Remodelling of the gut virome after long-term fasting.

Abstract

Long-term fasting is a promising strategy to restore metabolic health. Emerging evidence suggests that the gut microbiome may mediate some of fasting benefits, but the role of its viral component remains poorly understood. Using shotgun metagenomic data from a single-arm, monocentric fasting intervention, this study profiled the gut virome (n = 89 individuals, n = 241 samples) before and after 9.8 days of fasting ( ~ 250 kcal/day) as well as one and three months afterwards. Fasting induced a transient loss of viral diversity and a shift toward increased representation of virulent phages. External dataset validation identified 49 phages showing reproducible directional changes during fasting. Many were linked to bacterial hosts, showing concordant shifts, including depletion of Faecalibacterium-associated phages and enrichment of Bacteroides-associated phages. Cross-domain network analyses revealed denser viral-bacterial networks at the end of fast, with enriched connections to butyrate producers, suggesting phages may participate in the fasting-induced restructuring of microbial networks involving health-associated taxa. Collectively, these findings indicate that fasting remodels the gut virome cross-domain associations through reproducible, functionally relevant phage-host interactions, with reorganisation persisting for up to three months and occurring in parallel with improvements in cardiometabolic markers.