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TWO
All Diseases Begin in the Gut

Garden warblers are the very epitome of the birder’s greatest identification challenge – the LBJ, or ‘Little Brown Job’. Their most distinguishing feature is, in fact, the absolute lack of any distinguishing features, making recognition of this small bird through a pair of shakily held binoculars particularly difficult. But boring birds these are not. Just a few months after hatching, juvenile garden warblers embark on a 4,000-mile migration from their summer homes across Europe to their winter residences in sub-Saharan Africa. It is a route they have never taken before, and they do it without the help of either their more experienced parents, or a map.

Before these tiny birds head off on this incredible journey, they prepare themselves for the effort of flying and the lack of food en route by becoming fat. Over just a couple of weeks, the warblers double in weight, going from a slender 17 g to a distinctly portly 37 g. In human terms, they become morbidly obese. On each day of the pre-migration binge, a garden warbler gains around 10 per cent of its original body weight – the equivalent of a 10-stone man putting on a stone a day until he weighs 22 stone. Then, once the birds are plump enough, they undertake a feat of endurance beyond the imagination of most elite athletes – flying thousands of miles with just a handful of meals along the way.

Of course, to become that fat that fast, the warblers must gorge themselves on summer’s bounty of food. Practically overnight, the birds shift from a diet of insects to one of berries and figs. Although the fruit is ripe enough to eat for several weeks before their binge begins, the warblers leave it untouched until the time is right. It’s as if a switch flips inside them, and suddenly they dedicate themselves to eating.

For a long time, researchers assumed that the weight gain in warblers and other migratory birds was simply the consequence of hyperphagia – excessive eating. But the incredible speed of the shift in these birds from lean to morbidly obese suggested there was something else going on to help them store so much fat. Something that had less to do with how much food they ate, and more to do with how that food was stored in their bodies. By keeping a check on how many extra calories the warblers ate, and how many calories came out in their droppings, researchers realised that the additional food the birds were consuming did not fully account for the weight they were managing to gain.

The riddle continues when it comes to the birds losing the excess weight again. Of course, as the obese warblers make their journey across the Mediterranean Sea and the Sahara Desert, their fat supplies dwindle. By the time they have arrived and settled in to their African winter home, they have returned to a normal warbler weight. But here’s the strange thing: captive garden warblers are no different. During the pre-migratory period at the end of summer, these caged birds still gain weight, becoming thoroughly obese in preparation for a journey they will never make. And, at the exact point that wild warblers arrive at their destination, the captive warblers completely shed their excess fat. Despite not flying 4,000 miles, and having unlimited access to food, these captive birds still lose the weight again when the migratory period is over.

It is quite extraordinary that warblers deprived of cues in the weather, day length and seasonal food supplies are still able to rapidly gain enormous stores of fat for the migratory period and then slim down again apparently effortlessly, perfectly in sync with their wild cousins. These are birds, with brains the size of a pea. They don’t gain weight, then think to themselves: ‘I really must go on a diet.’ They don’t fast, or exercise madly, either. Their food intake does relapse after the binge, but again, not enough to account for losing that much weight, that fast. Imagine being able to drop a stone a day for seven days – that’s the degree of weight loss these little birds manage once the migratory period is over. Even eating nothing at all would not result in that kind of weight loss in humans.

Although we don’t yet know exactly how this astounding degree of weight change is regulated in the warblers’ bodies, the fact that these shifts happen beyond what is expected from changes in caloric intake makes one thing clear: maintaining a stable weight is not always a simple case of balancing calories-in and calories-out. In humans, the scientifically accepted explanation for weight gain is this: ‘The fundamental cause of obesity and overweight is an energy imbalance between calories consumed and calories expended.’

It seems obvious: if you eat too much and move too little, the extra energy must be stored and you will gain weight. And if you want to lose weight, you must eat less and move more. But the warblers are able to rapidly lay down fat reserves that appear to go far beyond the calories they eat, and then deplete those reserves far beyond the calories they burn. Clearly, there’s more to the weight-regulation game than meets the eye. If calories-in versus calories-out isn’t true for warblers, perhaps it’s not true for humans either?

