{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:58:14Z","timestamp":1792195094700,"version":"4.4.0"},"reference-count":37,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T00:00:00Z","timestamp":1667347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP19K16820"],"award-info":[{"award-number":["JP19K16820"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Cancer cachexia exerts a negative clinical influence on patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI). The prognostic impact of body weight change during ICI treatment remains unknown. The gut microbiota (GM) is a key contributor to the response to ICI therapy in cancer patients. However, the association between cancer cachexia and GM and their association with the response to ICIs remains unexplored. This study examined the association of cancer cachexia with GM composition and assessed the impact of GM on clinical outcomes in patients with NSCLC treated with ICIs. In this observational, prospective study, which included 113 Japanese patients with advanced NSCLC treated with ICIs, the prevalence of cachexia was 50.4% (57\/113). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in the cachexia group than in the non-cachexia group (4.3 vs. 11.6 months (p = 0.003) and 12.0 months vs. not reached (p = 0.02), respectively). A multivariable analysis revealed that baseline cachexia was independently associated with a shorter PFS. Moreover, a gain in body weight from the baseline (reversible cachexia) was associated with a significantly longer PFS and OS compared to irreversible cachexia. Microbiome profiling with 16S rRNA analysis revealed that the cachexia group presented an overrepresentation of the commensal bacteria, Escherichia-Shigella and Hungatella, while the non-cachexia group had a preponderance of Anaerostipes,\u00a0Blautia, and Eubacterium ventriosum. Anaerostipes and E. ventriosum were associated with longer PFS and OS. Moreover, a cachexia status correlated with the systemic inflammatory marker-derived-neutrophil-to-lymphocytes ratio (dNLR) and Lung Immune Prognostic Index (LIPI) indexes. Our study demonstrates that cachexia and longitudinal bodyweight change have a prognostic impact on patients with advanced NSCLC treated with ICI therapy. Moreover, our study demonstrates that bacteria associated with ICI resistance are also linked to cachexia. Targeted microbiota interventions may represent a new type of treatment to overcome cachexia in patients with NSCLC.<\/jats:p>","DOI":"10.3390\/cancers14215405","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T03:11:21Z","timestamp":1667445081000},"page":"5405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Cancer Cachexia among Patients with Advanced Non-Small-Cell Lung Cancer on Immunotherapy: An Observational Study with Exploratory Gut Microbiota Analysis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9980-4417","authenticated-orcid":false,"given":"Taiki","family":"Hakozaki","sequence":"first","affiliation":[{"name":"Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku, Tokyo 1628480, Japan"},{"name":"Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo 1130021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Nolin-Lapalme","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, QC H2X-0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Kogawa","sequence":"additional","affiliation":[{"name":"Research Organization for Nano and Life Innovation, Waseda University, 513 Wasedatsurumaki-cho, Shinjuku, Tokyo 1620041, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5743-0149","authenticated-orcid":false,"given":"Yusuke","family":"Okuma","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo 1130021, Japan"},{"name":"Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1Tsukiji, Chuo, Tokyo 1040045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo 1130021, Japan"},{"name":"Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo 1130021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Moreau-Amaru","sequence":"additional","affiliation":[{"name":"Service de Nutrition Clinique du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CHUM), Montr\u00e9al, QC H2X-0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taichi","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo 1130021, Japan"},{"name":"Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo 1130021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3849-5905","authenticated-orcid":false,"given":"Yukio","family":"Hosomi","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo 1130021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruko","family":"Takeyama","sequence":"additional","affiliation":[{"name":"Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku, Tokyo 1628480, Japan"},{"name":"Research Organization for Nano and Life Innovation, Waseda University, 513 Wasedatsurumaki-cho, Shinjuku, Tokyo 1620041, Japan"},{"name":"Computational Bio Big-Data Open Innovation Laboratory, National Institute of Advanced Industrial Science and Technology, 3-4-1 Okubo, Shinjuku, Tokyo 1698555, Japan"},{"name":"Institute for Advanced Research of Biosystem Dynamics, Waseda