Gut Microbiome Compositional and Functional Signatures Associated with Chemotherapy Response in Pancreatic Ductal Adenocarcinoma: An Exploratory Cohort Study

Background/Objectives: The gut microbiome modulates chemotherapy efficacy in pancreatic ductal adenocarcinoma (PDAC), yet its relationship with the clinically relevant endpoint of post-chemotherapy surgical eligibility remains poorly characterised. We explored whether baseline gut microbiome composition and metagenomically predicted metabolic function differ between chemotherapy responders and non-responders in PDAC. Methods: In this prospective single-centre exploratory cohort study, faecal samples were collected from 15 patients with non-immediately resectable PDAC at diagnosis, before chemotherapy. Whole-genome shotgun metagenomics was performed, and microbial functional capacity was inferred through an assembly-based pipeline. Patients were classified as responders (achieved surgical eligibility, n = 6) or non-responders (n = 9). Results: At baseline, responders showed enrichment of Collinsella aerofaciens (p = 0.026) and Butyrivibrio fibrisolvens (p = 0.012), while non-responders were enriched in oral-origin bacteria (Streptococcus gordonii, Actinomyces spp., Rothia dentocariosa). Predicted butyrate showed the largest effect size difference between groups but did not reach significance (p = 0.179); responders also had broadly elevated predicted SCFAs and bile acids. However, chemotherapy regimen (mFOLFIRINOX in 5/6 responders vs. 2/9 non-responders; Fisher p = 0.041) and disease stage were unevenly distributed between groups. Conclusions: This exploratory study identifies the compositional and functional microbiome features distinguishing PDAC chemotherapy responders from non-responders. These associations are confounded by disease stage and regimen and require validation in larger, regimen-stratified cohorts before predictive or mechanistic claims can be made.