Inflammatory Determinants of Pregravid Obesity in Placenta and Peripheral Blood
Suhas Sureshchandra1, Nicole E Marshall2, Randall M Wilson3
1Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States.
Insights
Pre-pregnancy obesity causes heightened maternal inflammation and immune dysregulation, impacting placental function and nutrient transport, potentially leading to adverse pregnancy outcomes.
Area of Science:
- Reproductive biology
- Immunology
- Metabolic disorders
Background:
- Pre-pregnancy obesity is linked to adverse maternal and offspring health outcomes.
- Systemic inflammation and placental dysfunction are suspected mediators, but molecular mechanisms remain unclear.
Purpose of the Study:
- To comprehensively analyze the impact of pre-pregnancy obesity on the maternal immune system and placental function.
- To investigate molecular mechanisms linking obesity to pregnancy complications.
Main Methods:
- Analyzed maternal circulating cytokines, chemokines, adipokines, and growth factors using Luminex assay.
- Assessed immune cell frequencies and cytokine production via flow cytometry.
- Profiled placental transcriptome and microbiome using RNA- and 16S-sequencing.
Main Results:
- Obesity associated with insulin/leptin resistance, elevated IL-6, CRP, and IL-8.
- Observed altered T-cell profiles (decreased naïve, increased memory CD4+ T-cells) and Th2 shift.
- Identified increased pro-inflammatory cytokine production by myeloid cells and altered placental gene expression and microbiome (Bacteroides).
Conclusions:
- Pre-pregnancy obesity induces systemic inflammation and immune dysregulation.
- Obesity alters placental gene expression related to nutrient transport and immunity.
- Findings offer insights into fetal reprogramming due to maternal obesity.
Abstract:
Pre-pregnancy (pregravid) obesity has been linked to several adverse health outcomes for both mother and offspring. Complications during pregnancy include increased risk for gestational diabetes, hypertension, preeclampsia, placental abruption, and difficulties during delivery. Several studies suggest that these negative outcomes are mediated by heightened systemic inflammation as well as changes in placental development and function. However, the molecular mechanisms by which pregravid obesity affects these processes are poorly understood. In this study, we aimed to address this question by carrying out a comprehensive analysis of the systemic maternal immune system coupled with placental gene expression and microbial profiling at term delivery (11 lean and 14 obese). Specifically, we examined the impact of pregravid obesity on circulating cytokines, chemokine, adipokines, and growth factors using multiplex Luminex assay. Innate and adaptive immune cell frequencies and their cytokine production in response to stimuli were measured using flow cytometry. Finally, changes in placental transcriptome and microbiome were profiled using RNA- and 16S-sequencing, respectively. Pregravid obesity is characterized by insulin and leptin resistance, high levels of circulating inflammatory markers IL-6 and CRP, in addition to chemokine IL-8 (p < 0.01). Moreover, pregravid obesity was associated with lower frequency of naïve CD4+ T-cells (p < 0.05), increased frequency of memory CD4+ T-cells (p < 0.01), and a shift towards Th2 cytokine production (p = 0.05). Myeloid cells from the obese cohort produced higher levels of pro-inflammatory cytokines but lower levels of chemokines following TLR stimulation (p < 0.05). Lastly, pregravid obesity is associated with increased abundance of Bacteroides and changes in the expression of genes important for nutrient transport and immunity (FDR < 0.05). Collectively, these data indicate that pregravid obesity is associated with heightened systemic inflammation and of dysregulated nutrient transport in the placenta and provide insight into the basis of fetal reprogramming.
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