Research Institute for Science and Engineering, 3-4-1 Okubo, Shinjuku, Tokyo 1698555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corentin","family":"Richard","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, QC H2X-0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahito","family":"Hosokawa","sequence":"additional","affiliation":[{"name":"Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku, Tokyo 1628480, Japan"},{"name":"Research Organization for Nano and Life Innovation, Waseda University, 513 Wasedatsurumaki-cho, Shinjuku, Tokyo 1620041, Japan"},{"name":"Computational Bio Big-Data Open Innovation Laboratory, National Institute of Advanced Industrial Science and Technology, 3-4-1 Okubo, Shinjuku, Tokyo 1698555, Japan"},{"name":"Institute for Advanced Research of Biosystem Dynamics, Waseda Research Institute for Science and Engineering, 3-4-1 Okubo, Shinjuku, Tokyo 1698555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Routy","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, QC H2X-0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3747\/co.27.5953","article-title":"Therapeutic landscape of metastatic non-small-cell lung cancer in Canada in 2020","volume":"27","author":"Elkrief","year":"2020","journal-title":"Curr. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1080\/19490976.2018.1527167","article-title":"The intimate relationship between gut microbiota and cancer immunotherapy","volume":"10","author":"Elkrief","year":"2019","journal-title":"Gut Microbes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1126\/science.aan4236","article-title":"Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients","volume":"359","author":"Gopalakrishnan","year":"2018","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1126\/science.aan3706","article-title":"Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors","volume":"359","author":"Routy","year":"2018","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1158\/2326-6066.CIR-20-0196","article-title":"The gut microbiome associates with immune checkpoint inhibition outcomes in patients with advanced non-small cell lung cancer","volume":"8","author":"Hakozaki","year":"2020","journal-title":"Cancer Immunol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41591-021-01655-5","article-title":"Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer","volume":"28","author":"Derosa","year":"2022","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1038\/s41591-021-01406-6","article-title":"Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade","volume":"27","author":"Andrews","year":"2021","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/s41591-022-01695-5","article-title":"Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma","volume":"28","author":"Lee","year":"2022","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/s41591-022-01698-2","article-title":"Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1","volume":"28","author":"McCulloch","year":"2022","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1158\/2159-8290.CD-21-0808","article-title":"A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiota","volume":"12","author":"Messaoudene","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1126\/science.abf3363","article-title":"Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients","volume":"371","author":"Davar","year":"2021","journal-title":"Science"},{"key":"ref_12","first-page":"309","article-title":"The interplay of immunology and cachexia in infection and cancer","volume":"2021","author":"Baazim","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_13","first-page":"9","article-title":"Inter-tissue communication in cancer cachexia","volume":"15","author":"Stemmler","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1007\/s00535-013-0787-0","article-title":"Cancer cachexia\u2014Pathophysiology and management","volume":"48","author":"Suzuki","year":"2013","journal-title":"J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.cmet.2012.06.011","article-title":"Cancer cachexia: Mediators, signaling, and metabolic pathways","volume":"16","author":"Fearon","year":"2012","journal-title":"Cell Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1007\/s00213-018-5159-2","article-title":"The gut microbiome in anorexia nervosa: Relevance for nutritional rehabilitation","volume":"236","author":"Ruusunen","year":"2019","journal-title":"Psychopharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"j5145","DOI":"10.1136\/bmj.j5145","article-title":"The role of the gut microbiome in systemic inflammatory disease","volume":"360","author":"Clemente","year":"2018","journal-title":"BMJ"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S1474-4422(19)30356-4","article-title":"The gut microbiome in neurological disorders","volume":"19","author":"Cryan","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4050","DOI":"10.1172\/JCI129194","article-title":"The gut microbiome and metabolic syndrome","volume":"129","author":"Dabke","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s00262-021-02997-2","article-title":"Prognostic significance of cachexia in advanced non-small