We are all familiar with “gut feelings”, “gut reactions” and “gut instincts”, but how much do we really know or care about our guts? As we become increasingly more aware of what we put in our stomachs, it’s striking how ignorant we remain of what takes place in our intestines. And it turns out there is an awful lot going on down there.
Microbiologists have made some startling advances in revealing our innermost secrets. It turns out that there is a complex ecosystem deep within us that is home to a fantastic diversity of life – of which very little belongs to our species.
For most of us, suspicious of foreign bodies, it’s a struggle to comprehend that at our very core we are less than – or rather much more than – human. But, the fact is, there are about 100 trillion organisms living in the gut. If you put them all together they would be about the size of a football. In terms of cells, the microbial kind outnumber their human counterparts by about three to one. And in terms of genes, the microbial advantage is more like 300 to one.
That means there is a tremendous amount of us that is not, so to speak, us. This raises a whole range of interesting philosophical and anatomical questions, of which the most urgent might be: should we be worried?
Well, I wasn’t much concerned about bacteria before I got the contents of my gut tested. I took a fairly relaxed view that as long as the lavatory was regularly bleached, I brushed my teeth and kept the kitchen surfaces reasonably clean then I didn’t have to think too much about what goes on at the microbial level. But there’s nothing like spooning your own faecal matter into a Perspex container to make you stop and contemplate just what it is that we’re full of. That unpleasant task is precisely what I found myself doing last October, as I gathered a stool sample to send off, cold-packed to the BioSciences Institute at University College Cork in Ireland.
The institute is one of Europe’s leading centres for the study of what is now referred to as the microbiome – that is all the bacteria, viruses, fungi, archaea and eukaryotes that inhabit the human body, inside and out. The simplistic view of these guests has traditionally centred on their parasitic or pathogenic aspects. Either they were fairly harmlessly hitching a free ride or were a direct threat to their host.
But the latest thinking presents this vast army of microbes as a vital component in furnishing and maintaining human health. Such is the microbiome’s importance that it is now viewed by scientists as a separate organ with its own dynamic metabolic activity. But what precisely is that activity and is it all going to plan with me?
Paul O’Toole is a professor at the School of Microbiology and Alimentary Pharmabiotic Centre, which is part of the BioSciences Institute at Cork. A keen marathon runner, he looks like he knows a thing or two about intestinal fortitude. He co-ordinated a government-funded study – fortuitously launched just before the Irish economy collapsed – entitled Eldermet, which was aimed at helping the Irish food industry develop food products for old people. To do that, they needed a knowledge base of the gut microbiota. So O’Toole began examining how diet affects the microbiota of Ireland’s elderly population.
There is an element of poacher-turned-gamekeeper to his career because he started out as something of a bacterial enemy. “I spent about 15 years working on pathogens where you’re trying to kill them,” he tells me in his office. “I did my PhD in staphylococcus. One organism, one gene. I worked on a condition called skull-to-skin syndrome where staphylococci infect the umbilical stump and if they produce a toxin all the baby’s skin peels off.”
From combatting staphylococci, he moved into probiotics – the organisms that are supposed to be good for us – which in commercial form have been decanted into capsules and yoghurts and advertised to the public as “friendly bacteria”. But he discovered that he couldn’t effectively study probiotics in isolation because their benefits were often indirect.
“I realised I needed to study the whole canvas,” he says. And that was how he came to find himself involved with the microbiome, just when it was starting to become the subject of intensive biomedical research.
There are two labs, O’Toole explains, that processed my sample. The first was the wet lab, where, through various molecular assaults, DNA was extracted, 95% of which was bacterial. This was then sent to an external company to be sequenced – there were over 30,000 sequences – and then a huge file of data was crunched by what O’Toole called “a bunch of computer nerds who sit around all day generating stats” in the institute’s data lab.
Just a year ago, that process cost upwards of £400. Now it can done for as little as £15. What you get are a couple of pie charts that list the microbiota found in the gut at different phylogenetic levels and a narrative explanation as to what their significance is. Phylogentic levels in this instance simply refer to different levels of resolution.