Attempting to treat over 10,000 cases of obesity made the Indian physician Dr Nikhil Dhurandhar wonder the exact same thing. His patients returned again and again, after regaining the small amounts of weight they’d lost, or failing to lose any weight whatsoever. Despite the difficulties, Dhurandhar and his father – another doctor specialising in obesity – ran one of the most successful obesity clinics in Mumbai in the 1980s. But after a decade of trying to help people to eat less and move more, he began to feel his efforts – and those of his patients – were futile. ‘After weight loss, you gain weight again: that is the big problem. And that has been my frustration.’ Dhurandhar wanted to know more about mechanisms behind obesity. If eating less and moving more didn’t permanently cure obesity, perhaps eating more and moving less wasn’t the only cause.

It’s something we desperately need to work out. Our species is in the midst of a warbler-like collective weight gain. And just as in warblers, the amount of weight we have gained does not quite tally with changes in ‘calories consumed’ and ‘calories expended’. Even the biggest and most comprehensive of studies show that most of the weight we have gained as a species is not accounted for by the extra food we are eating, nor by our lack of physical activity. Some even indicate that we are eating less than we used to, and exercising just as much. The scientific debate about whether gluttony and sloth alone can fully account for the exponential rise in obesity over the past sixty years rumbles quietly on. It is a mere scientific undercurrent lapping at the foundations of research that’s seen as more relevant: which diets work best?

At the time of Dhurandhar’s frustrations, a mysterious disease was spreading through India’s chickens, killing the birds and destroying livelihoods. Dhurandhar’s family were friends with a veterinary scientist who was involved in looking for the cause and finding a cure. The culprit was a virus, he told Dhurandhar over dinner, and the birds would die with large livers, shrunken thymus glands and a lot of excess fat. Dhurandhar stopped him. ‘The dead chickens are especially fat?’ he checked. The vet confirmed it.

Dhurandhar was curious. Animals dying of a viral infection would normally be skinny, not fat. Was it possible that a virus could induce weight gain in chickens? Could this be the explanation behind his patients’ difficulties in losing weight? Dhurandhar, excited to know more, set up an experiment. He injected one group of chickens with the virus, and left another group alone. Sure enough, three weeks later, he found that the infected birds were far fatter than the healthy ones. It seemed as if the virus had made them gain weight as they fell ill. Could it be that Dhurandhar’s patients, and countless other humans around the world, were also infected with the virus?

What is happening to our species is on such an enormous and unprecedented scale, that in the distant future, when humanity looks back on the twentieth century, they’ll remember it not just for two world wars, nor solely for the invention of the internet, but as the age of obesity. Take a human body from 50,000 years ago and one from the 1950s, and they will look more similar to one another than either does to the average human body today. In just sixty years or so, our lean, muscular, hunter-gatherer-like physiques have been encased inside a layer of excess fat. It’s something that has never happened to humans on this scale before, and no other animal species – apart from the pets and livestock we care for – has succumbed to this anatomy-changing disease.

One in every three adults on Earth is overweight. One in nine is obese. That’s the average across all countries, including those where under-nutrition is more common than being overweight. Looking just at the figures for the fattest of countries is even harder to believe. On the South Pacific island of Nauru, for example, around 70 per cent of adults are obese, and a further 23 per cent are overweight. Just 10,000 people live in this tiny country, and only about 700 of them are a healthy weight. Nauru is officially the fattest nation on Earth, but it is closely followed by most of the other South Pacific islands and several Middle Eastern states.

In the West, we have gone from being skinny enough that no one thought to comment on, worry about, or count the number of overweight people, to being fat enough that it would be quicker to count those that remain skinny. Roughly two in three adults are overweight, and half of those are not just overweight, but obese. The United States, despite its reputation, is seventeenth in the world rankings, with a mere 71 per cent of the population overweight or obese. As for the UK, it ranks thirty-ninth, with 62 per cent of adults overweight (including 25 per cent obese): the highest figures in Western Europe. Even among children in the Western world, being too fat is shockingly common, with up to one-third of under-twenty-year-olds overweight – half of them obese.

