Disruption of the Gut Microbiota Confers Cisplatin Resistance in Epithelial Ovarian Cancer

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death. Despite initial responses to intervention, up to 80% of patient tumors recur and require additional treatment. Retrospective clinical analysis of OC patients indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. Here, we assessed whether antibiotic (ABX) treatment would impact growth of EOC and sensitivity to cisplatin. Immunocompetent or immunocompromised mice were given untreated control or ABX-containing (metronidazole, ampicillin, vancomycin, and neomycin) water prior to intraperitoneal injection with EOC cells, and cisplatin therapy was administered biweekly until endpoint. Tumor-bearing ABX-treated mice exhibited accelerated tumor growth and resistance to cisplatin therapy compared with control treatment. ABX treatment led to reduced apoptosis, increased DNA damage repair, and enhanced angiogenesis in cisplatin-treated tumors, and tumors from ABX-treated mice contained a higher frequency of cisplatin-augmented cancer stem cells than control mice. Stool analysis indicated non-resistant gut microbial species were disrupted by ABX treatment. Cecal transplants of microbiota derived from control-treated mice was sufficient to ameliorate chemoresistance and prolong survival of ABX-treated mice, indicative of a gut-derived tumor suppressor. Metabolomics analyses identified circulating gut-derived metabolites that were altered by ABX treatment and restored by recolonization, providing candidate metabolites that mediate the crosstalk between the gut microbiome and ovarian cancer. Collectively, these findings indicate that an intact microbiome functions as a tumor suppressor in EOC, and perturbation of the gut microbiota with ABX treatment promotes tumor growth and suppresses cisplatin sensitivity.

TRAF3 suppression encourages B cell recruitment and prolongs survival of microbiome-intact mice with ovarian cancer

“…The presence of microbiota in the TME has been shown to play a role in many malignancies, either directly or indirectly through secreted metabolites. While this link has been studied primarily in the context of colorectal cancer using stool samples (as reviewed in [ 58 ]), some studies have linked several bacterial genera to OC in humans [ 15 , 16 , 59 ] and mice [ 60 ]. Although our cohort of patients was small, we found three genera in significant abundance in OC ascites – Brevundimonas , Enhydrobacter , and Asinibacterium .…”

TRAF3 Suppression Encourages B Cell Recruitment and Prolongs Survival of Microbiome-Intact Mice with Ovarian Cancer

“…The presence of microbiota in the TME has been shown to play a role in many malignancies, either directly or indirectly through secreted metabolites. While this link has been studied primarily in the context of colorectal cancer using stool samples (as reviewed in [58]), some studies have linked several bacterial genera to OC in humans [15,16,59] and mice [60].…”

Potential Role of Vaginal Microbiota in Ovarian Cancer Carcinogenesis, Progression and Treatment

“…In the recurrent endometrial, cervical and ovarian cancer cases, pretreatment with antibiotics leads to decreased response and survival rates in the following immunotherapy [ 92 ]. Similarly, in the explorations targeting gut microbiota, researchers pointed out the development of cisplatin resistance and accelerated tumor growth after antibiotic treatment in epithelial ovarian cancer was associated with disruption of the gut microbiota [ 93 ]. So far, there has not been a study testifying the actual effects and underlying mechanisms on the antibiotic-induced vaginal microbial change in ovarian cancer; however, the aspects mentioned above might provide the potential cut-in point for future research.…”