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

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

doi:10.3389/fimmu.2020.00189

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

8 Citations (Web of Science)

Abstract

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 S100 beta 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 S100 beta 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.

Original language	English
Article number	189
Number of pages	13
Journal	Frontiers in Immunology
Volume	11
DOIs	https://doi.org/10.3389/fimmu.2020.00189
Publication status	Published - 17 Mar 2020

Keywords

Ureaplasma parvum
intra-amniotic infection
chorioamnionitis
enteric nervous system
sheep
preterm birth
necrotizing enterocolitis
NECROTIZING ENTEROCOLITIS
GLIAL-CELLS
INTRAAMNIOTIC ENDOTOXIN
PRETERM BIRTH
FETAL
CHORIOAMNIONITIS
EXPOSURE
IMMUNE
INFLAMMATION
ASSOCIATION

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10.3389/fimmu.2020.00189Licence: CC BY

8 Citations
1 Erratum / corrigendum / retractions

Corrigendum: Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses
Heymans, C., de Lange, I. H., Huetten, M. C., Lenaerts, K., de Ruijter, N. J. E., Kessels, L. C. G. A., Rademakers, G., Melotte, V., Boesmans, W., Saito, M., Usuda, H., Stock, S. J., Spiller, O. B., Beeton, M. L., Payne, M. S., Kramer, B. W., Newnham, J. P., Jobe, A. H., Kemp, M. W., van Gemert, W. G., & 1 othersWolfs, T. G. A. M., 15 Apr 2020, In: Frontiers in Immunology. 11, 2 p., 672.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access

Cite this

Heymans, C., de Lange, I. H., Hutten, M. C., Lenaerts, K., de Ruijter, N. J. E., Kessels, L. C. G. A., Rademakers, G., Melotte, V., Boesmans, W., Saito, M., Usuda, H., Stock, S. J., Spiller, O. B., Payne, M. S., Kramer, B. W., Newnham, J. P., Jobe, A. H., Kemp, M. W., van Gemert, W. G., & Wolfs, T. G. A. M. (2020). Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses. Frontiers in Immunology, 11, [189]. https://doi.org/10.3389/fimmu.2020.00189

@article{62473dcbaac6458d8d61245f2ec68cf6,

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

abstract = "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 S100 beta 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 S100 beta 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.",

keywords = "Ureaplasma parvum, intra-amniotic infection, chorioamnionitis, enteric nervous system, sheep, preterm birth, necrotizing enterocolitis, NECROTIZING ENTEROCOLITIS, GLIAL-CELLS, INTRAAMNIOTIC ENDOTOXIN, PRETERM BIRTH, FETAL, CHORIOAMNIONITIS, EXPOSURE, IMMUNE, INFLAMMATION, ASSOCIATION",

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

year = "2020",

month = mar,

day = "17",

doi = "10.3389/fimmu.2020.00189",

language = "English",

volume = "11",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Media S.A.",

}

Heymans, C , de Lange, IH , Hutten, MC , Lenaerts, K, de Ruijter, NJE, Kessels, LCGA, Rademakers, G, Melotte, V , Boesmans, W, Saito, M, Usuda, H, Stock, SJ, Spiller, OB, Payne, MS, Kramer, BW, Newnham, JP, Jobe, AH, Kemp, MW, van Gemert, WG & Wolfs, TGAM 2020, 'Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses', Frontiers in Immunology, vol. 11, 189. https://doi.org/10.3389/fimmu.2020.00189

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 - Hutten, 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.

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 S100 beta 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 S100 beta 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 S100 beta 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 S100 beta 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 - intra-amniotic infection

KW - chorioamnionitis

KW - enteric nervous system

KW - sheep

KW - preterm birth

KW - necrotizing enterocolitis

KW - NECROTIZING ENTEROCOLITIS

KW - GLIAL-CELLS

KW - INTRAAMNIOTIC ENDOTOXIN

KW - PRETERM BIRTH

KW - FETAL

KW - CHORIOAMNIONITIS

KW - EXPOSURE

KW - IMMUNE

KW - INFLAMMATION

KW - ASSOCIATION

U2 - 10.3389/fimmu.2020.00189

DO - 10.3389/fimmu.2020.00189

M3 - Article

C2 - 32256485

VL - 11

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 189

ER -

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

Abstract

Keywords

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Research output

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

Cite this