March 31, 2009 -- Scientists who first established a link between obesity and the trillions of friendly microbes that live in the intestine now are investigating whether the organisms can contribute to the converse: severe malnutrition.
Researchers at Washington University School of Medicine in St. Louis, led by microbiologist Jeffrey Gordon, M.D., will study whether severely malnourished infants living in Malawi and Bangladesh have a different mix of intestinal microbes than healthy infants in the same areas, and whether those microbes might account for their illness. This three-year, $5.5 million project is funded by the Bill & Melinda Gates Foundation.
"This work is designed to understand the complex interplay among a child's diet and his or her gut microbial community, immune system and human genome in the development of the most severe forms of malnutrition, kwashiorkor and marasmus," says Gordon, who directs Washington University's Center for Genome Sciences. "Investigating how gut microbes contribute to malnutrition could provide a framework for developing more effective ways to treat and prevent these devastating diseases."
The research will focus on twins ages 6 months to 2 years, in which one or both twins is severely malnourished, and as a comparison, healthy twins. Identical and fraternal twins are being studied because they have identical or similar genetic backgrounds, and they share the same early environment after birth.
Malnutrition is a major health issue in both Malawi, in sub-Sahara Africa, and in Bangladesh, in East Asia, where it is inextricably linked to extreme poverty. The two countries also have very distinct cultures and diets - factors that likely influence the collection of microbes that colonize the human intestine.
Severe malnutrition has long been thought to stem simply from a lack of adequate food. Scientists now understand that the condition is far more complex. Indeed, it is not uncommon for a family with multiple children to have only one child who is malnourished, even though the children eat a similar diet and live in the same household. This has led scientists to suspect that other factors may be involved. Gordon and his group theorize that an imbalance of certain types of gut microbes conspires with other factors, such as a poor diet and infection with bugs that cause diarrhea, to trigger malnutrition.
The human body contains ten times as many microbial cells as human ones, with large numbers residing in the intestines. While some microbes cause illness, most perform vital tasks to ensure the body functions optimally, such as digesting complex carbohydrates found in grains, fruits and vegetables, which the body can't break down on its own. The nutrients and calories extracted by the microbes are used either as energy or stored as fat.
In earlier work, Gordon and his colleagues have studied the gut microbial communities and their genomes (collectively known as the gut 'microbiome') in lean and obese mice, and lean and obese adult identical and fraternal human twins. These studies support the notion that differences in gut microbiomes contribute to the risk of obesity.
Gordon is teaming with Washington University pediatrician Mark Manary, M.D., the Helene B. Roberson Professor of Pediatrics, who has spent more than two decades in Malawi treating malnourished children. Manary also helped develop a calorie-dense, enriched peanut-butter mixture that can be fed to malnourished children and has helped many of them recover. Gordon and members of his group are also working with members of the world-renowned International Center for Diarrheal Disease Research located in the city of Dhaka in Bangladesh.
As part of the project, malnourished infants will be given a nutritionally enriched food supplement. "We will monitor the collection of microbial species and genes in the gut before, during and after treatment with the supplement, and determine whether the collection of gut microbes and genes undergoes a change as a result of treatment," Gordon says. "If alterations in the gut community do occur with treatment, does its 'new state' persist after cessation of therapy or does it gradually revert to a state where the children are still at risk of malnutrition?"
The researchers also will analyze the gut microbes of the twins' mothers. A recent study by Gordon and his colleagues found that bacterial communities in the gut appear to be transmitted in a significant way from mothers to their offspring.
The grant to Washington University is part of a nearly $30 million initiative by the Gates Foundation to fund research into the root causes of malnutrition in the developing world. As part of this project, the Washington University investigators will join forces with scientists at the University of Virginia in Charlottesville, who will characterize the human genomes of identical and fraternal twins enrolled in this study to determine whether there are alterations in their human genes that regulate nutrient transport and processing.
The foundation is sponsoring work at eight sites in the developing world to address the root problems of malnutrition. By applying new genomic methods and computational tools for mining the massive data that emanate from the Malawi and Bangladesh sites, Gordon, Manary and their team, which also includes colleagues at the University of Colorado in Boulder, hope to develop a new understanding of the basis for malnutrition, and test their theories at other sites in the foundation's global network,
"It is a great privilege for us to conduct this research at a time when the revolution in genome sciences is allowing us to delve into the largely unexplored world of microbes that envelop our bodies," Gordon says. "We are looking forward to participating in this global effort to understand and treat a devastating disease that affects our most precious resource - our children."
|Contact: Caroline Arbanas|
Washington University School of Medicine