Gut virome remodeling after fecal microbiota transplantation is associated with virus-bacteria co-variation and metabolic response in obesity and type 2 diabetes.

Fecal microbiota transplantation (FMT) modifies gut bacterial composition and improves metabolic outcomes in subjects with obesity and type 2 diabetes (ObT2), but bacterial changes alone do not fully explain the heterogeneity in clinical response. We performed virus-like particle (VLP)-enriched metagenomic sequencing coupled with bulk-DNA metagenomic sequencing on longitudinal fecal samples from a randomized controlled FMT trial in ObT2. Using random forest classification, post-FMT virome changes showed accuracy comparable to bacteriome changes (84.8% vs 81.4%) in distinguishing LDL responders from non-responders. Donor-derived viral contig engraftment was detected in 64.7% (11/17) of recipients receiving FMT alone and 58.8% (10/17) receiving FMT with lifestyle intervention (LSI), versus 5.6% (1/18) in the sham with LSI group. FMT was associated with increased virome diversity, compositional shifts toward the donor virome, and coordinated virus-bacteria associations, with most responsive viral contigs classified as Caudoviricetes. FMT-responsive viral contigs that were shared between the two FMT groups were predicted to infect Roseburia and Bifidobacterium, while contigs associated with clinical responses were predicted to infect Escherichia, Roseburia, Blautia, and Enterococcus. These findings suggest that the gut virome is a complementary ecological component associated with FMT responses and metabolic outcomes in ObT2.