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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. 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.”

Kevin Stephenson, MD, co-senior author, assistant professor of medicine at WashU Medicine

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.”

A special MRI technique that detects iron levels in different regions of the brain can predict the onset of mild cognitive impairment and cognitive decline in cognitively unimpaired older adults, potentially creating a pathway to earlier interventions, according to a study published today in Radiology, a journal of the Radiological Society of North America (RSNA).

As the leading cause of dementia worldwide, Alzheimer’s disease is a growing public health crisis. The disease is characterized by the accumulation of abnormal proteins in the brain called amyloid beta and tau, which manifest years prior to the appearance of clinical symptoms and can be detected with positron emission tomography (PET) scans. Treatments targeting these proteins are only modestly effective, indicating that other factors may contribute to cognitive impairment.

Elevated levels of iron in the brain are one factor under investigation in recent years. Iron overload in the brain is known to drive neurodegeneration by inducing oxidative stress (an imbalance between two different types of molecules in your body: free radicals and antioxidants), exacerbating amyloid toxicity, disrupting tau protein function and promoting nerve cell death.

Brain iron can be measured noninvasively through a special MRI technique called quantitative susceptibility mapping (QSM).

QSM is an advanced MRI technique developed over the last decade to measure tissue magnetic susceptibility with good precision. QSM can detect small differences in iron levels across different brain regions, providing a reliable and non-invasive way to map and quantify iron in patients, which is not possible with conventional MR approaches.”

Xu Li, Ph.D., study’s senior author, associate professor of radiology at Johns Hopkins University and research associate at the F.M. Kirby Research Center for Functional Brain Imaging at the Kennedy Krieger Institute in Baltimore, Maryland

Dr. Li and colleagues studied QSM MRI on 158 cognitively unimpaired participants drawn from the Johns Hopkins BIOCARD Study, a research project focused on the early stages of Alzheimer’s disease and related disorders. PET data was available for 110 of the participants.

The researchers acquired baseline QSM MRI data on the participants and then followed them for up to seven and a half years. They found that higher baseline magnetic susceptibility on MRI in the entorhinal cortex and putamen-two brain regions important to memory and other cognitive functions-was associated with a higher risk of mild cognitive impairment, a transitional stage preceding Alzheimer’s disease-related dementia.

“Using QSM, we found higher brain iron in some memory related regions that are linked to a higher risk of developing cognitive impairment and faster cognitive decline,” Dr. Li said. “This risk is even higher when the participants have higher levels of amyloid pathologies.”

Even though amyloid burden and tissue susceptibility in the entorhinal cortex and putamen were independently associated with progression to mild cognitive impairment, they appeared to have synergistic effects, Dr. Li said, accelerating global cognitive decline over time.

If confirmed in larger studies with more diverse patient populations, the findings point to a role for QSM MRI in the workup of patients at risk of dementia.

“We can use this kind of tool to help identify patients at higher risk of developing Alzheimer’s disease and potentially guide early interventions as new treatments become available,” Dr. Li said. “Also, besides serving as a biomarker, brain iron may become a future therapeutic target.”

Going forward, the researchers hope to gain a better understanding of how brain iron contributes to Alzheimer’s disease, including its interaction with other Alzheimer’s disease-related pathologies like amyloid and tau proteins. On the therapeutic side, clinical trials could test iron-targeted therapies.

“At the same time, we hope to make the QSM technology more standardized, faster and more widely accessible in clinical practice,” Dr. Li said.

“Susceptibility MRI Helps Predicts Mild Cognitive Impairment Onset and Cognitive Decline in Cognitively Unimpaired Older Adults.” Collaborating with Dr. Li were Lin Chen, Ph.D., Anja Soldan, M.A., Ph.D., Andreia Faria, M.D., Ph.D., Marilyn Albert, Ph.D., and Peter C. M. van Zijl, Ph.D., for the BIOCARD Study Team.