{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:17:17Z","timestamp":1786123037821,"version":"build-2736575974"},"reference-count":32,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82360363"],"award-info":[{"award-number":["82360363"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372087"],"award-info":[{"award-number":["82372087"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2026Y0004"],"award-info":[{"award-number":["2026Y0004"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["20232BAB206136"],"award-info":[{"award-number":["20232BAB206136"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Integrative analysis of the gut microbiome and metabolome can help characterize colorectal cancer (CRC)-associated molecular changes that are difficult to resolve from either omics layer alone. However, microbiome\u2013metabolome data are high-dimensional, heterogeneous, and often contain nonlinear or locally confined associations that may be obscured by global linear models. Here, we propose a phenotype-guided topological framework that extends the Mapper algorithm for local interpretation of paired microbiome and metabolome profiles. Disease-associated variation from each omics block was summarized by partial least-squares regression and used to construct a two-dimensional filter space for Mapper graph construction. We further developed an Extended Spatial Analysis of Functional Enrichment strategy (eSAFE) to evaluate the spatial enrichment of phenotypes, individual features, and feature\u2013pair associations on the resulting graph. Applied to paired fecal metagenomic and metabolomic profiles from a CRC cohort, the framework organized samples into phenotype-aligned neighborhoods and identified localized microbial, metabolic, and cross-omics association patterns linked to CRC. Coenrichment analysis further prioritized disease-associated features and interaction modules that were partly distinct from those obtained by univariate differential analysis or supervised sparse multiblock integration. One disease-localized microbiome\u2013metabolome module showed moderate CRC discrimination in internal cross-validation and was enriched for metabolites involved in butanoate and amino acid-related pathways. These results suggest that phenotype-guided topological analysis can provide a complementary, interpretable view of localized multiomics organization in CRC-associated gut ecosystems.<\/jats:p>","DOI":"10.1021\/acs.jproteome.6c00192","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:34:20Z","timestamp":1784075660000},"page":"4177-4188","source":"Crossref","is-referenced-by-count":0,"title":["A Phenotype-Embedded\nMapper Framework Links Microbiome\u2013Metabolome\nInteraction Modules to Colorectal Cancer"],"prefix":"10.1021","volume":"25","author":[{"given":"Yiquan","family":"Feng","sequence":"first","affiliation":[{"name":"East China University of Technology , , ,","place":["Nanchang, China, 330013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genjin","family":"Lin","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenghong","family":"Jiang","sequence":"additional","affiliation":[{"name":"East China University of Technology , , ,","place":["Nanchang, China, 330013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Shi","sequence":"additional","affiliation":[{"name":"East China University of Technology , , ,","place":["Nanchang, China, 330013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingli","family":"Deng","sequence":"additional","affiliation":[{"name":"East China University of Technology , , ,","place":["Nanchang, China, 330013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1064-6548","authenticated-orcid":true,"given":"Jiyang","family":"Dong","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"issue":"3","key":"2026080709081717800_cit1","doi-asserted-by":"publisher","first-page":"kaf026","DOI":"10.1093\/jncics\/pkaf026","article-title":"Gut microbiome in colorectal cancer: metagenomics from\nbench to bedside","volume":"9","author":"Torshizi Esfahani","year":"2025","journal-title":"JNCI Cancer Spectr."},{"key":"2026080709081717800_cit2","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/s42255-022-00558-0","article-title":"The gut\nmicrobial metabolite formate exacerbates colorectal\ncancer progression","volume":"4","author":"Ternes","year":"2022","journal-title":"Nat. Metab."},{"issue":"1","key":"2026080709081717800_cit3","doi-asserted-by":"publisher","first-page":"7135","DOI":"10.1038\/s41467-023-42788-0","article-title":"Microbiome\nand metabolome features in inflammatory\nbowel disease via multi-omics integration analyses across cohorts","volume":"14","author":"Ning","year":"2023","journal-title":"Nat. Commun."