Modeling a devastating childhood disease on a chip: Environmental Enteric Dysfunction (EED) Chip reveals effects of nutrition and genetics on disease in children

Millions of children in low- and middle-income nations suffer from environmental enteric dysfunction (EED), a chronic inflammatory disease of the intestine that is the second leading cause of death in children under five years old. EED is a devastating condition that is associated with malnutrition, stunted growth, and poor cognitive development, permanently impacting patients’ quality of life. In addition, oral vaccines are less effective in children with EED, leaving them vulnerable to otherwise preventable diseases. While some cases of EED are treatable by simply improving a patient’s diet, better nutrition doesn’t help all children. A lack of adequate nutrients and exposure to contaminated water and food contribute to EED, but the underlying mechanism of the disease remains unknown.

Now, a team of researchers at the Wyss Institute at Harvard University has created an in vitro human model of EED in a microengineered Intestine Chip device, providing a window into the complex interplay between malnutrition and genetic factors driving the disease. Their EED Chips recapitulate several features of EED found in biopsies from human patients, including inflammation, intestinal barrier dysfunction, reduced nutrient absorption, and atrophy of the villi (tiny hair-like projections) on intestinal cells.

They also found that depriving healthy Intestine Chips of two crucial nutrients — niacinamide (a vitamin) and tryptophan (an essential amino acid) — caused morphological, functional, and genetic changes similar to those found in EED patients, suggesting that their model could be used to identify and test the effects of potential treatments.

“Functionally, there is something very wrong with these kids’ digestive system and its ability to absorb nutrients and fight infections, which you can’t cure simply by giving them the nutrients that are missing from their diet. Our EED model allowed us to decipher what has happened to the intestine, both physically and genetically, that so dramatically affects its normal function in patients with EED,” said co-first author Amir Bein, R.D., Ph.D., a former Senior Postdoctoral Research Fellow at the Wyss Institute who is now the VP of Biology at Quris Technologies.

The research is published today in Nature Biomedical Engineering.

Modeling a complex disease on-a-chip

The EED Chip project grew out of conversations between the Wyss Institute’s Founding Director Donald Ingber, M.D., Ph.D. and the Bill and Melinda Gates Foundation, which has an established interest in supporting research to understand and treat enteric diseases. Recognizing that there had been no in vitro studies of EED to study its molecular mechanisms, a Wyss team of more than 20 people set about creating a model of EED using its Human Organ Chip technology developed in Ingber’s lab.

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