Gut gold: How 'poo pills' could reverse obesityby Donna Chisholm
Could poo pills reverse obesity? Auckland scientists are about to start a clinical trial of a radical new treatment – transferring gut bacteria from healthy, lean teens into their overweight counterparts.
A therapy that seems gross and engrossing in equal measures, gut microbiome transfer (GMT) is capturing the attention of researchers around the world as a treatment not only for obesity but also for a range of disparate conditions.
The Liggins study is one of a number of clinical trials being done in response to findings from the mid-2000s that a less diverse gut microbiome might be linked to obesity. In animal studies, mice dramatically lost (or gained) weight after receiving bacteria from lean (or obese) mice.
In the Auckland trial, thought to be the first in the world to study GMT in obese teens, 80 participants aged 14-18 will swallow capsules containing gut bacteria from the faeces of four lean donors in an effort to repopulate their microbiome and potentially reverse their obesity. It’s O’Sullivan’s job to supervise the hour-long process that turns donor poo into pills, to keep track of the bacteria in them and to chart the changes in the gut of the teens who take them over the following six months.
In the double-blind study, half the teens will be given placebo capsules, but O’Sullivan hopes that weight loss in the treated group will be apparent in that time, although “if other things don’t change, like diet and lifestyle, it’s possible that effect will revert”.
The gut microbiome may become less diverse over generations, says O’Sullivan. The bug population, established in the first two or three years of life, is the product of the bacteria we pick up at birth, those we are exposed to in our environment and those that develop as a result of what we eat.
“Potentially, we are inheriting flora from our parents that are less diverse than their parents’ because of things such as the soaps we use and the reduction in the quality of our diet. Maybe we can reverse that by doing, in effect, one big inoculation with a very concentrated, diverse flora.”
GMT uses the same principle as probiotic supplements, albeit on a different scale. Using a probiotic is like planting a forest with two trees; a microbiome transfer is like planting it with 1000 different species, says co-lead investigator Professor Wayne Cutfield. “You create a more robust forest. A diverse forest can cope with more ecological impacts.”
One in three New Zealand children is overweight or obese, and paediatrician Cutfield says the research has important ramifications for their future health.
Hard to reverse
“There are a whole lot of medical conditions associated with obesity, including diabetes, hypertension, heart disease, cirrhosis of the liver, liver failure and major breathing problems. The longer they last, the harder they are to reverse, even if you reverse the obesity. Teenagers are an ideal group because you’re getting in before all the bad consequences become entrenched.”
There are three possible outcomes, says Cutfield: it might work for a long time, for only weeks or not at all. He likens the current state of knowledge on microbiome transfer to the early experiments on treatments for type 1 diabetes in children in the 1920s. “Scientists were taking a pancreas from a dog, mushing it up and injecting that into children who were dying of diabetes. It saved their lives.
“Over the decades, they refined the process and realised it was insulin [that was having the effect]. We’re giving the whole microbiome to create diversity, but in time we might be able to better identify the key bacteria and culture them.”
At present, the therapy is limited by the need for donors and by the encapsulation process, which uses fresh stools. “It’s more complicated than hand-made chocolates and without scalability, it’s like having only five chocolates.”
Cutfield says a robust trial needs to show that the technique works before it can be developed further. Outcomes will be tracked at six, 12 and 26 weeks. But ultimately, the question may be whether GMT can nullify the adverse effects – on weight at least – of a poor diet.
“We’re at the proof-of-concept stage. Can it work at all, and, if patients have a poor diet, will their bacteria change back?”
He says that of all the Liggins research – which focuses on mother and baby health, epigenetics and nutrition – microbiome transfers are of most interest to the people he speaks to socially.
“People are utterly fascinated by it. I’ve never talked about any aspect of medicine or research among friends or people I meet that engenders so much discussion. The concept that bugs in your bowel have a role in your health and well-being is frighteningly foreign to a lot of people.”
But he says when he asked several teens if they’d be prepared to take a treatment using bacteria from other people’s bowels if it meant they could lose a lot of weight, the answer was yes. And, he says, the immediate response of overweight adults has been, “When can I get these? When can I have them?”
An international race is on to publish results of the first significant clinical trials on gut microbiome transfer in obesity, and Cutfield hopes the Liggins work will win it – but it will not be at the cost of thoroughness. A few trials have been registered, but none has yet reported, and he believes that may be the result of design or funding problems.
