{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:37:28Z","timestamp":1789605448981,"version":"build-2803163510"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background<\/jats:title>\n Immune-related adverse events (irAEs) represent an urgent clinical challenge. Although accumulating evidence suggests that irAEs are associated with the gut microbiota and its metabolites, our understanding of the dynamic alterations in the gut microbiota and related metabolic profiles throughout the onset and progression of irAEs remains limited.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n A total of 48 fecal samples were collected from 32 lung cancer patients treated with immune checkpoint inhibitors, including 16 patients who developed irAEs and 16 who did not. Fecal samples were collected at baseline and, in patients with irAEs, at the time of irAEs onset. Metagenomic sequencing and untargeted metabolomics analyses were performed to identify baseline differences in gut microbiota and metabolites, characterize longitudinal dynamic changes in gut microbiota and metabolite profiles in patients with irAEs, and construct a machine learning based random forest model to predict the occurrence of irAEs.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n There were baseline differences in microbial communities and metabolites between the two groups. In the non-irAEs group,\n Phocaeicola coprocola<\/jats:italic>\n was enriched and\n Micrococales<\/jats:italic>\n decreased. At baseline, viomycin was positively correlated with irAEs, while metabolites such as calcitriol and L-isoleucine were negatively correlated with irAEs. The roles of valine, leucine and isoleucine metabolism and vitamin B6 metabolism pathways were downregulated in the irAEs group. Compared to baseline, there were significant changes in gut microbiota and metabolites during the onset of irAEs, and the abundance of\n Veillonella<\/jats:italic>\n increased during irAEs onset. Dynamic monitoring of metabolic changes in irAEs revealed decreased levels of trypsin butylester, BQ 123, DL-o-tyrosine, and nicotinamide-beta-riboside during irAEs attacks. Lysine degradation, arachidonic acid metabolism, folate biosynthesis, nicotinate and nicotinamide metabolism, and C5-branched dibasic acid metabolism were downregulated during the progression of irAEs. A model for predicting the occurrence of irAEs based on differential microbiota and metabolites was constructed, and after robust validation, the model showed good performance and excellent discriminative power.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n The occurrence and development of irAEs are associated with the composition of the gut microbiota and metabolites, as well as their dynamic changes over time. These findings highlight the potential of gut microbiota and metabolites as biomarkers for predicting the occurrence and progression of irAEs.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1731931","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T14:05:10Z","timestamp":1776348310000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Dynamic changes in gut microbiota and metabolites in advanced lung cancer patients with immune-related adverse events"],"prefix":"10.3389","volume":"17","author":[{"given":"Xu","family":"Han","sequence":"first","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Zang","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meixi","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Respiratory, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiangguo","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Hospital of Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"020","DOI":"10.1038\/s41572-020-0160-6","article-title":"Immune-related adverse events of checkpoint inhibitors","volume":"6","author":"Ramos-Casals","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"022","DOI":"10.1186\/s13046-022-02568-y","article-title":"Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States","volume":"42","author":"Yang","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.7711","article-title":"Association of immune-related adverse events with efficacy of atezolizumab in patients with non-small cell lung cancer: pooled analyses of the phase 3 IMpower130, IMpower132, and IMpower150 randomized clinical trials","volume":"9","author":"Socinski","year":"2023","journal-title":"JAMA Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.58.3708","article-title":"Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer","volume":"33","author":"Gettinger","year":"2015","journal-title":"J Clin Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.52302","article-title":"Immune-related adverse events and survival among patients with metastatic NSCLC treated with immune checkpoint inhibitors","volume":"7","author":"Cook","year":"2024","journal-title":"JAMA Netw Open"},{"key":"B6","doi-asserted-by":"publisher","first-page":"024","DOI":"10.1186\/s12931-024-02890-3","article-title":"Correlation between immune-related adverse events and efficacy of PD-(L)1 inhibitors in small cell lung cancer: a multi-center retrospective study","volume":"25","author":"Zhang","year":"2024","journal-title":"Respir Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/s41571-025-01026-w","article-title":"Roles of the gut microbiota in immune-related adverse events: mechanisms and therapeutic intervention","volume":"22","author":"Gao","year":"2025","journal-title":"Nat Rev Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2025.115221","article-title":"Gut microbiome and immune checkpoint inhibitor toxicity","volume":"216","author":"Verheijden","year":"2025","journal-title":"Eur J Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"024","DOI":"10.1186\/s13073-024-01285-9","article-title":"Gut microbiome for predicting immune checkpoint blockade-associated adverse events","volume":"16","author":"Hu","year":"2024","journal-title":"Genome Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105427","article-title":"Gut microbiome metabolites, molecular mimicry, and species-level variation drive long-term efficacy and adverse event outcomes in lung cancer survivors","volume":"109","author":"Liu","year":"2024","journal-title":"EBioMedicine"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1144534","article-title":"Dynamic gut microbiota changes in patients with advanced Malignancies experiencing secondary resistance to immune checkpoint inhibitors and immune-related adverse events","volume":"13","author":"Zeng","year":"2023","journal-title":"Front Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.06.001","article-title":"Molecular pathways of colon inflammation induced by cancer immunotherapy","volume":"182","author":"Luoma","year":"2020","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2022.12.007","article-title":"T follicular helper cells in cancer","volume":"9","author":"Guti\u00e9rrez-Melo","year":"2023","journal-title":"Trends Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0352-8","article-title":"Moving towards personalized treatments of immune-related adverse events","volume":"17","author":"Esfahani","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0218-0","article-title":"Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance","volume":"16","author":"Martins","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.05.357","article-title":"The positive effect of immune checkpoint inhibitor-induced thyroiditis on overall survival accounting for immortal time bias: a retrospective cohort study of 6596 