Gut reaction: the surprising power of microbes
Ed Yong reports in the Guardian:
‘So, what’s in the thermos?” I asked.
I was standing in a lift at Washington University in St Louis, with Professor Jeff Gordon and two of his students, one of whom was holding a metal canister.
“Just some faecal pellets in tubes,” she said.
“They’re microbes from healthy children, and also from some who are malnourished. We transplanted them into mice,” explained Gordon, as if this was the most normal thing in the world.
The lift doors opened, and I followed Gordon, his students, and the thermos of frozen pellets into a large room. It was filled with rows of sealed chambers made of transparent plastic. Peering inside one of these chambers, I met the eyes of one of the strangest animals on the planet. It looked like just a mouse, and that is precisely why it was so weird. It was just a mouse, and nothing more.
Almost every other animal on Earth, whether centipede or crocodile, flatworm or flamingo, hippo or human, is a teeming mass of bacteria and other microbes. Each of these miniature communities is known as a microbiome. Every human hosts a microbiome consisting of some 39 trillion microbes, roughly one for each of their own cells. Every ant in a colony is a colony itself. Every resident in a zoo is a zoo in its own right. Even the simplest of animals such as sponges, whose static bodies are never more than a few cells thick, are home to thriving microbiomes.
But not the mice in Gordon’s lab. They spend their entire lives separated from the outside world, and from microbes. Their isolators contain everything they need: drinking water, brown nuggets of chow, straw chips for bedding, and a white styrofoam hutch for mating in privacy. Gordon’s team irradiates all of these items to sterilise them before piling them into loading cylinders. They sterilise the cylinders by steaming them at a high temperature and pressure, before hooking them to portholes in the back of the isolators, using connecting sleeves that they also sterilise.
It is laborious work, but it ensures that the mice are born into a world without microbes, and grow up without microbial contact. The term for this is “gnotobiosis”, from the Greek for “known life”. We know exactly what lives in these animals – which is nothing. Unlike every other mouse on the planet, each of these rodents is a mouse and nothing more. An empty vessel. A silhouette, unfilled. An ecosystem of one.
Each isolator had a pair of black rubber gloves affixed to two portholes, through which the researchers could manipulate what was inside. The gloves were thick. When I stuck my hands in, I quickly started sweating.
I awkwardly picked up one of the mice. It sat snugly on my palm, white-furred and pink-eyed. It was a strange feeling: I was holding this animal but only via two black protrusions into its hermetically sealed world. It was sitting on me and yet completely separated from me. When I had shaken hands with Gordon earlier, we had exchanged microbes. When I stroked this mouse, we exchanged nothing.
The mouse seemed normal, but it was not. Growing up without microbes, its gut had not developed properly – it had less surface area for absorbing nutrients, its walls were leakier, it renewed itself at a slower pace, and the blood vessels that supplied it with nutrients were sparse. The rest of its body hadn’t fared much better. Compared with its normal microbe-laden peers, its bones were weaker, its immune system was compromised, and it probably behaved differently too. It was, as microbiologist Theodor Rosebury once wrote, “a miserable creature, seeming at nearly every point to require an artificial substitute for the germs [it] lacks”.
The woes of the germ-free mouse vividly show just how invaluable the microbiome is. Most of us still see microbes as germs: unwanted bringers of pestilence that we must avoid at all costs. This stereotype is grossly unfair. Most microbes do not make us sick. At worst, they are passengers or hitchhikers. At best, they are invaluable parts of our bodies: not takers of life but its guardians. They help to digest our food, educate our immune systems, protect us from disease, sculpt our organs, guide our behaviour, and maintain our health. This wide-ranging influence explains why the microbiome has, over the last decade, become one of the hottest areas of biology, and why Gordon – arguably the most influential scientist in the field – is so fascinated by it.
By studying our microbial companions, he is trying to unpick exactly how the microbiome is connected to obesity and its polar opposite – malnutrition. He is studying which species of microbes influence these conditions, and how they in turn are influenced by our diets, our immune systems, and other aspects of our lives. Ultimately, he wants to use that knowledge to manipulate the microbial worlds within us to improve our health.
