Researchers at Harvard’s Wyss Institute have modeled Environmental Enteric Dysfunction (EED), a childhood inflammatory intestinal disease, on a microfluidic chip and gained new insights into the genetic changes underlying the condition. This is the first in vitro model of the disease, and highlights the power of organ on a chip systems to provide insights into complex disease states. The intestinal chip used in the research has been announced previously, but this latest study puts it through its paces using cell samples from EED patients. The researchers identified nutrients that appear to be heavily involved in some of the features of EED and the cells in the EED chips also showed many of the genetic hallmarks of EED, highlighting the potential of the model to emulate the disease.
EED is a serious intestinal disease that typically affects children in low-income nations. It is a chronic intestinal condition and is linked with malnutrition, impaired cognitive development, and stunted growth. Despite affecting millions of children, an effective in vitro model of the disease had not been established until now, resulting in a missed opportunity to understand the disease and develop new treatments.
These Harvard researchers turned their attention to the disease and realized that their gut on a chip system is well suited to modeling and understanding the condition. “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,” said Amir Bein, a researcher involved in the study. “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.”
While there are physical differences between Healthy Chips (top row) and EED Chips (bottom row), both types of chips experience dramatic changes in response to malnutrition (right column).
The intestine on a chip device consists of two microfluidic channels, one which is lined with endothelial cells as a proxy for intestinal blood vessels, and the other is lined with intestinal epithelial cells to mimic the intestine itself. A nutrient-rich fluid flows through the blood vessel channel and a permeable membrane between the channels allows the nutrients to reach the intestinal cells.
To model EED, the researchers sourced intestinal cell samples from EED patients, and used them to line the intestinal channel of the chips. They then compared them to chips lined with cells from healthy cell donors. The EED chips showed changes in gene expression in a large number of genes, particularly when certain nutrients were excluded from the nutrient fluid. The chips also mimicked the disease in several ways, as the intestinal cells showed inflammation, intestinal barrier dysfunction, and reduced nutrient absorption, which are all found in human EED patients.
The study shows that organ chips are very useful at recreating complex disease states, and they will likely prove to be crucial in developing new treatments for such conditions.
Study in Nature Biomedical Engineering: Nutritional deficiency in an intestine-on-a-chip recapitulates injury hallmarks associated with environmental enteric dysfunction
Flashback: Intestine Chip to Study Human-Microbiome Interactions
