Gut-reproduction axis: genome-wide pleiotropic and prospective evidence linking inflammatory bowel disease with gynecological disorders

Objective We aimed to explore shared genetic architectures and potential causal associations between inflammatory bowel disease (IBD) and gynecological diseases, including ovarian cysts (OC), pelvic inflammatory disease (PID), and endometriosis (EMs), and to evaluate whether the findings are consistent with a gut-reproductive connection.

We used genome-wide association study (GWAS) data to assess genetic correlation between IBD and gynecological diseases. Cross-trait pleiotropic loci and genes were identified using PLACO, colocalization, and functional annotation analyses. Stratified LDSC and HyPrColoc were applied to explore immune-related enrichment and colocalized immune traits. Mendelian randomization (MR) was used to assess bidirectional causal effects, and UK Biobank cohort data were analyzed using Cox proportional hazards models.

Genetic correlation analyses supported shared genetic architecture between IBD and gynecological diseases. Pleiotropy and colocalization analyses highlighted representative loci including 6q22.33, 9q34, 1q21.3, 16q12.1, 6q27, and 1q32.1, with enrichment of immune-related pathways such as IL-23 and JAK-STAT signaling, particularly in the colon, small intestine, and spleen. Colocalization signals involving Ruminococcus gauvreauii suggested overlap with microbial abundance traits. MR analyses provided the most consistent evidence for directional associations from IBD and CD to PID, whereas UK Biobank analyses supported broader bidirectional associations, particularly for OC and PID.

This study identifies shared genetic loci, immune-related pathways, and complementary causal and observational associations between IBD and gynecological conditions. These findings support the gut-reproductive axis as a conceptual framework for future mechanistic investigation. Similar content being viewed by others Data availability The original contributions presented in the study are included in the article and Supplementary Material. Further inquiries can be directed to the corresponding author. Abbreviations - IBD: - Inflammatory bowel disease - CD: - Crohn’s disease - UC: - Ulcerative colitis - OC: - Ovarian cysts - PID: - Pelvic inflammatory disease - EMs: - Endometriosis - MR: - Mendelian randomization - IVW: - Inverse variance weighted - MR-PRESSO: - Mendelian randomization pleiotropy RESidual sum and outlier - DIVW: - Directionally inconsistent variance weighted - MR-RAPS: - Robust adjusted profile score - LDSC: - Linkage disequilibrium score regression - HDL: - High definition likelihood - PP.H4: - Posterior probability hypothesis 4 - GOBP: - Gene ontology biological process - PPI: - Protein–protein interaction - JAK: - Janus kinase - STAT: - Signal transducer and activator of transcription - TH17: - T-helper 17 cells - IL: - Interleukin - SNP: - Single nucleotide polymorphism - eQTL: - Expression quantitative trait loci - DEG: - Differentially expressed gene - FDR: - False discovery rate - PCOS: - Polycystic ovary syndrome - ISC: - Intestinal stem cell - SFRP5: - Secreted frizzled-related protein 5 - TGF-β: - Transforming growth factor beta - TNF: - Tumor necrosis factor - EBV: - Epstein-Barr virus - GFM: - Germ-free mice - AOA: - Autoimmune Addison’s disease - HT: - Hashimoto’s thyroiditis - RA: - Rheumatoid arthritis - B-ALL: - B-cell acute lymphoblastic leukemia - PLACO: - Pleiotropic analysis under composite null hypothesis - Tregs: - Regulatory T cells - TUDCA: - Tauroursodeoxycholic acid - GWAS: - Genome-Wide association study - GTEx: - Genotype-tissue expression - JH: - Janus homology - OR: - Odds ratio

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We thank all the studies for making the summary association statistics data publicly available. Funding This work was supported by the funds of Changzhou Sci & Tech Program (CJ20200004) to JHJ; The Research project on high quality development of Hospital pharmacy, National Institute of Hospital Administration, NHC, China (NIHAYSZX2549), the Changzhou Young Scientific and Technological Talent Support Program (CZTJ-2025–32), the Jiangsu Province Young Scientific and Technological Talent Support Program (JSTJ-2025–799), the Open Funding Project of the Jiangsu Provincial Key Laboratory of Anesthesiology, Xuzhou Medical University (XZSYSKF2023011), the Scientific Research Program of the Jiangsu Pharmaceutical Association (202495005), and the Changzhou Sci&Tech Program (CJ20242012) to YJ; The Hospital Pharmacy Management Research Special Project, Jiangsu Hospital Association (JSYGY-2–2024-YS26) to XML; The Suzhou Science and Technology Program Project (QNXM2024010), and the Jiangsu Provincial Health Commission Project (MQ2024022) to XHY. Author information Authors and Affiliations Contributions ZXJ and XHY: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data Curation, Writing—Original Draft, Visualization. HML and MZS: Validation, Formal analysis, Investigation, Writing—Original Draft. XML, QS and LJW: Conceptualization, Validation, Formal analysis, Investigation, Writing—Original Draft. JHJ: Conceptualization, Methodology, Visualization, Supervision, Project administration. YJ: Conceptualization, Methodology, Writing—Review & Editing, Visualization, Supervision, Project administration, Funding acquisition. Corresponding authors Ethics declarations Ethical approval Publicly available de-identified GWAS summary statistics were used for the genetic analyses; therefore, no additional ethical approval or informed consent was required for this secondary analysis. Ethical approval and participant consent for the original studies were obtained by the respective study investigators, as described in the corresponding publications. This research also used the UK Biobank Resource under application numbers 76875 and 41542. UK Biobank has ethics approval from the North West Multi-centre Research Ethics Committee (REC reference: 21/NW/0157), and all participants provided written informed consent at recruitment. Conflict of interest The authors declare no competing interests. Consent for publication Not Applicable. Trial registration Not applicable. This study is a secondary analysis of existing genome-wide association studies and a non-interventional observational analysis of the UK Biobank cohort; therefore, it does not meet the definition of a clinical trial, and trial registration was not required. Additional information Responsible Editor: John Di Battista. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Jiang, Z., Yu, X., Lu, H. et al. Gut-reproduction axis: genome-wide pleiotropic and prospective evidence linking inflammatory bowel disease with gynecological disorders. Inflamm. Res. 75, 133 (2026). https://doi.org/10.1007/s00011-026-02250-5 Received: Revised: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s00011-026-02250-5