Bifidobacterium animalis reshapes the bile acid pool and prevents neonatal jaundice: a clinical microbiome study from correlation to causation.

Neonatal jaundice (NJ) affects 60-80% of neonates, yet the underlying microbial mechanisms remain elucidated, despite known links between gut dysbiosis and bilirubin and bile acid (BA) metabolism. Through two-stage shotgun metagenomic-metabolomic analysis of 150 fecal samples from 120 neonates, we identified key taxa linked to bile acid (BA) metabolism in moderate-to-severe NJ. Furthermore, multi-omics integration revealed significant interkingdom correlations among gut phages, bacteria, and BAs. Dysbiosis featured enriched Streptococcus and Escherichia, depleted Bifidobacterium animalis, and group-specific phage signatures. In the independent clinical validation cohort, jaundice intervention normalized the dysbiotic profile, demonstrating significant suppression of pathogenic taxa concomitant with restoration of B. animalis abundance. In vitro, B. animalis subsp. lactis Y103-OTU5 remodeled BA via deconjugation. In a phenylhydrazine hydrochloride (PHZ)-induced murine model of hemolytic jaundice, oral administration of isolated B. animalis subsp. lactis Y103-OTU5 significantly attenuated hyperbilirubinemia and hepatic inflammation, likely via Cyp7a1/Cyp7b1-dependent modulation of BA synthesis and detoxification pathways. Structural equation modeling revealed a tripartite regulatory network: phages indirectly modulated BA through bacterial remodeling, while B. animalis directly regulated BA pathways, positioning it as a potential therapeutic candidate for hemolysis-associated neonatal jaundice. Collectively, these findings reveal a gut phage-bacteria-BA network in NJ, highlighting B. animalis as a therapeutic candidate with dual modulation of BA metabolism and phage-bacteria interactions.