me, it seems incredibly evident that when mums are feeding the microbes, they are investing on a greater return on their energetic investment,” says Hinde. By that, she means that setting up the right communities of microbes provides benefits for the baby above and beyond simple nutrition.

By taking up space and eating all the available food, B.infantis and its peers make it harder for pathogens—microbes that cause disease—to establish themselves. The HMOs deter these invaders more directly. Many pathogens launch their invasions by first recognising sugar molecules on the surface of intestinal cells. HMOs resemble those sugars, and so act like floating decoys that draw pathogens away from the gut itself. So, breast milk selects for beneficial microbes while also warding off harmful ones. It sets babies up with the right pioneers.

It’s important to get these first communities right. They steer the development of the immune system, creating a balanced set of sentries that can detect and respond to pathogens, without also going berserk at innocuous triggers like pollen or dust.

There’s also increasing evidence, at least in mice, that gut microbes can shape the early development of the nervous system. They can communicate with the brain via the vagus nerve—a long phone line that carries messages between the brain and gut. They can also release signalling chemicals like dopamine and serotonin. Through these means, they can affect an animal’s behaviour. Some groups have shown that mice which grow up inside sterile containers behave differently to their normal colonised peers: they tend to be less anxious and take more risks. And some teams have shown that specific microbes can reduce anxiety in normal, healthy rodents.

These mind-manipulating properties might be really useful to mothers. Parenting is costly. It takes time and energy. It’s in a baby’s best interests to monopolise as much of that effort as possible, so they get the strongest start in life. Mums, however, have to divide their effort over many children, both present and future ones. If they expend too much effort on one, they might not be in good enough shape to have more. If they can wean their current infant earlier, they can have another sooner.

These aren’t conscious decisions, mind you. I’m not trying to portray mums as cold and calculating. But it’s important to note that from a cold evolutionary standpoint, mothers and babies have slightly conflicting interests. Simply put, infants will tend to demand more investment than is ideal for a mother to give, and evolution has crafted ways for infants to get that investment—think of smiling, crying, nuzzling, and tantrums. Similarly, mothers should have countermeasures for giving themselves an edge in these inevitable conflicts.

Hinde thinks that the HMOs might act as one such countermeasure. If these sugars can nourish specific microbes, and if certain microbes can change a baby’s behaviour, then mothers could potentially change the HMO content o their milk to influence their babies. The infants might become less demanding. They might be less active, and spend more energy on simple growth rather than on play or exploration. They might be less anxious and more likely to become independent earlier.

Again, this isn’t far-fetched. In her own research, Hinde showed that the milk of younger monkey mothers contains fewer calories but more cortisol—a hormone involved in stress. Babies that drink this cortisol-laden milk tend to be more nervous and less exploratory. They also grow faster. Perhaps these things are connected. The cortisol could be a mother’s way of saying: “Don’t waste the precious calories in my milk; focus on getting bigger.” And perhaps the HMOs might convey similar messages, via microbial messengers.

“I liked the paper,” says John Cryan from University College Cork. “It further emphasises the importance of microbiota-brain interactions  in early life for health and development, and positions HMOs as positive drivers of such interactions. Indeed, this is very plausible.”

Plausible and, more importantly, testable. Scientists could see if different sets of HMOs promote the growth of bacteria that can affect the brain. What kinds of signalling chemicals are those microbes making? Do they affect parts of the brain involved in controlling emotions or motivation? Do these effects lead to noticeable changes in a baby’s behaviour? “Then we can look backwards at what are the HMOs that are really influencing the establishment and maintenance of those particular bacteria,” she says. If you load those specific microbes into germ-free mice, and load them with those specific HMOs, what happens?

“We can also look at the variation and abundance of those HMOs in various settings,” says Hinde. “Winning” the evolutionary conflict between parent and child might matter more to mothers who live in risky environments where food is scarce, or where they spend much of their energy on fighting diseases or evading predators. Likewise, younger mothers who are still growing might also fare better if they reserve more of their energy for themselves.

“This is likely to remain hypothetical for quite some time,” Hinde admits. “In humans, there’s hundreds of bacterial strains and oligosaccharides. Understanding what each one does will take forever, much less their complex interactions.” But as she writes in her paper: “An evolutionary perspective allows us to appreciate the essential tensions within the mother-infant dyad and recognize that the infant’s microbial ecology is a potential landscape for negotiating conflict and maintaining coordination. Among the many, many bacteria in the infant gut, may be lurking mother’s littlest helpers.”

