Obesity-Driven Microbial And Metabolic Changes With Cytotoxic Chemotherapy In The Lkb1(Fl/Fl)P53(Fl/Fl) Genetically Engineered Mouse Model Of Endometrioid Endometrial Cancer

Objectives: Obesity is associated with higher risk and worse outcomes for endometrial cancer (EC) as well as chemoresistance. The gut microbiome affects metabolic/immune pathways central to obesity and cancer, impacting efficacy of chemotherapy/immunotherapy; however, the effects of the uterine microbiome upon the progression and treatment of EC remain unknown. Given these complex relationships, we assessed the efficacy of paclitaxel/carboplatin (P/C) in the LKB1fl/flp53fl/fl mouse model of obesity-driven endometrioid EC and explored the microbiotic and metabolomic impact of this treatment. Methods: Starting at 3 weeks of age, mice were fed a control low fat diet (LFD; 10% calories from fat) versus a high fat diet (HFD; 60% calories from fat) to mimic diet-induced obesity. AdCre was injected at 6 weeks to induce invasive EC. Mice were treated with paclitaxel (20 mg/kg intraperitoneally [IP] weekly) and carboplatin (50 mg/kg IP weekly) in combination for 4 weeks. The microbiota profiles were characterized by bacterial 16S rRNA high throughput sequencing, and the data was analyzed using QIIME2 and MicrobiomeAnalyst. Global, unbiased metabolomics was used to identify the metabolic effects of P/C in the ECs. Results: Diet-induced obesity led to a >30% increase in tumor size (p Conclusions: Diet-induced obesity led to distinct microbiotic and metabolomic effects in the ECs of LKB1fl/flp53fl/fl mice. The efficacy of P/C was similar between obese versus lean mice; however, impact of this treatment on intra-tumoral metabolic and bacterial pathways aligned with obesity status. These findings suggest that different metabolic and microbial adjuvant interventions may be warranted in the setting of obesity to improve chemotherapeutic response.