Gut microbiota-derived trimethylamine N-Oxide: a novel target for the treatment of preeclampsia

ABSTRACT

Pre-eclampsia (PE) is the most common complication of pregnancy and seriously threatens the health and safety of the mother and child. Studies have shown that an imbalance in gut microbiota can affect the progression of PE. Trimethylamine N-oxide (TMAO) is an intestinal microbiota-derived metabolite that is thought to be involved in the occurrence of PE; however, its causal relationship and mechanism remain unclear. In this clinical cohort study, including 28 patients with eclampsia and 39 matched healthy controls, fecal samples were collected for 16S rRNA gene sequencing, and serum was collected for targeted metabolomics research. The results showed that the level of TMAO and the abundance of its source bacteria had significantly increased in patients with PE, and were positively correlated with the clinical progression of PE. Fecal microbiota transplantation (FMT) was applied to an antibiotic-depleted-treated mouse model and targeted inhibition of TMAO. The results of the FMT experiment revealed that mice that received fecal microbiota transplantation from patients with PE developed typical PE symptoms and increased oxidative stress and inflammatory damage, both of which were reversed by 3,3-Dimethyl-1-butanol (DMB), a TMAO inhibitor, which also improved pregnancy outcomes in the model mice. Similar results were obtained in the classical NG-Nitroarginine methyl ester (L-NAME) induced PE mouse model. Mechanistically, TMAO promotes the progression of PE by regulating inflammatory and oxidative stress-related signaling pathways, affecting the migration and angiogenesis of vascular endothelial cells, as well as the migration and invasion of trophoblast cells. Our results reveal the role and mechanism of gut microbiota and TMAO in the progression of PE, provides new ideas for exploring the pathogenesis and therapeutic targets of PE, and determines the potential application value of TMAO as a target for PE intervention.

GRAPHICAL ABSTRACT

KEYWORDS:

• Preeclampsia
• gut microbiota
• TMAO
• placental trophoblast cells
• vascular endothelial cells

Acknowledgments

Thanks to Laboratory Animal Center of Ningbo University for the technical support.We thank Mengjie Yang Xiqin Guo and Chao Dong from the Laboratory Animal Center of Ningbo University for their technical support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

RX, and YZ designed the study and supervised all the experiments. JW, and YG performed the phenotypic and mechanistic analyses. JW, JL, SC, and JF performed the in vivo experiments. SR, YG, and BH performed the bioinformatic analyses of RNA-seq data. All authors read and approved the final manuscript.

Data availability statement

The data that support these findings of the study are available upon request from the corresponding authors.

Ethics approval and consent to participate

This study involved human tissues and was approved by the Institutional Review Committee of the First Affiliated Hospital of Ningbo University (No.KY202011224). All materials were sourced from donors at the First Affiliated Hospital of Ningbo University who provided written informed consent and gave permission for their clinical information to be used for research purposes. All animal research and experimental procedures are approved by the Animal Care and Use Committee of Animal Facilities, Ningbo University (No. NBU20220129).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2311888

Additional information

Funding

This work was supported by the key Project of Zhejiang Provincial Natural Science Foundation of China(No. Q24 H040007), Natural Science Foundation of Ningbo (No. 2021J239), Public Welfare Technology Plan Project of Ningbo (No. 2021S101), Ningbo Top Medical and Health Research Program (No. 2023020612), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (No. 2023RC083), Ningbo key research and development plan and “reveal the list” project (No.2023Z175).