Antenatal Ureaplasma infection induces ovine small intestinal goblet cell defects: a strong link with NEC pathology

Charlotte van Gorp, Ilse H de Lange, Matthias C Hütten, Carmen López-Iglesias, Kimberly Ri Massy, Lilian Kessels, Boris Kramer, Willine van de Wetering, Brad Spiller, George M Birchenough, Wim G van Gemert, Luc J Zimmermann, Tim Gam Wolfs*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Disruption of the intestinal mucus barrier and intestinal epithelial endoplasmic reticulum (ER) stress contribute to necrotizing enterocolitis (NEC). Previously, we observed intestinal goblet cell loss and increased intestinal epithelial ER stress following chorioamnionitis. Here, we investigated how chorioamnionitis affects goblet cells by assessing their cellular characteristics. Importantly, goblet cell features are compared with those in clinical NEC biopsies. Mucus thickness was assessed as read-out of goblet cell function. Fetal lambs were intra-amniotically (IA) infected for 7d at 122 gestational age with Ureaplasma parvum serovar-3, the main microorganism clinically associated with chorioamnionitis. After preterm delivery, mucus thickness, goblet cell numbers, gut inflammation, epithelial proliferation and apoptosis and intestinal epithelial ER stress were investigated in the terminal ileum. Next, goblet cell morphological alterations (TEM) were studied and compared to human NEC samples. Ileal mucus thickness and goblet cell numbers were elevated following IA UP exposure. Increased pro-apoptotic ER stress, detected by elevated CHOP-positive cell counts and disrupted organelle morphology of secretory cells in the intestinal epithelium, was observed in IA UP exposed animals. Importantly, comparable cellular morphological alterations were observed in the ileum from NEC patients. In conclusion, UP-driven chorioamnionitis leads to a thickened ileal mucus layer and mucus hypersecretion from goblet cells. Since this was associated with pro-apoptotic ER stress and organelle disruption, mucus barrier alterations seem to occur at the expense of goblet cell resilience and may therefore predispose to detrimental intestinal outcomes. The remarkable overlap of these in utero findings with observations in NEC patients underscores their clinical relevance.

Original languageEnglish
Article number2158016
Number of pages16
JournalTissue Barriers
Issue number4
Early online date28 Dec 2022
Publication statusPublished - Nov 2023


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