Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium
David R. Hill1, Sha Huang1, Melinda S. Nagy1, Veda K. Yadagiri1, Courtney Fields 2, Dishari Mukherjee3, Brooke Bons2, Priya H. Dedia4, Alana M. Chin5, Yu-Hwai Tsai1, Shrikar Thodla1, Thomas M. Schmidt3,Seth Walk6, Vincent B. Young2,3,#, and Jason R. Spence1,5,#
1Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109 2Department of Internal Medicine, Division of Infectious Disease, University of Michigan, Ann Arbor MI 48109 3Department of Microbiology and Immunology, University of Michigan, Ann Arbor MI 48109 4Department of Surgery, University of Michigan, Ann Arbor MI 48109 5Department of Cell and Developmental Biology, University of Michigan, Ann Arbor MI 48109 6Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717
authors for correspondence: Jason R. Spence – spencejr@umich.edu Vincent B. Young – youngvi@umich.edu
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 naïve 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.
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