Obesity has crept upon us in a way that makes it seem almost normal. Yes, there is a steady stream of articles and news pieces about the obesity ‘epidemic’ to remind us that it is actually a problem, but we have very quickly adapted to living in a society where most people are overweight. We are quick to assume that fatness is the next step along from greediness and laziness, but if that’s the case, it’s quite an indictment of human nature. Looking at our other achievements as a species over the past century or so – the inventions of mobile phones, the internet, aeroplanes, life-saving medicines and so on – suggests we are not all just lying around, stuffing ourselves with cake. The fact that lean people are now in the minority in the developed world, and that this change has happened in just fifty or sixty years, after thousands upon thousands of years of human leanness, is shocking – just what are we doing to ourselves?

On average, people in the Western world have gained roughly a fifth of their own body weight in the last fifty years alone. If your allotted time on Earth had fallen so that your ‘today’ fell in the 1960s, not the 2010s, you would, in all likelihood, be considerably lighter. People who are 11 stone in 2015 might well have been just over 9 stone in 1965, no special efforts required. Today, to regain a pre-1960s weight, tens of millions of people are perpetually on a diet, attempting to deprive themselves of foods for which their brains have a deep-rooted desire. But despite the billions of dollars spent on fad-dieting, gym-going and pill-taking, obesity levels rise inexorably.

This rise has taken place in the face of sixty years of scientific research into effective weight-maintenance and weight-loss strategies. In 1958, back when being overweight was still relatively rare, one of the pioneers of obesity research, Dr Albert Stunkard, said: ‘Most obese persons will not stay in treatment for obesity. Of those who stay in treatment, most will not lose weight. And of those who do lose weight, most will regain it.’ He was broadly right. Even half a century later, success rates in trials of weight-loss intervention strategies are extremely low. Often, less than half of participants achieve weight loss, and for most it’s just a few kilos over a year or more. Why is it so very hard?

Up to now, among those looking for explanations – and perhaps excuses – for their weight, genetics has been the fashionable place to lay the blame. Differences in human DNA, though, have not proved to be particularly illuminating when it comes to weight gain, with only a tiny proportion of our susceptibility to obesity explained by genes. In 2010, a huge study was conducted by a team of hundreds of scientists who hunted through the genes of a quarter of a million people in the hope of finding some that were associated with weight. Astonishingly, they discovered just 32 genes in our 21,000-strong genome that seemed to play a role in weight gain. The average difference in weight between people with the very lowest genetic likelihood of obesity and the very highest was just 8 kg (17 lb). For those who would like to blame their parents, that equates to between 1 per cent and 10 per cent extra risk of becoming overweight, and that’s for those people who are in possession of the worst combination of those gene variants.

Regardless of the genes involved, genetics could never be the full explanation for the obesity epidemic, because sixty years ago almost everyone was slim, despite having broadly the same gene variants as the human population today. What probably matters far more is the impact that a changing environment – our diets and lifestyles, for example – has on the workings of our genes.

Our other favourite explanation is that of a ‘slow metabolism’. ‘I don’t have to watch what I eat, I’ve got a quick metabolism,’ must be one of the most irritating comments a lean person can make, but it has no basis in science. A slow metabolism – or more correctly, a low basal metabolic rate – means that a person burns relatively little energy whilst doing absolutely nothing at all – no moving, no watching TV, no doing mental arithmetic. Metabolic rates do vary from person to person, but it is actually overweight people who have the faster metabolisms, not lean people. It simply takes more energy to run a big body than a small one.

