Malnutrition is a leading cause of death in children under age 5, and nearly 150 million children globally under this age have stunted growth from lack of nutrition. Although an inadequate diet is a major contributor, researchers at Washington University School of Medicine in St. Louis found over a decade ago that dysfunctional communities of gut microbes play an important role in triggering malnutrition .
Now, in work done in collaboration with the Salk Institute and UC San Diego, WashU Medicine researchers have discovered that toddlers in Malawi — among the places hardest hit by malnutrition — who had a fluctuating gut microbiome showed poorer growth than kids with a more stable microbiome. All of the children were at high risk for stunting and acute malnutrition.
"We know gut microbes are important mediators of malnutrition," said Mark J. Manary, MD , the Helene B. Roberson Professor of Pediatrics at WashU Medicine, an internationally regarded expert in malnutrition and co-corresponding author on the new study. "By contributing to our understanding of how changes in gut microbes directly contribute to the condition, we pave the way for new methods to diagnose and treat millions of affected children worldwide."
The findings, published September 9 in Cell, establish a pediatric microbial genome library — a public health database containing complete genetic profiles of 986 microbes from fecal samples of eight Malawian children collected over nearly a year that can be used for future studies to help predict, prevent and treat malnutrition.
Better growth with a stable gut microbiome
More than two decades ago, Manary became a key player in introducing a peanut butter-based, therapeutic food to battle severe acute undernutrition in Malawi, a country in sub-Saharan Africa where 37% of children are affected by stunting. He developed and clinically tested the high-calorie, nutrient-rich paste, which has saved thousands of lives since its adoption as the global standard of care for severe acute malnutrition.
Children who survive the condition often face ongoing challenges in metabolism, bone growth, immune function and brain development. Providing food so that children have enough nutrients to recover isn't enough on its own to help them grow and thrive, Manary explained.
Among other effects, malnutrition causes an imbalance in the gut microbiome, the community of bacteria and other microorganisms living in the intestines, reducing beneficial microbes and increasing disease-causing ones. The researchers surmised that improving the health of malnourished children may lie in understanding the changes in a gut landscape that is composed of hundreds of bacterial species.
To understand microbial patterns associated with child growth, the researchers sequenced the genomic material from 47 fecal samples collected over 11 months from eight toddlers, who had previously been enrolled in a clinical trial testing the effect of legume-based complementary foods on reducing or reversing environmental enteric dysfunction, a chronic condition that affects the small intestine, and poor growth.
The children chosen for the study were between 12 and 24 months old and had either improving or worsening length-for-age scores (LAZ), an indicator of growth that measures children's heights against the expected averages for their age and sex. The researchers found that children with a collection of microbial genomes that remained stable — meaning, the microbial population did not undergo drastic changes — showed better growth compared to those with unstable microbial composition, suggesting that gut microbiome stability may be beneficial for supporting growth in children. Measuring such changes, Manary explained, may possibly be used to assess gut health.
Building genomic libraries
The study used a modern genetic sequencing technique known as long-read sequencing to reconstruct complete microbial pangenomes, which include the genetic material of all members of a microbial species. This approach captured 50 times more complete microbiota genomes compared to the traditional method and provided a more comprehensive genetic view of the microbial communities in children at high risk for stunting and acute undernutrition.
"Stunting and acute undernutrition are defined by easily measured, physical measurements, which result from complex and diverse underlying processes," said co-senior author Kevin Stephenson, MD , an assistant professor of medicine at WashU Medicine. "Improved resolution and accuracy in identifying microbial communities, how they change, and what they are doing may shed light on otherwise unmeasurable facets of undernutrition as well as the role the gut microbiome plays in causing it."
The technique made it possible to generate the study's novel pediatric microbial genome library. The researchers optimized a long-read sequencing workflow that other scientists can adapt to build genome libraries for various applications and is amendable to research performed in remote laboratories operating in difficult-to-access locations.
"When applied in remote, field-based molecular laboratories, the genome sequencing and pangenomic approaches we developed can deliver real-time insights not only into pandemic surveillance, antibiotic resistance and infectious disease, but also into agricultural productivity, environmental monitoring and biodiversity conservation," said senior co-corresponding author Todd Michael, PhD, a research professor at Salk. "It's a powerful technological advance that expands the reach of genomics and sets a new standard for scientific research in the field."
