"Childhood undernutrition is a global, vexing, challenging, tragic health problem," Washington University School of Medicine's Jeffrey Gordon, who oversaw two of the studies, told The Washington Post. And even though mortality rates have dropped thanks to high-calorie therapeutic foods and other interventions, the problem persists.
"We still see stunted growth in these treated children," Gordon said, explaining that many developmental and health problems seem to follow the malnourished patients. "There's something we're not repairing, something we're missing."
In previous studies, Gordon and his colleagues found a connection between childhood gut microbiota (the set of bacteria that colonize the gut) and developmental success. Children who were malnourished tended to have gut microbes similar to children younger than themselves, as if the microbial "organ" itself had been as stunted as the rest of their body. And the high-calorie therapeutic foods that saved their lives didn't boost their gut microbes.
The first of the new studies, published in Science and led by graduate student Laura Blanton, built on that idea by trying to determine whether these stunted microbes were a cause or an effect of malnutrition — or both.
The researchers took gut microbes from healthy and malnourished children from Malawi, then implanted those microbes in the guts of mice bred to be germ-free. The mice were all fed the same diet — an approximation of a typical diet for a young Malawian child — one that would fail to provide adequate nutrition.
With all other things being equal, the presence of "healthy" microbes allowed mice to grow bigger across the board.
"Then we had an experiment we could call 'the battle of the microbiota,' " Gordon said. "We wondered, could the good overcome the effects of the bad?"
For humans to "share" good bacteria with one another, you might need something like a fecal matter transplant. But mice engage in coprophagia, or feces eating. To get a pair of mice to swap microbes, all you have to do is raise them in the same cage. Blanton did just that, housing mice colonized with a healthy child's microbiota along with those colonized by a malnourished child's microbes. Sure enough, the healthy bacteria set up shop in the pseudo-malnourished mice.
"There were job vacancies in the undernourished donor's microbial community, and if the healthy microbes installed themselves, they were actually able to improve growth," Gordon said.
In another, unrelated Science study led by François Leulier, a biologist from the École Normale Supérieure de Lyon in France, researchers found a similar connection between gut microbes and nutrition. His team found that — again, all other things being equal — mice with with no gut bacteria didn't grow as well as those with a normal fleet of stomach microbes.
Leulier's team found a connection between these gut microbes and the hormones of the mice. The experimental mice all produced the same amount of growth factor hormone, but those without gut bacteria didn't have as much of the secondary growth hormone that first one usually produces. Giving the mice this secondary hormone as a supplement boosted their growth back up, even when they didn't have gut microbes. And they found at least one strain of the bacteria Lactobacillus that gave the microbe-less mice an instant hormone boost.
The second of Gordon's studies, led by grad student Mark Charbonneau and published in Cell, found another way in which this relationship between microbes and nourishment might play out. The researchers studied breast milk ("nature's most perfect food," in Gordon's opinion) to see how microbial changes might affect a child's ability to take advantage of its benefits.
The researchers screened breast milk from Malawian mothers with healthy and malnourished babies, looking for differences between the two. They found that sugars containing sialic acid, which is thought to be important in brain development, were far more abundant in the breast milk of mothers with healthy babies.
Once again, the team took germ-free animals and gave them the microbes of stunted children. Then they fed them the same, Malawian-toddler-inspired diet. Some of the animals lived on this alone, while others were given sialic acid (derived from cow milk) and others were given something approximating common infant formula.
"All of them had the same caloric intake, all had the same gut microbes," Gordon said. And yet the ones that received sialic acid in quantities comparable to healthy breast milk grew larger. And animals left germ-free saw no boost from the addition of these sugars.
Gordon and his colleagues believe that the growth benefits may hinge on products created by bacteria as they consume sialic acid. But he says the finding "isn't ready for prime time yet."
"There are food webs in the microbial community, and these bacteria living on sialic acid are just the primary consumers," Gordon explained. "They transform it into products used by other microbes in the community. We need to be sure that none of those secondary consumers are dangerous."
That's of particular concern in malnourished children in Malawi, where a lack of clean water means that many guts are full of potentially dangerous pathogens ready to pounce. Researchers can't recommend giving these children a boost of sialic acid — or any microbe-related food additive — without doing more research, as it could empower a pathogen to conquer their guts.
Stanford University School of Medicine's David A. Relman, a microbiologist who wasn't involved in the new studies, praised Gordon's research but urged caution in assuming its results would hold true in humans.
"Because germ-free animals are born with grossly altered anatomy and function, provision of a new first-time microbiota to these animals may not perfectly mimic what happens in a natural setting or mimic the much more complex circumstances of newborn children in diverse sociocultural and environmental settings," Relman told The Post. But he believes therapies that rely on cultivating our microbial communities are worth pursuing.
"Even if the microbiota is a relatively small contributory factor for nutritional status, it is potentially modifiable, and hence, extremely important," Relman added.
With more research, interventions like this could help doctors to truly cure malnutrition, allowing children to thrive. One aspect of the experiment is particularly intriguing in this regard: To get the sialic acid they needed to feed their lab animals, the researchers developed a process to refine it from whey produced as a waste product in cheese manufacturing.
"We’re very interested as a lab in trying to turn to the waste stream to capture things that are thrown out but are very valuable," Gordon said. So if scientists are able to strengthen the connection between sialic acid and infant success, there's a ready source of it to add to infant formula. Meanwhile, more research on the "good" versus "stunted" microbiota could allow scientists to develop microbe-based therapies to allow infants to better take advantage of sialic acid and other dietary components.
"The takeaway is that we have a microbial dimension, and we believe that this organ and its proper formation is really important to growth," Gordon said. "And that gives us hope for new types of therapeutic interventions to treat and ultimately prevent this."