Besides, as Hinde says, “Microbes are so hot right now.”

There will be more about milk, microbes, and mums in my upcoming book, I CONTAIN MULTITUDES, out next year.

Reference: Allen-Blevins, Sela, & Hinde. 2015. Milk Bioactives May Manipulate Microbes to Mediate Parent-Offspring Conflict. Evolution, Medicine, and Public Health. http://dx.doi.org/10.1093/emph/eov007  

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Surprises Emerge As More Hunter-Gatherer Microbiomes Come In

The study of the human microbiome—the motley assortment of microbes that live in our bodies—has largely been the study of the Western microbiome. The research has been heavily biased towards people from Europe, North America, and other WEIRD countries—that is, Western, Educated, Industrialised, Rich and Democratic. It’s like trying to understand how cities work by studying London and New York, and ignoring Mumbai, Mexico City, Sao Paulo, Cairo, and others.

Recognising this problem, scientists are starting to catalogue the microbes of rural populations, including hunter-gatherers. Early last year, I wrote about attempts by Maria Gloria Dominguez-Bello and Cecil Lewis Jr to study the microbiomes of the Yanomami of Venezuela and the Matses of Peru, respectively. A few months later, I covered the first study looking at the microbiomes of Hadza hunter-gatherers from Tanzania. All of these studies found similar trends: rural guts usually harbour microbes that aren’t found in Western guts, and are generally more diverse.

The Hadza guts had a few striking differences. They contained almost no Bifidobacteria, a group that is generally viewed as ‘healthy’, and that makes up to 10 percent of a Western gut microbiome. They also had more Treponema, a group that includes the species responsible for syphilis and yaws. These differences aren’t necessarily unhealthy. They just reflect the conditions in that particular corner of the world, its food supplies, water, climate, and more.

Lewis has now published the results of his Peruvian work. His team also found that people who lead traditional lifestyles—both Matses hunter-gatherers and Tunapuco farmers—had higher levels of Treponema than a comparable group of Americans. By studying these strains in detail, the team showed that they are distinct from those that cause human diseases, and more closely related to those that help other animals to digest carbohydrates.

These Treponema strains are also found in the Hadza and non-human primates, but are totally absent from industrialised populations. As such, the team suggests that they “may represent a part of the human ancestral gut microbiome that has been lost through the adoption of industrial agriculture and/or other lifestyle changes.” In other words, they’re part of an ancient package of microbes that our ancestors shared, and that people from developed countries have somehow broken ties with.

This interpretation fits with the “missing microbes” idea espoused by Martin Blaser, which says that various facets of our modern lifestyles—antibiotics, over-sanitation, poor diets, and more—have left us with depleted microbiomes, bereft of species that once played important roles. This, perhaps, explains the rise of several “diseases of civilisation”, like allergies, asthma, obesity, inflammatory bowel disease, diabetes, and more.

Hold on, though. The Hadza and the Matses are not ancient people, and their microbes are not “ancient bacteria”, as one headline stated. They are modern people, carrying modern microbes, living in today’s world, and practicing traditional lifestyles. It would be misleading to romanticise them and to automatically assume that their microbiomes are healthier ones.

After all, we also have no idea what’s behind the characteristics of their communities. It could be their traditional lifestyles, like their diets or lack of antibiotics. But it could equally be something else like their genes, climate, or parasites. You can’t work out which of these factors is important by studying a few scattered groups. Ideally, you’d want to study several groups of people who lead traditional lifestyles, live close to each other, and vary in important traits like diet or genetics.

That is exactly what Elise Morton from the University of Minnesota has done. She and her colleagues sequenced the gut microbiomes of 64 people from four groups in Cameroon: Pygmy hunter-gatherers, Bantu farmers from two villages, and Bantu from a fishing population. All of them practice subsistence lifestyles—that is, they live off whatever they themselves catch or grow. All of them co-exist in rural areas that are close to tropical rainforests. The results have just been uploaded to the bioRxiv pre-print server.

The team found a lot of variation between the four groups, “indicating that there are multiple signatures of rural, unindustrialized microbiomes”. The Pygmy hunter-gatherers stood out. Compared to the Bantu, their guts had more Proteobacteria, Succinovibrio and Ruminobacter, and fewer Ruminococcus—the same pattern that others saw when comparing Hadza and Italian guts. These microbes “seem to be a specificity of hunter-gatherer populations, rather than reflecting a difference between industrialized European and rural African populations,” Morton wrote.

