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

by Ed Yong

He bequeathed to them a black lacquered cabinet containing 26 of his amazing microscopes, complete with mounted specimens. Bizarrely, the cabinet disappeared and was never recovered; an especially tragic loss, since Leeuwenhoek never told anyone exactly how he made his instruments. In one letter, he complained that students were more interested in money or reputation than in “discovering things hidden from our sight”. “Not one man in a thousand is capable of such study, because it needs much time, and spending much money,” he lamented. “And over and above all, most men are not curious to know: nay, some even make no bones about saying: What does it matter whether we know this or not?”6

The weird biology of germ-free animals is most obvious in the gut. A well-functioning gut needs a big surface area for absorbing nutrients, which is why its walls are densely lined with long, finger-like pillars. It needs to constantly regenerate the cells at its surface, which get sloughed off by the passing tide of food. It needs a rich network of underlying blood vessels to carry nutrients to and fro. And it needs to be sealed – its cells must stick tightly to each other to prevent foreign molecules (and microbes) from leaking into those blood vessels. All of these essential properties are compromised without microbes. If zebrafish or mice grow up in the absence of bacteria their guts don’t develop fully, their pillars are shorter, their walls leakier, their blood vessels look more like sparse country lanes than a dense urban grid, and their cycle of regeneration pedals in a lower gear. Many of these glitches can be rectified simply by giving the animals a normal complement of microbes or even isolated microbial molecules.6

The human armpit is not unlike a hyena’s scent gland – warm, moist, and rich in bacteria. Each species creates its own aromas. Corynebacterium will convert sweat into something that smells like onions, and testosterone into something that smells either like vanilla, urine, or nothing, depending on the sniffer’s genes. Do these scents make useful signals? Apparently so! This armpit microbiome is surprisingly stable – and so are our armpit odours. Every person has their own distinctive pong, and in several experiments, volunteers have been able to distinguish people from the smell of their T-shirts. They’ve even managed to match the smells of identical twins.

Here’s the best guess: By mimicking a viral infection in the pregnant mothers, the team triggered an immune response that landed their offspring with an excessively permeable gut, and one with an unusual collection of microbes. Those microbes produced chemicals that entered the bloodstream and travelled to the brain, where they triggered atypical behaviours. The top culprit is a toxin called 4-ethylphenylsulfate (4EPS), which can trigger anxiety in otherwise healthy animals. When the mice swallowed B-frag, this microbe sealed up their guts and stemmed the flow of 4EPS (and other substances) to their brain, reversing their atypical symptoms.

Different microbes fare better on certain diets. Some are peerless at digesting plant fibres. Others thrive on fats. When you choose your meals, you are also choosing which bacteria get fed, and which get an advantage over their peers. But they don’t have to sit there and graciously await your decision. As we have seen, bacteria have ways of hacking into the nervous system. If they released dopamine, a chemical involved in feelings of pleasure and reward, when you ate the ‘right’ things, could they potentially train you to choose certain foods over others? Do they get a say in your menu picks?48

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

A cut or a bruise can split some of your cells apart and spill fragments of mitochondria into your blood – fragments that still keep some of their ancient bacterial character. When your immune system spots them, it mistakenly assumes that an infection is under way and mounts a strong defence. If the injury is severe, and enough mitochondria are released, the resulting body-wide inflammation can build into a lethal condition called systemic inflammatory response syndrome (SIRS).10 SIRS can be worse than the original injury. Absurdly, it’s simply the result of a human body mistakenly overreacting to microbes that have been domesticated for over two billion years. Just as a weed is a flower in the wrong place, our microbes might be invaluable in one organ but dangerous in another, or essential inside our cells but lethal outside them. “If you go immunosuppressed for a little bit, they’ll kill you. When you die, they’ll eat you,” says coral biologist Forest Rohwer. “They don’t care. It’s not a nice relationship. It’s just biology.” So, the world of symbiosis is one in which our allies can disappoint us and our enemies can rally to our side. It’s a world where mutualisms shatter for the matter of a few millimetres.

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.

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.25 Dietary fibre has the opposite effects. This is a catch-all term for various complex plant carbohydrates that our microbes can digest. 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. In the 1970s, Burkitt evangelically promoted the idea that this fibre-rich diet explained why Ugandans rarely suffer from diabetes, heart disease, colon cancer, and other diseases that are more common in the developed world. Some of this difference undoubtedly arises because these chronic diseases are more common in old age, and life expectancy is higher in the West. Nonetheless, Burkitt was on the right track. “America is a constipated nation,” he said, indelicately. “If you pass small stools, you have big hospitals.”26 He didn’t quite know why, though. He imagined fibre as a ‘colonic broom’, which swept the intestines free of carcinogens and other toxins. He wasn’t thinking about microbes. 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...

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.

Some 10 to 20 per cent of insects depend on such microbes, which provide vitamins, amino acids for making proteins, and sterols for making hormones.8 All of these living supplements allow their owners to subsist on deficient diets, from sap to blood. Carpenter ants – a diverse group with around 1,000 species – carry a symbiont called Blochmannia that allows them to live on a largely vegetarian diet and dominate the canopies of tropical forests.9 Mini-vampires like lice and bed bugs (along with non-insects like ticks and leeches) rely on bacteria for the B-vitamins that are missing in their bloody meals.

