{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T18:30:17Z","timestamp":1784140217479,"version":"3.55.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T00:00:00Z","timestamp":1706572800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T00:00:00Z","timestamp":1706572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    We elucidated the efficacy of gut microbiome\u2013altering drugs on pembrolizumab efficacy in patients with metastatic urothelial carcinoma (mUC). Clinical data were analyzed retrospectively from 133 patients with mUC who received second-line pembrolizumab therapy between January 2018 and January 2021, following failed platinum-based chemotherapy. We evaluated the effects of gut microbiome\u2013altering drugs (proton pump inhibitors [PPI]\/potassium-competitive acid blockers [P-CAB], H2 blockers, antibiotics, non-steroidal anti-inflammatory drugs [NSAIDs], metformin, antipsychotics, steroids, and opioids), taken by patients within 30\u00a0days before\/after pembrolizumab treatment, on progression-free survival (PFS) and overall survival (OS). Fifty-one patients received PPI\/P-CAB (37\/14, respectively); H2 blockers, 7; antibiotics, 35; NSAIDs, 22; antipsychotics, 8; metformin, 3; steroids, 11; and opioids, 29. Kaplan\u2013Meier curves revealed PPI or P-CAB users showed shorter PFS than non-PPI-P-CAB users (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.001,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.005, respectively). Multivariate analysis highlighted PPI\/P-CAB use as the only independent prognostic factor for disease progression (hazards ratio: 1.71, 95% confidence interval: 1.14\u20132.07,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.010) but not death (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.177). Proton pump inhibitors\/potassium-competitive acid blockers may decrease the efficacy of pembrolizumab therapy for mUC, possibly via gut microbiome modulation.\n                  <\/jats:p>","DOI":"10.1038\/s41598-024-53158-1","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T03:55:57Z","timestamp":1706673357000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Proton pump inhibitors and potassium competitive acid blockers decrease pembrolizumab efficacy in patients with metastatic urothelial carcinoma"],"prefix":"10.1038","volume":"14","author":[{"given":"Keitaro","family":"Iida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Naiki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiki","family":"Etani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Nagai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Sugiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruki","family":"Isobe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Nozaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Noda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiko","family":"Shimizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nami","family":"Tomiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakazu","family":"Gonda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kamiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Nakane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Ando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyasu","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Yasui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,30]]},"reference":[{"issue":"6371","key":"53158_CR1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1126\/science.aan4236","volume":"359","author":"V Gopalakrishnan","year":"2018","unstructured":"Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359(6371), 97\u2013103 (2018).","journal-title":"Science"},{"issue":"6285","key":"53158_CR2","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1126\/science.aad9358","volume":"352","author":"MJ Blaser","year":"2016","unstructured":"Blaser, M. J. Antibiotic use and its consequences for the normal microbiome. Science 352(6285), 544\u2013545 (2016).","journal-title":"Science"},{"issue":"6371","key":"53158_CR3","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1126\/science.aan3706","volume":"359","author":"B Routy","year":"2018","unstructured":"Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359(6371), 91\u201397 (2018).","journal-title":"Science"},{"issue":"6","key":"53158_CR4","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1093\/annonc\/mdy103","volume":"29","author":"L Derosa","year":"2018","unstructured":"Derosa, L. et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann. Oncol. 29(6), 1437\u20131444 (2018).","journal-title":"Ann. Oncol."},{"issue":"4","key":"53158_CR5","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2019.1568812","volume":"8","author":"A Elkrief","year":"2019","unstructured":"Elkrief, A. et al. Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors. Oncoimmunology 8(4), e1568812 (2019).","journal-title":"Oncoimmunology"},{"issue":"4","key":"53158_CR6","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1016\/j.eururo.2020.06.061","volume":"78","author":"AM Hopkins","year":"2020","unstructured":"Hopkins, A. M. et al. Concomitant antibiotic use and survival in urothelial carcinoma treated with atezolizumab. Eur. Urol. 78(4), 540\u2013543 (2020).","journal-title":"Eur. Urol."},{"issue":"5","key":"53158_CR7","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1136\/gutjnl-2015-310376","volume":"65","author":"F Imhann","year":"2016","unstructured":"Imhann, F. et al. Proton pump inhibitors affect the gut microbiome. Gut 65(5), 740\u2013748 (2016).","journal-title":"Gut"},{"issue":"9","key":"53158_CR8","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1136\/gutjnl-2016-313312","volume":"66","author":"T Otsuka","year":"2017","unstructured":"Otsuka, T. et al. Influence of potassium-competitive acid blocker on the gut microbiome of Helicobacter pylori-negative healthy individuals. Gut 66(9), 1723\u20131725 (2017).","journal-title":"Gut"},{"issue":"3","key":"53158_CR9","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1177\/1078155218771152","volume":"25","author":"S Mukherjee","year":"2019","unstructured":"Mukherjee, S. et al. Do proton pump inhibitors modulate the efficacy of anti-PD-1\/PD-L1 therapy? A retrospective study. J. Oncol. Pharm. Pract. 