},{"key":"2026080709081717800_cit4","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1039\/D3MO00089C","article-title":"Integrated multi-omics analyses of\nmicrobial communities: a review\nof the current state and future directions","volume":"19","author":"Ar\u0131kan","year":"2023","journal-title":"Mol. Omics"},{"issue":"4","key":"2026080709081717800_cit5","doi-asserted-by":"publisher","first-page":"112221","DOI":"10.1016\/j.isci.2025.112221","article-title":"Gut microbiota and metabolome\nsignatures in obese and normal-weight patients with colorectal tumors","volume":"28","author":"La Vecchia","year":"2025","journal-title":"iScience"},{"issue":"3","key":"2026080709081717800_cit6","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1093\/biostatistics\/kxu001","article-title":"Variable selection\nfor generalized canonical correlation\nanalysis","volume":"15","author":"Tenenhaus","year":"2014","journal-title":"Biostatistics"},{"issue":"4","key":"2026080709081717800_cit7","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1093\/bib\/bbv108","article-title":"Dimension reduction\ntechniques for the integrative\nanalysis of multi-omics data","volume":"17","author":"Meng","year":"2016","journal-title":"Briefings Bioinf."},{"issue":"1","key":"2026080709081717800_cit8","doi-asserted-by":"publisher","DOI":"10.2202\/1544-6115.1406","article-title":"Sparse\ncanonical correlation analysis with application to genomic data integration","volume":"8","author":"Parkhomenko","year":"2009","journal-title":"Stat. Appl. Genet. Mol. Biol."},{"issue":"17","key":"2026080709081717800_cit9","doi-asserted-by":"publisher","first-page":"3055","DOI":"10.1093\/bioinformatics\/bty1054","article-title":"DIABLO: an integrative approach for\nidentifying key molecular drivers from multi-omics assays","volume":"35","author":"Singh","year":"2019","journal-title":"Bioinformatics"},{"issue":"5","key":"2026080709081717800_cit10","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1093\/bioinformatics\/btab818","article-title":"3MCor: an integrative web server for metabolome-microbiome-metadata\ncorrelation analysis","volume":"38","author":"Sun","year":"2022","journal-title":"Bioinformatics"},{"key":"2026080709081717800_cit11","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1007\/978-1-0716-0239-3_23","article-title":"Network-Based Approaches for Multi-omics\nIntegration","volume-title":"Computational Methods and\nData Analysis for Metabolomics","author":"Zhou","year":"2020"},{"key":"2026080709081717800_cit12","doi-asserted-by":"publisher","first-page":"2621","DOI":"10.1038\/s41467-024-46888-3","article-title":"Multi-omic\nintegration of microbiome\ndata for identifying disease-associated modules","volume":"15","author":"Muller","year":"2024","journal-title":"Nat. Commun"},{"key":"2026080709081717800_cit13","doi-asserted-by":"publisher","first-page":"7265","DOI":"10.1073\/pnas.1102826108","article-title":"Topology based\ndata analysis identifies\na subgroup of breast cancers with a unique mutational profile and\nexcellent survival","volume":"108","author":"Nicolau","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.\nS. A."},{"issue":"1","key":"2026080709081717800_cit14","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1186\/s13059-019-1871-4","article-title":"tmap: an integrative\nframework based on topological data analysis for population-scale\nmicrobiome stratification and association studies","volume":"20","author":"Liao","year":"2019","journal-title":"Genome Biol."},{"issue":"25","key":"2026080709081717800_cit15","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1038\/s41591-019-0458-7","article-title":"Metagenomic and metabolomic\nanalyses reveal distinct\nstage-specific phenotypes of the gut microbiota in colorectal cancer","volume":"25","author":"Yachida","year":"2019","journal-title":"Nat. Med."},{"key":"2026080709081717800_cit16","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/s41522-022-00345-5","article-title":"The gut microbiome-metabolome\ndataset\ncollection: a curated resource for integrative meta-analysis","volume":"8","author":"Muller","year":"2022","journal-title":"Npj Biofilms Microbiomes"},{"issue":"29","key":"2026080709081717800_cit17","doi-asserted-by":"publisher","first-page":"861","DOI":"10.21105\/joss.00861","article-title":"UMAP: Uniform\nManifold Approximation and Projection","volume":"3","author":"McInnes","year":"2018","journal-title":"J. Open\nSource Softw."