Fecal microbiota transplantation restores gut microbiota diversity and butyrogenic taxa more effectively than fidaxomicin in recurrent Clostridioides difficile infection

Introduction Recurrent Clostridioides difficile infection (rCDI) is commonly treated with fidaxomicin or fecal microbiota transplantation (FMT). Although both achieve high clinical cure rates, their differential impact on gut microbiota composition and function remain uncharacterized. Methods Twenty-seven patients from the phase III ICD-01 trial (EudraCT 2020-004591-17) were included, 12 of them received FMT and the remaining 15 received fidaxomicin. Stool samples were collected at baseline and 8 weeks post-treatment. Microbiota composition was assessed by shotgun metagenomics and functionality by short-chain fatty acids (SCFAs) quantification. Metatranscriptomic sequencing was additionally performed in a subset of 7 patients (3 FMT and 4 fidaxomicin). Differential abundance, alpha/beta–diversity, resistome, and toxin-gene burden and expression were evaluated. Results No clinical recurrence occurred at 8 weeks in either group, however alpha–diversity (species richness, Shannon and Simpson indexes) only increased significantly after FMT. Both treatments induced significant shifts in beta–diversity. FMT produced marked enrichment of butyrate-producing taxa, including Ruminococcus , Oscillospiraceae , Fusicatenibacter , Anaerostipes , Roseburia and Dorea . Fidaxomicin expanded Blautia while reducing Enterobacteriaceae , Veillonella and Parvimonas . C. difficile abundance did not change significantly, although their toxin genes ( tcdA/tcdB ) decreased after both interventions, as well as the total abundance of antibiotic-resistance genes. Among the significant changes in fecal SCFA concentrations, increases in acetate, isovalerate, and hexanoate were observed in both groups; butyrate and isovalerate increased most after FMT, whereas propionate, isobutyrate, and valerate only with fidaxomicin. Conclusion FMT drives substantially greater restoration of microbial diversity and a selective expansion of butyrogenic taxa than fidaxomicin.