biostudies-literatureMeng JNIDA NIH HHSNIDDK NIH HHSNational Institutes of Health1362-1378https://www.ebi.ac.uk/biostudies/studies/S-EPMC10089971biostudies-literatureUnknown180(10)<h4>Background and purpose</h4>Opioids are commonly used for the management of cancer-associated pain and chemotherapy-induced diarrhoea. The chemotherapeutic irinotecan (CPT-11) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN-38 glucuronide (SN-38G) by bacterial β-glucuronidases to the active 7-ethyl-10-hydroxycamptothecin (SN-38). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT-11 anti-tumour efficacy and GI toxicity are exacerbated by opioid co-administration.<h4>Experimental approach</h4>Eight-week-old C57BL/6 male mice were co-administration with CPT-11 ± opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC-MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT-11. Histological analysis and quantitative real-time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome In vitro assay was performed to confirm the effects of opioids on CPT-11 metabolism.<h4>Key results</h4>Gut microbiome analysis showed that morphine treatment induced enrichment of β-glucuronidase-producing bacteria in the intestines of CPT-11-treated mice, resulting in SN-38 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-11 and morphine co-administration, implicating a microbiome-dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN-38 and compromised CPT-11 anti-tumour efficacy, this seemed to be microbiome independent.<h4>Conclusion and implications</h4>Gut microbiota play a significant role in opioid and chemotherapeutic agent drug-drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT-11 in patients on opioids.British journal of pharmacologyOpioid-induced microbial dysbiosis disrupts irinotecan (CPT-11) metabolism and increases gastrointestinal toxicity in a murine model.PMC10089971R01 DA047089R01 DK117576R01 DA050542R01 DA031202R01 DA043252R01DA044582R01DA047089R01 DA044582R01 DA034582F31 DA053795R01DA043252F31DA053795T32 DA045734R01 DA012104R01DA050542R01 DA037843R01 DA022935Tao JXie YZhang YRamakrishnan SRoy SMeng JAbu YFZhou YYan YChen CfalseOpioid-induced microbial dysbiosis disrupts irinotecan (CPT-11) metabolism and increases gastrointestinal toxicity in a murine model.<h4>Background and purpose</h4>Opioids are commonly used for the management of cancer-associated pain and chemotherapy-induced diarrhoea. The chemotherapeutic irinotecan (CPT-11) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN-38 glucuronide (SN-38G) by bacterial β-glucuronidases to the active 7-ethyl-10-hydroxycamptothecin (SN-38). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT-11 anti-tumour efficacy and GI toxicity are exacerbated by opioid co-administration.<h4>Experimental approach</h4>Eight-week-old C57BL/6 male mice were co-administration with CPT-11 ± opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC-MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT-11. Histological analysis and quantitative real-time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome In vitro assay was performed to confirm the effects of opioids on CPT-11 metabolism.<h4>Key results</h4>Gut microbiome analysis showed that morphine treatment induced enrichment of β-glucuronidase-producing bacteria in the intestines of CPT-11-treated mice, resulting in SN-38 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-11 and morphine co-administration, implicating a microbiome-dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN-38 and compromised CPT-11 anti-tumour efficacy, this seemed to be microbiome independent.<h4>Conclusion and implications</h4>Gut microbiota play a significant role in opioid and chemotherapeutic agent drug-drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT-11 in patients on opioids.2023-01-01T00:00:00Z2023 May2026-06-01T10:51:00.545Z2026-04-08T11:32:06.481ZS-EPMC100899713656210710.1111/bph.16020