More on this book
Community
Kindle Notes & Highlights
by
Ed Yong
Read between
February 21 - March 5, 2021
Turnbaugh had effectively transferred obesity from one animal to another, simply by moving their microbes across.
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 a ride; sometimes, they grab the wheel.
Akkermansia muciniphila, one of the more common species of gut bacteria, is over 3,000 times more common in normal mice than in those genetically predisposed to obesity. If obese mice eat it, they lose weight and show fewer signs of type 2 diabetes.
The microbiome does not replace or contradict other long-understood causes of obesity; it is thoroughly entangled with them.
Microbes are not completely to blame for obesity
Their success only evaporated when Ridaura fed the mice with fatty, low-fibre chow, designed to represent the worst extremes of the Western diet. Without fibre, the lean communities couldn’t establish themselves or stop the mice from putting on weight. They could only infiltrate the guts of mice that ate healthily. The old dietary advice still stands, overenthusiastic headlines be damned.
It is what you eat that matters
A rainforest isn’t just a rainforest because of the birds, insects, monkeys, and plants within it, but also because ample rain and sunlight fall from above, and bountiful nutrients lurk in the soil. If you threw the forest’s inhabitants into a desert, they would fare badly.
malnourishment comes in different forms. There’s marasmus, where kids end up emaciated and skeletal. There’s also kwashiorkor, where fluids leak from blood vessels, leading to puffy swollen limbs, distended stomachs, and damaged skin.
The standard treatment for malnutrition is an energy-rich, fortified blend of peanut paste, sugar, vegetable oil, and milk. But Gordon’s team found that the paste only has a brief effect on the bacteria of children with kwashiorkor (which perhaps explains why it doesn’t always work). As soon as they revert to their normal Malawian diet, their microbes also boomerang back to their earlier impoverished state.
Imagine a ball, sitting in a valley and surrounded by steep slopes. If you shove the ball, it will roll up a slope, slow down, and eventually fall back to its original starting position. To get the ball all the way up the slope, over the top, and into a neighbouring valley, you need one really big push, or several small sequential ones.
Interesting
Now, the ball is a child’s gut. A poor diet changes the microbes within. It also impairs the child’s immune system, changing its ability to control the gut microbiome and opening the door to harmful infections that disrupt the communities even further. And once these communities start wrecking the gut, they stop it from absorbing nutrients efficiently, leading to even worse malnutrition, more severe immune problems, more distorted microbiomes, and so on. Up and up the ball goes, until it crests the summit and slips into the next dysbiotic valley. Once microbiomes end up there, it can be hard
...more
Main
a thermostat. It’s an old one, and thus a dial rather than a digital display. If I turn it down, it sets the temperature of the house at a cool simmer; if I turn it up, it allows a fiery heat to build. Somewhere in the middle, always one tiny adjustment away, is the ideal setting, a point of perfect comfort. The immune system, for all its intricacy, is a lot like that dial. It works like an ‘immunostat’, which, rather than stabilising temperature, stabilises our relationships with our microbes.
Main
The IBD microbiome tends to be less diverse and less stable than its healthier counterparts. It lacks anti-inflammatory microbes, including fibre-fermenters like Faecalibacterium prausnitzii and B. fragilis. In their place are blooms of inflammatory species like Fusobacterium nucleatum and invasive strains of E. coli.
Those rodents developed inflamed guts, but only if they were infected by a virus that knocked out part of their immune system, and were exposed to an inflammatory toxin, and had a normal set of gut bacteria. If any of these triggers was missing, the mice stayed healthy. It was the combination of genetic susceptibility, viral infection, immune problems, environmental toxin, and their microbiome that gave them IBD. This complexity helps to explain why the disease is so variable. Every case has its own convoluted history of hits.
IBD Complexity
The more older siblings they had, the less likely they were to get hay fever. ‘These observations . . . could be explained if allergic diseases were prevented by infection in early childhood, transmitted by unhygienic contact with older siblings,’
Wow
The hypothesis, as it now stands, contends that children in developed countries no longer run the gauntlet of infectious diseases that they used to, and so grow up with inexperienced, jumpy immune systems.21 They are healthier in the short term, but they launch panicked immune responses to harmless triggers, like pollen. This concept delineated an unenviable trade-off between infectious and allergic disease, as if we were destined to suffer one or the other.