The team also found that one factor, above all others, heavily influenced the gut microbiomes of their Cameroonian groups. It wasn’t diet, ancestry, or location. It was the presence of Entamoeba, a parasitic amoeba. It had such a strong effect on the gut that the team could work out whether a person was infected with 79 percent accuracy, just by looking at their gut microbes.

In general, Entamoeba-infected guts have a greater diversity of bacteria, higher levels of Treponema, and lower levels of groups like Prevotella. The reasons behind these patterns aren’t clear. We know that our immune system affects the composition of our microbiome, so by triggering immune reactions, Entamoeba might indirectly dictate which species get to live in the gut and which do not. Alternatively, it might eat bacteria from dominant groups, creating vacancies that allow others to proliferate, and boosting the diversity in the gut. Or, it might prefer to colonise microbiomes that have already been altered by some other factor.

Regardless, these results throw up some interesting questions. Is the higher diversity of the hunter-gatherer microbiome down to the wider diets of their owners, or to a wider range of parasites? After all, Morton found that if the Cameroonians had a triple-bill of parasites, including a roundworm and a whipworm along with Entamoeba, their microbiomes were even more diverse. Diversity is generally seen as a good thing. Is it?

Likewise, when other groups see high levels of Treponema in the Hadza and Matses, does that just reflect a higher burden of intestinal parasites? Is that what they’re inadvertently talking about when they say “ancestral”? And speaking of Treponema, Morton found it in all four groups but at very low levels, including in the hunter-gatherers. If it’s really part of some ancestral microbiome that has been abandoned through agriculture and industrialisation, then why is it rare in the Pygmies?

We can only answer these questions by looking at the microbiomes of people from different regions around the world. That’s why studies of the Hadza, Matses, Yanomami, and Pygmies are important. But as results come in, we must be wary of concocting simple narratives to explain characteristics of hunter-gatherer microbes.


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Can Probiotic Bacteria Save An Endangered Frog?

I saw a ghost at the Vancouver Aquarium last summer. I was walking out of a room overlooking the main shark tank when I saw something in a glass cage embedded in the wall, something small, black and yellow. I mean Black and Yellow—colours so intense that you almost expect to turn the creature over and find a country of origin embossed on its underside. It was a Panamanian golden frog, and it is extinct in the wild. It only survives in zoos and aquariums. It is an ecological phantom, a ghost of nature.

Several factors took the frog to the edge of oblivion but the one that landed the most punishing blows was a chytrid fungus called Batrachochytrium dendrobatidis, or Bd for short. It is the same grim antagonist that has severely reaped the populations of some 200 amphibians and seems to be working its way through the rest. It is catholic in its choice of hosts and apocalyptic in its effects. The Panamanian golden frog is just one of its victims.

Conservationists have been incredibly successful at breeding the frog in captivity. But if they release these animals back into their native habitat, where Bd still persists, who’s to say they wouldn’t just die? Their ark is full, but there’s no Mount Ararat in sight.

In 2006, a team of researchers stumbled across a possible solution. They found that a few amphibians, including two salamanders and the mountain yellow-legged frogs, naturally carry a bacterium called Janthinobacterium lividum that stopped Bd from growing. It was an anti-Bd probiotic, a microbial shield that turned frogs into resistant fungus-fighters. And when the team applied the bacterium to yellow-legged frogs that didn’t already have it, those individuals also became resistant.

Could J.lividum protect other frogs too? To find out, Matthew Becker from James Madison University, who was part of the original team, teamed up with Brian Gratwicke from the Smithsonian Conservation Biology Institute, who had a group of lab-bred golden frogs. They soaked the frogs in a J.lividum bath and challenged them with Bd. If the approach worked and the frogs survived, perhaps they could be released into the wild, cloaked in their living armour.

It didn’t work. The probiotic microbe didn’t persist on the frogs’ skins, and it did nothing to save them from the fungus. “We thought maybe it wasn’t a good fit,” says Becker. “This bacterium was from California and these frogs are from Panama.” Perhaps frogs from different parts of their carry their own particular probiotic microbes that have adapted to thrive on their skins. If Becker was going to find a probiotic that could protect the golden frogs, he would need to go to Panama.