At the broadest level, the phylum level, my microbiota, in common with everyone else’s, was dominated by two types: firmicutes and bacteroidetes. The western diet, by which we tend to mean the North American diet, is high in fat and protein. In this diet bacteroidetes usually make up more than 55% of the gut microbiota, and sometimes, in North America itself, as much as 80%. In Europe, the average numbers vary from country to country. In my case I had 34%.
The opposite to a North American diet is what O’Toole calls a “natural diet”. “Our antecedents on the plains of Africa weren’t chewing on burgers,” he explains. “They were running around eating plant foods and leaves and occasionally eating a squirrel if they were lucky.”
On a plant-based diet, the microbiota is tipped in favour of the other major phylum, firmicutes. Some of the complex carbohydrates in plants cannot be digested by our bodies alone. They have to be broken down by the gut microbiota, which produce enzymes to chop up the long chains and ferment them into short-chain fatty acids such as butyrate – which is made exclusively by bacteria – acetate and propionate.
These fatty acids are beneficial to the body. Butyrate, for example, provides an energy source that the cells lining our intestines can directly access. It also controls the proliferation of cells in the intestine and is thought to possess anti-carcinogenic properties. All of which meant that my score of 51% firmicutes was a healthy sign.
Zooming into the genus level, which offers a more detailed look at my microbial composition, the good news continued. I had three times as much of the butyrate-producing roseburia than the healthy cohort used in O’Toole’s study. Many more lachnospira than normal but many fewer bacteroides (not to be confused with bacteroidetes) and alistipes – as O’Toole put it, in more scientific terms, “bugger all”.
Again these were positive results. Lachnospira degrade pectins and ferment dietary fibres and I have three times more than typical. And bacteroides are often associated with meat-based, high-protein, high-fat diets, just as alistipes tend to be more present in people who eat less plant-based food. In sum that meant my gut – the lack of six-pack notwithstanding – was probably in good shape. Of course, it’s not the sort of thing you can boast about at dinner parties. “I’ve got significantly higher than average amounts of lachnospira,” is unlikely to be a conversational gambit that will impress non-microbiologists, even if you do manage to pronounce the word correctly. But just as we now know that high cholesterol is something to be avoided, so too might we soon begin to become aware of the sorts of bacteria counts that are markers for good health, especially as the price of testing comes down.
There were, however, one or two results that O’Toole struggled to make sense of. In particular my high levels of natranaerobius, a genus of bacteria that thrive in high-salt, highly alkaline environments. Did I eat a lot of sushi? No, while I love fish, I tend to prefer it cooked. Did I prepare a lot of fish? No more than once a week.
Although he found nothing sinister in the natranaerobius, it perturbed him that he couldn’t quite put his finger on the cause of its abundance in my gut. But by then he had managed to make a blind prediction of my diet that was uncannily accurate. He saw very little evidence of meat-eating – I haven’t eaten meat for 30 years. But there was plenty of evidence of high fibre, which is good because bacteria feed on fibre. If we don’t feed bacteria, they feed off us – specifically the mucus lining in our large intestine. There was also evidence of lots of fish and a large range of vegetables. All of which exactly represents my diet.
I suggest that it must be satisfying to get his prediction so right.
“It’s a bit spooky all right,” he agrees. “But it made me think about the utility of it. I mean, it’s not particularly useful to tell people what they eat.”
O’Toole is interested in the diagnostic potential of the microbiome. “We could probably guess what your inflammatory parameters are,” he says, fixing me with one of those expressions in which GP’s specialise when looking up from studying your medical notes: neutral, unyielding, and anxiety-inducing. Not only do I not know what my inflammatory parameters are, I don’t know what inflammatory parameters means.
O’Toole explains that significant links have been established between gut microbiota and inflammation, sarcopenia and cognitive function.
“Inflammation,” he says, “is not a swollen thumb. Inflammation means how activated your immune system is. I would guess that your inflammatory markers are baseline. Flat. In old people they’re not. In old people, the immune system is typically turned on and that’s not good, because if it’s turned on, when they get a winter flu all their energies are expended chasing ghosts. So you want to turn down the inflammation.”
