For decades, undernourished infants across the world have been treated with a course of high-calorie, high-protein rich foods. The foods may come in various forms – from peanut-rich pastes to fatty milkshakes – but the common-sense philosophy is always the same: restore the most basic nutrients to the growing body as quickly as possible.
These “ready-to-use therapeutic foods” help to remove the immediate danger to the child’s life. But the battle is only half-won.
The period of undernourishment may be for just a few months, but consequences can last a lifetime. Throughout childhood and adolescence, the child will remain physically stunted and more vulnerable to infection. He or she also may show cognitive deficits, resulting in lower IQs, and reduced impulse control – which can mean falling behind at school and struggling to find employment as an adult.
We may be overlooking a key potential solution: friendly bacteria
But ground-breaking new research suggests that we may be overlooking a key potential solution: the tens of trillions of friendly bacteria living in our digestive tract, together known as the gut microbiota. “We are a sublime mixture of human and microbial parts,” says Jeffrey Gordon, the director of the Center for Genome Science and Systems Biology at Washington University in St Louis – and these teeming communities of invisible allies are now thought to be essential for our health and well-being. The gut microbiota is so important, in fact, that scientists such as Gordon often refer to it as a separate ‘organ’.
According to Gordon’s theory, many of the long-term consequences of malnutrition can be directly linked to a disruption of the gut microbiota. And by correcting that imbalance, you may be able to nudge a child’s growth back on the right path.
Funded by the Bill and Melinda Gates Foundation, Gordon has been leading pioneering studies in Malawi and Bangladesh to test the truth of this idea. And the early results look promising.
A better approach cannot come soon enough. More than 200 million children under five currently suffer from undernourishment.
The seeds of this new understanding can be found in a study by the South African doctor PM Smythe, first published in The Lancet in 1958. The exact role of our gut microbes in our health was still largely unknown at this time, but there was an emerging realisation that the mix was important – with some species helping to synthesise important nutrients and others consuming valuable resources before the host could absorb them.
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With this in mind, Smythe decided to examine children with kwashiorkor – a form of undernourishment that typically arises from a lack of protein, leading to fluid retention around the abdomen and a noticeably distended belly. Sure enough, he found that the pattern of species throughout the intestine was different for the children with kwashiorkor. In the stomach, for instance, he found several species of bacteria that normally inhabited the large intestine. This suggested that an imbalance in their gut microbiota might be linked to their weight loss. “The observation supported Smythe’s hypothesis that altered gut microbial communities might potentially contribute to the clinical picture of severe undernutrition,” explains Geoffrey Preidis at the paediatrics department of Baylor College of Medicine in Texas.
Crucially, Smythe also trialled treatments to restore the correct balance, giving the children antibiotics to reduce the colonisation of harmful bacteria and probiotic yogurts that aimed to seed the gut with the helpful species. The result, he reported, was a more rapid recovery.
It was only a small trial, however. A later attempt to replicate his particular treatment failed to show similar benefits. Scientists like Smythe also were limited by the technology of the day. They could only identify the relevant species of microbe by taking biological samples and then cultivating the bacteria in vitro – a laborious process.
Advances in genetic screening have now made this process a lot easier. “Today, we don’t have to grow bacteria to study them – we can determine which microbes are present in a sample just by sequencing their DNA,” says Preidis. “This is important because the vast majority of gut microbes are difficult to grow in the laboratory.” The availability of easy study methods has led, in turn, to a blossoming of new research on the many ways our gut microbiota can influence our health.
Species of ‘good’ bacteria such as Lactobacillus and Bifidobacterium can reduce inflammation and strengthen the gut barrier, for instance. They can also help to break down complex carbohydrates and proteins. Crucially, these good bacteria also aid the production and absorption of amino acids that are essential for growth. Given that the growing brain is one of the body’s hungriest organs, these benefits could be essential for healthy neural development.
A diverse gut microbiota can strengthen you against infections
Even more importantly, a diverse gut microbiota can strengthen you against infections such as shigella, listeria or salmonella. This is partly due to competition: the established bacteria make it harder for the pathogens to find a niche and thrive. A larger number of helpful – or at least, harmless – bacteria could also stimulate the immune system, which should also help us fight off infection from more damaging species.
If a poor diet reduces these natural defences, then undernourished children could quickly enter a vicious cycle, explains Jonathan Swann, an associate professor in microbiomics at Imperial College London. “Children who are undernourished often live in environments where they are exposed to a large amount of pathogens,” he says. “And this additive effect of greater pathogen exposure and reduced ability to clear them leads to more persistent infections, which can drive prolonged diarrhoea and leads to chronic inflammation of the gut. This, in turn, damages the gut structure and impairs its function.” The result would be further undernourishment, leading to stunting and cognitive deficits.
