In the nine months you were resting in your mother’s womb you had a comfortable life free of stresses and infections. Your gut was pristine: completely sterile, with no bugs or bacteria. Your skin was covered in a protective oily coating and there were no bacteria or parasites hiding on any skin surface or in any of the nooks and crannies of your body. At birth you were suddenly released into the infested world outside. Within a few minutes even in this supposedly sterile hospital delivery room, bacteria from your mother and the midwives had begun to colonise your skin, anus, vagina and nasal passages. On the first reflex suck of your mum’s nipples, bacteria started to flow into your mouth and down into your stomach and intestines. These bacteria grew and spread rapidly throughout your body. Within a few weeks your smooth baby skin was covered and your intestines swarming with millions if not trillions of different microbes. Amazingly you survived this onslaught. In fact this is a completely normal process that happens to all babies at birth and shows the intimate relationship we have all our lives with bugs. We are only just grasping how this special relationship influences our lives.
Stomach cancer is usually fatal and kills about a million people a year worldwide. It has, however, declined rapidly in the West over the last 50 years from its status as the major cause of cancer deaths in the 1980s, when it even beat lung cancer. In some parts of the globe like China and Korea, change has been slower, and stomach cancer is still a global problem.1 Yet despite hundreds of unlikely dietary theories – ranging from what type of bracken or grass sheep grazed on before they were eaten, to changes in drinking habits – the phenomenon perplexed epidemiologists for years. The only clear associations until recently were the usual suspects, cigarettes and alcohol.
At the same time as stomach cancer has been decreasing, stomach (peptic) ulcers have steadily increased. They were until recently seen as a twentieth-century disease related to stress, causing acid release and ulcers in the lining of the stomach. Stomach cancer was first reported only in 1835, fourteen years after Napoleon Bonaparte was supposed to have died of it. This was deduced after further autopsies carried out in 2007 showed him to have multiple stomach ulcers and invasive stomach cancer – a lethal combination even without the arsenic he was being fed (according to the French) by his British captors.2 Those painful stomach ulcers may have been the real reason his hand was always inside his coat.
Peptic ulcers and their treatments only really grabbed doctors’ attention in the 1940s and 1950s, when they often perforated or bled and could be fatal. There is a long list of celebrity deaths from perforated ulcers, including James Joyce, Pope John Paul II, Ayatollah Khomeini, Alfred Nobel and Charles Darwin. The pattern of the disease has also changed in Western countries. In the last century it mainly attacked the stomach. Nowadays the sac below it, the duodenum, is a much commoner target.3
Once doctors had worked out that the stomach glands produced acid, an overproduction of gastric acid caused by stress or bad diet was the obvious cause of the problem. This led in the 1970s to the development of some clever drugs that reduced acid secretion (called H2 blockers). However, as soon as the drugs were stopped the ulcers returned – not so good for patients, but great for the Pharma industry, whose drug sales, even by the 1980s, were making $3 billion a year. The only other treatments were crude surgical procedures removing large bits of the stomach and cutting the vagus nerve. They were expensive and risky, with many side effects, and not usually very successful, but they kept many influential surgeons gainfully employed.
Sometimes maverick individuals who fight the prevailing medical view can be a nuisance and sometimes they make amazing breakthroughs. Barry Marshall was a doctor in Western Australia who didn’t believe that stress caused ulcers, and he wanted to prove it. One day in 1982, without telling even his wife, he took a lab culture plate dish where he had grown millions of bacteria from a patient riddled with ulcers and poured the liquid into a small cup. He added some chicken broth to make the revolting brew semi-palatable and took a swig. ‘I thought I might develop ulcers in a few years, but after just two days I lost my appetite, was sweating, nauseous and felt unwell. By day five, I was vomiting clear fluid which strangely (because of the bacterial infection) had lost its acidity and I also had dreadful bad breath. Eventually – after ten days – my wife, who had noticed my deteriorating health, found out, and was not happy.’ She made him have an endoscopy and take antibiotics four days later. The samples taken from his stomach showed many dead bacteria, masses of defensive white cells, and damage to the stomach lining.
Barry Marshall’s research with his pathology colleague Robin Warren in 1982 had shown without any doubt that Helicobacter pylori (HP), a curly bacterium found only in humans, was the cause of peptic ulcers. They published their findings in The Lancet in 1984. ‘It took us another ten years to change the fixed opinions of other doctors who treated stress, acid and ulcers like a religious belief.’
