{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:19:27Z","timestamp":1769645967600,"version":"3.49.0"},"reference-count":17,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"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":["JGH Open"],"published-print":{"date-parts":[[2026,1]]},"abstract":"ABSTRACT<\/jats:title>\n \n Aim<\/jats:title>\n The gut microbiome modulates immune responses, and butyrate\u2010producing bacteria have been linked to improved immune checkpoint inhibitor (ICI) efficacy. Conversely, proton pump inhibitors (PPIs) may negatively impact ICI outcomes by altering gut microbiota. This study aims to elucidate their effects in hepatocellular carcinoma (HCC).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n This retrospective multicenter cohort study included 208 HCC patients treated with durvalumab plus tremelimumab at 25 hospitals in Japan. Patients were classified into a butyric acid group (\n n<\/jats:italic>\n \u2009=\u200927), who ingested drugs containing butyrate\u2010producing enterobacteria, and a non\u2010butyric acid group (\n n<\/jats:italic>\n \u2009=\u2009181), as well as a PPI group (\n n<\/jats:italic>\n \u2009=\u2009107) and a non\u2010PPI group (\n n<\/jats:italic>\n \u2009=\u2009101). Overall survival (OS) was analyzed using inverse probability of treatment weighting, and risk factors were assessed with Cox proportional hazards modeling. Tumor response was evaluated by RECIST v1.1.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n No significant OS differences were observed between the butyric acid and non\u2010butyric acid groups (\n p<\/jats:italic>\n \u2009=\u20090.921), or between PPI and non\u2010PPI groups (\n p<\/jats:italic>\n \u2009=\u20090.917). The objective response rate was 3.7% in the butyric acid group versus 15.5% in the non\u2010butyric acid group (\n p<\/jats:italic>\n \u2009=\u20090.543) and 15.8% in the PPI group versus 12.1% in the non\u2010PPI group (\n p<\/jats:italic>\n \u2009=\u20090.222). Disease control rates were comparable. Multivariate analysis identified ECOG performance status (\n p<\/jats:italic>\n \u2009=\u20090.019) and ALBI score (\n p<\/jats:italic>\n \u2009<\u20090.001) as independent prognostic factors, while butyrate\u2010producing bacteria and PPI use were not associated with survival outcomes.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Neither butyrate\u2010producing bacteria nor PPI use significantly influenced the efficacy of durvalumab plus tremelimumab in HCC. The liver's immunotolerant microenvironment may limit the impact of microbiome modulation on ICI efficacy.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jgh3.70346","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T06:43:47Z","timestamp":1769496227000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of Butyrate\u2010Producing Enterobacteria and Proton Pump Inhibitors on Advanced Hepatocellular Carcinoma Treatment With Durvalumab and Tremelimumab"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2018-0008","authenticated-orcid":false,"given":"Kazuhiro","family":"Nouso","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Okayama City Hospital Okayama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiko","family":"Wakuta","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Okayama City Hospital Okayama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shohei","family":"Shiota","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Okayama City Hospital Okayama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rio","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Okayama City Hospital Okayama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3996-7502","authenticated-orcid":false,"given":"Kazuya","family":"Kariyama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Okayama City Hospital Okayama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Hiraoka","sequence":"additional","affiliation":[{"name":"Gastroenterology Center Ehime Prefectural Central Hospital Matsuyama Ehime Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3374-7111","authenticated-orcid":false,"given":"Masanori","family":"Atsukawa","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine Nippon Medical School Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8801-2505","authenticated-orcid":false,"given":"Joji","family":"Tani","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Kagawa University Kita gun Kagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0976-6761","authenticated-orcid":false,"given":"Toshifumi","family":"Tada","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Japanese Red Cross Society Himeji Hospital Himeji Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichiro","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Japanese Red Cross Society Himeji Hospital Himeji Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2373-8601","authenticated-orcid":false,"given":"Kazuto","family":"Tajiri","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Toyama University Hospital Toyama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0577-3921","authenticated-orcid":false,"given":"Masaki","family":"Kaibori","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery Kansai Medical University Hirakata 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Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0663-0102","authenticated-orcid":false,"given":"Atsushi","family":"Naganuma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology NHO Takasaki General Medical Center Takasaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5470-9694","authenticated-orcid":false,"given":"Toru","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Saiseikai Niigata Hospital Niigata Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michitaka","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Niigata Cancer Center Hospital Niigata 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of Proton Pump Inhibitor Use With Survival Outcomes in Cancer Patients Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta\u2010Analysis","volume":"14","author":"Chen B.","year":"2022","journal-title":"Therapeutic Advances in Medical Oncology"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.13905"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan3706"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22034"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-051116-052415"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adl4100"}],"container-title":["JGH 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