Medical student Sophie* went on her first diet at the age of 8. It didn’t work, and nor did the dozens that followed in her childhood and early teens.
“From the very beginning of school, I was always ‘the fat kid’. I’ve never been a normal weight.”
At the age of 11, she was 72kg and by 16, her weight had ballooned to nearly 100kg. With her height at 1.72m, that gave her a grossly unhealthy BMI (body mass index) of 33.8.
She concedes her diet wasn’t that healthy: she enjoyed junk food, but says that was a product of her environment. “It’s so normalised and you don’t really have control over what you’re eating.”
And yet, by the time she finished high school, she had lost 30kg and gone from a size 20 to a size 10. In the seven years since, she has not been on a single diet, yet today she is a fit, active and lean 67kg with a BMI of 22.4 – safely in the “normal” zone. She’s energetic, enjoys exercise and no longer gets puffed going up a flight of stairs.
She has University of Auckland scientists to thank for her remarkable transformation. In 2018, Sophie was one of about 40 obese teens in a research study who received a pioneering treatment known as a faecal microbiota transplant: in other words, they swallowed pills made from the poo of slim and healthy donors. The main ingredients in these “crapsules” are bacteria, which together dictate whether our gut microbiome functions well or badly.
“The microbiome is literally the new frontier of health research,” says Liggins Institute paediatric endocrinologist Professor Wayne Cutfield, a co-leader of the study with his colleague, Liggins director Professor Justin O’Sullivan. “Changes in it occur in so many diseases, and if it could be altered by a treatment, that could be totally transforming.”
Poo does not contain just waste matter that the body no longer needs but beneficial bacteria. Healthier people have a greater diversity of this “good” bacteria in their stools and the “super donors” involved in the research stood out for this reason. Each recipient in the trial received pills contributed to by four donors.
Cutfield describes the overall effect as being similar to the differences between a pine forest and a tropical rainforest which has a diverse range of trees. “You know that with climate change, a pine forest could all fall over, but a tropical rain forest with a whole range of different species in it is going to be more robust.
“We know that there are healthy bacteria in the gut that are really important for our health and wellbeing and we want to maximise the diversity of healthy bacteria.”
The team’s next goal is to identify precisely what effect each bacteria is having, which may lead to the development of a more precise treatment involving fewer pills.
Poo diversity
Although diet, exercise and genetics have long been linked with obesity risk, research since the mid-2000s has targeted the microbiome, with studies revealing that people who are obese have a distinctly different and less diverse composition of bacteria in the gut.
In animal studies, mice dramatically lost or gained weight after receiving bacteria from lean or obese mice. The mice work was led by Professor Jeff Gordon, at Washington University in St Louis, Missouri, who described the finding in 2004, as an “Oh, my god” moment. “We were thrilled and inspired.”
The world’s media treated the discoveries as “both salvation and absolution for anyone who struggled with their weight,” science journalist Ed Yong wrote in The Guardian in 2016. “[But] the microbiome does not replace or contradict other long-understood causes of obesity, it is thoroughly entangled with them.”
In 2018, the Liggins team began treating more than 80 teens aged 14-18 with poo pills or placebos to find out if the effect in mice could be replicated in humans. Initial results from the first six months of follow-up were somewhat disappointing, with limited weight loss among the recipients of the “active” pills.
But what the scientists did notice was an improvement in the overall health of the gut. A deterioration in gut health is linked with the onset of so-called “metabolic syndrome” – indicators which put us at risk of high blood pressure, heart disease, abdominal obesity and diabetes.
Sustained benefits
Metabolic syndrome is relatively common in New Zealand, but its prevalence varies according to ethnicity, with 39% of Pacific people and 32% of Māori having the condition, compared with 16% of Europeans.
Between 30% and 40% of the teens in the Liggins study had metabolic syndrome, so the improvement in that condition became the impetus for a four-year follow-up study on 55 of the original participants which has just been published in the prestigious Nature Communications journal.
It’s the first long-term follow-up of microbiome transfers and shows that the transplanted microbiota are thriving. Those who received the poo pills showed sustained positive impacts on four elements crucial to the development of metabolic syndrome – high blood glucose, lipids, waist circumference and blood pressure – as well as an apparent weight-loss difference of an average 11kg. Although not all participants lost weight, most did – one person even dropped a staggering 50kg.
Obese people have a distinctly different and less diverse composition of bacteria in their gut.
The researchers are undertaking more follow-up studies to find out if the poo pills might also have an impact on other conditions linked to the microbiome, including anorexia, anxiety and autism.