Marshall and Warren from Perth were awarded the Nobel Prize for medicine 20 years later in 2004 and treatment for chronic ulcers was changed for ever. Simple specific antibiotic treatments now cured most ulcers. They estimated globally saving 500,000 lives a year from bleeding and perforated ulcers. But as we will see there may be a price to pay for this success.
Since the branding of Helicobacter pylori as the primary cause of ulcers, we have seen a massive leap forward in our understanding of the world we share with microbes. We carry within us all – in addition to the 25,000 genes contained in all our cells – a large number of other mysterious passenger genes. In fact we have twenty times more non-human genes: over 500,000 different bacterial genes in our intestines and feces, coming from as many as 100 trillion microbes. Genetic technologies in the last five years mean that we can now identify these microbes by sequencing their identifying sections without having to wait weeks to grow them in culture plates. The gene sequence of each microbe is called a microbial genome, and when all are combined is called a metagenome.
In the UK it takes days or weeks and costs the NHS about £10 to grow bacteria in culture to identify them. It can now be done within minutes and for the same money with a gene sequencing machine, and will revolutionise how we detect infections routinely. It is already having a major effect on investigating the origin of disease outbreaks. Examples include the proof that the recent German salad E. coli outbreak didn’t come from mutated bacteria on contaminated Spanish cucumbers, and that ‘careless’ surgeons were not the true sources of superbug infections such as MRSA (Methicillin-resistant Staphylococcus aureus) or Clostridium difficile in the UK.4 Epidemics from diseases like TB or influenza can now often be traced to the exact date of arrival of a single human ‘super infector’ by sequencing the exact genetic mutation of the bacteria or virus.
Helicobacter pylori, the recently discovered bacterium that causes ulcers, has co-evolved with humans who are its only known host. It has a pretty depressing life, has never seen the light of day and can’t live outside the human gut. About half of 50-year-old Americans now have the bacteria in their gut – but these seem only to cause ulcers in about one in five people.5 Rates vary around ten-fold across the world, and Korea reportedly has one of the highest rates of over 90 per cent. The HP bacterium has changed and adapted along with humans, and we believe it travelled with us out of East Africa around 80,000 years ago and is actually a ‘friendly bacterium’ in most cases. As we are its only host it has no interest in harming us. Surveys of stored historical fecal and blood samples suggest that the levels we carry have been dropping, even before we started trying to eradicate them to prevent ulcers. Rates in the US based on stored blood show a 50 per cent decline in HP since 1968. This is likely due to better hygiene and less transfer and mixing of species of bacteria from person to person – which often happens in early life.
While hygiene may have reduced some infections, it may have a downside, as suggested first by David Strachan, a clever epidemiologist I did my Master’s degree with in London. He first proposed a ‘hygiene’ hypothesis to explain why rural kids got less asthma and allergies.6 He suggested that overzealous cleanliness was partly responsible for the recent allergy epidemic since the war. Many common infections have in the same period decreased dramatically in the West, among them measles, mumps, TB, scarlet fever, and many bacterial infections. As gastric cancer has decreased, the disappearance or recent reduction in the levels of HP in our bowels has been linked to unexplained increases in a number of other cancers. These include cancer of the oesophagus (the gullet) and other parts of the stomach (called the gastric cardia) that used to be rare, as well as a dramatic increase in allergies and diabetes.7
The lesson from HP is that we interfere with our gut flora at our peril. Remember HP is one of hundreds of thousands of known and unknown bacteria species that we coexist with and whose genes produce thousands of different proteins. There is some evidence that ‘gut-friendly’ yogurts with acid-resistant lactic acid (Lactobacillus and Bifidobacillus) bacteria given after meals can suppress HP activity in the stomach.8 While if taken regularly this may be useful for eradicating HP-related ulcers, it may covertly be actually increasing other diseases. A recent study of 70,000 Danish pregnancies found that mothers who ate low-fat yogurts during pregnancy produced more allergic and asthmatic kids than those that didn’t.9
There is only one reliable method of curing type II diabetes in an obese patient within a few days. Although there are many drugs that help a bit, the treatment that works fast and keeps patients cured for over ten years is called gastric bypass (bariatric) surgery. This surgery (and its milder form gastric banding) has been around since the 1950s but has only recently begun to be performed on a large scale. In my hospital in London around 500 operations are now performed each year. The media in many countries – the UK included – have usually been opposed to it because of its costs and the perception that it is used in unworthy patients who are not ill, but just lack willpower.
