New research links unstable gut microbiome to poorer kids’ growth and higher malnutrition risks

Scientists discovered that toddlers in Malawi with more gut microbial genome changes had poorer growth than kids with a stable microbiome. All toddlers had a high risk of acute malnutrition and stunted growth — a condition that nearly 150 million children face.

The researchers collected stool samples from eight children over 11 months to determine microbial patterns potentially influencing child growth. They also used this data set to establish the “first-ever” pediatric undernutrition microbial catalog with the full genetic profiles of 986 microbes. 

Moreover, the team identified specific bacteria and genes linked to undernutrition, a form of malnutrition that results from poor nutrient uptake due to an inability to process nutrients effectively or a nutrient-lacking diet. 

“Despite a decade of research linking the microbiome with malnutrition, the genetic and biological factors have remained a mystery due to a lack of resolution on the microbes in the gut,” says senior co-corresponding author Todd Michael, research professor at the Salk Institute, US. 

“By using cutting-edge genome sequencing and pangenomic approaches in a longitudinal design, we were able for the first time to pinpoint specific microbial changes linked to poor growth, opening the door to new diagnostics or therapeutics that could help address a crisis impacting more than 150 million children worldwide.”

Gut microbiome imbalance

Over half of deaths in children under age five are caused by malnutrition, the researchers highlight. Kids who survive the condition may still experience lifelong consequences, such as challenges in metabolism, bone growth, immunity, and brain development. 

The researchers suggest that understanding gut microbiome changes may be key to improving the health of children with malnutrition. 

Their study builds on previous research, finding a direct link between microbiome health and malnutrition, as the condition causes an imbalance in the gut microbiome, potentially reducing beneficial microbes and increasing disease-causing bacteria. 

In 2013, scientists transplanted microbiota from severely malnourished children into mice, fed them Malawian-like diets, and found that the mice lost weight. 

Kids whose microbial population did not undergo drastic changes showed better growth than toddlers with an unstable composition.The latest research on Malawi toddlers was conducted by the US Salk Institute, the University of California San Diego, and Washington University School of Medicine in St. Louis. The report authors flag that Malawi has an especially high incidence of child stunting, at 35%. Children with this condition are often much too short for their age.

Mediators of malnutrition

For their paper published in Cell, the researchers used length-for-age scores (LAZ) to measure undernutrition. These scores track children’s heights compared to expectations based on age and sex. A low LAZ indicates insufficient growth for a kid’s age. 

The team collected 47 fecal samples over 11 months from eight kids aged 12–24 months. All participants had either improving or worsening LAZ. 

Kids whose microbial population did not undergo drastic changes showed better growth than toddlers with an unstable composition. 

“We know gut microbes are important mediators of malnutrition,” says co-corresponding author Mark Manary, M.D., professor of Pediatrics at Washington University School of Medicine. 

“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.”

Genomic library

To analyze the samples’ genomes, the research team used a modern technique called long-read sequencing to break DNA into smaller fragments, which are then reassembled “like putting together a puzzle.” 

They say that this approach captures 50 times more complete microbiota genomes than traditional methods of short-read sequencing, where DNA is broken down into much smaller fragments. 

The authors say their genome sequencing approach can deliver real-time insights across various applications, e.g., infectious diseases.“This would not have been possible with short-read technology,” says first author Jeremiah Minich, a postdoctoral researcher at the Salk Institute. “We found the most efficient, accurate, and cost-effective long-read workflow, applied that workflow to analyze 10- to 20-fold more human samples than anyone has analyzed before, and came out on the other end with a critically important genome resource for undernutrition.”

The resulting genome library contains dozens of microbial genomes that are entirely novel, highlight the authors. 

Moreover, they suggest that other scientists can adapt their long-read sequencing workflow to build genome libraries for various applications or for research conducted in difficult-to-reach 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,” says Michael. 

“It’s a powerful technological advance that expands the reach of genomics and sets a new standard for scientific research in the field.”

Microbial diversity

Co-senior author Kevin Stephenson, an assistant professor at Washington University School of Medicine, says the study’s sampling and measurement enabled a unique assessment of within- and between-child change over time in the microbiome and growth. 

“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,” he details.

Using the library of 986 microbiota, the researchers searched for microbiota patterns specific to undernutrition. They found genetic differences in genomes between kids with improving and worsening growth in four bacterial genera — Bifidobacterium, Megasphaera, Faecalibacterium, and Prevotella.

However, a more important finding was that children with improved growth, measured by LAZ, had stable microbial genomes within species. 

The authors call for further research, expanding into other regions in Malawi, to determine if microbial associations with stunting are consistent. They note that adding a “not stunted” group would present a better health baseline. 

Additionally, larger studies would help determine age-related effects on the gut.