Studies have suggested an association between antibiotic use in early childhood and later obesity, suggesting the drugs adversely affect the diversity of gut bacteria.
We’re born with a virtually sterile gut, and the micro-organisms that develop during the next two to three years depend on a range of things, including breastfeeding, diet and environmental exposure. If a child is in a neonatal intensive care unit and artificially fed, for example, their microbiome is completely different.
One of the major components of breast milk is a complex milk sugar called oligosaccharides, the principal role of which is to feed and nourish the gut bugs.
“It’s really only over the last few decades that we have realised that’s what its role is,” says Cutfield. “It’s likely that breastfeeding to six months at least is likely to provide the greatest start to your gut microbiome. You’re trying to develop it early on. But having said that, any breastfeeding is better than none.”
Excitement factor
Does the make-up 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? It’s a lot more complicated than that chicken-and-egg scenario – the answer is probably a bit of both.
Obviously, genetic risk is still a big contributor to obesity, along with poor diet and lack of exercise.
But Cutfield says the long-term benefits from a single course of the poo pills – participants took 28 capsules over two days – means the researchers have high hopes it may lead to an over-the-counter treatment.
“The natural history of most obesity treatments or interventions is some improvement and then deterioration, but this has lasted four years,” he says. “We didn’t see much effect after six months, so it took time to evolve and develop.”
The excitement factor is huge, he says. “I think it has enormous potential. We are on the journey of understanding the importance of our microbiome, and when you do intervention studies demonstrating benefit, it becomes a whole new avenue of treatment.”
O’Sullivan agrees. “We were blown away,” he says, but adds that the bigger surprise was not that the treatment worked, but how long it worked for. “We knew we could see them (the gut bacteria) at six months but this is another three and a half years – years when people aren’t doing anything … they’re not changing their diets or exercise.
“This is really important. I like to use the word ‘restore’. What we’re showing is that one treatment with no modification of lifestyle or anything else, can affect their metabolic syndrome scores. We don’t know that we’ve got it back to what it should be, but we’re showing that you can take organisms, put them back into the system and they will actually engraft and become part of that recipient. I didn’t think we would look four years later and still see the same ones there. We never thought about that longevity.”
But which bacteria?
The team has identified a small clutch of bacteria – about four or five species of the more than 250 transplanted – that are associated with or predict response.
“The way in which these gut bacteria influence metabolic syndrome and obesity is complex because they work in multiple ways,” says Cutfield. “Gut bacteria release products and chemicals into the gut that then get into the bloodstream. Those products have the capacity to influence appetite, behaviour, how well insulin works – if insulin works badly, that increases your risk of diabetes -- and they can influence inflammation.
“They can also influence the growth of fat cells, which you don’t want.
“However, there are a small number of bacteria that appear to be associated with improvement in metabolic syndrome. And what we are now trying to do is to select those out, isolate them, grow them and then test that combination of those handful of bacteria to see whether they do indeed improve metabolic syndrome and potentially obesity. And if that is the case, then that can be a commercially available product.”
The bigger surprise was not that the treatment worked, but how long it worked for.
O’Sullivan is now overseeing work to isolate and grow the bacteria identified as having the biggest positive effects. These will then be tested either in an animal model or a small group of people to find out whether taking a smaller, more targeted cocktail is effective on its own. This would mean future treatments involving far fewer pills than the dozens the first participants had to take.
The capsules are produced on site within an hour, with about 70-80% of bacteria from the donor poo surviving the process. The stool is blended, then goes through a series of washes and filtrations before the bacterial component is packaged into capsules, frozen and safety-checked.
When the work began, Cutfield likened the state of knowledge on microbiome transfer to the early experiments on treatments for type 1 diabetes in children in the 1920s.
“Scientists were taking the pancreas from dogs, 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. 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.”
It’s possible, he says, that an over-the-counter treatment might be available as soon as five years from now, in much the same way as probiotics are sold in supermarkets. He doesn’t think there will be major pushback from consumers reluctant to swallow a poo pill – Sophie told the Listener she had no side effects at all.
As Cutfield points out, the popular probiotics also come from the gut microbiome. “In part, it might depend on how it is perceived and regulated because it’s kind of a bit of an orphan … It’s not your classical drug that’s manufactured in the lab.”
Committed benefactor
An important advantage for the research done so far – and the studies to come which could bring the treatment to market – is that the work has been largely privately funded, thanks to the multimillion-dollar investment of property developer turned Otago high country farmer Tim Edney, who expects to keep paying for the ongoing research. The former engineer learnt about the Liggins work from a speech Cutfield gave to his Rotary club about a decade ago.