But it works. Within 48 hours of the operation to effectively bypass most of the stomach, sugar and insulin levels of patients return to normal and stay that way for ten years in over 70 per cent of cases.10 The conventional explanation is that this is due to malabsorption and that nutrients just pass through the gut quicker, but there is no hard evidence for this and many patients actually have constipation, suggesting that passage of food through the gut is if anything slower. Some of these rapid changes could be due to changes in the gut hormones that signal the brain when it’s hungry and full, which we discussed in chapter 7.11 However, patients’ eating habits don’t alter dramatically, although they have more frequent small meals and less fatty foods. What is also happening is that the gut bacteria change rapidly and suddenly take over new areas12 and alter metabolism.13 This could be the reason the operation works so well. We just know so little yet about which bacteria are good or bad for us.
But there may be other ways of changing bacteria and their genes without surgery or eradicating them via antibiotics. We now know that epigenetic mechanisms are not confined to humans and also work in other organisms.
Bacterial genes, like those of their human counterparts, can be methylated and so get activated and deactivated by external factors.14 Although they also have high gene-mutation rates, epigenetic change is another important factor in how they can adapt to new environments and possibly how they cope with antibiotics. Methylation also plays a role in the way that friendly or aggressive (virulent) bacteria behave towards the host human.15 A recent study looked at a mouse model of stomach cancer and found that giving folic acid supplements to these mice at birth, when they have no gut bacteria, protected them against later cancer – via methylating the new bacteria in their intestines. This process deactivated the bacterial genes and proteins that would normally kick-start the cancer process by disrupting the DNA in the cells of the stomach wall.16
The average child in the West takes 15 courses of antibiotics before the age of 18 – most of them unnecessary. This means that our gut bacteria, including their genes and proteins, are very different to those of our parents and grandparents 50 years ago. The drugs cause mutations in our bacteria to make them more resistant to antibiotics, but they also alter their normal protective functions. Bacteria like HP seem to act as our home defence system, actually reducing levels of harmful bacterial species. Some of this effect is through epigenetic mechanisms that influence the host’s immune genes. Kids are born usually without bacteria and most, like HP, are rapidly accumulated in the first year of life.17
Some experts predict that we will soon be actually giving newborn babies HP infections to redress the defensive balance and reduce allergies. The change in our bacteria could also be one reason that not just allergies, but diabetes and possibly even heart disease have also increased since the introduction of antibiotics. A recent study showed that feeding young mice different amounts of the key constituents of fat altered their gut flora, which – depending on the chemicals – in turn altered the amounts of fat produced by the liver which lead to increased or decreased fatty plaques lining the arteries (atherosclerosis). This suggests that drugs that alter our gut flora could reduce risk of heart disease.18 One of these fat metabolites was choline, which – as we discussed earlier – can alter methylation of key genes.
Other studies in humans have found that certain bacteria normally found in the gut are actually present in the damaged vessel wall of patients with heart disease – and may be partly responsible.19 Some other diseases like dental caries (tooth decay) and periodontitis (gum inflammation) are also closely related to the bacteria in our mouths, which are also affected by taking courses of antibiotics. Although caries has decreased in recent years due to fluoride, antibiotics could explain recent increases in gum disease. These gum infections are also weakly related to increases in heart disease, although we don’t yet fully understand the mechanisms.20
The fact that bacteria are so clever in adapting their genes via mutations or epigenetics to protect themselves against new antibiotics has come as a shock to doctors. However, a recent study has shown the bacteria have been practising survival techniques for millennia. Scientists digging in a permafrost site in the Yukon found some ancient uncontaminated DNA from bacteria that was over 30,000 years old, when mammoths roamed the earth.21 They found these ancient bacterial genes already contained a battery of antibiotic resistance genes – which they could quickly swap with each other. They were used to signal to each other and to defend themselves against other bacteria and fungi which also produce natural antibiotics. So bacteria have had millions of years of evolution arming themselves to deal with any antibiotic we can throw at them. It seems we can kill some of them, but often only at the expense of harming ourselves. Our personal bugs have more experience and complexity than we have given them credit for.
