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The chemotherapeutic irinotecan (CPT\u201011) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN\u201038 glucuronide (SN\u201038G) by bacterial \u03b2\u2010glucuronidases to the active 7\u2010ethyl\u201010\u2010hydroxycamptothecin (SN\u201038). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT\u201011 anti\u2010tumour efficacy and GI toxicity are exacerbated by opioid co\u2010administration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      Eight\u2010week\u2010old C57BL\/6 male mice were co\u2010administration with CPT\u201011\u2009\u00b1\u2009opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC\u2013MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT\u201011. Histological analysis and quantitative real\u2010time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome\n                      <jats:italic>In vitro<\/jats:italic>\n                      assay was performed to confirm the effects of opioids on CPT\u201011 metabolism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Gut microbiome analysis showed that morphine treatment induced enrichment of \u03b2\u2010glucuronidase\u2010producing bacteria in the intestines of CPT\u201011\u2010treated mice, resulting in SN\u201038 accumulation and exacerbation of GI toxicity in the small intestine. Oral administration of both antibiotics and glucuronidase inhibitor protected mice against GI toxicity induced with CPT\u201011 and morphine co\u2010administration, implicating a microbiome\u2010dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN\u201038 and compromised CPT\u201011 anti\u2010tumour efficacy, this seemed to be microbiome independent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Gut microbiota play a significant role in opioid and chemotherapeutic agent drug\u2013drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT\u201011 in patients on opioids.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16020","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T02:35:50Z","timestamp":1671762950000},"page":"1362-1378","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Opioid\u2010induced microbial dysbiosis disrupts irinotecan (CPT\u201011) metabolism and increases gastrointestinal toxicity in a murine model"],"prefix":"10.1111","volume":"180","author":[{"given":"Jingjing","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Surgery University of Miami  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaa F.","family":"Abu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Miami  Miami Florida 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