The reproductive tract microbiota and miscarriage
File(s)
Author(s)
Grewal, Karen
Type
Thesis
Abstract
Early miscarriage (pregnancy loss before 12 weeks) occurs in 20 % of pregnancies of which
half are due to aneuploidy. However, the mechanisms that drive euploid miscarriage are
poorly understood and, despite its prevalence, there are no interventions that prevent
sporadic miscarriage. Emerging evidence supports the role of the vaginal microbiota in
adverse pregnancy outcome. Our group has previously shown that miscarriage is associated
with vaginal dysbiosis but the cytogenetic status of those miscarriages was unknown. The
existence and origin of an early pregnancy placental niche and the interaction between the
rectal and vaginal microbiota in early pregnancy loss has not been addressed.
Bacterial 16S rRNA gene based metataxonomic analysis was used to interrogate the vaginal
microbiota in women who miscarried compared to term healthy pregnancies. The same
approach was used to compare the trophoblast and rectal microbiota of miscarriage patients
with termination of pregnancy patient controls. I have shown that, compared to aneuploid
miscarriage, euploid miscarriage is associated with a significantly higher prevalence of
Lactobacillus spp. deplete vaginal microbial communities. In women with Lactobacillus spp.
deplete vaginal microbial communities, euploid miscarriage associates with higher
concentrations of pro-inflammatory cytokines (measured using the Human Magnetic Luminex
Screening 8-plex Assay) when compared to viable term pregnancy. Prevotella bivia and
Streptococcus were identified as particularly common in euploid miscarriage and as drivers of
proinflammatory cytokines. This shows that it is a combination of an adverse vagina
microbiota and the maternal local immune response to it that predicts miscarriage. I have also
demonstrated that there is a bacterial signal in trophoblast above the background
contamination control, but it was difficult to account for cross contamination via the vaginal
niche due to sample collection methods. In those that had an adverse vaginal microbiota
significant rectal dysbiosis was seen in euploid compared to aneuploid miscarriage.
Furthermore, a healthy gut microbiome appears to dampen the cervicovaginal immune
response to Lactobacillus spp. deplete vaginal microbiota.
Overall the findings presented in this thesis support the hypothesis that the vaginal microbiota
plays an important aetiological role in euploid miscarriage and that the rectal or gut
microbiota may modulate the inflammatory reaction to vaginal dysbiosis. These findings
suggest that modulation of the vaginal and or rectal/gut microbiota, using prebiotics or live
biotherapeutics may reduce the risk of miscarriage.
half are due to aneuploidy. However, the mechanisms that drive euploid miscarriage are
poorly understood and, despite its prevalence, there are no interventions that prevent
sporadic miscarriage. Emerging evidence supports the role of the vaginal microbiota in
adverse pregnancy outcome. Our group has previously shown that miscarriage is associated
with vaginal dysbiosis but the cytogenetic status of those miscarriages was unknown. The
existence and origin of an early pregnancy placental niche and the interaction between the
rectal and vaginal microbiota in early pregnancy loss has not been addressed.
Bacterial 16S rRNA gene based metataxonomic analysis was used to interrogate the vaginal
microbiota in women who miscarried compared to term healthy pregnancies. The same
approach was used to compare the trophoblast and rectal microbiota of miscarriage patients
with termination of pregnancy patient controls. I have shown that, compared to aneuploid
miscarriage, euploid miscarriage is associated with a significantly higher prevalence of
Lactobacillus spp. deplete vaginal microbial communities. In women with Lactobacillus spp.
deplete vaginal microbial communities, euploid miscarriage associates with higher
concentrations of pro-inflammatory cytokines (measured using the Human Magnetic Luminex
Screening 8-plex Assay) when compared to viable term pregnancy. Prevotella bivia and
Streptococcus were identified as particularly common in euploid miscarriage and as drivers of
proinflammatory cytokines. This shows that it is a combination of an adverse vagina
microbiota and the maternal local immune response to it that predicts miscarriage. I have also
demonstrated that there is a bacterial signal in trophoblast above the background
contamination control, but it was difficult to account for cross contamination via the vaginal
niche due to sample collection methods. In those that had an adverse vaginal microbiota
significant rectal dysbiosis was seen in euploid compared to aneuploid miscarriage.
Furthermore, a healthy gut microbiome appears to dampen the cervicovaginal immune
response to Lactobacillus spp. deplete vaginal microbiota.
Overall the findings presented in this thesis support the hypothesis that the vaginal microbiota
plays an important aetiological role in euploid miscarriage and that the rectal or gut
microbiota may modulate the inflammatory reaction to vaginal dysbiosis. These findings
suggest that modulation of the vaginal and or rectal/gut microbiota, using prebiotics or live
biotherapeutics may reduce the risk of miscarriage.
Version
Open Access
Date Issued
2022-08
Date Awarded
2023-06
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Bennett, Phillip
MacIntyre, David
Bourne, Tom
Sponsor
Tommys Miscarriage Charity
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)