The gut virome and regulatory T cell axis in health and systemic disease

The gut virome, comprising bacteriophages and eukaryotic viruses, represents a complex and dynamic component of the intestinal microbiome whose functional significance has long been underestimated. Emerging evidence highlights the gut virome as a pivotal modulator of the host immune system, particularly in regulating the balance and function of regulatory T cells (Tregs), which are essential for maintaining immune homeostasis. This review distinguishes two mechanistic axes by which the virome influences Tregs: (i) an indirect 'virome-bacteriome-metabolite-Treg axis', and (ii) a direct 'viral pathogen-associated molecular patterns (PAMPs)-pattern recognition receptors (PRRs)-Treg' signaling axis. This review comprehensively examines the dualistic role of the gut virome in preserving intestinal equilibrium and its involvement in the pathogenesis or amelioration of intestinal inflammatory disorders such as inflammatory bowel disease (IBD). Furthermore, the influence of the gut virome extends beyond the gut, potentially impacting systemic immune-related diseases. By integrating recent advances in metagenomics, viromics, and immunology, we elucidate the molecular mechanisms through which the gut virome orchestrates immune regulation. This synthesis aims to provide a comprehensive understanding of the gut virome as a critical immune regulator and to explore its potential as a biomarker for disease diagnosis and a novel target for therapeutic intervention.