When children suffer from severe malnourishment, they don't just lose weight.
The condition wreaks havoc on biological systems throughout the body — including the microbiome, the healthy bacteria and other microbes that live in our digestive tracts. Those bacteria number in the trillions in every person and include hundreds of different species. They're essential for metabolism, bone growth, brain function, the immune system and other bodily functions.
In a study published Thursday in the peer-reviewed journal Science, scientists in a renowned microbiology lab at Washington University School of Medicine in St. Louis, report the development of a specialized food designed to rehabilitate gut microbes in severely malnourished children, a treatment that should facilitate both their immediate and long-term recovery.
The food — a spoon-fed paste made from chickpeas, soy, peanuts, bananas and a blend of oils and micronutrients — was shown to substantially boost microbiome health.
The researchers are still working to understand the exact biochemistry that causes certain foods to have a greater impact on restoring the microbiome than others. But Lawrence David, a leading gut microbe specialist at Duke University School of Medicine who was not involved in the study, says that the research represents an unprecedented step forward in understanding what a healthy gut microbiome should look like, how health conditions like malnourishment affect it and what interventions might work to repair damages.
"How systematic and thoughtful they are in designing this intervention is easily far and beyond field-leading," he says. "It's totally remarkable what they did."
Childhood malnutrition is a critical global health problem that affects more than 150 million children worldwide and accounts for nearly half of deaths in children under the age of 5, according to the World Health Organization.
The treatment usually centers on a diet of high-energy, nutrient-packed foods. While some specialized malnourishment recovery foods, like Plumpy'nut, have proven widely successful in saving lives by promoting rapid weight gain, malnourished children often continue to suffer long-term health impacts, says Justin Sonnenburg, a microbiologist at Stanford University who was not involved in the study.
Sonnenburg says there's a growing consensus among medical researchers that disruptions to the number and species diversity of gut microbes are likely behind many of the effects of malnourishment and also increase the risk of long-term diseases including inflammatory bowel disease, obesity, psoriasis and Type 2 diabetes.
The study, he says, offers the most promising avenue yet for finding clinical treatments specifically designed to treat disease by bolstering the microbiome.
"What they nicely show in this study," he says, "is that modulating the microbiome is a key part of navigating the path back to health."
Several years ago, Washington University microbiologist Jeffrey Gordon's lab began collaborating with the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh, to study the bacteria found in fecal samples from healthy children.
Their goal was to paint a picture of a healthy microbiome as it changes — in terms of the total quantity of bacteria, and the mixture of different species — through the first couple years of life. With the help of powerful computer algorithms that sorted through the vast menagerie of microbes in each sample, they developed a catalog of microbe "signatures," characteristic combinations of microbes that are typically found in healthy children of certain ages.
With that information in hand, they began to collect fecal samples from more than 60 children ages 12 to 18 months who were hospitalized for severe malnourishment (the samples, collected in Dhaka, were flash-frozen and flown to St. Louis). They found that the microbe "signature" in malnourished children was distorted and underdeveloped, lacking the number and diversity of microbes expected for a child of that age.
"It looked like that of a younger child," Gordon says.
The researchers wanted to develop specialized foods that could nudge the microbiome back toward its "signature" state. To test different possibilities, they transplanted microbes from the malnourished children into sterilized lab mice, and then fed the mice a variety of diets to see which tended to promote healthy microbe growth. They quickly realized that the rice- and lentil-based foods that were commonly used in Dhaka to treat malnourished children had little effect on the microbiome.
But they still wanted to use ingredients that would be locally available, cheap and culturally acceptable. So they began to systematically test combinations of different foods that are commonly fed to Bangladeshi children as they wean from breastfeeding to solid food, including tilapia, chickpeas, milk powder, potato, spinach and pumpkin.
The researchers developed a prototype combination of chickpeas, peanuts, soy and banana, known by the appetizing name Microbiome-Directed Complementary Food-2 (MDCF-2), that seemed to be highly effective in restoring the microbiome of mice. Subsequent tests in piglets, and later in children, replicated the results.
The researchers also took blood samples from malnourished children before and after the trial to monitor changes in more than 1,000 essential proteins for an even more precise measure of the foods' impact. One group of children was given MDCF-2, while other groups were given different experimental foods. MDCF-2 was the clear winner.
"MDCF-2 had a dramatic effect on multiple proteins associated with bone growth and moving the metabolic system towards a healthy state," Gordon says.
As for its culinary qualifications, MDCF-2 isn't likely to win any Michelin stars or become a new staple of Dhaka street food. Gordon says it was designed to be tolerable to children; it has a consistency like chalky peanut butter, he says, and although it's "relatively bland, it's not offensive at all."
The next challenge, Gordon says, is to dive deeper into how the chemical components of different foods interact with bacteria in the gut microbiome, to understand exactly how beneficial change occurs and why exactly the specific ingredients in MDCF-2 proved so successful.
A second paper published concurrently by the same group describes a mathematical model that could untangle that mystery by helping the researchers parse the astronomical number of chemical reactions that occur as individual microbes interact with other molecules in the body.
Long-term monitoring is also needed, Gordon says, to see whether the food's beneficial impact lasts after children stop eating it. He cautioned that even the best microbiome-focused treatment may not be enough to help the most severely malnourished children, who may also require feeding tubes or intravenous nutrient injections. And he says that the ingredients may need to be readapted for different local tastes if tested in locations outside Bangladesh. So it may be awhile before MDCF-2, or similar foods, become widely available in clinics.
Sonnenburg says the study "raises the bar for what we should be trying to achieve in gut microbiome studies." It opens the door, he says, for further research on whether some infants at risk for malnutrition could be given therapeutic foods to bolster their gut microbes in advance, potentially forestalling damage to symptoms like problems with bone development, brain function and the immune system.