Later versions of the hygiene hypothesis shifted the emphasis away from pathogens and more towards benevolent microbes that educate our immune systems, or environmental species that lurk in mud and dust, and even parasites that establish long-lasting but tolerable infections. They have been christened ‘old friends’.22 They have been part of our lives throughout our evolutionary history, but their tenure has become shakier of late. Their disappearance isn’t just due to stricter personal cleanliness, as the word ‘hygiene’ unhelpfully implies. It’s also due to the various trappings of
...more
When Lynch fed these dog-associated dust microbes to mice, she found that the rodents became less sensitive to various allergens. The dusty meals also increased the numbers of over 100 bacterial species in the rodents’ guts, at least one of which could protect the mice from allergens. This is the essence of the hygiene hypothesis and its various spin-offs: exposure to a broader range of microbes can change the microbiome and suppress allergic inflammation – at least in mice.
This might explain why C-section babies are more likely to develop allergies, asthma, coeliac disease, and obesity later in life. ‘The baby’s immune system is naïve at birth and whatever it sees first will start its education,’ says Dominguez-Bello.
Bottle-feeding might exacerbate these problems. As we saw, breast milk engineers a baby’s ecosystem. It provides more microbe colonists for a baby’s gut, and HMOs – those microbe-feeding sugars in breast milk – that nourish co-adapted companions like B. infantis. These abilities might overwrite any initial differences caused by a C-section birth, but ‘if you go for a C-section and bottle-feeding, I’d certainly say that [your baby] is on a different trajectory,’ says milk expert David Mills.
Once we are weaned onto solids, that trajectory can veer even further astray if we fail to feed our microbial friends with the right foods. Saturated fats can nourish inflammatory microbes. So can two common food additives, CMC and P80, used to lengthen the shelf life of ice cream, frozen desserts, and other processed foods; they also suppress anti-inflammatory bugs.
Saturated fat and inflammation
Fibre has been a mainstay of health advice ever since Denis Burkitt, an Irish missionary surgeon, noticed that rural villagers in Uganda eat up to seven times more fibre than Westerners. Their stools are five times heavier, but pass through the intestine twice as quickly.
We now know that when bacteria break down fibre, they produce chemicals called short chain fatty acids (SCFAs); these trigger an influx of anti-inflammatory cells that bring a boiling immune system back down to a calm simmer. Without fibre, we dial our immunostats to higher settings, predisposing us to inflammatory disease.
Fibre
To make matters worse, when fibre is absent, our starving bacteria react by devouring whatever else they can find – including the mucus layer that covers the gut. As the layer disappears, bacteria get closer to the gut lining itself, where they can trigger responses from the immune cells underneath. And without the restraining influence of the SCFAs, those responses can easily build to extreme proportions.
Fibre
Erica Sonnenburg, Justin’s wife and colleague, demonstrated this by putting mice on a low-fibre diet for a few months.28 The diversity in their gut microbiome crashed. It rebounded when the mice ate fibre again, but not fully; many species had gone AWOL and never returned.
When these mice bred, they gave birth to pups that started off with a slightly impoverished microbiome. And if those pups ate more low-fibre food too, even more microbes fell off the radar. As the generations ticked by, more and more old friends broke contact. This could explain why Westerners carry a much lower diversity of gut microbes than rural villagers from Burkina Faso, Malawi, and Venezuela.29 We not only eat fewer plants, we also heavily process the ones we do eat.
Fibre
the milling process that converts wheat into flour removes most of the fibre in the kernels. We are, in the words of the Sonnenburgs, ‘starving our microbial self’.
Fibre
Even subtler doses of antibiotics can have unforeseen consequences. In 2012, Martin Blaser gave antibiotics to young mice, at doses too low to treat any disease. Still, the drugs changed the rodents’ gut microbes, fostering communities that were better at harvesting energy from food. The mice became fatter.
Blaser’s team fed mice with low doses of penicillin either at birth or at weaning, and found that the former group put on more weight after they stopped getting the drugs. Their microbiomes normalised but they still became heavier, and when the researchers transplanted these microbial communities into germ-free mice, the recipients also put on weight. This tells us a couple of important things. First, there’s a critical window in early life during which antibiotics can have particularly potent effects. Second, those effects depend on changes in the microbiome, but endure even when it largely
...more
Antibiotics
The second point is important; the first is arguably old news. Farmers have been inadvertently doing the same experiment since the 1950s, by fattening their livestock with low doses of antibiotics. No matter the drug or the species, the result is always the same: the animals grow faster and end up heavier. Everyone knew that these ‘growth promoters’ worked but no one really understood why. Blaser’s work suggests one possible explanation: the drugs disrupt the microbiome, leading to weight gain.
Antibiotics
Blaser has repeatedly suggested that the overuse of antibiotics could be ‘fuelling the dramatic increase in conditions such as obesity’, not to mention other modern plagues.
