Unveiling the viral dimension: The paediatric gut virome as a key modulator of gastrointestinal metabolic, and neurodevelopmental health

Table 3 Viral-host immune interactions in the paediatric gut: Mechanisms, immune pathways, and clinical implications

Virome function	Key viral components	Host sensors/pathways	Primary immune effects	Clinical relevance
Innate immune priming (“tonic signaling”)	Bacteriophages; eukaryotic viruses	TLR9 (DNA); TLR3 (dsRNA); TLR7/8 (ssRNA) on IECs and dendritic cells	Basal interferon signaling; immune readiness without inflammation	Proper immune imprinting during the first 1000 days
Immune sensing and pattern recognition	Phage DNA; viral RNA/DNA	PRRs (TLRs, downstream interferon pathways)	Distinction between commensals and pathogens	Failure may predispose to immune dysregulation
Mucosal barrier reinforcement	Mucus-adherent bacteriophages	Bacteriophage adherence to mucus; epithelial junction signaling	Interception of invading bacteria; enhanced tight junction integrity	Protection against “leaky gut” and microbial translocation
Maintenance of immune tolerance	Commensal viruses (e.g., Anelloviridae)	Induction of regulatory immune pathways	Promotion of Treg differentiation; suppression of unnecessary inflammation	Reduced risk of food allergy and inflammatory disorders
Immune activation (pathological)	Viral overgrowth; phage lytic blooms	Excess PRR stimulation; cytokine release	Pro-inflammatory cytokine production; tissue injury	NEC, IBD, post-infectious inflammation
Immune maturation and adaptive transition	Early-life eukaryotic viruses	Adaptive immune control over viral load	Development of immune competence and stability	Long-term immune programming
Long-term immune programming	Early virome composition	Host-virome co-adaptation	Adult-like immune homeostasis	Dysregulation linked to allergy and autoimmunity
Viral translocation and systemic signaling	Limited passage of viral particles, bacteriophages, or viral nucleic acids across the intestinal barrier into the lamina propria and systemic circulation, particularly during early life or barrier disruption	Pattern recognition receptors (TLR3, TLR7/8, cGAS-STING), type I and III interferon signaling, dendritic cell and monocyte activation	Immune education, and calibration of antiviral immunity and peripheral immune tolerance during critical windows of immune development	Immune maturation and calibration of systemic antiviral responses; excessive translocation linked to systemic inflammation, necrotizing enterocolitis, inflammatory bowel disease, and extra-intestinal immune dysregulation

This table summarizes the principal mechanisms through which the paediatric gut virome interacts with the host immune system. Viral components, including bacteriophages and eukaryotic viruses, engage innate immune sensors to provide tonic immune priming essential for early-life immune imprinting. The virome also contributes to mucosal barrier integrity, promotes immune tolerance through regulatory pathways, and supports adaptive immune maturation. Disruption of these balanced interactions may result in pathological immune activation and contribute to inflammatory gastrointestinal and systemic diseases in childhood. In addition to local gut effects, the paediatric virome can influence systemic immunity through controlled viral translocation and immune signaling. This mechanism highlights the role of the gut virome as a long-range modulator of immune development beyond the gastrointestinal tract. cGAS-STING: Cyclic GMP-AMP synthase-stimulator of interferon genes; TLR: Toll-like receptor; IFN: Interferon; PRR: Pattern recognition receptor; IEC: Intestinal epithelial cell; Treg: Regulatory T cell; IBD: Inflammatory bowel disease; NEC: Necrotizing enterocolitis; HGT: Horizontal gene transfer; ssDNA: Single-stranded DNA; dsRNA: Double-stranded RNA.