WOOSTER, Ohio -- An $8.3 million grant from the Bill & Melinda Gates Foundation will fund an international team of scientists focused on finding new ways to diagnose, treat and prevent a critical global health problem: malnutrition in infants and children.
Linda Saif, a Distinguished University Professor at Ohio State University's Ohio Agricultural Research and Development Center (OARDC), is involved in the research, which will be led by Jeffrey I. Gordon, M.D., at Washington University School of Medicine in St. Louis. The 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 microbial communities process various components of the diet.
"A complex relationship exists between diet, gut microbial communities and the immune system in severely malnourished children," said 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."
Saif's role in the project includes the evaluation of new ways to improve the effectiveness of vaccines against rotavirus -- the leading cause of childhood diarrhea. For unexplained reasons, she said, current rotavirus vaccines fail in children in impoverished countries where malnutrition and diarrhea mortality are highest. Led by Saif, Ohio State researchers Anastasia Vlasova, Gireesh Rajashekara and Kuldeep Chattha will use a germ-free piglet model to complement the studies in mice.
"Studies at OSU using germ-free piglets will complement and extend results from initial comprehensive evaluations of the transplanted human gut microbe collections and the interventions tested in germ-free mice," said Saif, an internationally recognized virologist and immunologist who studies infectious diseases that can sicken both animals and humans.
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 Breast Milk, Gut Microbiome and Immunity Project, project 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 (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 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 these 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.
Saif and colleagues at Ohio State will add to the project by using germ-free piglets to assess the impact of human fecal microbiota, native diet and selected prebiotic/probiotic interventions on immune function as it relates to rotavirus diarrhea severity and death. Just like with the mice used in the study, communities of intestinal microbes from humans will be transplanted into the piglets. Because of their susceptibility to human rotavirus diarrhea, Saif said, germ-free piglets are a unique model to evaluate diarrhea interventions and effectiveness of rotavirus vaccines.
"Representative human gut microbiomes, in concert with the optimized nutritional or probiotic supplements that alleviate malnutrition and promote a healthy gut, will be examined in germ-free piglets for their effectiveness in resolution of malnutrition as well as rotavirus diarrhea and deaths," Saif explained. "Our future goal is to understand the influence of the gut microbiota and diet on responses to oral vaccines so as to implement similar novel interventions (prebiotics/probiotics/synbiotics) not only to ameliorate gastroenteritis, but also to enhance oral vaccine efficacy in children in impoverished countries."
Other scientists involved in the project include Per Ashorn, University of Tampere School of Medicine in Finland; Kathryn Dewey, University of California, Davis; Michael Gottlieb, Foundation for the National Institutes of Health (NIH); Rob Knight, University of Colorado, Boulder; Kenneth Maleta, University of Malawi College of Medicine; David Mills, University of California, Davis; and Jeremy Nicholson, Imperial College, London.
OARDC is the research arm of Ohio State's College of Food, Agricultural, and Environmental Sciences.