Time and again, bacteria and other microbes have allowed animals to transcend their basic animalness and wheedle their way into ecological nooks and crannies that would be otherwise inaccessible; to settle into lifestyles that would be otherwise intolerable; to eat what they could not otherwise stomach; to succeed against their fundamental nature. And the most extreme examples of this mutually assured success can be found in the deep oceans, where some microbes supplement their hosts to such a degree that the animals can eat the most impoverished diets of all – nothing.

It’s also counter-intuitive because so much of healthcare relies on basic arithmetic. Got scurvy? You are missing vitamin C, which you can add to your body via fruit. Got flu? You have a virus, which you need to remove from your airways by taking a drug. Add what’s missing. Subtract what’s unwanted. These simple equations still drive much of modern medical thought. By contrast, the maths of the microbiome are more complicated, because they involve large, changing networks of connected, interacting parts. To control a microbiome is to sculpt an entire world – which is as hard as it sounds. Remember that communities have a natural resilience: if you hit them, they bounce back. They are also unpredictable; if you tweak them, the consequences ripple outwards in capricious ways. Add a supposedly beneficial microbe, and it might displace competitors that we also rely on. Lose a supposedly harmful microbe, and an even worse opportunist might rise to take its place. This is why attempts at world-shaping have so far led to a few magnificent successes, but also many puzzling setbacks. In an earlier chapter, we saw that fixing a microbiome is not as simple as removing ‘bad bacteria’ with antibiotics. In this one, we’ll see that it isn’t as simple as adding ‘good bacteria’ either.

Given all the important roles that bacteria play in our bodies, it should be possible to improve our health by swallowing or applying the right microbes. It’s just that the strains in current use may not be the right ones. They make up just a tiny fraction of the microbes that live with us, and their abilities represent a thin slice of what the microbiome is fully capable of. We met more suitable microbes in earlier chapters. There’s the mucus-loving bacterium, Akkermansia muciniphila, whose presence correlates with a lower risk of obesity and malnutrition. There’s Bacteroides fragilis, which stokes the anti-inflammatory side of the immune system. There’s Faecalibacterium prausnitzii, another anti-inflammatory bug, which is conspicuously rare in the guts of people with IBD, and whose arrival can reverse the symptoms of that disease in mice. These microbes could be part of the probiotics of the future. Their abilities are relevant and impressive. They are well adapted to our bodies. Some are already abundant – in healthy adults, one in every twenty gut bacteria is F. prausnitzii. These are not D-listers of the human microbiome like Lactobacillus; they are the stars of the gut. They won’t be shy about colonising it.20 Then again, effective colonisation carries greater risk along with greater reward. So far, probiotics have enjoyed a mostly clean safety record,21 but that might well be because they’re poor at maintaining a foothold in the body. What would happen if more commo...

Take the case of oxalate. It’s found in beetroot, asparagus, and rhubarb, among other foods. At high concentrations, it stops your body from absorbing calcium, which congeals into a hard lump. That’s one way in which kidney stones form. We can’t digest oxalate; only microbes can do that. One species – a gut bacterium called Oxalobacter formigenes – is so good at it that it uses oxalate as its one and only source of energy. At first glance, this situation looks identical to the Leucaena dilemma. There’s one chemical (oxalate), which causes a defined problem (kidney stones), and can be destroyed by one microbe (Oxalobacter). The solution, surely, is to swallow an Oxalobacter probiotic if you are prone to kidney stones. Unfortunately, such probiotics exist and they aren’t very effective.23 Why? There are two likely answers, and both provide valuable lessons. First, it is not enough to infuse an animal with bacteria and hope for the best. Microbes are living things. They need to eat. Oxalobacter eats nothing but oxalate, and people with kidney stones often go on an oxalate-free diet. They can ingest the bacterium, but it will instantly starve.24 Conversely, farmers are told to feed their herds on Leucaena for at least a week before drenching them in Synergistes. That way, the inoculated bacteria have enough food to digest. Substances that selectively nourish beneficial microbes are called prebiotics – a term that could include oxalate or Leucaena but normally describes plant c...

There’s no such thing as alternative medicine; if it works, it’s just called medicine.

For hundreds of years, doctors have used digoxin to treat people whose hearts are failing. The drug – a modified version of a chemical from foxglove plants – makes the heart beat more strongly, slowly, and regularly. Or, at least, that’s what it usually does. In one patient out of every ten, digoxin doesn’t work. Its downfall is a gut bacterium called Eggerthella lenta, which converts the drug into an inactive and medically useless form. Only some strains of E. lenta do this. In 2013, Peter Turnbaugh showed that just two of the bacterium’s genes distinguish the problematic drug-deactivating strains from the neutral ones.46 He thinks that doctors might be able to use the presence of these genes to guide their treatments. If they are absent from a patient’s microbiome, fine – give them digoxin. If they are there, the patient needs to eat a lot of protein, since that seems to stop the genes from decommissioning the drug.