So if genetics and low basal metabolic rates aren’t behind the obesity epidemic, and the amount we eat and move doesn’t fully explain our collective weight gain, what is the explanation? Like many people, Nikhil Dhurandhar wondered if there’s more to it than we assume. The possibility that a virus could be causing or exacerbating obesity in some people played on his mind. He tested fifty-two of his human patients in Mumbai for antibodies to the chicken virus – evidence that they had been infected by it at some stage. To his surprise, the ten most obese of these patients had had the virus at some point. Dhurandhar made up his mind; he would stop trying to treat obesity and start researching its causes instead.

We have reached the point in human history where we are considering, in the United Kingdom at least, that redesigning and re-routing the digestive system that evolution has given us is the best way to prevent us from eating ourselves to death. It seems that gastric bands and bypasses, which reduce the size of the stomach and prevent people from consuming everything that their brains and bodies tell them to, are the most effective and the cheapest way to get a grip on the obesity epidemic and its consequences for our collective health.

If diets and exercise are so futile that gastric bypasses are our only hope for significant weight loss, what does that say for the straightforward application of the laws of physics – energy intake minus energy burned equals energy stored – to us as animals governed by the laws of biochemistry?

As we are just beginning to learn, it’s not that simple. As the warblers and many hibernating mammals show, there’s more to managing weight than counting calories. Subscribing to a simple one-in, one-out system of balancing the body’s energy books utterly undermines the great complexities of nutrition, appetite regulation and energy storage. As George Bray, a doctor who has been researching obesity since the start of the epidemic, once said: ‘Obesity isn’t rocket science. It’s much more complicated.’

Two and a half thousand years ago, Hippocrates – the father of modern medicine – believed that all diseases begin in the gut. He knew little of the gut’s anatomy, let alone of the 100 trillion microbes that live there, but as we are learning two millennia later, Hippocrates was on to something. Back then, obesity was relatively uncommon, as was another twenty-first-century illness that clearly has its origins in the gut: irritable bowel syndrome. It’s with this most unpleasant of maladies that our microbes come into the picture.

In the first week of May 2000, unseasonably heavy rain drenched the rural town of Walkerton, Canada. As the rainstorms passed, Walkerton’s residents began to fall ill in their hundreds. With ever more people developing gastroenteritis and bloody diarrhoea, the authorities tested the water supply. They discovered what the water company had been keeping quiet for days: the town’s drinking water was contaminated with a deadly strain of E. coli.

It transpired that bosses at the water company had known for weeks that the chlorination system on one of the town’s wells was broken. During the rains, their negligence had meant that run-off from farmland had carried residues from manure straight into the water supply. A day after the contamination was revealed, three adults and a baby died from their illnesses. Over the next few weeks, three more people succumbed. In total, half of Walkerton’s 5,000-strong population were infected in just a couple of weeks

Even though the water supply was quickly cleaned and made safe to drink, the story didn’t end there for many of those that had fallen ill. The diarrhoea and cramps just kept coming. A full two years later, one-third of the people affected were still ill. They had developed post-infectious irritable bowel syndrome (IBS), and more than half of them still had it eight years after the outbreak.

As new IBS sufferers, these unfortunate Walkerton residents had joined the growing ranks of people in the West whose bowels rule their lives. For most with the condition, severe abdominal pain and unpredictable bouts of diarrhoea determine the freedom of their days. For others, it’s the opposite – constipation, and the pain that goes with it, lasting days and sometimes weeks at a time. ‘At least,’ says the British gastroenterologist Peter Whorwell of those with constipation-predominant IBS, ‘these patients can get out of the house.’ For a minority, the double difficulty of both diarrhoea and constipation makes daily life particularly unpredictable.

The trouble is, even though nearly one in five people in the West – mostly women – are stuck with this life-changing illness, we don’t actually know what it is. It’s not normal, that much is clear. The word ‘irritable’ belies the impact that IBS has on the lives of its sufferers; the disease is consistently ranked as reducing quality of life even more than for patients on kidney dialysis and diabetics reliant on insulin injections. Perhaps it’s the hopelessness that comes with not knowing what’s wrong, nor how to fix it.