“The devil is in the detail. How the bacteria are managed, for example. If it doesn’t work, is that because a lot of the bacteria were dead before the transfer, and did they check that? A negative study, if it hasn’t been designed well enough, doesn’t give you an answer.”
Safety is paramount in the study, which gained ethics committee approval at the end of last year: stool donors are screened even more rigorously than blood donors.
The trial, which is expected to cost up to $1 million, is being funded mainly by Liggins philanthropic donors and the Government’s A Better Start National Science Challenge.
International scientific interest in microbiome transplants exploded after experiments in germ-free mice by Professor Jeff Gordon’s team at Washington University in St Louis, Missouri, in the 2000s. In 2004, they colonised the guts of germ-free mice – those born and raised with no gut bacteria at all – with microbes from normal mice. The germ-free mice ate the same amount of food as the normal ones, or only slightly less, but started putting on more weight.
A graduate student in the lab then transferred microbes from fat and lean mice into the germ-free mice. The mice with the lean donors put on 27% more fat; those with obese donors 47%. It was, Gordon told British science journalist and author Ed Yong in a feature in the Guardian last year, an “Oh, my God!” moment. “We were thrilled and inspired.”
They also showed the reverse to be true – that gut bacteria more common in lean mice can cause obese mice that eat them to lose weight.
“The world’s media treated these discoveries as both salvation and absolution for anyone who struggles with their weight,” Yong wrote. “Why bother adhering to strict dietary guidelines when a quick microbial fix is seemingly around the corner? ‘Fat? Blame the bugs in your guts,’ wrote one newspaper. ‘Overweight? Microbes might be to blame,’ said another. These headlines are wrong. The microbiome does not replace or contradict other long-understood causes of obesity; it is thoroughly entangled with them.”
Many hypotheses have been proposed as to how our gut bacteria affect weight gain and loss. One is that so-called obesogenic gut bacteria are more efficient at taking calories out of waste. For an adult, they can add another 150-200 calories a day to the dietary intake, by breaking down some otherwise indigestible material, typically short-chain fatty acids and carbohydrates, into absorbable calories. They also release chemicals within the bowel, some of which will disrupt the barrier between the gut and the rest of the body, allowing proinflammatory short-chain fatty acids to “leak” out, increasing the risk of insulin resistance and promoting fat deposition in places such as the liver. The bacteria also release other chemicals that may affect appetite and brain function.
As the Liggins work offers the hope of a new tool in obesity treatment, a three-year Massey University research project should provide new information on the links between obesity, the microbiome, diet and exercise.
About 250 women of either Pasifika or New Zealand European descent, half of them obese and half with a normal body mass index (BMI), will be studied and their gut bacteria genetically sequenced. The DNA of the bacteria will show researchers not only what types of bacteria are present, but also what they are capable of doing metabolically.
Lead researcher Professor Bernhard Breier says the research will assess the relationships between diet, perceptions of taste, eating habits, sleep and physical behaviour and how that may influence the microbiome and metabolism. The microbiomes of the “normal” and obese individuals will be compared.
Diversity or diet
Researchers around the world have hypothesised that thinness is linked with greater diversity of gut bacteria, but it’s yet to be shown whether a lack of microbiome diversity is a possible cause of obesity or simply the result of a poor diet.
“We don’t know the nature of the microbiota associated with certain dietary patterns,” says Breier. “For example, we don’t know how a complete Western diet compares with a Mediterranean diet. And we don’t know what the gene expression looks like in Pacific people who follow a traditional Pacific diet, versus those who follow a Western diet.”
The Massey study, to which the Health Research Council has contributed more than $1 million, is about half-way through.
In recent years, the potential role of the microbiome in conditions ranging from acne and arthritis to cancer and cardiovascular disease has excited the interest of research scientists – and media – worldwide. Our population of gut bacteria has become an unlikely poster child for the covers of magazines such as the New Yorker and the Economist.
But are we getting carried away by the hype? University of Otago microbiologist Professor Gerald Tannock, an expert in the microbiome, thinks we may be.
“The microbiome literature is very exciting and it’s wonderful that it’s promoted interest in this area. It has a high profile now, but it has been romanticised. People’s expectations are very high and may never be fulfilled.”
He’s also sceptical about books, such as the bestsellers by American gastroenterologist Robynne Chutkan, that claim to show how a change in diet can improve the microbiome.
“Really radical changes in diet will produce changes in the microbiota,” says Tannock, “but most of us are not [making them]. A lot of data shows that, for an individual, we have pretty much the same microbiota over long periods of time. Our impression is it’s a stable community and that fits well with ecological theory in general that microbial communities in nature are self-regulating and remarkably stable.”
