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Growing evidence suggests that the occurrence of irAE may be correlated with enhanced ICI efficacy, although the underlying mechanisms remain unknown. Most studies investigating the role of the gut microbiome in oncology have relied on sequencing approaches, particularly shotgun metagenomics. Although microbiome profiling revealed strong associations between specific bacterial taxa and clinical outcomes, it has limitations, including an inability to detect low-abundance bacteria and to recover live cultivable bacteria. To overcome these limitations, we combined shotgun metagenomics and culturomics on fecal samples collected from patients with melanoma and non-small cell lung cancer (NSCLC), at baseline and at the onset of immune related (ir)-colitis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We first validated across three independent cohorts of 589 patients with melanoma or NSCLC treated with ICI that grade\u2009\u2265\u20092 irAE were associated with significantly longer overall survival (OS) and progression-free survival (PFS). Complementary analysis using shotgun metagenomics and culturomics revealed that patients who developed grade\u2009\u2265\u20092 irAE had a lower alpha diversity compared to those who did not develop grade\u2009\u2265\u20092 irAE. Metagenomics results showed enrichment of\n                      <jats:italic>Ruminococcus gnavus<\/jats:italic>\n                      and\n                      <jats:italic>Streptococcus vestibularis<\/jats:italic>\n                      at baseline in grade\u2009\u2265\u20092 irAE patients, while\n                      <jats:italic>Clostridium paraputrificum<\/jats:italic>\n                      and\n                      <jats:italic>Streptococcus<\/jats:italic>\n                      spp. were isolated by culturomics from baseline stool samples from ir-colitis patients. Longitudinal analysis of paired stool samples revealed a shift in microbiome composition with enrichment of\n                      <jats:italic>Paraclostridium bifermentans<\/jats:italic>\n                      and\n                      <jats:italic>Clostridium paraputrificum<\/jats:italic>\n                      , lower lipopolysaccharide and higher flagellin concentrations at baseline compared with the time of ir-colitis. Fecal microbiome transplantation from a patient with ir-colitis into mice induced surrogate markers of colonic inflammation and enhanced the anti-tumor activity of combined anti-PD-1\/CTLA-4.\n                      <jats:italic>P. bifermentans<\/jats:italic>\n                      isolated from this patient sample demonstrated direct epithelial barrier disruption in Caco-2 monolayers, characterized by decreased ZO-1 and Occludin\u00a0immunofluorescence signal and increased\n                      <jats:italic>TNF-\u03b1<\/jats:italic>\n                      and\n                      <jats:italic>IL-1\u03b2<\/jats:italic>\n                      expression. Moreover, in the dextran sodium sulfate (DSS) colitis model,\n                      <jats:italic>P. bifermentans<\/jats:italic>\n                      worsened weight loss. In a separate tumor model, it amplified the anti-tumor effect of dual ICI. This beneficial effect was also\u00a0maintained after treatment with\n                      <jats:italic>P. bifermentans<\/jats:italic>\n                      \u2009&lt;\u20093\u00a0kDa filtered supernatant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Altogether, our results suggest that\n                      <jats:italic>P. bifermentans<\/jats:italic>\n                      promotes subclinical colitis while increasing the efficacy of dual ICI. This provides a potential microbiome-derived link between irAE and improved anti-tumor responses.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40168-026-02419-4","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T07:32:08Z","timestamp":1777879928000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metagenomics and culturomics reveal the dual role of the gut microbiome in the development of immune-related toxicities and the efficacy of immune checkpoint inhibitors in cancer"],"prefix":"10.1186","volume":"14","author":[{"given":"Khoudia","family":"Diop","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Benla\u00effaoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eder Orlando","family":"M\u00e9ndez-Salazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiki","family":"Hakozaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corentin","family":"Richard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diogjena Katerina","family":"Prifti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylva","family":"Kourtian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Proulx-Rocray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrine","family":"Naimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayra","family":"Ponce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meriem","family":"Messaoudene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Cauchois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiam","family":"Belkaid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Bataille","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalin","family":"Mihalcioiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian Robert","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arielle","family":"Elkrief","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Routy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"2419_CR1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2502931","author":"PM Forde","year":"2025","unstructured":"Forde PM, Spicer JD, Provencio M, Mitsudomi T, Awad MM, Wang C. 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Participating centers, McGill and King\u2019s College London, patient clinical information and samples were respectively collected under the protocol number 2019\u20134778 and from the clinical trial PRIMM (NCT03643289).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"BR declares research funding from Davolterra, Kanvas Bioscience, consulting fees from Merck, AstraZeneca, Vendata and BMS, and is a co-founder of Curebiota. AE declares grant support from Kanvas Bioscience, GMT Science, Astrazeneca, Merck, and BMS. AE declares honoraria from Astrazeneca, Merck, BMS, and EMD Soreno. AE is inventor on a patent 4872-8531-1934.1 regarding the microbiome and immunotherapy response.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"170"}}