The key to ending malnutrition may lie in the gut microbiome

In his work as a clinical nutritionist in Accra, Ghana, Ishawu Iddrisu knew there must be a better way to treat the roughly 15 children with severe acute malnutrition who landed in his office each month. The primary option available to him was the nutrient-dense paste known as ready-to-use therapeutic food, or RUTF, which combines ingredients such as peanuts and milk powder and can help severely malnourished children gain weight quickly. The problem was that Iddrisu was treating some of these children with RUTFs, only to see them return months later, once again malnourished. “We were using food supplements that have been imported from Europe, but there was often a cycle of relapse because it’s a temporary solution,” he said. But a potential breakthrough to prevent and treat malnutrition is finally on the horizon. The key is understanding the gut microbiome, the collection of trillions of microorganisms that help synthesize foods and produce nutrients critical to the body’s function. A growing field of researchers like Iddrisu believes that if they can unlock treatments that will interact better with the microbiome and improve overall gut health, they can make more nutrients available to malnourished children than through traditional RUTFs. “It’s not just about how many calories,” said Vanessa Ridaura, a senior program officer at the Bill & Melinda Gates Foundation focused on microbiome products and maternal newborn and child health. “It’s really about the quality of the food and the functional ingredients of the food and how they interact with the gut microbiome.” The Gates researchers are at the forefront of emerging work on the microbiome’s role in malnutrition. They have pushed forward an array of interventions, including refined versions of RUTFs targeted at the microbiome, as well as probiotic supplements that could improve the nutrition of both mothers and newborns. Some of these products could be ready for distribution in a matter of years depending on the outcome of ongoing trials. “These new types of supplementary foods are really promising to me, because it’s a matter of embracing all of the complexity of the gut and because it really is a complex mix of biological and environmental factors,” said Renaud Becquet, a director at the French research institute Inserm, whose research on malnutrition is independent of the Gates Foundation. Gut check Each person’s microbiome is unique, first developing at birth and then evolving with diet and environmental exposure. Though there is still a lot of research to be done on the relationship between malnutrition and the microbiome, there are clear links, said Iddrisu, who is now pursuing a doctorate in the food microbial sciences unit at the University of Reading. “If the microbiome doesn’t really mature or doesn’t grow into the adult-like microbiome, then it is susceptible to pathogenic infections that can cause malnutrition,” he said. There may be many reasons why the microbiome doesn’t develop in a child — environmental factors, a child’s diet, or its mother’s nutritional status. At the same time, experts are beginning to experiment with targeting foods that might take maximum advantage of the microbiota that do exist, while also potentially strengthening the microbiome. That led experts at the Gates Foundation to develop microbiome-directed RUTFs, or MD-RUTFs, which may resemble regular RUTFs in their consistency. The idea is to source local foods to create geographically specific combinations that will interact better with the microbiota of children in that region to magnify the treatment’s effects. Early trials of the Gates Foundation’s MD-RUTFs have been positive in children with moderate acute malnutrition. In Bangladesh, children who received the microbiota-directed food had outcomes that may be linked to increased growth and improved gut repair, compared to children who received standard RUTFs. “Feeding infants this probiotic helps them move their microbiome into that positive state so they can grow up and achieve their full potential.” --— Bill Gates, co-chair, Bill & Melinda Gates Foundation And a large-scale confirmatory trial is underway in Asia and sub-Saharan Africa among children with moderate acute malnutrition. Additional studies, some involving children with severe malnutrition, are planned to begin this year, a Gates Foundation spokesperson confirmed. In total, the foundation is planning to spend $47 million over a 10-year period on MD-RUTF discovery and development, according to the spokesperson. The results could pave the way for traditional providers of RUTFs, such as UNICEF, to switch over to MD-RUTFs within the next two to five years, Rahul Rawat, deputy director of maternal and child nutrition at the Gates Foundation, told Devex. Conversations with those procuring agencies have already started, he added. In addition to improving malnutrition outcomes, Rawat said MD-RUTFs often have the benefit of being cheaper and more readily accessible than standard RUTFs because they are sourced from local products. In his own research at the University of Reading, Iddrisu has also turned to locally available products, including the dandelion in West Africa. Along with other members of his team, he is looking for foods that are rich in prebiotics — nonliving compounds in food that spur the development of the microbiome. “We need to focus more on microbiota-directed foods that can actually prevent malnutrition,” he said. “These prebiotics have been shown to really improve gut health and, in general, the health of kids.” Improving the microbiome can have long-lasting benefits. The bugs in the microbiome feed off the dietary fiber in the food, producing short-chain fatty acids as a byproduct, which can help improve the barrier of the gut. That may make children less susceptible to the illnesses that can cause severe malnutrition to recur. Prevention Even as researchers at the Gates Foundation look for improved treatments, they are also pursuing microbiome-focused interventions that they hope will prevent children from developing moderate or severe acute malnutrition in the first place. There is an emerging understanding that wasting, the most lethal form of malnutrition, can begin within the first six months of life — earlier than most researchers previously considered. Ridaura said they began to wonder why that would happen in some infants and not others and if it might be related to the underdevelopment of the microbiome. “There are key species that are important for assembly of the microbiome,” Ridaura said. “This early pattern of assembly that you kickstart with the right bacteria, which is important for these babies to respond to nutrition and interventions later in life.” If there were options to ensure babies had those bacteria early, that might make it easier for them to reap the benefits of food or — if undernutrition does occur — of RUTFs or MD-RUTFs. The Gates Foundation is developing a probiotic intervention to give to infants who might be at risk of not receiving those crucial species — whether because their mother is also undernourished or because of environmental concerns. Unlike prebiotics, probiotics are live microorganisms that can improve or restore the microbiome. The Gates Foundation’s intervention would involve delivering shelf-stable sachets of bacteria that could be mixed with expressed breast milk or sterilized water and given to babies. The initiative is currently in the late-stage testing of clinical trials to determine guidelines on issues like manufacturing and dosing. Depending on the outcomes of the trials and securing the necessary approvals, Ridaura said the infant probiotics could be ready for distribution in three or four years. Bill Gates himself highlighted the intervention in his GatesNote predictions for 2024, writing, “The results so far are amazing: Feeding infants this probiotic helps them move their microbiome into that positive state so they can grow up and achieve their full potential. This could be a tremendously helpful tool for preventing malnutrition.” The Gates researchers are also looking at a similar probiotic intervention to give to undernourished pregnant women even before they give birth, which might impact growth in the womb. In total, they are committing $150 million over an eight-year period to the development of maternal microbial interventions and probiotics for infants, according to the Gates Foundation spokesperson. There are still gaps in the broader research around the microbiome and malnutrition. Iddrisu is looking for researchers to conduct a major multinational study that would compare healthy and malnourished microbiota. “If we are able to identify microbiota patterns for malnourished children, we would then be able to match what are the possible causes and prevent that,” he said. “Or we can look at prebiotics, which are mostly available to local communities, as well, that can prevent or that can boost microbiota and then prevent malnutrition in the long run.” But in an underfunded field, Rawat said Gates and other researchers are taking advantage of the money that is available to push existing interventions forward. “We have to think about the next generation of existing tools to address these conditions,” he said.