He went in 2011 and spent a week surveying the skin bacteria of local frogs, focusing on species that were as closely related to the golden frog as possible. Over a week, he collected 450 samples and found several microbes that stopped Bd from growing, at least in lab tests. He focused on four of these, and applied them to captive golden frogs, to see whether they could then survive a bout with Bd.

They couldn’t. On average, the treated frogs survived no longer than untreated ones. And once again, “nothing persisted,” says Becker. “Their existing microbial community didn’t even shift in response to [the new microbes].”

The same problem plagues human probiotics. When they’re swallowed, they don’t take up permanent residence in the gut and they don’t affect the make-up of the local bacteria communities (although they do seem to change the activity of certain genes). After all, a typical yoghurt contains several billion bacteria, whereas our gut contains tens of trillions. It’s like a raindrop falling into a lake. Perhaps this explains why probiotics can help with a small number of diseases, like diarrhoea caused by infections, but have largely failed to live up to the hype that surrounds them.

With the frogs, Becker wonders if he applied too many microbes rather than too few. “I think we may have activated the frogs’ immune systems and prevented the probiotics from establishing,” he says. Alternatively, we know that even closely related animal species can host distinctive microbiomes, so what persists on one frog may just not thrive on another. It’s also possible that the skins of captive golden frogs are already colonised by microbes that stop the bacteria of their former Panamanian neighbours from colonising.

In the midst of their disappointment, the team found a silver lining. Five of the frogs managed to clear the fungus on their own. “That’s pretty unheard of in golden frogs,” says Becker. When he focused on these animals, he found that they differed from those that died, in the groups of bacteria on their skin and the chemicals that those bacteria produced.

What are these microbes? Do they actually protect against Bd or are they indicators of some inherent resistance, perhaps some immune genes that both resist the fungus and select for specific skin microbes? If they do protect against Bd, would they do so in the wild? Are they part of a golden frog’s natural repertoire, or did they only start colonising these animals in captivity? The team is now working to answer these questions. Becker is sampling 200 of golden frogs at Maryland Zoo in Baltimore to see if he can find these potentially protective communities, and then apply them to other frogs to see if they also become Bd-resistant.

The concept of using probiotics to protect amphibians (and perhaps other animals at risk from widespread epidemics, like bats) makes sense. Many animals, from humans to corals, carry skin microbes that protect us from incursions by disease-causing species, by secreting natural antibiotics, mobilising our immune systems, and simply filling up niches that the invaders might otherwise exploit.

But our own experience with probiotics, and Becker’s frog experiments, tell us that deploying these seemingly beneficial bacteria is easier said (and marketed) than done. Probiotics may help to save the frogs but it’s unlikely that we’ll see a one-size-fits-all solution, and the same could be said for the use of microbes in human medicine.


There will be more about frogs and conservation probiotics in my book, I Contain Multitudes, out next year.

Reference: Becker, Walke, Cikanek, Savage, Mattheus, Santiago, Minibiole, Harris, Belden & Gratwicke. 2015. Composition of symbiotic bacteria predicts survival in Panamanian golden frogs infected with a lethal fungus. Proc Roy Soc B http://dx.doi.org/10.1098/rspb.2014.2881

More on Bd:

Update: The post originally said that the 200 golden frogs that will feature in upcoming experiments were at the Smithsonian; they actually live at Maryland Zoo in Baltimore.

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Fishing For the Microbes Behind Malnutrition

Malnutrition seems like an intuitive problem: you don’t eat enough food, so your health suffers. But it’s not that simple. One mysterious type of malnutrition known as kwashiorkor—characterised by leaky blood vessels, puffy limbs, distended stomachs, and fragile skin—often affects children who eat just as much as their healthy neighbours. And even if these kids get to munch on protein-rich food, some don’t recover.

A team of scientists, led by Jeff Gordon at the Washington University School of Medicine, has shown that children with kwashiorkor harbour 11 species of gut bacteria that, together with their poor diets, conspire to damage their guts.

These results suggest that this particular type of malnutrition isn’t just caused by the absence of food, but also by the presence of the wrong microbes.

The team first started studying kwashiorkor in Malawi a few years ago, after noticing that some children developed the condition while their identical twins did not. Why the difference? The twins had the same genes. They ate the same food. They lived in the same village. But their gut microbes were very different.