Worse still, they are also missing the microbes necessary to break down any food they do receive. “The microbiota is not able to finish the digestion – so first, they don’t have enough food, and then, they can’t digest the food you do give to them,” says Didier Raoult at the Aix-Marseille Universite, who studies kwashiorkor.
It’s clear that many plausible mechanisms exist through which an impoverished gut microbiota could contribute to the lingering long-term effects of malnutrition. The real challenge for Gordon has been to establish more direct evidence that the one causes the other.
Much of this research has taken place in Dhaka, Bangladesh and Malawi. Gordon is still moved by the close cooperation of the local doctors and nurses and by the families of the affected children who, despite their hardships, must take regular trips to the hospital to contribute to the project.
“The trust and the devotion of the mothers for their children are enormous at these sites,” he says. “And the trust they have in the healthcare providers is extraordinary and truly inspiring.”
One such study involved taking monthly faecal samples of children who had suffered periods of acute undernourishment. Using an advanced algorithm to sequence genetic material within the sample, the team identified 24 key species that appeared to be associated with healthy growth and compared their abundance in the two groups. Sure enough, they found the microbiota of healthy children evolved over time, while the microbiota of the undernourished children seemed to stay in an “immature” state, with less overall diversity and less ability to produce and absorb the nutrients they needed at each stage of their growth.
Crucially, the standard therapeutic foods failed to repair the balance in the long term. “So the children were walking around with a persistent developmental problem affecting their ‘microbial organ’,” says Gordon.
To prove the long-term consequences of this, Gordon next created a group of “gnotobiotic” mice, raised in extremely sterile conditions so that their bodies lack their own microbiota. He implanted these “empty vessels” with the gut microbiota of children who had and hadn’t developed the symptoms of undernourishment, such as stunting. This allowed the researchers to isolate the effects of the microbial diversity on the mice’s long-term growth and development while controlling all other factors.
In one of the first papers to use this technique, Gordon’s post-doctoral student Laura Blanton showed that the mice receiving the samples from the undernourished children experienced stunted growth compared with those receiving the samples from the healthier children. This confirmed the idea that the imbalanced microbiota can be a cause of the long-term developmental problems.
Gordon’s team have recently found similar results using gnotobiotic piglets, the biology of which is even closer to the human body. Once again, the state of their gut microbes predicted the piglets’ long-term prospects.
These findings have already won widespread acclaim, helping Gordon to earn the Royal Society’s prestigious Copley Medal earlier this year – a prize previously bestowed on the likes of Dorothy Hodgkin, who deciphered the structure of the hormone insulin, and Albert Einstein.
There is still much more work to be done. Preidis, for instance, points out that we still need to understand the exact chain of events that leads a child’s body into the vicious cycle of undernourishment and infection.
But given these strong associations, Gordon’s team is already looking for potential treatments designed to correct the imbalances in the child’s microbiota and restore healthy growth before it is too late. Taking place in Dhaka, the project is again a close collaboration with the local community to identify a therapeutic food that would be suitably adapted to the child and mother’s tastes, culturally acceptable, and potentially beneficial to the local economy.
They started by examining the foods given to the child during the weaning period, in case these might offer any hints about components that may be more or less beneficial. “We hypothesised that over the generations, mothers have made insightful observations linking certain foods to healthy growth,” he says. “We wanted to mine this inventory of affordable and available complementary foods, much like you would search a library, to identify ingredient combinations that could repair defective microbial community development in malnourished children.” The team then whittled down that list to develop new therapeutic foods and conducted short-term studies to test their effectiveness in restoring the development of the microbiota.
Gordon discussed some of his early results at the Society for Neuroscience meeting in Washington, DC in November 2017, and the team has recently submitted a paper to a journal. He is wary of disclosing too many of the details until they have passed through the rigours of peer-review – a standard process in which a new finding is subject to the scrutiny of other scientists. But he confirms that they look “promising.”
Gordon’s caution is understandable. Humans have spent millennia getting to grips with the human body, while the study of our invisible “microbial organ” still has a long way to catch up. We are only just beginning to understand the importance of that organ and the ways to encourage its long-term health. But if the treatments currently being tested do work, they could be a vital first step toward relieving millions of people’s suffering. As Gordon puts it: “this is just the beginning of the journey.”
David Robson is a science writer based in the UK. He is @d_a_robson on Twitter.
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