Exploring the role of sodium-glucose cotransporter 3 (SGLT3) in pregnancy and lactation
File(s)
Author(s)
Beckwith, Hannah
Type
Thesis
Abstract
Pregnancy and lactation produce unique physiological challenges for a female: she needs to adapt and support the dividing cells which ultimately will become her offspring, without compromising her own survival. To do that, the mother must absorb and synthesise key nutrients to support development, adjusting anatomically to cope with the physical and mechanical demands of a growing foetus. In this thesis, I have shown that reproduction induces significant changes in the maternal intestine, at both microscopic and macroscopic levels.
I have first focused on adaptations that are seen in wildtype mice, presenting changes to small intestine (SI) length, gene expression and histomorphometric features in both pregnancy and lactation. One of the genes differentially upregulated during reproduction, Slc5a4a codes for a protein, SGLT3a; I have characterised the expression of Slc5a4a during pregnancy and lactation, as well as localising its expression to the mid-villus.
Using transgenic knockout mice, I have phenotyped the effects of single and second pregnancies, demonstrating that the significant villous elongation seen in wildtype mice during lactation is limited in SGLT3 knockout mice. Furthermore, there is a differential growth in the SI of knockout and wildtype mice following a second pregnancy, suggesting a putative role for SGLT3a in the remodelling seen during reproduction. Collaboration with electrophysiology experts at Harvard has suggested that SGLT3a may transport protons and sodium, in a pH dependent manner, potentially coinciding with changes to luminal pH during reproduction.
Finally, I have demonstrated alterations to human SI length following reproduction in a Magnetic Resonance Imaging study, and highlighted changes to morphology seen in the intestine of females with children.
Together, these results illustrate the substantial intestinal remodelling that occurs after reproduction, exacerbated by successive pregnancies. To our knowledge, Slc5a4a would be the first enterocyte gene identified in mice to be involved in reproductive remodelling.
I have first focused on adaptations that are seen in wildtype mice, presenting changes to small intestine (SI) length, gene expression and histomorphometric features in both pregnancy and lactation. One of the genes differentially upregulated during reproduction, Slc5a4a codes for a protein, SGLT3a; I have characterised the expression of Slc5a4a during pregnancy and lactation, as well as localising its expression to the mid-villus.
Using transgenic knockout mice, I have phenotyped the effects of single and second pregnancies, demonstrating that the significant villous elongation seen in wildtype mice during lactation is limited in SGLT3 knockout mice. Furthermore, there is a differential growth in the SI of knockout and wildtype mice following a second pregnancy, suggesting a putative role for SGLT3a in the remodelling seen during reproduction. Collaboration with electrophysiology experts at Harvard has suggested that SGLT3a may transport protons and sodium, in a pH dependent manner, potentially coinciding with changes to luminal pH during reproduction.
Finally, I have demonstrated alterations to human SI length following reproduction in a Magnetic Resonance Imaging study, and highlighted changes to morphology seen in the intestine of females with children.
Together, these results illustrate the substantial intestinal remodelling that occurs after reproduction, exacerbated by successive pregnancies. To our knowledge, Slc5a4a would be the first enterocyte gene identified in mice to be involved in reproductive remodelling.
Version
Open Access
Date Issued
2022-08-19
Date Awarded
01/07/2023
License URL
Advisor
Miguel-Aliaga, Irene
Publisher Department
Institute of Clinical Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)