Sarcopenia means loss of muscle mass. It happens as we get older because the body becomes less efficient at turning protein into muscle, which is why older people need to have more protein. “We think that the narrowing of gut bacteria in old people is making the intestine less efficient at absorbing proteins,” says O’Toole.
Cognitive function is partly related to what’s known as the brain-gut access. As all those phrases like “gut wrenching” and “gut feeling” suggest, there is indeed an intimate link between the brain and the gut. Our intestines are acutely responsive to shifts in our emotions and mental states. But it’s a two-way street: studies suggest that our brains and emotions are also sensitive to what’s going on in our guts.
T ypically, cognitive function is only slowly diminished as we get older, but in some cases it can quickly accelerate.
“There are physiological reasons like Alzheimer’s and senile dementia that explain rapid cognitive impairment,” O’Toole says. “But the rate of loss could also be affected by compounds made by bacteria, and that’s what we’re targeting. Bacteria produce chemicals which are analogues – in other words they look identical to normal human transmitters. What we hope is that we can improve the ability of old people to process data.”
Common to all these issues, particularly among the aged, is the narrowing of the gut microbiota which, in turn, is usually the result of a narrowing of diet. This is a point that O’Toole repeatedly emphasises.
“Diversity is the key. What we see with people on narrow diversity diets is that the microbiota collapses. A good analogy would be an ecosystem like a rainforest, where you’ve got loads of plants and animals interacting. It’s evolved over tens of thousands of years, then one of the key species, a tree, gets cut down and you get ecological collapse.
“And if you had a gentleman whose wife died and she had done all the cooking, and then he’s suddenly eating toast and marmalade, the diversity of gut microbiota will collapse – because diversity of diet correlates with diversity of microbiota – and you will get a range of health problems associated with that.”
He goes on to tell me that my microbial diversity is impressively wide and that, by way of summary, he would suggest that my diet is “pretty bloody good”. Forget the 5-2 diet, I suddenly feel like writing a bestselling diet book entitled Guts: The Microbial Guide to Healthy Eating. In one sense, of course, it’s no great achievement. Studies show that it only takes a short time of a changed diet to dramatically change the microbiota, although it changes back just as quickly as soon as the diet is dropped.
But this apparently superficial relationship between food and microbes is in reality rather profound because first it speaks of a co-evolution with the human body over tens of thousands of years. Like all organisms and species, humans have evolved to have a particular relationship with a particular set of microbes.
There are hundreds of thousands of kinds of microbes on Earth but only about a thousand enjoy an association with humans. Thus, secondly it suggests that we need to stop thinking of ourselves as separate entities from the microbes that have colonised our bodies.
“We came through the period of medicine in which we developed antibiotics,” says O’Toole. “Until the second world war we were dying from stupid things like pneumonia and galloping septicemia from a small wound. So antibiotics were a major success. Then we’ve had the backlash where we’ve prescribed them too much and can’t control the pathogens. But now we have a more intelligent understanding of humans as chimeras.”
A germ-free existence would be an unhappy one. Tests have shown that a mouse raised in a lab devoid of bacteria fails to develop a proper immune system or an effective digestive system. It has to consume a lot more food to extract calories. Humans are first colonised by microbes during birth. Then through breast milk, which contains both probiotics (beneficial microbes) and prebiotics (compounds that foster the growth of probiotics).
“There is strengthening evidence,” says O’Toole, “that the explosion of auto-immune diseases and immune disregulation diseases in western society may be due to suppression of gut bacteria from infancy onwards.
“The immune system in babies is probably taught to distinguish between self and non-self in the context of bacteria. There are two recent papers in the publication Nature showing that butyrate is important in enlisting regulatory T-cells, a branch of immune cells that control the processes involved in inflammatory bowel disease and irritable bowel syndrome.”
It takes about two years from birth through a process of selection for a child to attain a mature microbiome. There are several phenomena that may contribute to childhood microbial diminishment. One is the increase in caesarian sections.