Jeff Gordon may be one of the most respected scholars of the human microbiome, but he is also one of the hardest to get in touch with. It took me six years of writing about his work to get him to answer my emails, so visiting his lab was a hard-won privilege. I arrived expecting someone gruff and remote. Instead, I found an endearing and affable man with crinkly eyes, a kindly smile, and a whimsical demeanour. As he walked around the lab, he called people “professor” – including his students. His aversion to the media comes not from aloofness, but from a distaste for self-promotion. He even refrains from attending scientific conferences, preferring to stay out of the limelight and in his laboratory.
Ensconced there, Gordon has done more than most to address how microbes affect our health. But whenever I asked Gordon about his influence, he tended to deflect credit on to students and collaborators past and present – a roster that includes many of the field’s biggest stars. Their status testifies to Gordon’s – he’s not just a king, but a king-maker, too. And his figurehead status is all the more remarkable because long before the microbiome crossed his mind, he was already a well-established scientist who had published hundreds of studies on how the gut develops in a growing human body.
In the 1990s, he started to suspect that bacteria influence this process, but he was also struck by how difficult it would be to test that idea. The gut contains thousands of species of microbes. Gordon aimed to isolate parts of this daunting whole and examine it under controlled conditions. He needed that critical resource that scientists demand but biology withholds: control. In short, he needed germ-free mice – and lots of them – so he bred them himself. He could load these rodents with specific microbes, feed them with pre-defined diets, and do so again and again in controlled and repeatable conditions. He could treat them as living bioreactors, in which he could strip down the baffling complexity of the microbiome into manageable components that he could systematically study.
In 2004, Fredrik Bäckhed, a member of Gordon’s team, used the sterile rodents to run an experiment that would set the entire lab on a focused path – one devoted to understanding the connections between the microbiome, nutrition, and health. They inoculated germ-free mice with microbes harvested from the guts of conventionally raised rodents. Normally, the sterile rodents can eat as much as they like without putting on weight, but this ability disappeared once their guts were colonised. They didn’t start eating any more food – if anything, they ate slightly less – but they converted more of that food into fat and so put on more pounds.
Mouse biology is similar enough to that of human beings for scientists to use them as stand-ins in everything from drug testing to brain research; the same applies to their microbes. Gordon reasoned that if those early results apply to humans, our microbes must surely influence the nutrients that we extract from our food, and thus our body weight. That was a powerful insight. We typically think of weight as a simple balance between the calories we take in through food and those we burn through physical activity. By contrast, the idea that multitudes of organisms in our bodies could influence that balance was outlandish at the time. “People weren’t talking about it,” says Gordon.
And yet, in 2004, team member Ruth Ley found another connection between microbes and weight, when she showed that obese people (and mice) have different communities of microbes in their guts. The most obvious difference lay in the ratio of the two major groups of gut bacteria – the firmicutes and the bacteroidetes. Obese people had more firmicutes and fewer bacteroidetes than their leaner counterparts. This raised an obvious question: does extra body fat cause a relative increase in firmicutes – or, more tantalisingly, does the tilt make individuals fatter? Is the connection, as Gordon likes to put it, causal or casual? The team couldn’t answer that question by relying on simple comparisons. They needed experiments.
That’s where Peter Turnbaugh came in. Then a graduate student in the lab, he harvested microbes from fat and lean mice, and then fed them to germ-free rodents. Those that got microbes from lean donors put on 27% more fat, while those with obese donors packed on 47% more fat. It was a stunning result: Turnbaugh had effectively transferred obesity from one animal to another, simply by moving their microbes across. “It was an ‘Oh my God’ moment,” said Gordon. “We were thrilled and inspired.”
These results showed that the guts of obese individuals contain altered microbiomes that can indeed contribute to obesity, at least in some contexts. The microbes were perhaps harvesting more calories from the rodents’ food, or affecting how they stored fat. Either way, it was clear that microbes don’t just go along for the ride; sometimes, they grab the wheel. . .