Jeffrey I. Gordon, MD, at Washington University School of Medicine in St. Louis, will lead an international team of scientists to find new ways to diagnose, treat and prevent a critical global health problem: malnutrition in infants and children. The work is funded by an $8.3 million grant from the Bill & Melinda Gates Foundation.
Gordon's research first established a link between obesity and the trillions of friendly microbes that live in the intestine, where they extract nutrients and calories from food. His studies have shown that diet helps shape the mix of microbes in the intestine and that these microbes, in turn, influence how efficiently nutrients and calories are harvested from foods. This dynamic interplay has led Gordon to suspect that an imbalance of certain types of gut microbes conspires with an inadequate diet to trigger malnutrition.
"A complex relationship exists between diet, gut microbial communities and the immune system in severely malnourished children," says Gordon, the Dr. Robert J. Glaser Distinguished University Professor and director of Washington University's Center for Genome Sciences and Systems Biology. "We now have a way to tease apart these influences. This project seeks to discover novel dietary and microbial therapeutics that can be targeted to infants and children living in countries with rampant malnutrition."
Severe malnutrition has long been thought to stem simply from a lack of adequate food. But now scientists understand the condition is far more complex and may involve a breakdown in the way gut microbes process various components of the diet.
The community of intestinal microbes and their vast collection of genes, known as the gut microbiome, are assembled right from birth and influenced by babies' early environments and the first foods they consume, such as breast milk. As part of the Breast Milk, Gut Microbiome and Immunity Project, Gordon will work with other scientists to evaluate the relationship among first foods, the developing community of microbes in the intestine and the developing immune system.
The new research builds on ongoing clinical studies in Africa, South Asia and South America of malnourished and healthy infants and children and their mothers. Gordon has played a key role in that research, which also is funded by the Gates Foundation.
As part of the new project, scientists will evaluate the function of gut microbial communities in malnourished and healthy infants and children living in countries where malnutrition is prevalent. They also will characterize the nutritional content and immune activity present in breast milk samples obtained from the children's mothers during periods of exclusive and supplemental breastfeeding. In parallel, the scientists will use a preclinical discovery pipeline recently developed in Gordon's laboratory to identify next-generation probiotics and nutrient supplements or combinations of the two (synbiotics) that may promote healthy growth in infants and children.
The investigators also will transplant communities of intestinal microbes, obtained from stool samples, from both malnourished and healthy children into germ-free mice raised under sterile conditions. These mice will harbor collections of human gut microbes that mimic those found in the children, and they will be fed the same diets as the children.
Then, using the mice, Gordon and his colleagues can carefully evaluate how various nutritional interventions influence gut microbiomes obtained from these children. They will be able to determine which microbes respond, how they respond and how they affect the overall function of the gut microbial communities. The researchers also will evaluate certain aspects of childhood development.
"It's extremely difficult to study individual triggers for malnutrition because there are so many variables to consider," Gordon says. "Recreating the human gut ecosystem in mice gives us a way to control these variables. The lead compounds derived from these well-controlled, pre-clinical studies then can be considered for future clinical trials in malnourished infants and children."
Gordon's research underscores the need understand the workings of gut microbiomes among people of different ages living in different parts of the world, especially as scientists consider manipulating intestinal microbes to improve health and nutrition. In a study published online May 9 in Nature, he and his colleagues surveyed the gut microbiomes of more than 500 healthy individuals, ranging in age from one month to more than 80 years, who lived in villages in Malawi, the Amazon region of Venezuela and in three U.S. cities.
The researchers found a similarity across cultures in the way the gut microbiome matures, especially in the first three years of life. But they also noted distinct differences in the microbiomes of babies, children and adults depending on where they lived.
The differences were most notable between individuals living in the U.S. compared to those in Malawi or Venezuela, and seemed to be linked to diet. Malawian and Venezuelan gut communities were rich in genes that break down complex sugars and starches, like those found in cassava and corn, while gut communities in individuals in the U.S., who typically eat high-protein diets, were more heavily loaded with genes for breaking down amino acids.
Other scientists involved in the Gates Foundation project include: Per Ashorn, MD, PhD, at the University of Tampere School of Medicine in Finland; Kathryn Dewey, PhD, University of California, Davis; Michael Gottlieb, PhD, Foundation for the National Institutes of Health (NIH); Rob Knight, PhD, University of Colorado, Boulder; Kenneth Maleta, PhD, University of Malawi College of Medicine; David Mills, University of California, Davis; Jeremy Nicholson, PhD, Imperial College, London; Linda Saif, PhD, The Ohio State University.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.