He disagrees with Cutfield, who estimates that about 30-40% of the microbiome is stable, with the rest changing in response to lifestyle, diet and use of antibiotics and alcohol. “If you have a bad weekend and drink lots of alcohol, you’re going to really disrupt your gut microbiome. It recovers, but how quickly is still not clear.”
Work led by Justin O’Sullivan that has looked at Billy Apple’s microbiome (see box page 20) supports the idea that the microbiome changes over your lifetime, but that some of it is conserved.
Tannock says the differing opinions reflect the fact that our knowledge about the microbiome is far from perfect. And, he says, it’s more complex than just counting the types of bacteria present. Bacterial cells can switch their biochemical pathways, depending on the type of food they’re required to process.
“When they are presented with indigestible food A, they have a particular metabolism, but the next day, if they are presented with a different [molecule], they switch to a different pathway.”
Just because different people have a proportion of their microbiome made up of different species of bacteria doesn’t mean it’s going to work differently, Tannock says.
“In the bacterial world, there is a huge degree of redundancy, so different kinds of bacteria can carry out the same function.”
Much has been made of the number of bacteria in our gut and the significance of their potential impact on our health. A widely quoted, but incorrect, figure from 1972 suggested microbes outnumbered human cells 10 to 1. More recent estimates suggest the ratio is about 1:1, says cell biologist Professor Mike Berridge of the Malaghan Institute in Wellington. “We all have about 30-40 trillion microbes, 95% of them in our gut, and roughly the same number of cells in the body. The important thing is we need to recognise this and come to grips with the fact that as humans, we need to understand how to work with them, and that human diseases are very much related to our interface with our microbial population.”
Cause or effect?
It’s a lot more complicated than the chicken-and-egg scenario: does the makeup of the microbiome we inherit and develop as children predispose us to particular health outcomes, or do our lifestyle choices alter our microbiome in problematic ways? The answer is probably a bit of both.
“Bacteria and products from bacteria are talking to the immune system all the time,” Berridge says. “You might have a gene that predisposes you to obesity, but you can influence the way that gene or set of genes plays out by lifestyle choices. If you try to get the best diet you can, you’re going to end up with the best microbiome you can have.”
Berridge is particularly interested in the links between the quality of the diet and, in particular, how sugar affects obesity. “Sugars are produced in the digestive processes that the microbiome contributes to, and it’s going to be tweaking and modifying those.”
Some researchers believe the microbiome plays a very big role in weight control, but Berridge estimates it may be only a 10-20% contributor.
So, could poo pills inoculate us against our typically crappy diet? “Good question,” says Cutfield. “We’re hedonists; we eat too much and we don’t exercise enough. But we’ll untangle that from the study.” If the experiment works, he says, it’s potentially a sustainable treatment and should eventually be able to be produced relatively easily and cheaply in the lab with cultured bacteria. Most importantly, he says, based on clinical trials of GMT in other conditions, “we know it’s safe”.
Balancing gut bacteria
A checklist of common risk factors
Bacteria are our friends, not our foe, says American gastroenterologist Robynne Chutkan in her 2016 book The Microbiome Solution.
“In medical school, I was taught how to eradicate people’s germs. A quarter-century later, I’m teaching my patients how to restore theirs.”
When gut bacteria get out of balance – a state known as “dysbiosis” – a number of conditions can ensue, she writes, among them acne, allergies, bad breath and gum disease, bloating, yeast infections, fatigue, poor digestion and unexplained diarrhoea.
She says answering yes to even one of the questions from this checklist can indicate you’re at risk of dysbiosis:
- Have you taken antibiotics more than four times per year or for longer than two weeks at a time?
- Have you been on contraceptive pills or hormone replacement therapy in the past five years?
- Have you taken corticosteroids such as prednisone or cortisone for longer than two weeks at a time?
- Have you been on acid-suppressive therapy with proton pump inhibitors or histamine blockers for more than a month at a time?
- Do you regularly take ibuprofen, aspirin or other NSAIDS?
- When you were growing up, were you a picky eater who rarely ate green vegetables?
- Have you consumed large amounts of sugar and starchy foods?
- Do you drink more than 10 alcoholic drinks a week?
- Do you drink one or more soft drinks or diet soft drinks daily?
From The Microbiome Solution, Robynne Chutkan MD, Scribe Publications.
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