Ellen and Eva are British twins married and in their fifties and both on the heavy side, weighing around 12 stone. Both twins were small at birth, and Ellen, the lighter, weighed only 1,400 grams (3 lb). Ellen became a vegetarian age 25 for 15 years and felt healthier and lighter, but got fed up with red peppers and tofu and reverted to white meat. Both sisters have suffered for the last ten years from an intermittent bloating feeling in the abdomen and cramp-like pain that was sometimes relieved by going to the toilet.
When their pain is bad they vary widely in symptoms – from being constipated to having runny stools. ‘We both tried changing our diets, but nothing seemed to help much,’ says Eva. Ellen remembers ‘having less symptoms when I was vegetarian’. Both went to see their different GPs, who did a few tests to rule out infections and bleeding, and they got similar advice. ‘My GP said it was probably just stress and related to depression. I was told to relax and forget about it and come back for anti-depressant tablets if it didn’t improve,’ said Ellen. Eva said: ‘My GP told me much the same. Neither of us believed stress was the main cause and we didn’t go back, as we didn’t want to take those tablets.’
Irritable bowel syndrome (IBS) is a relatively modern diagnosis and is made mainly by excluding other more serious illnesses. IBS doesn’t kill you but is a source of pain and discomfort for many people. Some estimates suggest it affects up to 20 per cent of the population at some time of their lives. This high prevalence and lack of obvious evidence of pathology have made many doctors believe it is a modern invention, dreamed up by greedy drug companies to try and ‘medicalise’ a normal range of human variation. It has been linked to other similar disorders with similar obscure causes like fibromyalgia and chronic fatigue syndrome. All three conditions have been called psychosomatic, as patients often have associated anxiety and depression, thereby creating a vicious circle of symptoms. Many patients and their patient groups sadly feel very threatened by the perceived stigma of a psychological component, and some of my colleagues researching chronic fatigue syndrome have faced death threats and subsequently changed research areas, much to the detriment of science.
Two large twin studies have been performed on IBS,22 one by our group in collaboration with a gastroenterologist. Nigel Trudghill found that out of 5,000 female twins tested, 17 per cent had mild symptoms of IBS, but it was not clearly heritable. A larger Norwegian study of 12,000 twins used stricter criteria and consequently identified more severe disease. It found a clear genetic heritability of 48 per cent in these more badly affected women.23 The study also found that rates were much higher in the smaller twins at birth – below 1,500 grams – suggesting that early life events were also important. The view of most doctors is still that this is not a ‘real disease’ and just a manifestation of anxiety and depression common in middle-aged women. But could something else be going on beneath the surface? Again discordant twins might give us a clue.
Rosemary was chatting to her friends at a birthday party lunch in the Barley Mow restaurant outside Guildford, enjoying her steak and onions with a side salad. She had drunk half a glass of rosé wine and was having fun. All at once she started getting stomach pains and felt hot and sweaty. She got up to go to the bathroom, but before she could start walking she was gripped by a vice-like stomach cramp and had uncontrollable explosive diarrhoea – just before she fainted. ‘I will never forget that meal – it was so embarrassing,’ she remembers, ‘My friends helped me get to the local Frimley Park Hospital, where I was given a drip and antibiotics and stayed for several days.’
The doctors did all kinds of tests with endoscopy tubes at both ends in her stomach and colon, but couldn’t find anything wrong. ‘They asked me all kinds of odd questions about whether I was depressed and was I still sleeping with my husband. I think they were checking whether I was a bit mad.’ Her symptoms settled down slightly, but her bowels were still alternating between constipation for several days with episodes of bloating, cramps and diarrhoea. She took advice from the hospital on changing her eating habits – they advised her to eat little and often – and through trial and error she cut out various foods that aggravated it. ‘I found that if I ate fruit with skin, porridge, muesli, bran, nuts or granary bread, I would be running to the loo half an hour later.’ Twenty years later she feels she has it under control.