25(3), 762\u2013764 (2019).","journal-title":"J. Oncol. Pharm. Pract."},{"issue":"1","key":"53158_CR10","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1186\/s12885-020-06882-6","volume":"20","author":"D Spakowicz","year":"2020","unstructured":"Spakowicz, D. et al. Inferring the role of the microbiome on survival in patients treated with immune checkpoint inhibitors: Causal modeling, timing, and classes of concomitant medications. BMC Cancer 20(1), 383 (2020).","journal-title":"BMC Cancer"},{"key":"53158_CR11","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.ejca.2020.09.033","volume":"142","author":"S Buti","year":"2021","unstructured":"Buti, S. et al. Effect of concomitant medications with immune-modulatory properties on the outcomes of patients with advanced cancer treated with immune checkpoint inhibitors: Development and validation of a novel prognostic index. Eur. J. Cancer 142, 18\u201328 (2021).","journal-title":"Eur. J. Cancer"},{"issue":"4","key":"53158_CR12","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.annonc.2020.01.006","volume":"31","author":"M Chalabi","year":"2020","unstructured":"Chalabi, M. et al. Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: Pooled post hoc analyses of the OAK and POPLAR trials. Ann. Oncol. 31(4), 525\u2013531 (2020).","journal-title":"Ann. Oncol."},{"issue":"1","key":"53158_CR13","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/s41416-021-01606-4","volume":"126","author":"AM Hopkins","year":"2022","unstructured":"Hopkins, A. M. et al. Efficacy of first-line atezolizumab combination therapy in patients with non-small cell lung cancer receiving proton pump inhibitors: post hoc analysis of IMpower150. Br. J. Cancer 126(1), 42\u201347 (2022).","journal-title":"Br. J. Cancer"},{"issue":"20","key":"53158_CR14","doi-asserted-by":"publisher","first-page":"5487","DOI":"10.1158\/1078-0432.CCR-20-1876","volume":"26","author":"AM Hopkins","year":"2020","unstructured":"Hopkins, A. M. et al. Concomitant proton pump inhibitor use and survival in urothelial carcinoma treated with atezolizumab. Clin. Cancer Res. 26(20), 5487\u20135493 (2020).","journal-title":"Clin. Cancer Res."},{"issue":"2","key":"53158_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2021.100090","volume":"6","author":"J Ruiz-Ba\u00f1obre","year":"2021","unstructured":"Ruiz-Ba\u00f1obre, J. et al. Rethinking prognostic factors in locally advanced or metastatic urothelial carcinoma in the immune checkpoint blockade era: A multicenter retrospective study. ESMO Open 6(2), 100090 (2021).","journal-title":"ESMO Open"},{"issue":"7698","key":"53158_CR16","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/nature25979","volume":"555","author":"L Maier","year":"2018","unstructured":"Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555(7698), 623\u2013628 (2018).","journal-title":"Nature"},{"issue":"2","key":"53158_CR17","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1111\/cas.14762","volume":"112","author":"T Kobayashi","year":"2021","unstructured":"Kobayashi, T. et al. Risk stratification for the prognosis of patients with chemoresistant urothelial cancer treated with pembrolizumab. Cancer Sci. 112(2), 760\u2013773 (2021).","journal-title":"Cancer Sci."},{"issue":"11","key":"53158_CR18","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1056\/NEJMoa1613683","volume":"376","author":"J Bellmunt","year":"2017","unstructured":"Bellmunt, J. et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med. 376(11), 1015\u20131026 (2017).","journal-title":"N. Engl. J. Med."},{"issue":"5","key":"53158_CR19","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1001\/jamainternmed.2015.42","volume":"175","author":"EG McDonald","year":"2015","unstructured":"McDonald, E. G. et al. Continuous proton pump inhibitor therapy and the associated risk of recurrent clostridium difficile infection. JAMA Intern. Med. 175(5), 784\u2013791 (2015).","journal-title":"JAMA Intern. Med."},{"issue":"9","key":"53158_CR20","doi-asserted-by":"publisher","first-page":"2047","DOI":"10.1111\/j.1572-0241.2007.01275.x","volume":"102","author":"J Leonard","year":"2007","unstructured":"Leonard, J., Marshall, J. K. & Moayyedi, P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am. J. Gastroenterol. 102(9), 2047\u201356 (2007).","journal-title":"Am. J. Gastroenterol."},{"issue":"5","key":"53158_CR21","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1136\/gutjnl-2015-310861","volume":"65","author":"MA Jackson","year":"2016","unstructured":"Jackson, M. A. et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut 65(5), 749\u2013756 (2016).","journal-title":"Gut"},{"issue":"1","key":"53158_CR22","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1124\/jpet.110.170274","volume":"335","author":"Y Hori","year":"2010","unstructured":"Hori, Y. et al. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases. J. Pharmacol. Exp. Ther. 335(1), 231\u2013238 (2010).","journal-title":"J. Pharmacol. Exp. Ther."},{"issue":"2","key":"53158_CR23","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1093\/dnares\/dsw002","volume":"23","author":"S Nishijima","year":"2016","unstructured":"Nishijima, S. et al. The gut microbiome of healthy Japanese and its microbial and functional uniqueness. DNA Res. 23(2), 125\u2013133 (2016).","journal-title":"DNA Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53158-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53158-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53158-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T04:02:14Z","timestamp":1706673734000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53158-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,30]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["53158"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-53158-1","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-2158631\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,30]]},"assertion":[{"value":"12 October 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2520"}}