Gut feeling

C&I Issue 1, 2013

They say ‘You are what you eat’. Now scientists are starting to realise the extent of the truth in this pearl of wisdom. Recent research suggests that everything from psychiatric disorders to rheumatoid arthritis could be caused by the bacteria that live in the gut. Scientists are beginning to understand the key role that the human gut – and in particular the microbes living within it – has on human health.

What’s more, a deeper understanding of this emerging science could mean that these and other conditions might be alleviated – or even prevented – with something no more complex than a probiotic drink.

Microbes within the human microbiome outnumber the number of human cells in the body by 10 to one. A greater understanding of these ‘microbiota’ could help to improve the effectiveness of medical treatments, including some cancer therapies.

But much of this is some way in the future. At present, scientists are picking their way through the complexities of a field that has, up to now, been largely ignored.

‘We have a lot more bacteria in the gut than there are cells in the human body,’ says Veena Taneja, a research scientist at the Mayo Clinic in the US. ‘This suggests that they must be doing something.’

While in the womb, we have a ‘sterile’ gut, but the process of birth introduces bacteria into our intestines. This colonisation continues, and depends on the food that we eat and where we live. ‘We think that there’s a “core” of bacteria, determined partly by our genes,’ says Taneja.

She has been studying how the gut controls the body’s immune response. Many bowel-related diseases – such as irritable bowel syndrome (IBS) – are linked to gut bacteria. But the bacteria are also implicated in other autoimmune conditions.

Taneja had already looked at how a particular human gene, called HLA, makes the carrier susceptible to arthritis. Genetically engineered mice with the inserted HLA gene were also found to develop the disease.

However, Taneja wanted to look at what triggered arthritis – and in particular the likely role of gut bacteria. She found that two types of mice – whose genetic make-up differed by just a few amino acids within the HLA gene – developed different gut bacteria, suggesting there was a link. ‘But which came first: the immune system or the gut flora? Which one affects the other?’ she asks. ‘That’s the million dollar question.’

In Taneja’s study, the mice susceptible to arthritis had a much higher abundance of a specific family of bacteria – Allobaculum, which is similar to the hospital bug Clostridium.

However, the mechanism by which genes help to determine the microbiome is still not understood: the HCA gene could influence the immune system, and determine which bacteria stay in the gut and which do not. At the same time, an individual’s diet can alter the make-up of the gut flora.

‘The same species may still be there, but the balance will be different,’ Taneja says, adding that the presence of these species is not necessarily a bad thing, and the important factor may be their abundance. ‘We’re doing studies in mice to see if we can alter the balance of gut flora, and make the disease stop – or decrease its severity,’ she says. ‘We may even be able to prevent it.’

Adding enough ‘good’ or commensal bacteria may shift the balance in the gut towards a non-allergic response. Arthritis usually starts 10 years before any symptoms appear. Taneja says it might one day be possible – armed with information on a patient’s genes and the make-up of their gut flora – to feed them commensal bacteria, and alter the balance of their gut flora in a positive way.

‘This kind of therapy might stop arthritis in its tracks – but right now we are just at the start,’ she says. There are further leads to follow: genetic sequences from bacteria have been found in bones. Taneja will also see whether any bacterial DNA can be found in joints. And, like many mechanisms in the body, there is rarely a simple cause.

It’s a HIT

Researchers in the pan-European MetaHIT (Metagenomics of the Human Intestinal Tract) project are interested in another aspect of gut health. They have developed a method to determine who is at risk of developing diseases such as irritable bowel syndrome (IBS). The method, which they are now preparing for publication, is based on their earlier work to sequence the entire genetic information of the human microbiome.

‘We have identified prognostic markers that will allow us to predict a patient’s response to dietary or medical treatment, for inflammatory diseases,’ says Joel Dore, research director at the Institut National de la Recherche Agronomique (INRA) in France, and a project member.

Any medical treatment is likely to see ‘responders’ and ‘non-responders’. Dore says that non-responders could be turned into responders by altering the balance of their microflora. ‘Around 50% of people will always be non-responders, and this can’t be predicted,’ he says. ‘We hope we’ll be able to do something about it.’

He points to a parallel with CPT-1 – a treatment for stomach cancer – which is activated by microbiotic metabolism. This illustrates that there can be close links between bacterial activity and response to a treatment.

MetaHIT’s new prediction method has grown out of its use of genomic sequencing to identify the 3.3m genes contained in the human microbiome. This ‘catalogue’ of information was published in 2010, and was based on the analysis of faecal samples of 124 people across Europe – some healthy, some obese, some overweight and some with irritable bowel disease (IBD).