},{"issue":"3","key":"2026080709081717800_cit18","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1145\/3068335","article-title":"DBSCAN Revisited,\nRevisited: Why and How You Should (Still) Use DBSCAN","volume":"42","author":"Schubert","year":"2017","journal-title":"ACM Trans. Database Syst."},{"issue":"1","key":"2026080709081717800_cit19","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and\nPowerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R.\nStat. Soc. Ser. 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Microbiol."},{"issue":"9","key":"2026080709081717800_cit23","doi-asserted-by":"publisher","first-page":"2061","DOI":"10.3390\/microorganisms13092061","article-title":"Changes\nin Probiotic Lachnospiraceae\nGenera Across Different Stages of COVID-19: A Meta-Analysis of 16S\nrRNA Microbial Data","volume":"13","author":"Taufer","year":"2025","journal-title":"Microorganisms"},{"key":"2026080709081717800_cit24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.aca.2018.05.031","article-title":"A review on human\nfecal metabolomics: Methods, applications and the human fecal metabolome\ndatabase","volume":"1030","author":"Karu","year":"2018","journal-title":"Anal. Chim. Acta"},{"issue":"1","key":"2026080709081717800_cit25","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/srep00336","article-title":"Consensus\nclustering in complex networks","volume":"2","author":"Lancichinetti","year":"2012","journal-title":"Sci. Rep."},{"issue":"7285","key":"2026080709081717800_cit26","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/nature08821","article-title":"A human gut microbial gene catalogue established by metagenomic sequencing","volume":"464","author":"Qin","year":"2010","journal-title":"Nature"},{"issue":"W1","key":"2026080709081717800_cit27","doi-asserted-by":"publisher","first-page":"W398","DOI":"10.1093\/nar\/gkae253","article-title":"MetaboAnalyst\n6.0: towards a unified platform for metabolomics data\nprocessing, analysis and interpretation","volume":"52","author":"Pang","year":"2024","journal-title":"Nucleic\nAcids Res."},{"issue":"1","key":"2026080709081717800_cit28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0169-7439(00)00122-2","article-title":"Monte Carlo cross validation","volume":"56","author":"Xu","year":"2001","journal-title":"Chemom. Intell. Lab. Syst."},{"issue":"9","key":"2026080709081717800_cit29","doi-asserted-by":"publisher","first-page":"4082","DOI":"10.1021\/acs.jproteome.4c00394","article-title":"Identification of Blood Biomarkers\nin Ischemic Stroke by Integrated\nAnalysis of Metabolomics and Proteomics","volume":"23","author":"Zhao","year":"2024","journal-title":"J.\nProteome Res."},{"issue":"6","key":"2026080709081717800_cit30","doi-asserted-by":"publisher","first-page":"2100","DOI":"10.1021\/acs.jproteome.3c00894","article-title":"Multiomics\nAnalysis\nRevealed Colorectal Cancer Pathogenesis","volume":"23","author":"Xu","year":"2024","journal-title":"J.\nProteome Res."},{"issue":"14","key":"2026080709081717800_cit31","doi-asserted-by":"publisher","first-page":"2510","DOI":"10.7150\/jca.25324","article-title":"Effects of\nthe intestinal microbial metabolite butyrate on the development of\ncolorectal cancer","volume":"9","author":"Wu","year":"2018","journal-title":"J. Cancer"},{"issue":"3","key":"2026080709081717800_cit32","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.cell.2016.09.031","article-title":"L-arginine modulates\nT cell metabolism and enhances survival and anti-tumor activity","volume":"167","author":"Geiger","year":"2016","journal-title":"Cell"}],"container-title":["Journal of Proteome Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jproteome.6c00192","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/25\/8\/4177\/65945720\/acs.jproteome.6c00192.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/25\/8\/4177\/65945720\/acs.jproteome.6c00192.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T13:13:33Z","timestamp":1786108413000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jprobs\/article\/25\/8\/4177\/5210155\/A-Phenotype-Embedded-Mapper-Framework-Links"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":32,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,7,14]]},"published-print":{"date-parts":[[2026,8,7]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jproteome.6c00192","relation":{},"ISSN":["1535-3893","1535-3907"],"issn-type":[{"value":"1535-3893","type":"print"},{"value":"1535-3907","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]}}}