{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:03:24Z","timestamp":1784887404979,"version":"3.55.0"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T00:00:00Z","timestamp":1780790400000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,6]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Cancer cachexia exemplifies a high medical need condition without effective treatment. Recent studies implicated bacterial gut microbiome alterations to cancer cachexia. Whether the gut bacteriophage profile, an important microbiome component for health and disease, is also related to cancer cachexia remains unknown. We aimed to profile gut microbiome alterations in human cancer cachexia with attention on bacteriophages.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We performed shotgun metagenomic sequencing in stool samples from 78 cachectic and 42 noncachectic patients (53% male, mean age 67\u2009\u00b1\u20098\u2009years) with newly diagnosed, advanced\u2010stage (UICC IV) gastrointestinal cancers. Cachexia was defined according to the main criterion agreed upon international consensus (weight loss [WL] adjusted to body mass index [BMI]). Obtained DNA short\u2010reads were used for\n k<\/jats:italic>\n \u2010mers\u2010based, phage\u2010inclusive matching with reference databases, de novo phage assembly and inferring microbiome\u2010encoded functions. We replicated significance\u2010based statistical and prediction\u2010oriented machine\u2010learning analyses in 2022 and 2025 generated metagenome datasets to incorporate the recent change by the International Committee on Taxonomy of Viruses (ICTV) from morphology\u2010based (valid until 2022) to revised genome\u2010based phage taxonomy into microbiome findings of cachexia.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Cachectic and noncachectic patients differed significantly regarding BMI (mean 20.9 vs. 26.4\u2009kg\/m2), WL (mean \u22126.5 vs. \u22120.2\u2009kg), survival (median 5 vs. 13\u2009months) and clinical cachexia domains (e.g., C\u2010reactive proteine and appetite loss) (all\n p<\/jats:italic>\n \u2009<\u20090.001) but not for other clinical covariables (e.g., cancer type) (all\n p<\/jats:italic>\n \u2009>\u20090.05). Read\u2010based mapping (2022\/2025) identified 1.312\/1.513 species (74\/39 phage species), and de novo assembly resulted in 4.184\/4.209 contigs (corresponding to 65\/39 phage species). Concordantly, both analyses (2022 and 2025) showed that prevalent cachexia associated significantly with beta\u2010diversity (Bray\u2010Curtis distance, PERMANOVA,\n p<\/jats:italic>\n \u2009<\u20090.05), but not to alpha\u2010diversity (Shannon\u2010Index, ANOVA,\n p<\/jats:italic>\n \u2009>\u20090.05), reduced microbiome\u2010encoded detoxification functions (e.g., enriched microbial \u03b2\u2010glucuronidase and depleted bacterial efflux pumps) and lowered abundance of bacterial species with false\u2010discovery\u2010rate (FDR)\u2010corrected\n p\u2009<<\/jats:italic>\n \u20090.05 (2022:\n \n Faecalibacterium prausnitzii<\/jats:italic>\n <\/jats:styled-content>\n ,\n \n Roseburia intestinalis<\/jats:italic>\n <\/jats:styled-content>\n ,\n Streptococcus<\/jats:italic>\n species and\n Lachnospiraceae<\/jats:italic>\n species; 2025:\n Faecalibacterium<\/jats:italic>\n species,\n \n Ruminococcus gauvreauii<\/jats:italic>\n <\/jats:styled-content>\n and\n Intestinibacter bartlettii<\/jats:italic>\n ). Further, lowered abundance of bacteriophages associated with cachexia, predominantly affecting double\u2010stranded (2022:\n Caudovirales<\/jats:italic>\n ,\n Siphoviridae<\/jats:italic>\n , FDR\u2010corrected\n p<\/jats:italic>\n \u2009<\u20090.05; 2025:\n Myoviridae<\/jats:italic>\n ,\n Siphoridae<\/jats:italic>\n ,\n p<\/jats:italic>\n \u2009<\u20090.05) but also single\u2010stranded (2022:\n Inoviridae<\/jats:italic>\n ,\n Microviridae<\/jats:italic>\n ,\n p<\/jats:italic>\n \u2009<\u20090.05; 2025:\n Inoviridae<\/jats:italic>\n ;\n p<\/jats:italic>\n \u2009<\u20090.05) DNA phage species. In machine\u2010learning models, bacteriophages were top\u2010ranked cachexia predictors (2022:\n Caudovirales<\/jats:italic>\n ,\n Siphoviridae<\/jats:italic>\n ; 2025:\n Myoviridae<\/jats:italic>\n ,\n Siphoridae<\/jats:italic>\n ). Accuracy was highest when only phage contigs were taken into account (correctly classified instances: 75.0%\u201385.8%; AUC: 0.703\u20130.916).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n The previously unknown link between gut bacteriophages and human cancer cachexia expands the scope for basic, translational and clinical microbiome\u2010targeted research in an area of significant unmet medical need.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n Study Box of the German Cancer Society (Registration Number ST\u2010U069, Date: 29 May 2018)<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70324","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T06:32:36Z","timestamp":1780900356000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lowered Abundance of Gut Bacteriophage Species Is Associated With Human Cancer Cachexia"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8715-3349","authenticated-orcid":false,"given":"Axel","family":"Stang","sequence":"first","affiliation":[{"name":"Department of Haematology, Oncology and Palliative Care Medicine Asklepios Hospital Barmbek Hamburg Germany"},{"name":"Asklepios Tumorzentrum Hamburg Hamburg Germany"},{"name":"Asklepios Medical School Hamburg Germany"},{"name":"Asklepios Campus Hamburg Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Illig","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Hannover Medical School Hannover Germany"},{"name":"Hannover Unified Biobank (HUB) Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Hiller","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS) Technische Universit\u00e4t Braunschweig Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hauke","family":"Weilert","sequence":"additional","affiliation":[{"name":"Department of Haematology, Oncology and Palliative Care Medicine Asklepios Hospital Barmbek Hamburg Germany"},{"name":"Asklepios Tumorzentrum Hamburg Hamburg Germany"},{"name":"Asklepios Medical School Hamburg Germany"},{"name":"Asklepios Campus Hamburg Semmelweis University Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Asklepios Medical School Hamburg Germany"},{"name":"Immunetrue Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Gronauer","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics Universit\u00e4t Innsbruck Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Seifert","sequence":"additional","affiliation":[{"name":"Asklepios Medical School Hamburg Germany"},{"name":"10x Genomics Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70218-7"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12756"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12402"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.105"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2409515"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41396-021-00998-8"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12804"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2023.284138"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14215405"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13816"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.01.017"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104113"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2025.2481178"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2023.963173"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-022-05694-2"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.002111"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.1032186"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2024.110016"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciad539"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-023-01533-x"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-022-00738-y"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaa490"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-020-00867-0"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-022-02655-5"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbz155"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12684"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0377-7"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104163"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom13040584"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2025.01.006"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2116197119"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-091919-074551"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102287"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00612-5"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-330001"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000003565"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2023.04.008"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41329-z"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01799-4"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1518285112"}],"container-title":["Journal 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