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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Gut microbial dysbiosis is common in inflammatory bowel disease (IBD), but whether specific taxa are causal, and through which host genes, remains unclear. We integrated two-sample Mendelian randomization (MR), replication, cis-eQTL colocalization, and single-cell mapping to identify microbial taxa with genetically predicted associations and candidate host mediators. Instruments for 211 taxa from MiBioGen (p &lt; 1\u00d710\u22125, r2 &lt; 0.001) were used in two-sample MR (inverse-variance weighted IVW primary; sensitivity: Egger, weighted median, MR-PRESSO) against IBD, Crohn\u2019s disease (CD), and ulcerative colitis (UC) in the International IBD Genetics Consortium (IIBDGC), with false discovery rate (FDR) correction. Replication was conducted in FinnGen R12; gene prioritization was performed via cis-SMR\/coloc.abf using GTEx v8\/CAGE eQTLs, and localization in 11,175 colonic cells. MR identified 15 significant associations (FDR &lt; 0.05) across eight features; applying a pre-specified heterogeneity-based rule, 13 across seven independent features were retained as primary associations (strongest NB1n \u2192 CD, OR 1.32) and two were downgraded to suggestive; at the independent-signal level, three of 11 associations were replicated and seven were direction-concordant in FinnGen. Colocalization supported shared variants at SENP7 (blood, CD PP.H4 = 0.86, IBD = 0.70) and ZBTB11-AS1 (colon, IBD = 0.76, CD = 0.74); single-cell analysis mapped SENP7 to T\/NK, and ZBTB11-AS1\/VIPR1 to epithelial\/goblet. Replicated MR and colocalization prioritized SENP7 (whole-blood eQTL; minor T\/NK-cell detection) and ZBTB11-AS1 (colon epithelium) as candidate effectors, though the latter lacks functional characterization.<\/jats:p>","DOI":"10.3390\/ijms27198718","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:33:12Z","timestamp":1790699592000},"page":"8718","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut Microbiota, Inflammatory Bowel Disease and the Prioritization of Host Effector Genes: A Two-Sample Mendelian Randomization Study with Independent Replication, cis-eQTL Colocalization and Single-Cell Localization"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9497-847X","authenticated-orcid":false,"given":"Qiyuan","family":"Zou","sequence":"first","affiliation":[{"name":"School of Medicine, Guangxi University, No. 100 Daxue East Road, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3917-8327","authenticated-orcid":false,"given":"Jianyi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, Guangxi University, No. 100 Daxue East Road, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1053\/j.gastro.2016.10.020","article-title":"Understanding and preventing the global increase of inflammatory bowel disease","volume":"152","author":"Kaplan","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrgastro.2017.88","article-title":"Gut microbiota and IBD: Causation or correlation?","volume":"14","author":"Ni","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/s41586-019-1237-9","article-title":"Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases","volume":"569","author":"Arze","year":"2019","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zuo, T., and Ng, S.C. (2018). The gut microbiota in the pathogenesis and therapeutics of inflammatory bowel disease. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.02247"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104947","DOI":"10.1016\/j.phrs.2020.104947","article-title":"Microbiota-derived butyrate regulates intestinal inflammation: Focus on inflammatory bowel disease","volume":"159","author":"Couto","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gao, H., Cao, M., Yao, Y., Hu, W., Sun, H., Zhang, Y., Zeng, C., Tang, J., Luan, S., and Chen, P. (2021). Dysregulated microbiota-driven gasdermin D activation promotes colitis development by mediating IL-18 release. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.750841"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/nature11582","article-title":"Host\u2013microbe interactions have shaped the genetic architecture of inflammatory bowel disease","volume":"491","author":"Jostins","year":"2012","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/ng.3359","article-title":"Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations","volume":"47","author":"Liu","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/ng.3760","article-title":"Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease","volume":"49","author":"Moutsianas","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R89","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: Genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Hemani","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s10654-015-0011-z","article-title":"Using published data in Mendelian randomization: A blueprint for efficient identification of causal risk factors","volume":"30","author":"Burgess","year":"2015","journal-title":"Eur. J. Epidemiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s41588-020-00763-1","article-title":"Large-scale association analyses identify host factors influencing human gut microbiome composition","volume":"53","author":"Kurilshikov","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e38101","DOI":"10.1016\/j.heliyon.2024.e38101","article-title":"Intestinal flora and inflammatory bowel disease: Causal relationships and predictive models","volume":"10","author":"Bi","year":"2024","journal-title":"Heliyon"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e38551","DOI":"10.1097\/MD.0000000000038551","article-title":"Inflammatory proteins may mediate the causal relationship between gut microbiota and inflammatory bowel disease: A mediation and multivariable Mendelian randomization study","volume":"103","author":"Huang","year":"2024","journal-title":"Medicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s13167-024-00384-2","article-title":"Mendelian randomization reveals predictive, preventive, and personalized insights into inflammatory bowel disease: The role of gut microbiome and circulating inflammatory proteins","volume":"15","author":"Zhao","year":"2024","journal-title":"EPMA J."