Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium

David R Hill, Sha Huang, Melinda S Nagy, Veda K Yadagiri, Courtney Fields, Dishari Mukherjee, Brooke Bons, Priya H Dedhia, Alana M Chin, Yu-Hwai Tsai, Shrikar Thodla, Thomas M Schmidt, Seth Walk, Vincent B Young, Jason R Spence

Abstract

The human gastrointestinal tract is immature at birth, yet must adapt to dramatic changes such as oral nutrition and microbial colonization. The confluence of these factors can lead to severe inflammatory disease in premature infants; however, investigating complex environment-host interactions is difficult due to limited access to immature human tissue. Here, we demonstrate that the epithelium of human pluripotent stem-cell-derived human intestinal organoids is globally similar to the immature human epithelium and we utilize HIOs to investigate complex host-microbe interactions in this naive epithelium. Our findings demonstrate that the immature epithelium is intrinsically capable of establishing a stable host-microbe symbiosis. Microbial colonization leads to complex contact and hypoxia driven responses resulting in increased antimicrobial peptide production, maturation of the mucus layer, and improved barrier function. These studies lay the groundwork for an improved mechanistic understanding of how colonization influences development of the immature human intestine.