This feature story was first published in print and online by The Medical Republic on the 24th February 2016
A consumer website proclaims, “Explore your microbiome” and “uncover the greatest enigma in medicine today.”
All it takes is a faecal swab and a postage stamp and Mu-biome.com will send you back a census of all the denizens that colonise your gut. Also trending are probiotics and faecal micriobiota transplants.
The benefits of yoghurt for gastroenteritis were proclaimed as far back as pre-Christian Rome. And in 1907 Elie Metchnikoff gave credit to gut microflora for the longevity and cognitive wellbeing of Bulgarian peasants, starting a craze for yoghurt cafés among the European gentry.
But it’s only in the last 15 years that research has shown just how much bacteria help us exploit nutrients in our diet and maintain health.
Conversely, an imbalance or a dysbiosis of bacteria, is now increasingly being linked as a contributing factor in obesity, inflammatory diseases, asthma, liver disease and even affects mood and cognition. Other experts believe, however, that it is infectious strains of bacteria, not the imbalance, that are to blame.
Perhaps we shouldn’t be so surprised about the influence that the gut wields over our health.
If we consider, for example, a typical tennis court, that’s about the area our lungs would cover if we flattened them out. Our skin, however, peeled off and spread out would cover only one of the service courts. That’s one of the reasons lung diseases such as pneumonia are so common; there is a lot of surface area for bacteria to colonise.
But when it comes to the gastrointestinal tract, the numbers become really amazing. If flattened out, the GI tract would cover 400 square metres and with about 100 trillion bacterial cells living there, the tract is the densest known ecosystem in the world.
Since 2012 the National Institute of Health has been investing in the Human Gut Microbiome Project to catalogue these bacteria and their genetic baggage. There are tens of thousands of known species, of which typically no more than a third are common between individuals with each population highly personalised by diet and lifestyle.
So we know gut bacteria perform a number of critical functions in our body, and we know that the makeup of every person’s gut population is unique. We don’t know what exactly makes for a good microbial signature, other than that greater biodiversity in the GI tract seems to improve overall health.
WHAT HAVE YOU DONE FOR ME LATELY?
For example, in the chronically overweight there are fewer separate populations of microbes than in healthy people, says Professor Andrew Holmes, a microbial ecologist who leads a research team at the Charles Perkins Centre at Sydney University.
But what comes first? Is the person overweight because of lower gut microbe diversity, or vice versa?
Research suggests gut microbes are critical to how food is processed in the gut. Clostridial species, among others, break down dietary fibre and resistant starches that would otherwise defeat the digestive capabilities of the GI tract. Colonic fermentation by such microbes is responsible for satisfying between 10% and 30% of our daily energy requirements, and producing vitamins B and K and short chain fatty acids, says Professor Holmes. Bacteria also transform 95% of dietary polyphenols (found in dark chocolate and red wine) into absorbable metabolites.
A recent study in Cell found that people had different glycemic responses immediately after identical meals depending on their microbial mix.
Professor Holmes thinks the gut microbiome determines whether energy is available to burn right away, is stored as fat or glycogen, or is excreted.
So can we start thinking about microbiotic weight-loss pills? Not yet, says Professor John Dixon, Head of Clinical Obesity Research at the Baker IDI Heart and Diabetes Institute.
Research such as that behind the Cell study harnesses extremely sensitive genetic technology that can detect micriobiota we never knew existed. “You can see thousands of things and say ‘Ooh, I see a pattern there and a pattern there’,” says Professor Dixon. “But is the pattern cause or effect? We don’t know that yet until we can do intervention studies.”
But we do know that metabolic health is much more complex than simply balancing calories in and calories out, says Professor Dixon. “The relevance of that to human obesity in an open biological environment is almost zip. If people think we just eat less and exercise more and we’re going to solve the problem of obesity, they’re nuts.
“Because we regulate. In our brains, in our hormones in our fat and, it now appears that the gut microbiome has a part of that regulatory process – but only a part of it.”
Professor Dixon is going to “let the dust settle” before making any strong predictions.
But if there is a causal link between gut bacteria and a healthy body weight, research suggests humans require a diversity of microbe populations in the GI tract. Unfortunately, Western societies seem to have evolved lifestyles that do no favours for the microflora.
The shift to a more agricultural diet 10,000 years ago was the first step in the homogenisation of our diets, coupled with the more recent trend of stripping fibre off grains. And from the mid-20th century a barrage of processed foods and antibiotics has been responsible for the collateral damage destruction of many innocent bacteria. Even modern-day hunter-gatherers carry microbial species that have long been lost from our gut.
A 2015 study in Nature Communications showed that rural South Africans fed American-style food for only two weeks showed an increase in bile acid and in bile-tolerant micro-organisms and a decrease in the presence of the fibre and starch-degrading bacteria that promote a healthy gut lining. What’s worse, there was an increase in mucosal inflammation and proliferation of other histological biomarkers for cancer risk.
