Chemotherapy-driven gut microbiota remodeling in ovarian cancer: a prospective longitudinal study

The gut microbiome shapes chemotherapy efficacy and outcomes in several cancers, but evidence in ovarian cancer (OC) remains limited and largely cross-sectional. Despite high initial response rates, long-term relapse in OC remains frequent, while conventional markers capture only short-term therapeutic sensitivity. Whether longitudinal gut-microbiome trajectories during chemotherapy are associated with long-term recurrence remains unknown.

Within the prospective SOCFCP cohort (N = 91; 13 recurrences), 100 serial fecal samples from a 33-patient sub-cohort were analyzed by 16S rRNA sequencing across the early, middle and late chemotherapy phases. Microbial successional trajectories and their association with recurrence were assessed by linear mixed-effects modeling, multivariable MaAsLin3 and repeated-measures correlation (rmcorr) networks, alongside stratified and covariate-adjusted sensitivity analyses and patient-level bootstrap assessment. The cumulative severe-toxicity-recurrence relationship was estimated by Firth penalized-likelihood regression, suited to sparse, separation-prone events.

Microbial α-diversity rose progressively across the chemotherapy course (Shannon time effect p = 0.002), consistent with ecological succession, with higher turnover among peripheral than in core taxa (p = 0.005). Cumulative severe toxicity was not associated with recurrence (Firth OR = 0.99, 95% CI 0.68-1.39). Crucially, recurrent patients exhibited a progressive depletion of Fusicatenibacter (recurrence × time coefficient = -5.35, q < 0.001) that persisted across all sensitivity analyses-stratified, medication-adjusted, antibiotic-depleted and clinically-adjusted models (coefficient -4.60 to -5.66, all q < 0.001). PICRUSt2-based functional inference identified recurrence-associated differences in predicted de novo nucleotide-biosynthesis and cell-wall-assembly pathway abundance (q < 0.05). A bootstrap-supported co-variation network further linked specific taxa, notably Escherichia-Shigella and Roseburia, to these recurrence-associated pathways.

Chemotherapy-driven gut-microbiome remodeling, in particular the recurrence-associated depletion of Fusicatenibacter, was associated with long-term OC relapse, whereas cumulative severe toxicity showed no significant association with recurrence. These longitudinal microbial dynamics support a candidate non-invasive marker that warrants external validation, and provide a hypothesis-generating rationale for testing whether targeting specific predicted bacterial functional pathways can modulate the host anti-tumor milieu.