Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy

Epithelial Ovarian Cancer (EOC) is the leading cause of gynecologic cancer death. Despite many patients achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Retrospective clinical analysis of OC patients indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. We assessed whether antibiotic (ABX) therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given control or ABX containing water (metronidazole, ampicillin, vancomycin, and neomycin) before being intraperitoneally injected with murine EOC cells. Stool was collected to confirm microbiome disruption and tumors were monitored, and cisplatin therapy was administered weekly until endpoint. EOC tumor-bearing mice demonstrate accelerated tumor growth and resistance to cisplatin therapy in ABX treated compared with nonABX treatment. Stool analysis indicated most gut microbial species were disrupted by ABX treatment except for ABX resistant bacteria. To test for role of the gut microbiome, cecal microbiome transplants (CMTs) of microbiota derived from ABX or nonABX treated mice were used to r ecolonize the microbiome of ABX treated mice. nonABX cecal microbiome was sufficient to ameliorate the chemoresistance and survival of ABX treated mice indicative of a gut derived tumor suppressor. Mechanistically, tumors from ABX treated compared to nonABX treated mice contained a high frequency of cancer stem cells that were augmented by cisplatin. These studies indicate an intact microbiome provides a gut derived tumor suppressor and maintains chemosensitivity that is disrupted by ABX treatment. Significance Platinum resistance is associated with poor prognosis and reduced therapeutic options for ovarian cancer patients. We identifed a tumor suppressive role of the gut microbiome that is disrupted upon antibiotic therapy. ### Competing Interest Statement The authors have declared no competing interest. * EOC : epithelial ovarian cancer ABX : antibiotic CMT : cecal microbiome transplant C57BL/6J : BL/6 TAUS : transabdominal ultrasound NSG : NOD.Cg-PrkdcIl2rgSzJ AVS : amplified sequence variants bps : base pairs GSEA : gene set enrichment analysis CSC : cancer stem cell BCS : body composition score IVIS : in vivo imaging system DADA : divisive amplicon denoising algorithm PCoA : principal coordinate analysis MDS : multidimensional scaling PERMANOVA : permutational multivariate analysis of variance FDR : false discovery rate