The spread of IBS is an unremarked global pandemic. One in ten visits to the doctor relate to the condition, and gastroenterologists are kept in a job by the steady flow of sufferers who make up half of their patients. In the United States, IBS leads to 3 million visits to the doctor, 2.2 million prescriptions, and 100,000 hospital visits each year. But we keep it quiet. No one wants to talk about diarrhoea.

The cause, however, remains elusive. Whereas the colon of a person suffering from inflammatory bowel disease would be coated with ulcers, the intestines of people with IBS appear as pink and smooth as those of a healthy person. This lack of physical signs has led to IBS becoming tainted by the historical assumption that it is all in the mind. Though for most sufferers their IBS is at its worst when they are stressed, it’s unlikely that stress alone is the sole cause of such a persistent illness. The staggering proportion of people with IBS deserves an explanation – we haven’t been through millions of years of evolution just to need to be within thirty seconds of a loo.

A clue is to be found in the Walkerton tragedy. The people stuck with IBS after the water-contamination incident are not the only IBS sufferers to blame their illness on a gastrointestinal infection of some kind. Around a third of patients pinpoint the moment their gut troubles started on an episode of food poisoning or similar, which never seemed to resolve. Traveller’s diarrhoea is often the beginning – people who pick up a bug abroad are up to seven times more likely to get IBS. But testing for the original bug yields nothing – they are no longer suffering from the gastroenteritis itself. It’s as if the original infection has thrown the gut’s normal residents into disarray.

For others, the onset of their IBS coincides not with an infection, but with a course of antibiotics. Diarrhoea is a common side effect of taking certain antibiotics, and for some patients it continues long after all the pills have been popped. There’s a paradox though, as antibiotics can also be used to treat IBS, apparently staving off the problem for weeks or months at a time.

So what’s going on? These clues – the gastroenteritis and the antibiotics – hint at a common theme: that short-term disruption of the gut’s microbes can have long-lasting effects on the microbiota’s composition. Imagine a virgin rainforest, verdant and dense with life: insects rule the undergrowth and primates hoot from the canopy. Now see the loggers move in, chainsawing the forest’s leafy infrastructure, established over millennia, and bulldozing the rest. Imagine too a weed invading, perhaps having hitchhiked as a seed on the wheels of the diggers, and then crowding out the natives as it takes hold. The forest will regrow, given time, but it will not be the same pristine, complex, unspoilt habitat it was before. Diversity will drop. Sensitive species will die out. Invaders will flourish.

For the complex ecosystem of the gut, on a scale a million times tinier, the principle still stands. Antibiotic chainsaws and invasive pathogens pull apart the web of life that’s forged a balance through countless subtle interactions. If the destruction is large enough, the system cannot bounce back. Instead, it collapses. In the rainforest, this is habitat destruction. In the body, it causes dysbiosis – an unhealthy balance of microbiota.

Antibiotics and infections are not the only causes of dysbiosis. An unhealthy diet or a nasty medication might have the same effect, throwing off the healthy balance of microbial species and reducing their diversity. It is this dysbiosis, in whatever form it takes, that sits at the heart of twenty-first-century illnesses, both those that start – and end – in the gut, like IBS, and those that affect organs and systems all around the body.

In IBS, the impact of antibiotics and gastroenteritis suggests that the chronic diarrhoea and constipation might be rooted in gut dysbiosis. You can detect what species are living in people’s guts and what their abundances are using DNA sequencing. Doing that with people with IBS and healthy people shows that most people with IBS have distinctly different microbiotas than people without it. Some IBS patients, though, have microbiotas that are no different from those of healthy people. These patients tend to report being depressed, suggesting that for a small subset of IBS sufferers, psychological illness drives the IBS, whereas for others, dysbiosis is the primary cause, and stress simply worsens it.

Amongst IBS sufferers with dysbiosis, some research has found differences in the composition of their microbiotas according to the type of IBS they have. Patients who complained of being bloated and feeling full quickly when eating had higher levels of Cyanobacteria, whereas those who suffered a lot of pain had a greater quantity of Proteobacteria. For constipated patients, a whole community of seventeen bacterial groups were present in the gut in increased numbers. Other studies have found that not only is an altered microbiota present, but it is highly unstable compared with that of healthy people, with different groups of bacteria waxing and waning over time.

