Abstract

The enteric microbiome and nutrient sensing within the small intestine play critical roles in maintaining host metabolic homeostasis. Although various bacteria and some fungi have established functions in nutrient metabolism, the role of the enteric virome remains poorly understood. Here, we demonstrate that the enteric virome significantly influences carbohydrate digestion and absorption independently of the bacteriome. Furthermore, the virome elicits distinct responses across different intestinal cell types. Specifically, it activates programs for carbohydrate digestion and absorption in intestinal epithelial cells while simultaneously stimulating antigen-presenting cells―Th17 cells―to produce interleukin-22, a cytokine that curbs excessive carbohydrate uptake. The virome’s effect on carbohydrate digestion and absorption—whether suppressive or stimulatory—depends on the presence or absence of immune surveillance. This intricate interplay between metabolic and immune pathways establishes the enteric virome as a pivotal regulator of metabolism and reveals the virome’s intrinsic capacity to autonomously modulate vertebrate intestinal physiology.