Her sister Jennifer, now aged 65, who lives about 50 miles away in southern England, never had any similar problems, although they both think they remember ‘sitting as toddlers on our potties for long periods of time, waiting for something to happen. Our mother said we had “lazy bowels”.’ Jennifer never had the constipation that Rosemary had in her life, although ‘for half our life we had pretty much the same diet. Strangely, as long as I can remember I’ve always had a bigger appetite than Rosemary, and actually am less active. But I must have a better metabolism. Rosemary thinks I eat double what she does, but I think it’s closer to 50 per cent more. She is always struggling to finish her plate and I have no problem eating any kind of food.’ Nowadays, although she has been heavier in the past, Jennifer weighs around 8 stone – about a stone lighter than Rosemary. She says she also has different sleeping habits and is unable to have naps in the daytime like her sister.
What could be going on in Rosemary that is not in Jennifer, her identical twin, to cause these major differences in their bowel habits and perhaps their appetite and metabolism? What also might be similar in Ellen and Eva, to give them such similar symptoms? It might have something to do with the half-million or so bacterial genes in our intestines and the trillions of microbes. Although about 40 per cent of our own microbes are shared with most other humans, many are specific to just a few of us, leading to a potential pool of over 3 million unique bacterial genes – 150 times more variety than the human genome.24 These genes make proteins that have a key role in many processes from breaking down carbohydrates and sugars to creating fats and vitamins. Thus we possess a huge accessory genome that can influence how we filter and metabolise our diet and derive energy from it – as well as many other processes that we can only guess at.25
Our gut is only one part of where bacteria and their genes hang out. Skin, urine, vagina, hair and armpits are other sites where different bacteria cluster together, the exact blend of bugs reflecting a mixture of the influence of the host human and a preference for the individual site.26 In the 1970s NASA scientists were very interested in what happened to bacteria sent into space with astronauts, and importantly – for obvious practical reasons – how they could control the fecal waste of astronauts in the weightless environment. They found that while they could modify the bugs slightly with diet, they noticed enormous differences between astronauts which they couldn’t easily alter.27
We worked with Cornell University to get a better estimate of the heritability of gut flora of twins. Our helpful volunteers sent us a bit of their poo on a plastic spoon and Ruth Ley ran a genetic sequence analysis of the contents to identify the range and proportion of common bacteria in each individual. So far the results on a few hundred twins show a wide variation between people, but identical twins definitely share more types of bugs than do the non-identicals. We are extending this study to next fully sequence in depth all the microbe species (the metagenome) contained in each of the intestines of our 7,000 twins. This huge task is being done with the considerable help of the largest gene-sequencing facility in the world: the BGI (originally the Beijing Genomics Institute) in Shenzhen in China. They have invested billions, and their visionary director Wang Jun clearly sees a huge future potential in epigenetics and the metagenome project to identify and understand all the bacteria that live within us.28
These twin results show that bacteria can recognise and prefer the genes of certain humans to others. Some of these bacterial species prefer younger or older hosts, and as there are major differences in gut flora between young and old people, some of these bacteria may turn out to be important in the ageing process itself. Deep sequencing of 22 gut microbiomes from individuals in four countries has shown that our gut contents belong to three main distinctive groups, called ‘enterotypes’ – a bit like blood groups.29 Strangely, these are not related to race or place of birth, and the groups may well behave very differently in affecting how we interact with our environment, diet, and even ageing. Each of these has some dominant bacterial species. Some bacterial species also prefer to live in hosts that produce different amounts of body fat. This may not be just chance or a passive process.
The biggest surprise in this field came in 2006 when a team from St Louis compared the feces of a genetically fat and a genetically lean strain of mice.30 They found they had very different bacterial species. What was more exciting is that the bacteria of the fat mice could metabolise and extract much more energy and calories from food than those of the skinny ones. They then confirmed the same result in fat and skinny humans. This means that some people carry for most of their lives some bugs that greedily grab all the calories they can from their guts – which means that for the same amount of food the host will store more fat and put on more weight.31 Having these microbes in our guts was probably a good thing in our early evolution, and by storing fat helped survival in hard times – but not great nowadays.
