There’s evidence from two new studies that it might be possible to treat and even prevent malnutrition in children, which kills more than 2 million kids every year, by manipulating the makeup of microbes in the gut.
Both studies were carried out in germ-free mice with gut microbes transferred from either healthy or malnourished young children living in Malawi in Africa.
The first study, published in the journal Science, implicates underdeveloped gut microbial communities as a cause of childhood malnutrition, rather than an effect, and identifies specific microbes that direct healthy growth.
The second study, published in Cell, demonstrates that a component of human breast milk interacts with gut microbes in ways that may help promote healthy growth and metabolism in malnourished children.
“Current ‘ready-to-use’ therapeutic foods have reduced mortality from malnutrition, but these children continue to show lingering longterm effects, including stunted growth, impaired neurodevelopment, and dysfunctional immune systems,” says Jeffrey L. Gordon, professor and director of the Center for Genome Sciences and Systems Biology at Washington University in St. Lous.
The work offers likely explanations for these persistent maladies: a failure of a malnourished child’s gut microbial community—known as the microbiota—to develop along a normal, healthy trajectory, and a failure of current treatments to permanently repair and restore proper functions mediated by gut microbes, such as synthesizing vitamins and nutrients.
Growth problems in mice
For the Science study, first author Laura V. Blanton, who carried out the research as a graduate student in Gordon’s lab, identified a scenario of microbial community development that is shared among healthy children and develops in the first two years of life. Having defined normal development, she determined that malnourished children have defects in this developmental scenario, leaving them with gut microbial communities that look younger than what would be expected based on their chronological ages.
To determine whether this persistent immaturity of the gut microbiota was a cause rather than an effect of malnutrition, Blanton modeled the gut microbes of Malawian children in young mice that were still actively growing and that were born without gut microbes of their own (germ-free mice).
Like their human counterparts transitioning to solid foods, these young mice ate a Malawian diet—primarily corn flour cooked with vegetables, peanuts, and kidney beans. On its own, this diet does not meet nutritional requirements for humans or mice. The researchers then monitored the growth of the mice over the next month.
“The impaired growth we see in malnourished children was transmitted to the mice that received gut microbes from these children,” Gordon says. “These differences in growth between the different groups of mice occurred even though they were consuming the same amount of food. The only difference between the groups was in the makeup of their human microbial communities.”
And the disparities went beyond size. Imaging studies showed that most of the increased weight of the mice with healthy microbes was in the form of lean body mass, characteristic of healthy growth, rather than fat mass. Further, there was better skeletal development in the mice with healthy microbes and healthier metabolism in their livers, muscles, and brains.
The researchers also identified members of the healthy microbiota whose presence correlated to more robust growth. In a series of experiments, they determined that good bacteria could compensate for growth impairments seen in mice receiving malnourished microbial communities.
The researchers saw this effect when they let mice that received microbial communities from healthy infants and children live together with mice that had received communities from undernourished individuals. Like other rodents, mice consume each other’s feces and thereby exchange gut bacteria.
“In this battle of good microbes versus bad, good triumphed,” Gordon says. “Beneficial growth-promoting microbes established themselves in the guts of cagemates containing microbiota from undernourished infants and prevented poor growth.”
The researchers cultured these organisms and showed that adding two of them, Ruminococcus gnavus and Clostridium symbiosum, directly to unhealthy gut microbes and giving this mixture to mice also corrected growth impairments and metabolic abnormalities typical of mice harboring a malnourished child’s microbiota alone.
Sugar in milk
Compared with mothers of healthy infants, those with undernourished infants had breast milk with lower levels of sugars that carry sialic acid, the study in Cell shows. Other research has linked sialic acid to brain development. First author Mark R. Charbonneau carried out this research as a graduate student in Gordon’s lab along with colleagues at the University of California, Davis, University of Malawi, and the University of Tampere in Finland.
Because of the difficulty obtaining significant quantities of human breast milk, the researchers looked for these sugars in cow’s milk. They found them but at 20-fold lower concentrations. Researchers purified the sugars from whey produced during cheese manufacturing and then studied the effects of these sialylated bovine milk oligosaccharides (S-BMOs) using young mice that had been colonized with gut bacteria from a malnourished Malawian child.
One group of the mice received a Malawian diet supplemented with S-BMO; a second group received the Malawian diet plus a different type of sugar commonly added to infant formula but that does not contain sialic acid. A third group received the unsupplemented Malawian diet alone.
The group eating the diet supplemented with S-BMO showed significantly better growth than the other two groups, despite the fact that all of the diets contained the same number of calories. The benefit of this supplement also was dependent on the presence of gut bacteria, as the growth promotion produced by S-BMO disappeared when given to germ-free mice reared under sterile conditions.
Like the Science study, the Cell study demonstrates that the improved growth produced by S-BMO supplementation went beyond size, with mice gaining significantly more lean body mass, improved skeletal development, and a better metabolic profile in the blood, brain, and liver.
In piglets, too
In a final series of experiments, the researchers reproduced their results in piglets that were born germ-free and then colonized with the malnourished child’s gut microbial community. As in the mouse experiments, the piglets were fed the Malawian diet with or without S-BMO. The piglets were studied because their physiologic and metabolic properties are closer to humans than mice.
“The next steps we are actively pursuing are development of new microbiota-directed food interventions that enhance the representation and beneficial functions of the growth-promoting gut microbes we have identified,” Gordon says. “We hope that these next-generation, food-based interventions will produce durable repair of microbiota immaturity in malnourished children and produce better long-term clinical outcomes.”
Researchers from Duke University, the University of California, Davis, University of Malawi, University of Tampere in Finland, Centre National de la Recherche Scientifique and Aix-Marseille Université in France, King Abdulaziz University in Saudi Arabia, Russian Academy of Sciences in Moscow, Sanford Burnham Prebys Medical Discovery Institute in La Jolla, Calif., and the Hilmar Cheese Co., in California are coauthors of the study.