Dr Priscilla Day-Walsh

Dr Day-Walsh is CTR's 2022 newly appointed Next Generation Research Fellow, working in the Departments of Obstetrics & Gynaecology and Physiology, Development & Neuroscience, University of Cambridge

Mechanistic understanding of the role of maternal gut microbiota derived metabolites on placental 
function in relation to pregnancy complications

Abstract

Pregnancy complications can lead to high maternal and fetal mortality and morbidity and increased risk of the offspring developing chronic diseases such as diabetes, cardiovascular and neurodegenerative diseases in adulthood. Microorganisms (microbiome) residing in the mother’s gut can consume nutrients that are important to the mother and the fetus to produce substances that are potentially toxic or beneficial to the mother and the fetus.

The effects of the maternal gut microbiota and their metabolites on the maternal-placental-fetal unit are poorly understood. I aim to provide insights into the mechanisms through which metabolites produced by the maternal gut microbiota act as signals and regulate key processes involved in placental function and development, to highlight important microbial products that may be used as novel tools for screening, preventing, and possibly treating pregnancy complications.

Lay abstract

The placenta is an organ that develops during pregnancy and acts as a barrier between the maternal and fetal blood, eliminating toxins and transporting nutrients and oxygen to the fetus. Placental development and function can be affected by substances from the mother, the placenta and the fetus, leading to pregnancy complications such as high blood pressure during pregnancy (preeclampsia), poor fetal growth, and stillbirth. Pregnancy complications can lead to high maternal and fetal mortality and morbidity and increased risk of the offspring developing diseases such as diabetes, cardiovascular and neurodegenerative diseases in adulthood.

Microorganisms (microbiome) residing in the mother’s gut can consume nutrients that are important to the mother and the fetus to produce substances that are toxic or beneficial to the mother and the fetus. While most studies on the effects of these substances in health and disease have been carried out in adults, their effects on the mother, the placenta, and the fetus are poorly understood.

Here, I will investigate how these substances may affect processes involved in placental development and function such as cellular signalling, substrate metabolism, and transport, using placental cellular models. I will also use blood samples collected from 4,512 mothers who were recruited to the “Pregnancy Outcome Prediction Study (POPs)” at the Rosie Hospital (Cambridge, UK) to establish whether the levels of these microbial derived substances in the mother’s blood are associated with pregnancy complications.

I propose that the consumption of essential nutrients by the maternal microbiota will:

(i) limit the availability of these nutrients to the maternal-placenta-fetal unit and therefore lead to deprivation

(ii) produce toxic substances that may affect processes critical to placental development and function and therefore will influence pregnancy outcomes. The presence of these substances in the mother’s blood may be useful for identifying, preventing, and treating pregnancy complications.

References

1. Shehata, E., Parker, A., Suzuki, T., Swann, J. R, Suez, J., Kroon, P. A., & Day-Walsh, P*. (2022). Microbiomes in physiology: insights into 21st century global medical challenges. Experimental Physiology, 107, 257– 264. https://doi.org/10.1113/EP090226. *Corresponding author
2. P. Day-Walsh, E. Shehata, S. Saha, G.M. Savva, B. Nemeckova, J. Speranza, L. Kellingray, A. Narbad, P.A. Kroon, The use of an in-vitro batch fermentation (human colon) model for investigating mechanisms of TMA production from choline, l-carnitine and related precursors by the human gut microbiota, Eur J Nutr(2021). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437865.
3. P.E. Day, G. Ntani, S.R. Crozier, P.A. Mahon, H.M. Inskip, C. Cooper, N.C. Harvey, K.M. Godfrey, M.A. Hanson, R.M. Lewis, J.K. Cleal, Maternal Factors Are Associated with the Expression of Placental Genes Involved in Amino Acid Metabolism and Transport, Plos One 10(12) (2015) e0143653 https://pubmed.ncbi.nlm.nih.gov/26657885/.
4. Cleal JK, Day PE*, Crosier SR, Hanson MA, Harvey NCH, Robinson SM, Cooper C, Godfrey KM, and Lewis, RM, SWS team. Placental amino acid transport may be regulated by maternal vitamin D and vitamin D-binding protein: results from the Southampton Women's Survey. British Journal of Nutrition, 2015, (10.1017/S0007114515001178). https://pubmed.ncbi.nlm.nih.gov/25940599/* Equal contribution to first author
5. J.K. Cleal, J.D. Glazier, G. Ntani, S.R. Crozier, P.E. Day, N.C. Harvey, S.M. Robinson, C. Cooper, K.M. Godfrey, M.A. Hanson, R.M. Lewis, Facilitated transporters mediate net efflux of amino acids to the fetus across the basal membrane of the placental syncytiotrophoblast, J Physiol 589(Pt 4) (2011) 987-97. https://pubmed.ncbi.nlm.nih.gov/21224231/.