Gut DNA virome enterotype dictates inflammation heterogeneity through tuning the phage-bacteria-sphingosine-intestine axis in Crohn's disease.

Two distinct mucosal DNA virome enterotypes (E1 and E2) were identified in humans.

• The two enterotypes were identified from human gut mucosal virome samples.
• E2 subjects exhibited higher virome diversity compared to E1 subjects.
• E2 subjects showed nuanced bacteriophage-bacteria correlations distinct from E1.
• These enterotypes were associated with differential host inflammation phenotypes.

E2-enterotyped Crohn's disease patients exhibited higher Wulfhauvirus abundance than healthy controls.

• Wulfhauvirus abundance was specifically elevated in the E2 virome enterotype.
• This enrichment was observed in CD patients relative to healthy controls.
• Wulfhauvirus enrichment was a distinguishing feature of the E2 virome in the disease context.
• This finding links a specific phage genus to CD-associated virome configuration.

The E2 virome is causally more proinflammatory in inducing intestinal inflammation compared to the E1 virome.

• Causal proinflammatory capacity of the E2 virome was demonstrated in mouse experiments.
• Mice receiving E2 virome showed greater intestinal inflammation than those receiving E1 virome.
• This causal relationship was established through transplantation or colonization experiments in mice.
• The finding supports a functional role of virome configuration in disease outcome.

A novel E2-virome-enriched phage, φBTZT001P (belonging to Wulfhauvirus), lysogenically infects Bacteroides thetaiotaomicron.

• φBTZT001P was identified as a novel phage enriched in the E2 virome.
• The phage belongs to the genus Wulfhauvirus.
• φBTZT001P infects Bacteroides thetaiotaomicron through lysogenic infection.
• Lysogenic infection of B. thetaiotaomicron by φBTZT001P increased sphingosine production in the host bacterium.

Sphingosine produced downstream of φBTZT001P lysogeny suppresses the commensal bacterium Blautia obeum, leading to worsened intestinal inflammation.

• Increased sphingosine production resulting from φBTZT001P infection of B. thetaiotaomicron suppressed B. obeum in the gut.
• Reduction of B. obeum was associated with worsened intestinal inflammation.
• This establishes a mechanistic phage-bacteria-metabolite-intestine axis.
• The axis links virome configuration to downstream microbial and metabolic changes that modulate host inflammation.

Configurational differences in the gut virome dictate disease outcome through a phage-bacteria-metabolite-intestine axis.

• The axis operates through φBTZT001P → B. thetaiotaomicron → sphingosine → suppression of B. obeum → intestinal inflammation.
• This axis highlights the importance of gut phage-bacteria crosstalk in health and disease.
• The findings reveal that virome enterotype, not just virome composition alone, is functionally relevant to disease outcome.
• The study positions gut virome configuration as a determinant of inflammation heterogeneity in Crohn's disease.