An $8.3 million grant from the Bill & Melinda Gates Foundation will fund an international team of scientists, including a University of Colorado Boulder professor focused on finding new ways to diagnose, treat and prevent a critical global health problem: malnutrition in infants and children.
Rob Knight, a scientist at CU-Boulder’s BioFrontiers Institute, will be working with a research team led by Dr. Jeffrey I. Gordon at Washington University School of Medicine in St. Louis. The goal is to discover novel dietary and microbial therapeutics targeting infants and children living in countries with rampant malnutrition.
“Our hope is that by understanding the differences in individual gut microbial communities in both healthy and malnourished individuals, together with influences in diet including compounds and microbes transferred in breast milk, we will be able to better understand and develop new treatments for malnutrition,” said Knight, also an associate professor in CU-Boulder’s chemistry and biochemistry department. “Such treatments could include prebiotics, probiotics, antibiotics or nutrition which might help reverse severe malnutrition in different individuals.”
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 microbial communities process various diet components.
“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. 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 can be considered for future clinical trials in malnourished infants and children.”
Research led by Knight has shown that people carry “personalized” bacteria on many individual areas of the body, including the intestine. His CU-Boulder lab will host the Gates Foundation study database integrating various types of information, including whole-genome sequencing and microbial community analyses.
As part of the project, Knight and his CU-Boulder team will develop methods for high-throughput sequencing and analysis of bacterial genomes from “personalized culture collections,” in which hundreds of strains of bacteria will be isolated and characterized from the intestines of individual people. The personalized culture collections will be used to colonize lab mice in different combinations to test which strains are most important, said Knight.
The community of intestinal microbes and its 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 Gates Foundation’s Breast Milk, Gut Microbiome and Immunity, or BMMI, Project, the scientists will 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, which also are 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 multiple 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 -- known as synbiotics -- that may promote healthy growth in infants and children.
The investigators 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 essentially 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, the scientists can carefully evaluate how various nutritional interventions influence the workings of the gut microbiomes obtained from the children. They will be able to determine which microbes respond, how they respond and how they affect the overall function of the gut microbiomes. The researchers also will evaluate certain aspects of childhood development.
CU-Boulder graduate students will be involved in the BMMI Project, including doctoral students in the Interdisciplinary Quantitative Biology, or IQ Biology, program recently launched by the BioFrontiers Institute directed by Nobel laureate Tom Cech. The students are involved in semester-long rotations that immerse them in mathematical biology, computational biology, biophysics and bio-imaging as they work toward doctoral degrees.
“IQ Biology students are being trained with the exact mixture of mathematical, computational and biological techniques essential for progress on complex, challenging projects like the Gates BMMI Project,” said Knight. Dan Knights, the first graduate of the IQ Biology program, helped to lay the groundwork for the CU portion of the BMMI effort with novel research on applying machine learning to studies of the human microbiome, said Knight, who also is a Howard Hughes Medical Institute Early Career Scientist.
Other scientists involved in the Gates BMMI project include Per Ashorn of the University of Tampere School of Medicine in Finland; Kathryn Dewey of the University of California, Davis; Michael Gottlieb of the Foundation for the National Institutes of Health; Kenneth Maleta of the University of Malawi College of Medicine; David Mills of the University of California, Davis; Jeremy Nicholson of Imperial College, London; and Linda Saif of Ohio State University.