{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T06:02:18Z","timestamp":1789624938087,"version":"build-2803163510"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ebm-journal.org"],"crossmark-restriction":true},"short-container-title":["Exp. Biol. Med."],"abstract":"<jats:p>Observational studies have frequently reported an association between primary biliary cirrhosis (PBC) and inflammatory bowel disease (IBD). In this study, we leveraged summary-level data from genome-wide association studies (GWAS) to conduct a two-sample bidirectional Mendelian randomization (MR) analysis, with the primary objective of investigating the genetic causal relationship between PBC and IBD, comprising ulcerative colitis (UC) and Crohn\u2019s disease (CD). Additionally, a validation analysis was performed by repeating the bidirectional MR framework, alternately defining PBC and IBD as the exposure and outcome variables to confirm the directionality of the observed associations. A comprehensive panel of sensitivity analyses was implemented to test the robustness of the findings. We first examined the genetic causality at the subtype level. In the forward MR, PBC exerted a significant positive causal effect on UC (P &amp;lt; 0.001, OR 95% CI = 1.081 [1.037\u20131.127]) and on CD (P = 0.002, OR 95% CI = 1.136 [1.047\u20131.232]). In the reverse MR, only UC showed a significant negative causal influence on PBC (P &amp;gt; 0.003, OR 95% CI = 0.788 [0.672\u20130.924]), whereas no significant effect was detected from CD on PBC (P = 0.431, OR 95% CI = 0.956 [0.856\u20131.068]). We then extended the analysis to the overall IBD phenotype. The forward MR demonstrated a significant positive genetic relationship between PBC on IBD (P &amp;lt; 0.001, OR 95% CI = 1.076 [1.042\u20131.110]). Conversely, the reverse MR did not support a causal effect of IBD on PBC (P = 0.357, OR 95% CI = 0.898 [0.714\u20131.129]). The robustness of all these findings was confirmed by comprehensive sensitivity analyses, which showed no evidence of heterogeneity, horizontal pleiotropy, or undue influence from individual instrumental variables. Our MR analysis demonstrates that PBC serves as a genetic determinant of IBD as a whole and of UC\/CD separately, whereas reverse causation is limited to a protective effect of UC on PBC. This direction-dependent and subtype-specific causal architecture provides novel insights into the shared etiological pathways between PBC and IBD.<\/jats:p>","DOI":"10.3389\/ebm.2026.10940","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:10:12Z","timestamp":1789621812000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Primary biliary cirrhosis and inflammatory bowel disease: a two-sample bidirectional Mendelian randomization study"],"prefix":"10.3389","volume":"251","author":[{"given":"Mingyi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiale","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Radiotherapy, Tangdu Hospital, The Fourth Military Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Practice, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changliang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, Honghui Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yani","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Radiotherapy, Tangdu Hospital, The Fourth Military Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"318","DOI":"10.5694\/mja17.01001","article-title":"Management of inflammatory bowel disease","volume":"209","author":"Wright","year":"2018","journal-title":"Med J Aust"},{"key":"B2","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/nrgastro.2015.34","article-title":"Epidemiology and risk factors for IBD","volume":"12","author":"Ananthakrishnan","year":"2015","journal-title":"Nat Rev Gastroenterol and Hepatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3998","DOI":"10.3748\/wjg.v26.i28.3998","article-title":"Secondary causes of inflammatory bowel diseases","volume":"26","author":"Ghouri","year":"2020","journal-title":"World J Gastroenterol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.jaut.2015.07.013","article-title":"Understanding inflammatory bowel disease via immunogenetics","volume":"64","author":"de Lange","year":"2015","journal-title":"J Autoimmun"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1053\/j.gastro.2021.07.051","article-title":"Is prevention the best way to modify inflammatory bowel disease? 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