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Li, F., Yu, C., Zhao, Q., Wang, Z., Wang, Z., Chang, Y., Xu, Z., Han, X., Li, H., and Liu, Y. (2023). Exploring the intestinal ecosystem: From gut microbiota to associations with subtypes of inflammatory bowel disease. Front. Cell Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1304858"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Xiao, J., Guo, X., Lin, Y., and Wang, Z. (2024). The causal relationship between immune cell-mediated gut microbiota and ulcerative colitis: A bidirectional two-sample, mediation Mendelian randomization analysis. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1433545"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16265","DOI":"10.1038\/s41598-020-73400-w","article-title":"SENP7 knockdown inhibited pyroptosis and NF-\u03baB\/NLRP3 inflammasome pathway activation in Raw 264.7 cells","volume":"10","author":"Li","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nature18629","article-title":"Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores","volume":"535","author":"Liu","year":"2016","journal-title":"Nature"},{"key":"ref_22","first-page":"4218","article-title":"Epithelial-derived gasdermin D mediates nonlytic IL-1\u03b2 release during experimental colitis","volume":"130","author":"Bulek","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eaaz6717","DOI":"10.1126\/sciadv.aaz6717","article-title":"Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation","volume":"6","author":"Ma","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3522","DOI":"10.1016\/j.celrep.2019.11.028","article-title":"DeSUMOylase SENP7-mediated epithelial signaling triggers intestinal inflammation via expansion of gamma-delta T cells","volume":"29","author":"Suhail","year":"2019","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"114180","DOI":"10.1016\/j.jpeds.2024.114180","article-title":"Biallelic loss of function variants in SENP7 cause immunodeficiency with neurologic and muscular phenotypes","volume":"274","author":"Kobayashi","year":"2024","journal-title":"J. Pediatr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"111484","DOI":"10.1016\/j.yexcr.2019.06.029","article-title":"Long non-coding RNA CRNDE promotes cell apoptosis by suppressing miR-495 in inflammatory bowel disease","volume":"382","author":"Yang","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.gastha.2021.11.005","article-title":"The G protein-coupled receptor VPAC1 mediates vasoactive intestinal peptide-dependent functional homeostasis of the gut microbiota","volume":"1","author":"Ericsson","year":"2022","journal-title":"Gastro Hep Adv."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Bains, M., Laney, C., Wolfe, A.E., Orr, M., Waschek, J.A., Ericsson, A.C., and Dorsam, G.P. (2019). Vasoactive intestinal peptide deficiency is associated with altered gut microbiota communities in male and female C57BL\/6 mice. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.02689"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/ije\/dyy262","article-title":"An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings","volume":"48","author":"Sanderson","year":"2019","journal-title":"Int. J. Epidemiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: The STROBE-MR statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"GTEx Consortium (2020). The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science, 369, 1318\u20131330.","DOI":"10.1126\/science.aaz1776"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ajhg.2016.12.008","article-title":"The genetic architecture of gene expression in peripheral blood","volume":"100","author":"Holloway","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"1000 Genomes Project Consortium, Auton, A., Brooks, L.D., Durbin, R.M., Garrison, E.P., Kang, H.M., Korbel, J.O., Marchini, J.L., McCarthy, S., and McVean, G.A. (2015). A global reference for human genetic variation. Nature, 526, 68\u201374.","DOI":"10.1038\/nature15393"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41586-019-0992-y","article-title":"Colonic epithelial cell diversity in health and inflammatory bowel disease","volume":"567","author":"Parikh","year":"2019","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: A tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet. Epidemiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Hemani, G., Tilling, K., and Davey Smith, G. (2017). Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet., 13, Erratum in PLoS Genet. 2017, 13, e1007149.","DOI":"10.1371\/journal.pgen.1007149"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0166-4328(01)00297-2","article-title":"Controlling the false discovery rate in behavior genetics research","volume":"125","author":"Benjamini","year":"2001","journal-title":"Behav. Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Giambartolomei, C., Vukcevic, D., Schadt, E.E., Franke, L., Hingorani, A.D., Wallace, C., and Plagnol, V. (2014). Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004383"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/gepi.20359","article-title":"Bayes factors for genome-wide association studies: Comparison with P-values","volume":"33","author":"Wakefield","year":"2009","journal-title":"Genet. Epidemiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1002\/gepi.21765","article-title":"Statistical testing of shared genetic control for potentially related traits","volume":"37","author":"Wallace","year":"2013","journal-title":"Genet. Epidemiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8718\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:12:55Z","timestamp":1791519175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":44,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198718"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198718","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]}}}