One of Blaser’s own showed that infants who get doses of antibiotics aren’t any likelier to be overweight by the age of seven. And even the animal studies are inconsistent: in other mouse experiments, scientists have seen that high doses of some antibiotics, given early, can actually stunt growth or reduce body fat.
Much of modern medicine is built upon the foundations that antibiotics provide, and those foundations are now crumbling. We have used these drugs so indiscriminately that many bacteria have evolved to resist them, and some nigh-invincible strains can now shrug off every medicine we throw at them.36 At the same time, we have utterly failed to develop new drugs to replace the ones that are becoming obsolete. We are heading into a terrifying post-antibiotic era.
All of these people have microbiomes that are far more diverse than those in the West. Their multitudes are more multitudinous. They also contain species and strains that are undetectable in Western samples.
As yet, no one has shown that people with less diverse microbiomes are more prone to acquiring disease. And there are cases where people with diverse microbiomes are more likely to carry certain intestinal parasites.
as our needs have shrunk, so has our pool of partners.
Hmm
Scientists will talk about Occam’s razor – the principle that favours simple, elegant explanations over convoluted ones.
transplanted microbes can reproduce those problems in germ-free mice, they strongly hint at a causal effect.
This practice makes little sense because the microbiome is highly contextual.50 The same microbes can have very different relationships with their hosts in different situations. H. pylori can be both hero and villain. Beneficial microbes can trigger debilitating immune responses if they bypass the mucus wall and penetrate the lining of the gut. Seemingly ‘unhealthy’ communities can be normal, even necessary.
The microbiome is not a constant entity. It is a teeming collection of thousands of species, all constantly competing with one another, negotiating with their host, evolving, changing. It wavers and pulses over a 24-hour cycle, so that some species are more common in the day while others rise at night. Your genome is almost certainly the same as it was last year, but your microbiome has shifted since your last meal or sunrise.
It would be easier if there was a single ‘healthy’ microbiome that we could aim for, or if there were clear ways of classifying particular communities as healthy or unhealthy. But there aren’t. Ecosystems are complex, varied, ever-changing and context-dependent – qualities that are the enemies of easy categorisation.
Main
Remember how obese people and mice have more Firmicutes and fewer Bacteroidetes than their lean counterparts? This result, the F/B ratio, is one of the most famous in the field – and it’s a mirage. In 2014, two attempts to re-analyse past studies found that the F/B ratio is not consistently connected to obesity in humans.53 You can tell the difference between obese and lean microbiomes within any single study, but there are no consistent differences across studies.
This doesn’t refute a connection between the microbiome and obesity. You can still fatten germ-free mice by loading them with microbes from an obese mouse (or person). Something about these communities affects body weight; it’s just not the F/B ratio, or at least not consistently so.
‘The problem is that they end up being like the Tarot,’ says Rob Knight. ‘You can tell a good story with any arbitrary combination.’ Imagine that I pulled ten people off the street who are wearing blue shirts and ten who are wearing green shirts. If I ask them enough questions, I guarantee you that I can find at least a couple of striking differences between the two groups. The blue-shirts might prefer coffee while the green-shirts prefer tea. The green-shirts have bigger feet than the blue-shirts. I might propose that blue shirts produce coffee cravings and shrink one’s feet. But if I
...more
Wow
It’s likely that many symbioses started this way, with random environmental microbes – some parasitic and others more benign – that somehow sneaked into animal hosts. Such incursions are common and inevitable.
The average human swallows around a million microbes in every gram of food they eat. Since microbes are everywhere, virtually every source of food, whether a patch of water, the stem of a plant, or the flesh of another animal, is a potential source of new symbionts.
any road that a pathogen can travel down is one that beneficial symbionts can also use to reach new hosts.
the one that does more than any other to seal a symbiosis – is inheritance.
After a beewolf digs her burrow, and before she adds an egg, she presses her antennae against the soil and squeezes a white paste out of them, like toothpaste from a tube. She then shakes her head from side to side to daub this secretion against the burrow’s ceiling. The paste is an exit sign: it tells the young beewolf where to start digging when it is ready to leave the burrow. But when Kaltenpoth examined the paste under a microscope, he was stunned to see that it also swarmed with bacteria. A wasp that secretes microbes from its antennae? No one had heard of such a thing. Stranger still,
...more
beewolf
Streptomyces are microbes that excel at killing other microbes; this one group is the source of two-thirds of our own antibiotics. And a young beewolf certainly needs antibiotics.
antibiotics
When Kaltenpoth deprived the young wasps of the white paste, almost all died from fungal infestations within a month.7 If he gave them access to the paste, they usually survived. And come the spring, when new adult wasps emerge from their cocoons, they take up into their antennae the same Streptomyces that guarded them over the winter.