These microbial communities change over time, much like plants colonising a burnt forest or a new island. Lichens and mosses come first, before giving way to shrubs, then trees. Likewise, in the gut, milk-eating microbes give way those that digest plant matter. Waves of species succeed and replace each other, until they settle on a stable, mature, and more diverse community. In a normal gut, this takes about three years. But in the kwashiorkor kids, the changing communities had stagnated, leaving them with immature microbes for their age.

When Gordon’s team transplanted these immature communities into mice with no microbes of their own, the rodents lost weight—but only if they also ate the equivalent of a poor Malawian diet. The combination of poor food and immature microbes triggered the symptoms of kwashiorkor.

But which microbes are important? Is it the entire community, with its hundreds or thousands of species? Or does the problem lie with a smaller cabal? To find out, Gordon relied on an antibody called IgA. Immune cells release this substance into the gut, where it piles onto microbes to create immobilising coats. Around half the bacteria in our gut are restrained in this way. By looking for these targeted species, “you can use the immune system to mine the microbiota,” says Gordon.

His postdocs Andrew Kau and Joseph Planer began by transplanting microbes from a pair of 21-month-old Malawian twins—one with kwashiorkor and one without—into germ-free mice. They then used a technique called BugFACS to pull out any bacteria that were restrained by IgA. They effectively used the antibody as a fishing rod to hook microbes that draw the immune system’s attention.

In the mice colonised by the ‘kwashiorkor’ microbes, IgA pulled out large numbers of Enterobacteriaceae (prounounced En-ter-oh-back-tee-ree-ay-see-ay). The team then loaded this IgA-targeted set of microbes into more germ-free mice. The rodents fared badly. Half of them died within five days. When the team looked at their guts under a microscope, they saw carnage.

A normal gut has tightly packed cells to prevent microbes from slipping through, and dense forests of tall pillars for absorbing nutrients. In these guts, the cells were pulling away from each other, and the pillars were shrunken and shredded. Imagine a fence with wide gaps between rotting slats. “The [lining] was really just torn apart,” says Gordon. “It was pervasive and dramatic.”

Kau and Planer isolated several of the bacteria within this lethal community and identified a set of 11 species that collectively destroy the gut. These included three Enterobacteriaceae, and several common gut inhabitants like Bacteroides fragilis and Bacteroides thetaiotamicron. Individually, these microbes did very little. Collectively, they led to shredded guts and severe weight loss. “It’s not just one actor,” says Gordon. “It’s the concentred effort of several organisms.”

And as before, the team showed that this cabal only harmed mice that ate a Malawian diet. If the rodents ate more nutritious meals, the microbes were benign. As the team showed in their earlier work, it’s the combination of diet and microbes that makes for poor health.

The team used the same techniques to show that healthy twins, who don’t get kwashiorkor, have guts that are rich in two particular bacteria. The first of these, Akkermansia muciniphila, can protect mice from being obese; it seems that it protects them from malnutrition too. The second one, Clostridium scindens, is part of a group that stops the immune system from overreacting. It was recently shown to single-handedly block infections by its deadlier cousin—Clostridium difficile, a bug that causes severe diarrhoea. These two microbes were enough to defend mice from the more destructive ones.

Having done all these experiments in mice, the team then returned to humans. They used their BugFACS technique on 19 more pairs of Malawian twins, to pull out the IgA-targeted microbes in their guts. And they found the same patterns: more Enterobacteriaceae meant a greater risk of kwashiorkor.

“This is a major advance in the field,” says Charlotte Kaetzel from the University of Kentucky, who studies IgA. “Of course, Jeff Gordon’s lab brings the most state-of-the-art methods to this type of study.” It’s important, she says, that the team combined experiments in germ-free mice, where microbes can be precisely controlled, with direct analyses of the stools of healthy and undernourished children.

This kind of approach is a staple of Gordon’s group. It lends weight to their claims that the microbes are actually causing kwashiorkor, rather than just going along for the ride, and that the patterns in mice are relevant to humans.

The team are now trying to understand how the 11 microbes that they identified damage the gut, and how C.scindens and A.muciniphila thwart them. They also want to know if the same patterns apply to malnourished people from other parts of the world, with different genes, diets, and cultural practices. In the long-term, they hope to develop ways of analysing a child’s microbes (perhaps, using BugFACS) to diagnose their risk of malnutrition before symptoms show, or even to develop probiotics containing bacteria that can forestall these diseases in places where food is scarce.

