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The causality between gut microbiota and ectopic pregnancy based on genome-wide association: A Mendelian randomization study

Ning Zhang(1), Zhige Wang(2), Feixiang Yang(3), Tianrui Liu(4), Dongmei Ji(5),


(1) Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; First School of Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, China
(2) First School of Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, China
(3) First School of Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, China; Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, China
(4) Second School of Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, China
(5) Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Second School of Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, China4; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei 230032, Anhui, China
Corresponding Author

Abstract


Ectopic pregnancy represents a prevalent gynecological emergency with incompletely characterized pathophysiology, creating substantial clinical challenges in timely diagnosis and effective management. The causal interplay between gut microbiota and ectopic pregnancy, particularly through plasma proteomics mediation, remains undefined. We derived Gut microbiota GWAS data (n=412) from the Dutch Microbiome Project meta-analysis and Ectopic pregnancy data from IEU OpenGWAS and FinnGen project. The results revealed nine kinds of gut microbiotas demonstrating causal associations with ectopic pregnancy risk. A total of 67 plasma proteins causally impact the risk of ectopic pregnancy. In addition, three kinds of gut microbiotas were mediated by 25 kinds of plasma proteins on ectopic pregnancy. Microbiota enriched in L.rhamnose.degradation.I affected ectopic pregnancy through 22 kinds of plasma proteins. This study establishes causal relationships between specific gut microbial pathways and ectopic pregnancy risk, mediated through distinct plasma protein signatures, providing directions for clinical interventions and future research..

References


Vukas Radulovic N, Bullarbo M and Ekerhovd E. A Case of Chronic Ectopic Pregnancy Manifested by Rectal Bleeding. Case Rep Obstet Gynecol. 2017;2017:5974590.

Xu H, Feng G, Wei Y, Feng Y, Yang R, Wang L, Zhang H, Li R and Qiao J. Predicting Ectopic Pregnancy Using Human Chorionic Gonadotropin (hCG) Levels and Main Cause of Infertility in Women Undergoing Assisted Reproductive Treatment: Retrospective Observational Cohort Study. JMIR Med Inform. 2020;8(4):e17366.

Iwe ABC, Nwafor JI, Asiegbu OG, Adebayo JA, Uche-Nwidagu BN and Ali VC. Spontaneous Ruptured Bilateral Tubal Ectopic Pregnancy Following Natural Conception: A Rare Case Report. J Hum Reprod Sci. 2021;14(2):196-9.

Zeng P, Zhou H, Guo P, Xia W, Huang J and Zeng Q. Efficacy and safety of traditional Chinese herbal medicine in the treatment of threatened abortion: A protocol for systematic review and meta-analysis. Medicine (Baltimore). 2021;100(5):e23288.

Callahan R, Yacobson I, Halpern V and Nanda K. Ectopic pregnancy with use of progestin-only injectables and contraceptive implants: a systematic review. Contraception. 2015;92(6):514-22.

Chouinard M, Mayrand M-H, Ayoub A, Healy-Profitós J and Auger N. Ectopic pregnancy and outcomes of future intrauterine pregnancy. Fertil Steril. 2019;112(1):112-9.

Wu H, Ganguly S and Tollefsbol TO. Modulating Microbiota as a New Strategy for Breast Cancer Prevention and Treatment. Microorganisms. 2022;10(9):1727.

Huang L and Chen C. Employing pigs to decipher the host genetic effect on gut microbiome: advantages, challenges, and perspectives. Gut Microbes. 2023;15(1):2205410.

Walker J, Joy AA, Vos LJ, Stenson TH, Mackey JR, Jovel J, Kao D, Madsen KL and Wong GK-S. Chemotherapy-induced weight gain in early-stage breast cancer: a prospective matched cohort study reveals associations with inflammation and gut dysbiosis. BMC Med. 2023;21(1):178.

Ye J, Peng H, Huang X and Qi X. The association between endometriosis and risk of endometrial cancer and breast cancer: a meta-analysis. BMC Womens Health. 2022;22(1):455.

Macpherson AJ, de Agüero MG and Ganal-Vonarburg SC. How nutrition and the maternal microbiota shape the neonatal immune system. Nat Rev Immunol. 2017;17(8):508-17.

Xiao L, Zhou T, Zuo Z, Sun N and Zhao F. Spatiotemporal patterns of the pregnancy microbiome and links to reproductive disorders. Sci Bull (Beijing). 2024;69(9):1275-85.

Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, VanderWeele TJ, Higgins JPT, Timpson NJ, Dimou N, Langenberg C, Golub RM, Loder EW, Gallo V, Tybjaerg-Hansen A, Davey Smith G, Egger M and Richards JB. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021;326(16):1614-21.

Lopera-Maya EA, Kurilshikov A, van der Graaf A, Hu S, Andreu-Sánchez S, Chen L, Vila AV, Gacesa R, Sinha T, Collij V, Klaassen MAY, Bolte LA, Gois MFB, Neerincx PBT, Swertz MA, Harmsen HJM, Wijmenga C, Fu J, Weersma RK, Zhernakova A and Sanna S. Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project. Nat Genet. 2022;54(2):143-51.