Some good news from the study was that African-Americans put on a traditional African diet high in beans and vegetables showed recovery of butyrate and bile to healthy levels for the gut lining.
Excess bile acids don’t just aggravate the epithelial barrier, they lead to oxidative stress and DNA damage that can precede colon cancer. In population studies, colon cancer occurs at a 13-fold higher rate in African Americans, so the microbes may play a crucial role in this disease.
But there are some microbes that play a more sinister role in carcinogenesis.
Helicobacter pylori is implicated in half of all cases of gastric cancer because it produces mutagenic ammonia and phenols, and a recent study showed that serrated polyps in the caecum could be locally seeded by infectious invasion of the epithelium. A rich native microbiota may keep these invaders at bay.
Two recent findings spell bad news for the native bacteria. Consuming a diet of highly processed food even a few days a week is as bad for microbial diversity as eating that food every day would be, according to breaking research from the University of NSW. In other words, that salad you had for lunch isn’t enough to make up for junk-food binges on the weekend. Conspicuously absent in the gut of experimental rats in this study were the microbial species capable of metabolising flavonoid polyphenols and reducing gut inflammation.
A report in January’s Nature showed that the variety of gut microbiota diminished progressively between each generation of rats fed a diet low in fibre and resistant starch. And once a particular type of bacteria was completely gone they did not reappear in later generations if the diet was changed to include more fibre and resistant starch. However, if a type of gut microbiota was only suppressed, but not eliminated, within a generation it could recover with dietary changes. This might explain how obesity and some metabolic and inflammatory disorders could be inherited.
FRIEND AND FOE
Gut microbes might also explain the link between obesity and some forms of inflammatory bowel disorder, such as Crohn’s disease and ulcerative colitis.
Clostridial bacteria release the short chain fatty acid, butyrate, which activates regulatory T cells to suppress the more trigger-happy components of the immune system. These microbes also stimulate gut endothelia to produce mucous which they burrow into to shield themselves from the acidic environment of the gut. When clostridial populations are compromised and the mucous layer is thinned, other bile-resistant bacteria can get closer to the gut lining to aggravate epithelial cells.
The poster child of the anti-inflammatory bacteria is Faecalibacterium prausnitzii. It was identified in 2008 as being highly depleted in ileal biopsies of French patients with Crohn’s disease, and similar associations were found in East Asian populations with heritable colitis. Supplementing the diet with the soluble fibre, inulin, can reduce systemic inflammation in obese patients and increase the count of F. prausnitzii.
But gastroenterologist Professor Thomas Borody, founder and director of Sydney’s Centre for Digestive Diseases, suspects that currently unidentified organisms are to blame for provoking the immune response that arouse inflammation.
He says that subtle changes in microbial balance from dietary changes aren’t enough to explain disease. “That’s not a sick poo. Real dysbiosis is a result of the stool being infected with something.”
Of course, infection by the nasty cousin C. difficile or even Salmonella, Shigella or Campylobacter, leads to distal colitis detectable by endoscope. “But colitis is caused by a group of different infections that live in the biofilm underlying this dysbiosis,” Professor Borody speculates.
The Centre for Digestive Diseases have treated about 20 cases of apparently idiopathic ulcerative colitis with faecal transplantation. These were sporadic cases, and randomised clinical trials for the treatment are now underway in Australia and the US. Professor Borody is confident that the infectious culprit will be revealed for the inflammatory bowel disorders, and that less invasive therapies will emerge. “Hopefully before I die we’ll have it solved,” he says.
The intimate relationship between our own cells and our gut microbiota also has profound implications for the maturation of the immune system and emergence of allergies. The GI tract of the newborn immediately becomes colonised with bacteria through the birth canal and later during breastfeeding.
During a critical programming window, the infant’s immune system learns which bacteria to consider normal and best left unmolested.
A poor diversity of gut microbes at three months of age has been associated with later sensitivity to foods such as egg, milk and peanuts. And a recent study in Science Translational Medicine showed that relative depletion of four particular gut bacterial genera during early infancy was linked to an increased risk of asthma by the age of five. Infants given antibiotics in the first six months also have a much greater risk of developing allergies, underlining the hazards of wiping the bacterial slate clean.
We’ve all experienced that feelings of butterflies in the stomach. Who would have thought that microbes might be playing a part instead?
There is compelling evidence linking the nutrient-poor and energy-dense industrialised diet to changes in mental health and cognition, according to a recent review in The Lancet.
A decade ago, leading author Professor Felice Jacka of Deakin University was one of the first to demonstrate associations between diet and clinical depression and anxiety, independent of socio-economic status and other well-known predictors.
Her team is now looking at intervening in depression with a Mediterranean diet, which is also known to nourish friendly bacteria and metabolic health. It’s no coincidence that what’s good for the brain is also good for our bacterial chaperones since the brain’s high metabolic rate demands a ready supply of vitamins, fatty acids and minerals.
Furthermore, it is believed that some neurodegenerative and psychiatric conditions, including depression and schizophrenia, may be partly inflammatory in origin.