patients","volume":"32","author":"Street","year":"2021","journal-title":"Ann Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01440","article-title":"Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update","volume":"39","author":"Schneider","year":"2021","journal-title":"J Clin Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31629","article-title":"High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma","volume":"124","author":"Faje","year":"2018","journal-title":"Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-3181","article-title":"Corticosteroids and cancer immunotherapy","volume":"29","author":"Goodman","year":"2023","journal-title":"Clin Cancer Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.5041","article-title":"Association of immune-related adverse event management with survival in patients with advanced melanoma","volume":"8","author":"Van Not","year":"2022","journal-title":"JAMA Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2023.04.010","article-title":"Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer","volume":"31","author":"Jiang","year":"2023","journal-title":"Cell Host Microbe"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1109281","article-title":"Gut microbiota composition in patients with advanced Malignancies experiencing immune-related adverse events","volume":"14","author":"Liu","year":"2023","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.02.022","article-title":"Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer","volume":"187","author":"Jia","year":"2024","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1921223117","article-title":"Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade","volume":"117","author":"Sun","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1136\/jitc-2021-003779","article-title":"Association of antibiotic treatment with immune-related adverse events in patients with cancer receiving immunotherapy","volume":"10","author":"Jing","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1164724","article-title":"Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor","volume":"14","author":"Hamada","year":"2023","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","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":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2023.1099063","article-title":"Correlation of the gut microbiome and immune-related adverse events in gastrointestinal cancer patients treated with immune checkpoint inhibitors","volume":"13","author":"Zhang","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.756872","article-title":"Intestinal microbiome associated with immune-related adverse events for patients treated with anti-PD-1 inhibitors, a real-world study","volume":"12","author":"Liu","year":"2021","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-0605","article-title":"Faecalibacterium prausnitzii abrogates intestinal toxicity and promotes tumor immunity to increase the efficacy of dual CTLA4 and PD-1 checkpoint blockade","volume":"83","author":"Gao","year":"2023","journal-title":"Cancer Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"024","DOI":"10.1186\/s13099-024-00630-y","article-title":"Gut microbiota shifts from onset to remission in immune checkpoint inhibitor-induced enterocolitis: a case report","volume":"16","author":"Hirata","year":"2024","journal-title":"Gut Pathog"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20232079","article-title":"Baseline colitogenicity and acute perturbations of gut microbiota in immunotherapy-related colitis","volume":"222","author":"Shang","year":"2025","journal-title":"J Exp Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1136\/jitc-2022-004779","article-title":"Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma","volume":"10","author":"Lee","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B34","doi-asserted-by":"publisher","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":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01965-2","article-title":"Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome","volume":"28","author":"Simpson","year":"2022","journal-title":"Nat Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"021","DOI":"10.1186\/s13046-021-02201-4","article-title":"Prevotellaceae produces butyrate to alleviate PD-1\/PD-L1 inhibitor-related cardiotoxicity via PPAR\u03b1-CYP4X1 axis in colonic macrophages","volume":"41","author":"Chen","year":"2022","journal-title":"J Exp Clin Cancer Res"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1136\/jitc-2021-003725","article-title":"Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite","volume":"10","author":"Renga","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115127","article-title":"Potential therapeutic implications of calcitriol administration and weight reduction on CD4 T cell dysregulation and renin angiotensin system-associated acute lung injury in septic obese mice","volume":"165","author":"Yeh","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2025.101687","article-title":"Injectable hydrogel microsphere orchestrates immune regulation and bone regeneration via sustained release of calcitriol","volume":"32","author":"Chen","year":"2025","journal-title":"Mater Today Bio"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.817583","article-title":"L-isoleucine administration alleviates DSS-induced colitis by regulating TLR4\/MyD88\/NF-\u03baB pathway in rats","volume":"12","author":"Mao","year":"2022","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"025","DOI":"10.1186\/s13046-025-03378-8","article-title":"Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy","volume":"44","author":"Costantini","year":"2025","journal-title":"J Exp Clin Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10391","article-title":"Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis","volume":"7","author":"Dubin","year":"2016","journal-title":"Nat Commun"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06061-0","article-title":"Lysine catabolism reprograms tumour immunity through histone crotonylation","volume":"617","author":"Yuan","year":"2023","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2025.03.002","article-title":"Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer","volume":"58","author":"Yu","year":"2025","journal-title":"Immunity"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15041300","article-title":"The role of microbiota-derived vitamins in immune homeostasis and enhancing cancer immunotherapy","volume":"15","author":"Gholami","year":"2023","journal-title":"Cancers"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2022.12.007","article-title":"Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors","volume":"4","author":"Nu\u00f1ez","year":"2023","journal-title":"Med"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2024","DOI":"10.1136\/jitc-2024-009399","article-title":"Plasma metabolomics of immune-related adverse events for patients with lung cancer treated with PD-1\/PD-L1 inhibitors","volume":"12","author":"Chen","year":"2024","journal-title":"J Immunother Cancer"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1731931\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T14:05:12Z","timestamp":1776348312000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1731931\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":47,"alternative-id":["10.3389\/fimmu.2026.1731931"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1731931","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]},"article-number":"1731931"}}