Ferkingstad E, Sulem P, Atlason BA, Sveinbjornsson G, Magnusson MI, Styrmisdottir EL, Gunnarsdottir K, Helgason A, Oddsson A, Halldorsson BV, Jensson BO, Zink F, Halldorsson GH, Masson G, Arnadottir GA, Katrinardottir H, Juliusson K, Magnusson MK, Magnusson OT, Fridriksdottir R, Saevarsdottir S, Gudjonsson SA, Stacey SN, Rognvaldsson S, Eiriksdottir T, Olafsdottir TA, Steinthorsdottir V, Tragante V, Ulfarsson MO, Stefansson H, Jonsdottir I, Holm H, Rafnar T, Melsted P, Saemundsdottir J, Norddahl GL, Lund SH, Gudbjartsson DF, Thorsteinsdottir U and Stefansson K. Large-scale integration of the plasma proteome with genetics and disease. Nat Genet. 2021;53(12):1712-21.

Li P, Wang H, Guo L, Gou X, Chen G, Lin D, Fan D, Guo X and Liu Z. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med. 2022;20(1):443.

Shim H, Chasman DI, Smith JD, Mora S, Ridker PM, Nickerson DA, Krauss RM and Stephens M. A multivariate genome-wide association analysis of 10 LDL subfractions, and their response to statin treatment, in 1868 Caucasians. PLoS One. 2015;10(4):e0120758.

Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, Laurin C, Burgess S, Bowden J, Langdon R, Tan VY, Yarmolinsky J, Shihab HA, Timpson NJ, Evans DM, Relton C, Martin RM, Davey Smith G, Gaunt TR and Haycock PC. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018;7.

Liu T, Yang F, Wang Z, Mei Y, Li H, Wang K, Zhang X, Chen Y, Zhang Y and Meng J. Sex hormones, blood metabolites and proteins mediating the causal associations between gut microbiota and prostatic diseases: evidences from Mendelian randomization study. Prostate Int. 2025;13(1):49-59.

Carter AR, Sanderson E, Hammerton G, Richmond RC, Davey Smith G, Heron J, Taylor AE, Davies NM and Howe LD. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol. 2021;36(5):465-78.

Huang T, Li Z, Tye KD, Chan SN, Tang X, Luo H, Wang D, Zhou J, Duan X and Xiao X. Probiotic supplementation during pregnancy alters gut microbial networks of pregnant women and infants. Front Microbiol. 2022;13:1042846.

Neu J. Developmental aspects of maternal-fetal, and infant gut microbiota and implications for long-term health. Matern Health Neonatol Perinatol. 2015;1:6.

Sajdel-Sulkowska EM. The Impact of Maternal Gut Microbiota during Pregnancy on Fetal Gut-Brain Axis Development and Life-Long Health Outcomes. Microorganisms. 2023;11(9).

Crusell MKW, Hansen TH, Nielsen T, Allin KH, Rühlemann MC, Damm P, Vestergaard H, Rørbye C, Jørgensen NR, Christiansen OB, Heinsen F-A, Franke A, Hansen T, Lauenborg J and Pedersen O. Gestational diabetes is associated with change in the gut microbiota composition in third trimester of pregnancy and postpartum. Microbiome. 2018;6(1):89.

Li G, Yin P, Chu S, Gao W, Cui S, Guo S, Xu Y, Yuan E, Zhu T, You J, Zhang J and Yang M. Correlation Analysis between GDM and Gut Microbial Composition in Late Pregnancy. J Diabetes Res. 2021;2021:8892849.

Huang T, Liang X, Bao H, Ma G, Tang X, Luo H and Xiao X. Multi-omics analysis reveals the associations between altered gut microbiota, metabolites, and cytokines during pregnancy. mSystems. 2024;9(3):e0125223.

Zhou Z, Guille C, Ogunrinde E, Liu R, Luo Z, Powell A and Jiang W. Increased systemic microbial translocation is associated with depression during early pregnancy. J Psychiatr Res. 2018;97:54-7.

Ozcan G, Tanyolaç Talay ZG, Paerhati E, Eren OC, Coskun N, Sahin D, Alnajjar I, Albayrak O, Gursoy A, Keskin O, Celik E and Can F. Dysbiosis in pregnant mice induced by transfer of human vaginal microbiota followed by reversal of pathological changes in the uterus and placenta via progesterone treatment. BMC Pregnancy Childbirth. 2024;24(1):427.

Peuranpää P, Holster T, Saqib S, Kalliala I, Tiitinen A, Salonen A and Hautamäki H. Female reproductive tract microbiota and recurrent pregnancy loss: a nested case-control study. Reprod Biomed Online. 2022;45(5):1021-31.

Dong C, Liu Z, Zhu C, Zhang Y, Yang X, Xu X, Guan Qa and Xia Y. Contribution of serum elements to blood pressure during pregnancy by impacting gut microbiota: A prospective cohort study. J Hazard Mater. 2024;465:133383.

Bu T, Li X, Wang L, Wu X, Gao S, Yun D, Li L, Sun F and Cheng CY. Regulation of Sertoli cell function by planar cell polarity (PCP) protein Fjx1. Mol Cell Endocrinol. 2023;571:111936.

Huang M, Guo T, Meng Y, Zhou R, Xiong M, Ding J, Zhang Y, Liu S and Zhuang K. Comprehensive analysis of the prognosis and immune effect of the oncogenic protein Four Jointed Box 1. Front Oncol. 2023;13:1170482.


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