cell lung cancer patients treated with pembrolizumab","volume":"71","author":"Jo","year":"2022","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_21","first-page":"100020","article-title":"Desensitizing effect of cancer cachexia on immune checkpoint inhibitors in patients with advanced NSCLC","volume":"1","author":"Miyawaki","year":"2020","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1007\/s00520-021-06572-4","article-title":"Impact of weight loss on treatment with PD-1\/PD-L1 inhibitors plus chemotherapy in advanced non-small-cell lung cancer","volume":"30","author":"Miyawaki","year":"2022","journal-title":"Support. Care Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1950411","DOI":"10.1080\/2162402X.2021.1950411","article-title":"Impact of cancer cachexia on the therapeutic outcome of combined chemoimmunotherapy in patients with non-small cell lung cancer: A retrospective study","volume":"10","author":"Morimoto","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1470-2045(10)70218-7","article-title":"Definition and classification of cancer cachexia: An international consensus","volume":"12","author":"Fearon","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline; version 1.1","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/annonc\/mdw016","article-title":"Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: Prognostic relevance in metastatic melanoma patients receiving ipilimumab","volume":"27","author":"Ferrucci","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1001\/jamaoncol.2017.4771","article-title":"Association of the Lung Immune Prognostic Index with Immune Checkpoint Inhibitor Outcomes in Patients with Advanced Non-Small Cell Lung Cancer","volume":"4","author":"Mezquita","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/s41587-019-0209-9","article-title":"Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2","volume":"37","author":"Bolyen","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nmeth.3869","article-title":"DADA2: High-resolution sample inference from Illumina amplicon data","volume":"13","author":"Callahan","year":"2016","journal-title":"Nat. Methods"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"R60","DOI":"10.1186\/gb-2011-12-6-r60","article-title":"Metagenomic biomarker discovery and explanation","volume":"12","author":"Segata","year":"2011","journal-title":"Genome Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1002\/cncr.31128","article-title":"Anamorelin (ONO-7643) for the treatment of patients with non-small cell lung cancer and cachexia: Results from a randomized, double-blind, placebo-controlled, multicenter study of Japanese patients (ONO-7643-04)","volume":"124","author":"Katakami","year":"2018","journal-title":"Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.1002\/cncr.32406","article-title":"A multicenter, open-label, single-arm study of anamorelin (ONO-7643) in advanced gastrointestinal cancer patients with cancer cachexia","volume":"125","author":"Hamauchi","year":"2019","journal-title":"Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Oberm\u00fcller, B., Singer, G., Kienesberger, B., Klymiuk, I., Sperl, D., Stadlbauer, V., Horvath, A., Miekisch, W., Gierschner, P., and Grabherr, R. (2020). The effects of prebiotic supplementation with OMNi-LOGiC \u00ae FIBRE on fecal microbiome, fecal volatile organic compounds, and gut permeability in murine neuroblastoma-induced tumor-associated cachexia. Nutrients, 12.","DOI":"10.3390\/nu12072029"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12321","DOI":"10.1038\/s41598-018-30569-5","article-title":"Klebsiella oxytoca expands in cancer cachexia and acts as a gut pathobiont contributing to intestinal dysfunction","volume":"8","author":"Brossel","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Bindels, L.B., Neyrinck, A.M., Salazar, N., Taminiau, B., Druart, C., Muccioli, G.G., Fran\u00e7ois, E., Blecker, C., Richel, A., and Daube, G. (2015). Non digestible oligosaccharides modulate the gut microbiota to control the development of leukemia and associated cachexia in mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131009"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1038\/s41396-021-00998-8","article-title":"Distinct composition and metabolic functions of human gut microbiota are associated with cachexia in lung cancer patients","volume":"15","author":"Ni","year":"2021","journal-title":"ISME J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1002\/jcsm.12804","article-title":"Gut microbiota and short-chain fatty acid alterations in cachectic cancer patients","volume":"12","author":"Ubachs","year":"2021","journal-title":"J. Cachexia Sarcopenia Muscle"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/21\/5405\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:09:26Z","timestamp":1760144966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/21\/5405"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,2]]},"references-count":37,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["cancers14215405"],"URL":"https:\/\/doi.org\/10.3390\/cancers14215405","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,2]]}}}