Ameliorative effect of “intestinal–vaginal” probiotics on 5-fluorouracil-induced microbial dysbiosis in colorectal cancer

The interaction between the gut microbiome and cancer chemotherapy has been extensively studied. However, the exact role of the vaginal microbiome in chemotherapy remains unknown. To address this issue, we established a colorectal cancer chemotherapy mouse model. Here, we confirmed that 5-fluorouracil induced dysbiosis in both the vaginal and gut microbiomes, presenting a new challenge for conventional chemotherapy. Therefore, we innovatively propose an "intestinal-vaginal" probiotics administration strategy, which involves the simultaneous delivery of probiotics to both the gut and vagina, aiming to enhance chemotherapy efficacy while alleviating dysbiosis and associated side effects. Our results indicate that, compared to gut-only probiotic intervention, "intestinal-vaginal" probiotics administration significantly enhanced the anticancer efficacy of 5-fluorouracil by upregulating the p53 pathway. Furthermore, regarding gastrointestinal side effects, "intestinal-vaginal" probiotics more effectively reduced the release of vomit-associated neurotransmitters (<i>e.g.</i>, 5-HT and SP), while also alleviating mucositis by downregulating the NF-κB pathway. Additionally, "intestinal-vaginal" probiotics outperformed the oral probiotic by increasing beneficial microbiota and reducing pathogenic bacteria. Notably, regarding vaginal side effects, "intestinal-vaginal" probiotics significantly inhibited the NF-κB inflammatory pathway and pro-apoptotic proteins, and improved vaginal dysbiosis compared to vaginal-only probiotics. These findings provide the first evidence of the significant potential of the "intestinal-vaginal" probiotics delivery approach as an adjunctive cancer therapy, which offers a novel perspective on the synergistic interactions between host microbiota communities.