AUTHOR=Heymans Cathelijne , de Lange Ilse H. , Hütten Matthias C. , Lenaerts Kaatje , de Ruijter Nadine J. E. , Kessels Lilian C. G. A. , Rademakers Glenn , Melotte Veerle , Boesmans Werend , Saito Masatoshi , Usuda Haruo , Stock Sarah J. , Spiller Owen B. , Beeton Michael L. , Payne Matthew S. , Kramer Boris W. , Newnham John P. , Jobe Alan H. , Kemp Matthew W. , van Gemert Wim G. , Wolfs Tim G. A. M. 

TITLE=Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00189

DOI=10.3389/fimmu.2020.00189

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Materials and Methods:</bold> 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), <italic>Ureaplasma parvum</italic> (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS).</p><p><bold>Results:</bold> 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.</p><p><bold>Conclusion:</bold> The <italic>in utero</italic> 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.</p>