“I’ve always been interested in the connection between the brain and the gut,” says Edney. “You can’t be an engineer without marvelling at the human body. I was in the control system side of engineering and you couldn’t make a control system that was 1% as good as the human being.”
He says his investment in the work has enabled the researchers to be more nimble than they may have been with traditional funding. He wants to encourage other philanthropists to support research of this type “which is no constraints, blue-sky research, outside the system”.
At the start, he says, there were discussions about whether the researchers could afford expensive DNA tests for each participant. “I just said, ‘Don’t worry, I’ll cover it.’
“But unfettered research is not fashionable for philanthropy. I just let the research run; you don’t dictate what they want to do. I’m so outcome-focused, it’s just not funny. I don’t care how we get there. I won’t flout the ethics, but I just want it to be done.”
His three children are “very supportive”, he says, despite the fact “I’m spending their inheritance”.
The Liggins team has been inspiring to work with, he says, because of their “sense of purpose”. He meets with them about once a month and has also met many of the participants in the study.
For him, the success so far is no surprise. “I expected us to be successful because we were doing all the right things. We didn’t go down blind paths.”
For Cutfield, what makes the work potentially the most important of his career is the prospect of making people metabolically healthier without drugs with a one-off treatment that has a long-lasting effect.
“There is a general sense from many people that they like to try a more natural, healthier option than say, drug treatment. But ultimately, if we were to isolate and culture these bacteria up, that wouldn’t be outrageously expensive. Even if one treatment was moderately expensive, that’s a hell of a lot cheaper than drugs that currently aren’t funded.”
Far-reaching change
For Sophie*, her involvement in the 2018 research has been literally life-changing. She had originally planned to study for a bachelor’s degree in biology, but after participating in the research decided on a medical career and is now well on her way to becoming a doctor. “When I signed up, I didn’t know what to expect. The environment was exciting, but the kindness and passion of the staff were most influential in me pursuing medicine as a career, something I hadn’t considered until then.”
She says the initial weight loss she experienced during the study was the first time she’d seen a meaningful change in the scales.
“That sense of momentum gave me hope I hadn’t had before. Over the following year, I leaned into that motivation. I changed how and when I ate, paid attention to what made me feel well and slowly reclaimed my body.”
The experience has also made her reflect on society’s attitudes to weight.
“As a teen, I always felt that my weight arrived before me. The assumptions and biases people hold around obese people are immense, and losing weight only highlighted this further for me. People who had bullied me because of my weight were suddenly inviting me to join them at lunch. It was both exciting and unsettling – my worth hadn’t changed, I was still the same person, but the response I received was so different.”
*Not her real name.
The sniff test
When it comes to suitable donor selection, not just any old poo will do.
Just four people provided the donor poo that was processed into the pills for the Liggins research, in part because the bar for their health and fitness was set so high.
“We needed to screen well over 100 people who thought they were eligible,” says Professor Wayne Cutfield. “That just shows you how hard it is to make it as a donor.
“If you were to ask me what the risks are for our donors of metabolic syndrome, I would say it will be zero because they’re so rigorously screened. They’re not just your average person, they are the best of the best. This is a person who eats well, exercises well and who’s completely healthy.”
The screenings also included family history – the researchers did not want to risk transferring conditions linked with the microbiome, including asthma and other allergies – and scans to check body fat. “They needed to be squeaky clean.”
The donors ranged in age from 18 to 32. One of them was Auckland physiotherapist and personal trainer Tim Chen, now 31. Chen emigrated to New Zealand from China with his parents at age 6.
A keen basketballer and football player since his school days, Chen became a regular gymgoer at 18 – focusing on weightlifting and “functional fitness”, mainly he concedes, to impress the girls.
“I’ve seen photos of myself at that age and I was pretty skinny, so the goal there was to gain some muscle.”
When he took part in the research, he weighed about 77kg and was 1.76m tall. His bone density scan estimated his body fat at a healthy 15-18% – male competitive athletes typically have 6-13%.
Now married with a 3-year-old daughter, he still hits the gym at least three times a week.
Although he’s always had a high-fibre, healthy diet, he confesses he probably eats more junk food these days, including chips, and sweet treats if they’re around.
He was unfazed by his role as a poo donor in the study. “I’ve always been quite proud of my bowel movements. They’re very regular.”
But he’s most proud of his involvement in research that is having such positive results. “I think it’s awesome, I hope this goes on to help a lot of people.”