Reference: Kau, Planer, Liu, Rao, Yatsunenko, Trehan, Manary, Liu, Stappenbeck, Maleta, Ashorn, Dewey, Houpt, Hsieh & Gordon. 2015. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. Science Translational Medicine. http://dx.doi.org/10.1126/scitranslmed.aaa4877

PS: I’ve written two pieces today about the microbiome. In this one, Akkermansia protected mice from malnutrition caused by other microbes and a poor diet. In the other, Akkermansia was associated with inflammatory disease, in mice that ate a diet rich in food additives. In other rodent studies, it stops mice from getting fat, but is more common in cases of bowel cancer. All of this illustrates a point I’ve made before: any one microbe can have very different effects in different contexts and circumstances. There is no universally “good” bacterium, no universally “healthy” microbiome.

More on the microbiome and malnutrition:

Does Your Microbiological Age Match Your Biological One?

Gut Microbes Contribute to Mysterious Malnutrition

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Food Additives Inflame Mouse Guts By Disturbing Microbes

If you walk down the aisles of any supermarket, you’ll see what dietary emulsifiers can accomplish. This common class of food additives binds water and oils together, preventing mixtures of the two from splitting. They stabilise ice-cream and other frozen desserts, mayonnaise, salad dressings, and virtually every kind of processed food. “Anything that sits in a package on a supermarket shelf, and can stay there for a while, probably has emulsifiers in it,” says Andrew Gewirtz from Georgia State University.

These additives may confer stability to food, but they can also bring discord to the gut—at least in mice. Gewirtz has found that two common emulsifiers—caboxymethylcellulose (CMC) and polysorbate-80 (P80)—can change the roll call of bacteria in a mouse’s gut. They also make the gut more porous, allowing microbes to slip through its walls and reach the immune cells and blood vessels on the other side. As a result, the mice developed severe inflammation. They also put on weight, and their blood sugar went up.

The team only looked at laboratory mice, so it’s not clear if emulsifiers have the same effects in humans at the doses we normally eat (more on this later). Still, “this work cannot be ignored,” says Fergus Shanahan from University College Cork, who was not involved in the study. He doubts that most people would be significantly affected by occasionally eating foods with emulsifiers. But the calculus of risk might change for those who have a genetic predisposition to inflammatory bowel disease (IBD), or who eat lots of processed foods.

“The other implication is that current methods for testing food additives for safety are not adequate,” says Gewirtz. CMC and P80 are both “generally regarded as safe”, since they’re not toxic at the levels found in food, and they don’t cause cancer. But such tests say nothing about their ability to disturb the relationship between us and the microbes we carry—disturbances that have been linked to obesity, IBD, and other conditions.

The immunostat

Your immune system needs to spot and thwart infectious microbes, while maintaining a truce with trillions that live in your body and carry out important tasks. If it’s too twitchy, it will constantly go berserk whenever it notices our microbial companions and trigger chronic inflammation. If it’s too relaxed, it wouldn’t detect dangerous threats. It must react without overreacting.

It achieves this balance through a bewilderingly complex network of cells and molecules that I’m going to boil down into a single image. Think of the thermostat that stabilises the temperature of your room. Now picture an “immunostat” that, in a similar way, dictates how responsive the immune system is. Set it too low and you become vulnerable to infections; too high, and your run the risk of inflammatory diseases.

Many things affect where the immunostat is set, including genes, diet, infections, and more. Your gut microbes are also involved. Some groups provoke the parts of the immune system that exacerbate inflammation. Others stimulate the pacifying components that calm everything down. Physical barriers are also important. The simplest way of stopping the immune system from overreacting to microbes is to keep them separate. Our gut achieves this by keeping its cells tightly fused and covering them with a thick layer of mucus. Microbes sit on one side of this Great Wall of Mucus; immune cells on the other.

The experiments

Gewirtz suspects that emulsifiers disrupt both the mucus and the microbe communities, pushing the immunostat towards a twitchier setting.

His postdoc Benoit Chassaing fed lab mice with either CMC or P80, by adding both substances to their food or water at one part per hundred. When he looked at their guts under a microscope, he saw that their mucus wall was thinner than usual, and bacteria had penetrated deep into what was once a No Microbe’s Land. Some were actually touching the gut itself. The gut had also become leakier, so many microbes found their way through to the immune cells and blood vessels on the other side.

