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Intrauterine Growth Restriction Is Associated with Unique Features of the Reproductive Microbiome

  • Maternal Fetal Medicine/Biology: Original Article
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Abstract

Intrauterine growth restriction (IUGR) is an obstetrical complication with an increased risk of perinatal mortality and morbidity. The uterus, once considered to be a sterile environment, has now been described in recent microbiome studies to harbor diverse commensal placenta microbiota, as well as potentially pathogenic flora known to cause infection. Therefore, in this pilot study, we tested whether IUGR was associated with changes to the reproductive microbiome. The reproductive microbiome was surveyed using 16S sequencing (20 IUGR, 20 controls). Alpha and beta diversity were compared, and differential taxa features associated with IUGR were identified. Microbial screening of the placenta demonstrated a diverse range of flora predominantly including Proteobacteria, Fusobacteria, Firmicutes, and Bacteroidetes. Neither alpha- nor beta-diversity was significantly different by IUGR status. However, at the taxa level, IUGR patients had significantly higher prevalence of Neisseriaceae, mucosal β-hemolytic bacteria known to uptake iron-bound host proteins including hemoglobin. Moreover, the increase in anaerobic bacteria such as Desulfovibrio reflects the emergence of a hypoxic environment in the IUGR placenta. Further analysis of the reproductive microbiome of IUGR samples showed lower levels of H202-producing Bifidobacterium and Lactobacillus that switch from respiration to fermentation, a less energetic metabolic process, when oxygen levels decrease. Source tracking analysis showed that the placental microbial contents were predominantly contributed from an oral source, as compared to a gut or vaginal source. Our results suggest that the reproductive microbiome profiles may, in the future, constitute potential biomarkers for fetal health during pregnancy, while Neisseriaceae may constitute promising therapeutic targets for IUGR treatment.

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Data Availability

16S rRNA gene sequencing data has been deposited into the EMBL Nucleotide Sequence Database (ENA) with Project ID PRJEB25504.

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Acknowledgments

We thank the OCS genome technology center of the New York University Langone Medical Center for the library preparation and sequencing services.

Funding

This work was funded by the MSSM seed fund (JZH), Henan provincial science and technology research and development special funds #182102410020 (YJX), and NICHD HD00849/RSDP/Wyeth (MJL).

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Authors and Affiliations

  1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jianzhong Hu, Michelle Wang & Inga Peter

  2. Department of Obstetrics, Gynecology and Women’s Health, University of Hawaii at Manoa, Honolulu, HI, USA

    Paula Benny & Men-Jean Lee

  3. Washington University at St. Louis, Saint Louis, MO, USA

    Michelle Wang

  4. Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Yula Ma & Luca Lambertini

  5. The Third Affiliated Hospital of Zhangzhou University, Zhengzhou, Henan, China

    Yajuan Xu

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  1. Jianzhong Hu
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Contributions

JZH supported this study, designed the study, performed sequencing analysis and bioinformatics, and drafted the manuscript. MW, YM, and LL collected and processed the samples and performed 16S PCR experiments. IP supported the study, participated in the design of the study, and helped to draft the manuscript. YJX supervised the design of the study and helped to draft the manuscript. MJL conceived the overall study, supervised all the experiments, collected clinical samples and clinical information, and coordinated and drafted the manuscript. PB wrote and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Men-Jean Lee.

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This study was approved by the Institutional Review Board at the Icahn School of Medicine at Mount Sinai.

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Supplementary Information

Figure S1

Measurement of bacterial loading and richness of bacterial community in placental samples. 1A. Measurement of bacterial loading. The relative bacterial loading was calculated using the base 2 with the exponent of the difference between the real-time PCR Cp values from the bacterial 16S rDNA gene and the human beta-actin gene. 1B. Measurement of richness of bacterial community in placental samples. Box plots compared the mean and variance of the microbial alpha-diversity measured by Shannon index and Inverse Simpson index between IUGR and AGA placental samples. (PDF 982 kb)

Table S1

Mean comparison of LEfSe selected genera. The mean abundance of LEfSe selected genera was compared between IUGR and normal placenta samples between C-section and vaginal deliveries. P-values were obtained from non-parametric Wilcoxon test. (XLSX 9 kb)

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Hu, J., Benny, P., Wang, M. et al. Intrauterine Growth Restriction Is Associated with Unique Features of the Reproductive Microbiome. Reprod. Sci. 28, 828–837 (2021). https://doi.org/10.1007/s43032-020-00374-5

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