Abstract

The human gut harbors a diverse virome, believed to play a crucial role in maintaining intestinal homeostasis. However, the magnitude of heterogeneity of the gut mucosal virome, and how it differentially regulates host inflammation phenotypes, such as those observed in Crohn’s disease (CD), remains unclear. Here, we identify two mucosal DNA virome enterotypes (E1 and E2) in humans, with E2 subjects exhibiting higher virome diversity and nuanced bacteriophage-bacteria correlations. Moreover, E2-enterotyped CD patients exhibited higher Wulfhauvirus abundance than healthy controls. The E2 virome is causally more proinflammatory in inducing intestinal inflammation in mice. Mechanistically, the novel E2-virome-enriched phage øBTZT001P (belonging to Wulfhauvirus ) lysogenically infects Bacteroides thetaiotaomicron , increasing sphingosine production. Downstream, sphingosine suppresses the commensal bacterium Blautia obeum in the gut, leading to worsened intestinal inflammation. Our findings reveal that configurational differences in the gut virome may dictate disease outcome through a phage-bacteria-metabolite-intestine axis, highlighting the importance of gut phage-bacteria crosstalk in health.