“Babies who were previously colonised in the birth canal with their mother’s microbiota now have a gut microbiota that is more like the walls of the hospital than it is mum’s vaginal microbiota.”
Another is lack of breast milk, and a third is the increased use of antibiotics. O’Toole says that one study suggests that repeated use of antibiotics tips the microbiota towards one that promotes obesity. In fact there are many studies around the globe that are still in their infancy but which point up connections between the microbiota and diseases and complaints as diverse as irritable bowel syndrome, inflammatory bowel disease, type-two diabetes, Parkinson’s, Alzheimer’s, autism, depression, cardiovascular disease and colon cancer.
But so far none of it is conclusive and much is highly speculative. After the initial claims about the potential health benefits of microbiome research – the kind that tend to help funding – there has been a bit of a sceptical backlash.
Several articles have pointed out that there has been plenty of hyperbole but not enough substance. And as yet the medical profession isn’t rushing to produce microbiome specialists.
“Medicine is notoriously slow to adopt new ideas,” says O’Toole. He cites the case of Barry Marshall, an Australian doctor whose claim to have established a bacterial cause of peptic ulcers and gastric cancer was comprehensively ridiculed by the medical establishment in the 1980s. “About 20 years later he got the Nobel prize.”
The problem, he says, is that microbiologists have been very good at discovering gut bacteria and identifying what roles they might play, but they have been slow to develop mechanisms to establish firm causal links and practical applications.
“I personally hope it doesn’t become the solution for everything because it’s not going to be credible, it’s simply not true. There’s plenty of evidence that most human major diseases have a physiological or lifestyle basis, but it’s probable in some of those that the gut microbiota is a modulating factor that contributes to the overall risk.”
Right now, O’Toole would like to like to reduce the lower diversity microbiota in the elderly by means of dietary supplements. “But we worry that, as the World Wildlife Fund says, extinction may be forever. That if a particularly good bacterium is missing from an elderly person, we may not be able to get it back by diet alone.”
The solution in that case might be fecal microbiota transplantation, which O’Toole helpfully clarifies, “is the idea of transplanting someone else’s poo into a recipient”. Which neatly brings us back to where I started. If collecting your own excrement is counter-intuitive, then injecting it into someone else runs against every decent human instinct.
But it’s already happening in North America and O’Toole suggests that such transplants may help prevent ulceration of the colon – a condition that nearly killed my father some years back.In the end, it’s all comes back to what you put in and take out. And in that tireless cycle of life, we shouldn’t be appalled if not even our waste need go to waste.
It was commonly believed that too much stress was the primary cause of chronic gastritis and peptic ulcers. Then, in 1984, Australian physician Barry Marshall drank a petri dish of Helicobacter pylori taken from a patient with gastritis, and eight days later developed massive inflammation of the gut – he later shared a Nobel prize for his trouble.
Normally they cause few problems, turning sucrose into a “glue” to cohere to teeth, helping to form dental plaques. However, if S. mutans is given other types of sugar – glucose, fructose or lactose, for example – in addition to the plaques, it also starts producing lactic acid.
While dental plaques comprise hundreds of species of bacteria, it is this combination of lactic acid and plaque caused by S. mutans that is a primary cause of tooth decay.
It is already known that type 2 diabetes can be caused by a number of genetic and environmental components, but recent research has shed some light on a possible microbial element. It was found that patients with type 2 diabetes had lower rates of butyrate-producing bacteria, an important food for cells lining the colon.
It was also found that there was a clear relationship between people with type 2 diabetes and the specific species of bacteria found in their gut. This association is so great that the analysis of gut microbiomes can be used as a diagnostic test for type 2 diabetes.
Gut bacteria produce hundreds of neurotransmitters, which are used by the body to regulate learning, memory and mood. In addition, gut bacteria are also known to produce up to 95% of the body’s supply of serotonin, which is a contributor to feelings of wellbeing and happiness. The evidence suggests that an increased understanding of gut microbiota may produce novel treatments for anxiety and depression.
From TheTimelineProject.com