In retrospect, it might seem predictable that irritable bowel syndrome is likely to be a consequence of bowels ‘irritated’ by the ‘wrong’ microbes. As a logical extension it is highly plausible: from a quick bout of diarrhoea brought on by bacteria in dirty water or undercooked chicken, to chronic bowel dysfunction, all because the gut’s bacteria have got out of balance. But whereas a diarrhoeal illness can often be blamed on a particular pathogenic bacterium – for example, Campylobacter jejuni in the case of food poisoning from raw chicken – IBS can’t be pinned on one nasty bug. Instead, it seems to be something about the relative numbers of what are normally seen as ‘friendly bacteria’. Perhaps not enough of one variety, or too many of another. Or even a species that behaves itself under normal circumstances but turns nasty given a chance to take over.

If the gut community found in IBS patients has no overtly infectious player, how exactly does dysbiosis wreak such havoc with the functioning of the gut? The groups of bacteria present in the gut of a person with IBS also seem to be present in the gut of a healthy person, so how can changes in their numbers alone be responsible? At the moment, this is proving a difficult question for medical scientists to answer, but studies have revealed some interesting clues. Although IBS sufferers do not have ulcers on the surface of their intestines as in inflammatory bowel disease, their guts are more inflamed than they should be. It’s likely the body is attempting to flush the microbes out of the gut, by opening tiny gaps between the cells lining the gut wall and allowing water to rush in.

It’s easy to imagine how having the wrong balance of microbes in the gut could cause IBS. But what about gut trouble of a different kind – the expansion of the human waistline? Could the microbiota be the missing link between calories-in and calories-out?

Sweden is a country that takes obesity very seriously. Although ranked as only the ninetieth-fattest country on the planet, and one of the slimmest in Europe, Sweden has the highest rate of gastric bypass surgeries in the world. The Swedish have considered implementing a ‘fat tax’ on high-calorie foods, and doctors are able to prescribe exercise to overweight patients. Sweden is also home to a man who has made one of the biggest contributions to forwarding obesity science since the epidemic began.

Fredrik Bäckhed is a professor of microbiology at Gothenburg University, although it’s not Petri dishes and microscopes you’ll find in his lab, but dozens of mice. Like humans, mice play host to an impressive collection of microbes, mainly living in their guts. But Bäckhed’s mice are different. Born by Caesarean section and then housed in sterile chambers, they do not have any microbes in them. Each one is a blank canvas – ‘germ-free’, which means that Bäckhed’s team can colonise them with whichever microbes they wish.

Back in 2004, Bäckhed took a job with the world’s leading expert on the microbiota, Jeffrey Gordon, a professor at Washington University in St Louis, Missouri. Gordon had noticed that his germ-free mice were particularly skinny, and he and Bäckhed wondered if this was because they lacked gut microbes. Together, they realised that even the most basic studies on what microbes did to an animal’s metabolism had not yet been done. So Bäckhed’s first question was simple: Do gut microbes make mice gain weight?

To answer that question, Bäckhed reared some germ-free mice to adulthood, and then dotted their fur with the contents of the caecum – the chamber-like first part of the large intestine – of mice who had been born normally. Once the germ-free mice had licked the caecal material off their fur, their guts took on a set of microbes like any other mouse. Then something extraordinary happened: they gained weight. Not just a little bit, but a 60 per cent increase in body weight in fourteen days. And they were eating less.

It seemed it wasn’t only the microbes that were benefiting from being given a home inside the mice’s guts, but the mice as well. Everybody knew that microbes living in the gut were eating the indigestible parts of the diet, but no one had ever looked into how much this second round of digestion contributed to energy intake. With microbes helping them to access more of the calories in their diets, the mice could get by on less food. In terms of our understanding of nutrition, it really rocked the boat. If the microbiota determined how many calories mice could extract from their food, did that mean they might be involved in obesity?