Knowledge Generation

Peter Rabinowitz of the University of Washington in the U.S., along with colleagues at Washington State University and CDC Kenya, will test whether unhealthy gut microbes in livestock that co-reside with humans in smallholder households can negatively influence the gut microbes in the humans, and whether this can be exploited to improve human health. The microbial community (microbiota) living in the gut is important for childhood health, growth and development.

Marie Lewis of the University of Reading in the United Kingdom will establish pig models of environmental enteric dysfunction (EED) and acute secretory diarrhea (ASD) to develop and test new therapeutic approaches. Rodents are commonly used to model human enteropathies, but their physiology is quite different and often therapies that work in rodents fail in humans. Pigs may be a more valuable disease model as their biology is more comparable to humans.

Mark Donowitz and Nicholas Zachos of Johns Hopkins University in the U.S. will develop human epithelial cell cultures that mimic the human intestine as a model for acute diarrhea, which is the second leading cause of death worldwide. They will culture the cells as polarized monolayers, which can be infected with disease- causing pathogens, and use them to measure the effect on NaCl absorption, which is blocked in almost all diarrheal diseases. They will also upgrade their model to mimic the mechanical forces experienced by the human intestine during the passage of food.

Seth Walk of Montana State University in the U.S. will develop an in vitro model system composed of three dimensional intestinal tissue (organoids) and microfluidics to quantitate the effect of diarrhea-causing bacteria on intestinal function. They have already grown stable multicellular intestinal organoids displaying typical intestinal structures and function from human intestinal stem cells. Now, they will incorporate fluidics to represent flow inside the gastrointestinal tract to more closely mimic gut physiology in vivo.

Michel Bagnat of Duke University in the U.S. will study new genetic zebrafish models of acute secretory diarrhea and environmental enteric dysfunction, which are normally caused by infectious pathogens in humans, to study disease pathogenesis and facilitate development of new therapies. The zebrafish intestine has a similar physiology to the human organ, making zebrafish a valuable genetic model for studying human intestinal diseases. They have already isolated zebrafish mutants displaying characteristics of the relevant human diseases.

Marcela Pasetti of the University of Maryland in the U.S. will generate an in vitro model of the gut using intestinal stem cells and immune cells to better mimic the damaged and inflamed guts of young children in developing countries for testing new treatments. Current so-called human enteroid models lack additional relevant cell types found in the intestine, particularly immune cells, which are known to play an important role in gut health and function.

Steve Lindsay of the London School of Hygiene and Tropical Medicine in the United Kingdom seeks to demonstrate that flies are transmitters of diarrheal diseases due to their attraction to fecal matter and to food sources, and proposes to design traps that attract, capture and kill flies in latrines. If successful, the reductions in flies may reduce diarrheal diseases in local communities.

Elmer Sayre of the WAND Foundation in the Philippines will explore how to close the loop between sanitation, health and food consumption by testing low-cost dry toilets appropriate for most conditions and using the human waste in small-scale agriculture efforts. Results and best practices will then be shared for future scale-up of the project.

James Tsuruta and Paul Dayton of the University of North Carolina, Chapel Hill will study the ability of therapeutic ultrasound to deplete testicular sperm counts. Characterizing the most beneficial timing and dosage could lead to the development of a low-cost, non-hormonal and reversible method of contraception for men.

Mahua Choudhury of University of Colorado in the U.S. will develop a database of epigenetic signatures, changes in DNA and proteins caused by non-genetic factors such as poor nutrition, smoking and environmental contaminants, that could be used as predictors of pre-eclampsia. This information will be used to develop a cost- effective diagnostic tool to detect these markers in blood or urine.