So within us all lies a parallel universe of warring personalised bacterial colonies, each of them with genes and proteins with a possible role in our health of which we remain largely ignorant. We are only just scratching the surface of this hidden universe, but so far it offers us a glimpse of their potentially huge importance. The type of bacteria and the extra genes we have in our guts could explain around 50 per cent of obesity, compared with the paltry 1–2 per cent explained by the common human genes we have discovered so far.32
Other common diseases could also be affected by our bacterial guests and their genes. Colon (bowel) cancer is very common and has only a 15 per cent genetic component. It varies a lot between countries and geographical regions, and red meat diet and high fat intakes have been implicated in its cause. However, studies of the intestinal flora of populations at high risk of colon cancer have shown very high numbers of Bifidobacillus species and low levels of Lactobacillus.33 There is emerging evidence that these bugs and their genes interact closely with our own genes and proteins. They have been found to alter the leakiness of the gut wall and alter the regulation of the immune system, and even cause DNA damage in our own genes.34 These processes are seen as crucial in many diseases, like the bowel diseases (Crohn’s disease, coeliac disease, IBS), as well as other allergies and cancer. The use of tests of our gut flora for diagnostics of early disease or high risk is suddenly a big research area and could explain much of bowel-cancer risk.35
Diseases like IBS, as we saw with our twins, are often associated with other problems like depression or anxiety, and this is often thought to be the cause of the symptoms. However, several rodent studies have shown that manipulating the gut flora by adding or removing certain species can actually alter their mood and behaviour.36 Recent research has shown that in mice, changing their gut flora by being given Lactobacillus yogurt can quite rapidly alter their mood and drive.37 They found differences in the expression of GABA neurotransmitter receptors in the brain of the happier yogurt-fed mice. We don’t yet really understand how these effects occur, although epigenetic modifications and the nerve supply between the gut and the brain (vagus nerve) both appear to be important. We are bound to find many more unexpected links between our bacteria and our immune system and brains soon.38
In terms of novel treatments for diseases like IBS, you probably can’t get more thought-provoking than one early-stage trial: fecal transplant, or less technically ‘poo transfusion’. This distasteful procedure takes healthy gut feces from a generous donor, puts it in a blender, and via a tube through nose or bottom (you don’t have to drink it), passes it on to the patient. The new bacteria make themselves right at home in the new gut, taking over from the old residents within a few days, and produce a dramatic and long-lasting reduction in symptoms.
Tom Borody in Sydney has been pioneering fecal transplants since the mid-1980s.39 They have been shown to be an excellent cure for persistent bowel infections with the superbug Clostridium difficile, which kills 300 people a day in the US, that can actually be caused by broad-spectrum antibiotics.40 It also shows promising early results in Crohn’s disease and colitis and more recently IBS. It is not clear if Professor Borody has yet copied his Nobel-winning compatriot Barry Marshall in self-treatment.
The future may bring a new form of super-poo that we will be taking routinely to boost our gut defences. For those too squeamish, a new form of broad-spectrum antibiotics have been tested in IBS patients that are able to get past the acid in the stomach and target the gut flora in the colon. The trial of rifaximin was pretty successful, with 40 per cent of patients improving after two weeks’ treatment compared with 25–30 per cent with placebo.41 However, as these broad attacks on the gut flora could harm some of the good guys, the natural solution may in theory be preferable.
So if some bugs can make us lose or gain weight, give or prevent allergies or prevent ulcers and cancer, we should know how we can safely change our gut bacteria. As usual, Grandma’s advice may be best. Eat more greens. This may be good for us epigenetically with the help of our bacteria. When our gut bacteria break down and metabolise these plants they produce the natural chemical butyrate, which is protective against infections and acts as a weak chemical (an anti-histone deacetylator) that could change our genes epigenetically.42
What is clear is that we should think much more carefully when using antibiotics without good reason, and need to be cautious with so-called ‘gut-friendly’ yogurts43 or bacteria ‘health’ teas like kombucha,44 which at certain times of life could be helpful, and at others just the opposite. Animal studies have shown that manipulating the diets even of larger mammals like cats can change gut flora over a few months.45 Evidence is sparse in humans, but although differences in bacteria can be seen due to breast or bottle feeding,46 in adults effective dietary changes probably need to be over a longer time frame.
In the future we may need to personalise our and our children’s diets depending on our enterotype, or even exchange bowel contents with skinny healthy humans to modify our own bacterial lodgers. We are actually super-complex organisms made up of many different species that may be controlling our bodies and minds much more than we think.