Chorioamnionitis-induced fetal gut injury is mediated by direct gut exposure of inflammatory mediators or by lung inflammation

Tim G. A. M. Wolfs, Boris W. Kramer, Geertje Thuijls, Matthew W. Kemp, Masatoshi Saito, Monique G. M. Willems, Paranthaman Senthamarai-Kannan, John P. Newnham, Alan H. Jobe, Suhas G. Kallapur*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Intra-amniotic exposure to proinflammatory agonists causes chorio-amnionitis and fetal gut inflammation. Fetal gut inflammation is associated with mucosal injury and impaired gut development. We tested whether this detrimental inflammatory response of the fetal gut results from a direct local (gut derived) or an indirect inflammatory response mediated by the chorioamnion/skin or lung, since these organs are also in direct contact with the amniotic fluid. The gastrointestinal tract was isolated from the respiratory tract and the amnion/skin epithelia by fetal surgery in time-mated ewes. Lipopolysaccharide (LPS) or saline (controls) was selectively infused in the gastrointestinal tract, trachea, or amniotic compartment at 2 or 6 days before preterm delivery at 124 days gestation (term 150 days). Gastrointestinal and intratracheal LPS exposure caused distinct inflammatory responses in the fetal gut. Inflammatory responses could be distinguished by the influx of leukocytes (MPO (1), CD3 (1), and FoxP3 (1) cells), tumor necrosis factor-alpha, and interferon-gamma expression and differential upregulation of mRNA levels for Toll-like receptor 1, 2, 4, and 6. Fetal gut inflammation after direct intestinal LPS exposure resulted in severe loss of the tight junctional protein zonula occludens protein 1 (ZO-1) and increased mitosis of intestinal epithelial cells. Inflammation of the fetal gut after selective LPS instillation in the lungs caused only mild disruption of ZO-1, loss in epithelial cell integrity, and impaired epithelial differentiation. LPS exposure of the amnion/skin epithelia did not result in gut inflammation or morphological, structural, and functional changes. Our results indicate that the detrimental consequences of chorioamnionitis on fetal gut development are the combined result of local gut and lung-mediated inflammatory responses.
Original languageEnglish
Pages (from-to)G382-G393
JournalAmerican Journal of Physiology-Gastrointestinal and Liver Physiology
Issue number5
Publication statusPublished - Mar 2014


  • endotoxin
  • fetal inflammatory response
  • necrotizing enterocolitis
  • sheep


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