S2047 Fecal Microbiota Transplantation Therapy Alters Resistome Burden and Mobilization Potential in a Disease-Dependent Manner

Introduction: Antimicrobial resistance (AMR) is a global health threat that contributes to millions of deaths annually. Fecal microbiota transplantation (FMT) offers a non-antibiotic strategy to treating gastrointestinal microbiome-related disorders, especially recurrent Clostridioides difficile (rCDI), yet its impact on AMR gene (ARG) dynamics and mobile genetic elements (MGEs) remains poorly understood. Understanding these effects is crucial as FMT adoption broadens into new clinical indications beyond rCDI treatment. Methods: We analyzed 263 publicly available metagenomic samples from FMT donors and recipients across rCDI, multidrug-resistant bacterial (MDRB) infections, and melanoma, reflecting disease processes with variable disruptions to patients’ native intestinal microbiota. Resistome and mobilome profiles were characterized using AMR++ and MGE classification pipelines with longitudinal comparisons and differential abundance assessed via ANCOM-BC2 (FDR-adjusted P < 0.05). Colocalization analyses were performed using the TELCoMB pipeline to evaluate ARG mobility risk potential. Results: In rCDI samples, both ARG and MGE diversity shifted markedly across donor, pre-FMT, and post-FMT samples. Differential abundance analysis revealed several significantly altered ARG and MGE genes pre- and post-FMT (FDR-adjusted P < 0.05). Among the ARGs shared between pre- and post-FMT samples, ∼12% significantly changed in abundance, with a majority (∼67%) being enriched. In contrast to rCDI, melanoma and MDRB cohorts exhibited minimal shifts in ARG and MGE diversity post-FMT, with >97% of genes stable and <2% showing significant change. Colocalization analysis showed that FMT recipients–especially rCDI patients–harbored more unique ARG–MGE colocalizations than donors. Both pre- and post-FMT rCDI samples exhibited colocalization rates >10× higher than donors, indicating sustained or elevated resistomes amenable to horizontal gene transfer. Conclusion: Our findings, which accounted for prior antibiotic treatment, FMT preparation, and FMT route, highlight that FMTs reshape the resistome and mobilome in a disease-specific manner. These findings underscore the need for careful resistome surveillance in FMT recipients and highlight the potential of FMTs to modulate both AMR burden and gene mobility in the human gastrointestinal tract.