TY - JOUR
T1 - Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses
AU - Heymans, Cathelijne
AU - de Lange, Ilse H.
AU - Hütten, Matthias C.
AU - Lenaerts, Kaatje
AU - de Ruijter, Nadine J.E.
AU - Kessels, Lilian C.G.A.
AU - Rademakers, Glenn
AU - Melotte, Veerle
AU - Boesmans, Werend
AU - Saito, Masatoshi
AU - Usuda, Haruo
AU - Stock, Sarah J.
AU - Spiller, Owen B.
AU - Payne, Matthew S.
AU - Kramer, Boris W.
AU - Newnham, John P.
AU - Jobe, Alan H.
AU - Kemp, Matthew W.
AU - van Gemert, Wim G.
AU - Wolfs, Tim G.A.M.
N1 - Funding Information:
This work was supported by the National Institutes of Health (Bethesda, MD, USA) grant (HD 57869) and the Kinderonderzoekfonds Limburg (TW).
Publisher Copyright:
© Copyright © 2020 Heymans, de Lange, Hütten, Lenaerts, de Ruijter, Kessels, Rademakers, Melotte, Boesmans, Saito, Usuda, Stock, Spiller, Payne, Kramer, Newnham, Jobe, Kemp, van Gemert and Wolfs.
PY - 2020/3/17
Y1 - 2020/3/17
N2 - Background: Chorioamnionitis, inflammation of the fetal membranes during pregnancy, is often caused by intra-amniotic (IA) infection with single or multiple microbes. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). Neonates with NEC have structural and functional damage to the intestinal mucosa and the enteric nervous system (ENS), with loss of enteric neurons and glial cells. Yet, the impact of acute, chronic, or repetitive antenatal inflammatory stimuli on the development of the intestinal mucosa and ENS has not been studied. The aim of this study was therefore to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs. Materials and Methods: A sheep model of pregnancy was used in which the ileal mucosa, submucosa, and ENS were assessed following IA exposure to lipopolysaccharide (LPS) for 2 or 7 days (acute), Ureaplasma parvum (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS). Results: IA LPS exposure for 7 days or IA UP exposure for 42 days caused intestinal injury and inflammation in the mucosal and submucosal layers of the gut. Repetitive microbial exposure did not further aggravate injury of the terminal ileum. Chronic IA UP exposure caused significant structural ENS alterations characterized by loss of PGP9.5 and S100β immunoreactivity, whereas these changes were not found after re-exposure of chronic UP-exposed fetuses to LPS for 2 or 7 days. Conclusion: The in utero loss of PGP9.5 and S100β immunoreactivity following chronic UP exposure corresponds with intestinal changes in neonates with NEC and may therefore form a novel mechanistic explanation for the association of chorioamnionitis and NEC.
AB - Background: Chorioamnionitis, inflammation of the fetal membranes during pregnancy, is often caused by intra-amniotic (IA) infection with single or multiple microbes. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). Neonates with NEC have structural and functional damage to the intestinal mucosa and the enteric nervous system (ENS), with loss of enteric neurons and glial cells. Yet, the impact of acute, chronic, or repetitive antenatal inflammatory stimuli on the development of the intestinal mucosa and ENS has not been studied. The aim of this study was therefore to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs. Materials and Methods: A sheep model of pregnancy was used in which the ileal mucosa, submucosa, and ENS were assessed following IA exposure to lipopolysaccharide (LPS) for 2 or 7 days (acute), Ureaplasma parvum (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS). Results: IA LPS exposure for 7 days or IA UP exposure for 42 days caused intestinal injury and inflammation in the mucosal and submucosal layers of the gut. Repetitive microbial exposure did not further aggravate injury of the terminal ileum. Chronic IA UP exposure caused significant structural ENS alterations characterized by loss of PGP9.5 and S100β immunoreactivity, whereas these changes were not found after re-exposure of chronic UP-exposed fetuses to LPS for 2 or 7 days. Conclusion: The in utero loss of PGP9.5 and S100β immunoreactivity following chronic UP exposure corresponds with intestinal changes in neonates with NEC and may therefore form a novel mechanistic explanation for the association of chorioamnionitis and NEC.
KW - Ureaplasma parvum
KW - chorioamnionitis
KW - enteric nervous system
KW - intra-amniotic infection
KW - necrotizing enterocolitis
KW - preterm birth
KW - sheep
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UR - http://www.scopus.com/inward/citedby.url?scp=85082686403&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.00189
DO - 10.3389/fimmu.2020.00189
M3 - Article
C2 - 32256485
AN - SCOPUS:85082686403
SN - 1664-3224
VL - 11
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 189
ER -