Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia

Mingjing Hu; David Eviston; Peter Hsu; Eliana Mariño; Ann Chidgey; Brigitte Santner-Nanan; Kahlia Wong; James L Richards; Yu Anne Yap; Fiona Collier; Ann Quinton; Steven Joung; Michael Peek; Ron Benzie; Laurence Macia; David Wilson; Ann-Louise Ponsonby; Mimi L K Tang; Martin O'Hely; Norelle L Daly; Charles R Mackay; Jane E Dahlstrom; BIS Investigator Group; Peter Vuillermin; Ralph Nanan

doi:10.1038/s41467-019-10703-1

Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia

Nat Commun. 2019 Jul 10;10(1):3031. doi: 10.1038/s41467-019-10703-1.

Authors

Mingjing Hu^{1

2}, David Eviston², Peter Hsu^{3

4}, Eliana Mariño⁵, Ann Chidgey⁶, Brigitte Santner-Nanan^{1

2}, Kahlia Wong⁶, James L Richards⁵, Yu Anne Yap⁵, Fiona Collier^{7

8

9}, Ann Quinton^{2

10}, Steven Joung^{2

11}, Michael Peek^{2

12}, Ron Benzie^{11

13}, Laurence Macia¹⁴, David Wilson¹⁵, Ann-Louise Ponsonby^{9

16}, Mimi L K Tang^{9

17

18}, Martin O'Hely^{7

9}, Norelle L Daly¹⁵, Charles R Mackay⁵, Jane E Dahlstrom¹⁹; BIS Investigator Group; Peter Vuillermin^{7

8

9

20}, Ralph Nanan^{21

22}

Collaborators

BIS Investigator Group:
Richard Saffery, Katrina J Allen, Sarath Ranganathan, David Burgner, Leonard C Harrison, Peter Sly, Terry Dwyer

Affiliations

¹ Charles Perkins Centre Nepean, The University of Sydney, Penrith, 2750, NSW, Australia.
² Sydney Medical School Nepean, The University of Sydney, Penrith, 2750, NSW, Australia.
³ Discipline of Paediatrics and Child Health, Sydney Medical School, The University of Sydney, Sydney, 2006, NSW, Australia.
⁴ Department of Allergy and Immunology, The Children's Hospital at Westmead, Sydney, 2145, NSW, Australia.
⁵ Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, 3800, VIC, Australia.
⁶ Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, 3800, VIC, Australia.
⁷ Deakin University, Geelong, 3220, VIC, Australia.
⁸ Barwon Health, Geelong, 3220, VIC, Australia.
⁹ Murdoch Children's Research Institute, Parkville, 3052, VIC, Australia.
¹⁰ School of Health, Medical and Applied Science, Central Queensland University, Sydney, 2000, NSW, Australia.
¹¹ Nepean Hospital, Penrith, 2750, NSW, Australia.
¹² ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, 0200, ACT, Australia.
¹³ Discipline of Obstetrics, Gynaecology and Neonatology, Sydney Medical School Nepean, The University of Sydney, Penrith, 2750, NSW, Australia.
¹⁴ Department of Pathology, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, Sydney, 2006, NSW, Australia.
¹⁵ Centre for Molecular Therapeutics, AITHM, James Cook University, Cairns, 4814, QLD, Australia.
¹⁶ National Centre for Epidemiology and Population Health, Research School of Population Health, College of Health and Medicine, The Australian National University, Canberra, 0200, ACT, Australia.
¹⁷ The Royal Children's Hospital, Parkville, Melbourne, 3052, VIC, Australia.
¹⁸ Department of Paediatrics, University of Melbourne, Melbourne, 3010, VIC, Australia.
¹⁹ Anatomical Pathology, ACT Pathology, Canberra Hospital and ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, 0200, ACT, Australia.
²⁰ Centre for Food and Allergy Research, Parkville, 3052, VIC, Australia.
²¹ Charles Perkins Centre Nepean, The University of Sydney, Penrith, 2750, NSW, Australia. ralph.nanan@sydney.edu.au.
²² Sydney Medical School Nepean, The University of Sydney, Penrith, 2750, NSW, Australia. ralph.nanan@sydney.edu.au.

Abstract

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4⁺ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AIRE Protein
Acetates / administration & dosage
Acetates / blood*
Acetates / immunology
Acetates / metabolism
Adult
Animals
Animals, Newborn
Case-Control Studies
Child Development
Child, Preschool
Dietary Supplements
Female
Fetus / cytology
Fetus / diagnostic imaging
Fetus / immunology*
Gastrointestinal Microbiome / immunology
Germ-Free Life / immunology
Humans
Immune Tolerance / immunology
Infant
Infant, Newborn
Longitudinal Studies
Maternal-Fetal Exchange / immunology
Mice
Organ Size / immunology
Pre-Eclampsia / blood
Pre-Eclampsia / diagnosis
Pre-Eclampsia / immunology*
Pregnancy
Prenatal Exposure Delayed Effects / immunology*
Prenatal Exposure Delayed Effects / pathology
Prenatal Exposure Delayed Effects / prevention & control
Prospective Studies
T-Lymphocytes, Regulatory / immunology*
Thymus Gland / cytology
Thymus Gland / diagnostic imaging
Thymus Gland / growth & development
Thymus Gland / immunology
Transcription Factors / immunology
Transcription Factors / metabolism
Ultrasonography, Prenatal
Young Adult

Substances

Acetates
Transcription Factors