The emulsifiers also changed the communities of microbes within the rodents’ guts. Chassaing saw a rise in species that excel at triggering inflammation, and in those that eat mucus like Ruminococcus and Akkermansia. Other microbes shrank away, including groups that produce anti-inflammatory substances by digesting dietary fibre.

These changes lead to a vicious cycle of even more inflammation, even leakier guts, and even thinner mucus. The result: low-grade inflammation in normal lab mice, and a more severe form—colitis—in mutant rodents that were genetically susceptible to IBD.

After swallowing the emulsifiers, both breeds of rodents ate more food. They put on body fat and gained 10 grams in weight (on top of their normal 140). Their blood sugar levels went up. They became less sensitive to the hormone insulin. In other words, they showed many symptoms of metabolic syndrome—a condition that increase the risk of diabetes and heart disease.

Do the microbes cause these problems, or are they just along for the ride? It’s probably the former. None of these changes—the thinner mucus, the inflammation, or the metabolic problems—happened to germ-free mice that were raised in sterile conditions. Without their microbes, those rodents ate emulsifiers to no effect. But when Chassaing loaded them with microbes from individuals that had eaten emulsifiers, they too developed all the same symptoms. Whatever the additives are doing, they’re doing it via gut microbes.

The implications

Inflammatory bowel disease was once very rare, but has become more common since World War II. Many things that change our relationship with our microbes could have contributed to that rise, including antibiotics, sanitation, and dietary shifts, including an abundance of fat, a lack of fibre, or the presence of artificial sweeteners.

What about emulsifiers? It’s hard to say. To state the obvious, mice aren’t people. “Many observations in mice tell us a lot about host-microbe interactions but either don’t translate to humans or have far less significance in humans,” adds Shanahan. “The microbiota of a lab mouse is very simple and much simpler than that of humans. It doesn’t take much to significantly disturb it.” Many things can, including drugs like aspirin, antibiotics, other bacteria, and more. To Shanahan, it’s not surprising that dietary emulsifiers join the list. “What is surprising is that this would occur at such low levels, including levels that humans may be exposed to,” he adds.

But that’s another limitation: it’s hard to compare the doses that Chassaing used to the levels of emulsifiers we eat, because no good measurements of those levels exist. According to one report from the Food Safety Commission of Japan said, “In Western countries, the daily intake of polysorbates, based on their usage in food, was estimated at 12-111 milligrams per person per day.” That’s proportionally much less than what Chassaing’s rodents ate, but we have no idea if the Japanese estimates are reliable—the report provides no data or sources for its figures.

In the absence of such data, the team used the limits set by the US Food and Drug Adminstration, which approves the use of P80 at up to 1 percent in foods, and CMC at up to 2 percent. Chassaing used 1 percent levels in his experiments, but he also found signs of inflammation at 0.1 percent. “We gave amounts that approximate the total consumption of a person who eats a lot of processed food,” says Gewirtz. “It’s the best we could do at this time, but we need better estimates.”

“I went over the data, and they did a thorough job,”says Eugene Chang from the University of Chicago Medical Centre, who studied IBD. “There’s also precedent for this.” He points to other studies showing that carrageenan—another common emulsifier, derived from seaweed—can cause inflammatory bowel disease in mice.

Then again, there’s also some conflicting evidence from other animal studies—none of them have looked at microbes but a few have measured body weight. A Dutch team showed that CMC doesn’t affect the body weight of broiler chickens, and the US National Toxicology Program found that P80 doesn’t change the body weight of rats. Meanwhile, a Japanese study found that pregnant rats actually lost weight when given P80.

The FDA certainly isn’t changing its position. In a statement, it said, “The FDA closely monitors the scientific literature for information that might indicate a potential public health concern with a food substance. At this time, the FDA does not have sufficient evidence to alter its previous conclusion that polysorbate 80 and carboxymethyl cellulose are considered safe under their intended conditions of use in food.”

Meanwhile, Gewirtz says, “We’re certainly eating less processed food since we’ve been doing this work. It took a lot of effort, but we did find one type of ice-cream in the supermarket that’s emulsifier-free.”

Reference: Chassaing, Koren, Goodrich, Poole, Srinivasan, Ley & Gewirtz. 2015. Dietary emulsifiers impact themouse gutmicrobiota promoting colitis and metabolic syndrome. Nature http://dx.doi.org/10.1038/nature14232