Given the novelty of the field, the research on the role of gut microbes in mental health is still patchy. One 2014 intervention published in Psychopharmacology showed that the taking prebiotic carbohydrates over three weeks reduced stress in healthy people.
More direct evidence of links between bowel and behaviour have come from rodent studies. In a mutant mouse model, oral treatment with probiotics corrected both gut permeability as well as the stereotypic, anxious and impaired social behaviour.
The authors suggest that a leaky gut permits harmful metabolites to enter the circulation that then disturb brain function and development. Anxious behaviour in germ-free mice can also be reduced by recolonising the rodents with normal gut microbiota and depressed behaviours have been treated with specific probiotics.
These recovery effects were blocked by transection of the vagus nerve, which in human patients can be stimulated to relieve depressive symptoms. In fact, the enteric nervous system itself has more neurons than the spinal cord or the peripheral nervous system and gut microbes stimulate local synthesis of dopamine, norepinephrine and serotonin.
Long-term changes to the brain have also been observed when you mess with the gut. In the gut-free mouse studies described above, the behavioural changes were associated with altered expression of transmitter receptors and other synaptic proteins in several brain regions. The recolonisation intervention was more effective in juvenile mice than in adults suggesting a developmental window during which the neural network is most sensitive to change.
The network between the gastrointestinal, immune and nervous systems is revealing itself to be ever more intricate, with the gut microbiota playing a bewildering role that could never have been imagined a decade ago.
The implications for human health are so profound that according to some experts it is as if science has just discovered a previously overlooked organ of the body.
These organisms have been so intimate with our inner workings for so long that certain species have co-evolved to prefer hosts with specific genotypes. The future of personalised medicine will therefore have to be very well-informed about the army within. It’s no longer a case of You are what you eat, so much as You are what you feed.
Prebiotics and poo pills
The prebiotic recipe for feeding a healthy gut biome includes complex carbohydrates in the form of dietary fibres and starch, and polyphenols, organic metabolites that promote the abundance of bifidobacteria and lactobacilli.
Soluble fibre: Dissolves in water and is contained in oats, barley and green vegetables. Inulin is a soluble fibre particularly enriched in garlic, leeks, banana and asparagus.
Insoluble fibre: Non-fermentable roughage found in cereals, wheat-bran and brown rice, promotes regular bowel movements.
Resistant starch: Root vegetables, whole grains and legumes such as beans and lentils (also known as fermentable insoluble fibre)
Polyphenols: Dark chocolate, red wine (tannin), olives, nuts, tea and coffee
Meanwhile, commercial probiotics such as Yakult and Activia are a $40 billion per year industry but do they do any good?
A review of clinical findings suggests consuming these cultures can sometimes help deal with traveller’s diarrhoea or recolonisation of gut bacteria after a course of antibiotics. However the Lactobacilli and Bifidobacteria usually found in these formulations represent just a minute fraction of the overall gut biota and their functional repertoire is limited.
“Claims for those commercial strains generically improving immune function are neither here nor there,” says Professor Holmes of Sydney’s Charles Perkins Centre. “There’s been a lot of quite poor science that’s tarnished that field.”
It’s also been reported that only three of the eight products typically found on the shelves survive 90 minutes of exposure to gastric acid and that capsule forms often don’t deliver as many bugs as claimed on the packaging.
None of the probiotics currently on the shelves have been registered with the TGA with claims of a specific health benefit.
“The unambiguous thing you can say about them is that they are safe, so people shouldn’t be afraid of taking them,” says Professor Holmes. And he warns against getting too hung up over the curative properties of individual bacterial species. “It’s the net output of the whole community that’s important,” he says, and across different human populations the same functional role may be performed by different bacterial species based on their genetic profiles.
Professor Thomas Borody, of Sydney’s Centre for Digestive Diseases, is more sceptical still of current probiotics. “It’s very hard to culture pure bugs. The potential for contamination is enormous.” By contrast, diverse faecal microbiota are resistant to colonisation. “If you put faeces on a culture plate and try and grow another bug it just will die. Why? Because bacteria make a million antibiotics,” says Professor Borody.
Faecal micriobiota enemas taken from healthy donors are clinically very effective at displacing infections by C. difficile, particularly where multi-drug resistance has ruled out antibiotic therapy.
“We have close to a 100% success rate,” says gastroenterologist Professor Borody, who has performed these on thousands of patients.
But Professor Borody is particularly excited about the capsules of lyophilized faecal bacteria his team has refined to a purity of 99%.
“We have now commenced treating patients in-house with encapsulated full spectrum micribiota which has no crud in it. It doesn’t smell. It’s just a powder.”
Just two capsules replace the need for an enema or colonoscopy in patients with recurrent C. Difficile infection, he says Professor Borody. “So far we’ve succeeded in treating eight out of eight patients, so it’s early days.”
Once clinical trials have been completed, Professor Borody expects to get TGA approval within two years.