‘We tolerate these microbes because we have built this tolerance from birth,’ Dore says. ‘Microbes tell our immune cells not to over-react. If there’s a distortion in the dialogue between the two, we get inflammation. It can be low-grade – like obesity – or high grade, like IBS.’

His team has been looking at what he calls ‘disbiosis’ – a distortion in the composition of the human gut microbiota. He says the ‘population spread’ of bacteria in the gut can be an indicator of disease. ‘There’s plenty of research to show that unhealthy people can have a different microbiota to healthy people,’ he says. ‘This is especially true in immune-mediated diseases, such as IBS, obesity, Type 2 diabetes.’

The 3.3m genes in the ‘metagenome’ equates to around 160 species of bacteria. Every person hosts around half a million of these genes in their gut, but the specific genes, and specific bacterial species, within each person can vary. Half of the genes in any person’s gut will be common with half of the population. But most of the genes –around 2.4m in total – are quite rare. ‘We only see these genes in around 20% of people,’ says Dore.

Geography, age and race did not seem to be a factor in determining different ‘entero-types’ – which seemed to break down into three distinct groups. Rather than a typical ‘bell curve’ – which would be seen for a population’s height distribution, for example – he says that people split quite neatly into three defined entero-types.

‘There’s currently a battle among specialists as to why this happens,’ he says. ‘My view is that this separation is related to differences in genes.’

Dore believes that bacterial species in the gut are arranged in networks, and communicate with one another. And understanding this could be the key to planning therapies based on diet. ‘Ten years from now, a doctor will be able to identify the genes important to your disease – as well as having a profile of your microbiota to help to manage it,’ he says. ‘I’m convinced that a better understanding of microbiota will be crucial in the treatment of patients.’

Brain function

It seems only logical that diseases related to the gut might have a connection with the millions of ‘foreign’ bacteria that are lurking within it.

But, in addition to autoimmune diseases like rheumatoid arthritis, scientists are finding that gut flora can also have a direct effect on the brain – and on behaviour.

‘There’s an increasing realisation that the microbiome can have a profound impact on all types of health,’ says John Cryan, head of the department of anatomy & neuroscience at University College Cork in Ireland.

Cryan is a neuroscientist, and one of the few with an interest in gut flora. He is interested in behaviour and stress, and says that both can be modulated by altering gut flora. ‘Giving an animal a probiotic for six weeks had an anxiolytic [anti-anxiety] effect. The bacteria reduced behaviours related to stress, and reduced the stress response in general,’ he says. ‘It’s as if we were giving it Valium.’

The particular bacterium was a strain of Lactobacillus rhamnosus, but one that is not commercially available.

In a second study – published recently in Molecular Psychiatry (doi: 10.1038/mp.2012.77) – he used germ-free mice to assess how a ‘sterile’ gut affected brain activity, and made a startling discovery: levels of serotonin – a hormone that regulates mood and emotion – were increased in germ-free mice.

‘We found changes in serotonin levels, and in other factors that are very important for brain development,’ he says. ‘That was a big finding.’

There were changes in the way that serotonin was metabolised, and reductions in levels of a brain protein called brain-derived neurotrophic factor (BDNF). ‘This is further evidence that it’s due to direct communication between the brain and gut,’ he says. ‘These animals also had an altered response to anxiety.’

More tellingly, when the animals were re-colonised with bacteria, some of their ‘normal’ behaviour and brain chemistry could be restored, but serotonin levels could not – suggesting that this element is irreversible.

‘We think that extra serotonin may increase susceptibility to psychiatric disorders,’ he says.

Cryan’s team is yet to look at specific bacteria in this study, but he believes it will be an important step. ‘We need to understand why some bacteria have an effect and some don’t,’ he says.

This part of the study could fit neatly with the work done by MetaHIT, to identify people with specific compositions of gut flora – and tailor a personal cure. He also sees a time when doses of specific bacteria could be used as a therapy – but in this case, to treat psychiatric disorders. ‘We may be able to identify that a particular strain of bacteria will help a specific person,’ he says.

His next step is to start testing this on patients, to see if probiotics can affect stress in humans. ‘Our findings highlight the role that bacteria play in the communication between gut and brain,’ he says. ‘This opens up the opportunity of developing microbial-based strategies for treatment for brain disorders.’

Despite this increased understanding, it is unlikely that a quick slurp of a yogurt drink will work on its own. MetaHIT’s Joel Dore says that future therapies will rely on an improved knowledge of gut bacteria, but will not work alone to ‘cure’ conditions such as obesity. ‘It would probably be one component of the overall treatment,’ he says. ‘Current recommendations – such as exercise and eating healthily – will still be important. But we hope we can identify specific microbiota that need to be modulated.’

Lou Reade is a freelance science writer based in Kent, UK

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