Environmental enteric dysfunction (EED), a chronic inflammatory condition of the intestine, affects millions of children in low- and middle-income countries, leading to stunted growth and cognitive impairment. While the pathophysiology of EED is poorly defined, it is known that malnutrition, dysbiosis, and pathogen exposure contribute to structural and functional intestinal damage, including villus blunting, compromised barrier function, and reduced nutrient absorption. Using a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by organoid-derived intestinal epithelial cells from EED patients and cultured in niacinamide- and tryptophan-deficient (-N/-T) medium, we were able to create an in vitro model of EED that directly associates key genotypic and phenotypic features of EED-associated intestinal injury with nutritional deficiency and intestinal genetic and epigenetic changes. Exposure of EED Intestine Chips to -N/-T deficiencies (EED -N/-T Chips) resulted in transcriptional changes similar to those seen in clinical EED biopsy specimens from patients in Pakistan, Bangladesh, and Zambia. Using unsupervised hierarchical clustering, EED -N/T Chips showed the closest relationship to the EED clinical signature when compared to chips lined by healthy intestinal epithelium and exposed to -N/-T medium or EED Chips cultured in complete media. This included upregulation of antimicrobial genes capable of shaping the microbiome and downregulation of metallothioneins, metabolic, and digestive genes. The congruence was most striking amongst the top ten upregulated genes of the clinical EED signature, 6 of which (60%) were also upregulated when EED Chips were exposed to nutritionally deficient medium. Phenotypically, exposure of EED Intestine Chips or Healthy Intestine Chips to -N/-T medium resulted in severe villus blunting and barrier dysfunction, as well as impairment of fatty acid uptake and amino acid transport. EED Intestine Chips exhibited reduced secretion of cytokines at baseline, but their production was significantly upregulated compared to healthy Intestine Chips when exposed to -N/-T deficiencies. Given the modular design of the Intestine Chip and its ability to support co-culture with complex human gut microbiota, we are now incorporating immune cells and EED patient-derived duodenal bacterial isolates to further define their separate and combinatorial role in the intestinal dysfunction of EED.

Nutritional deficiency recapitulates intestinal injury associated with environmental enteric dysfunction in human patient-derived Organ Chips

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