Microbiota–bile acid–host axis dysregulation drives enteropathogenesis in <i>Escherichia coli</i> K99-induced neonatal calf diarrhea

Neonatal calf diarrhea caused by <i>Escherichia coli</i> K99 remains a critical challenge in livestock health, yet its precise pathogenic mechanisms are poorly defined. In this study, we identify bile acid (BA) metabolic dysregulation as a key pathogenic mechanism in <i>E. coli</i> K99-induced diarrhea. Using a neonatal calf infection model integrated with multi-omics profiling (including 16S rRNA sequencing, untargeted metabolomics, and targeted bile acid metabolomics), we demonstrate that <i>E. coli</i> K99 infection leads to significant disruption of the gut microbiota, compromises intestinal barrier integrity, and causes region-specific alterations in BA receptor signaling pathways (including FXR, TGR5, RAR, and ABST). Targeted metabolomic analysis revealed the accumulation of toxic primary and secondary BAs, driven by microbial shifts favoring BA-transforming pathogens and depleting BA-sensitive commensals. This microbial dysbiosis-BA imbalance-receptor dysfunction axis provokes immune activation, metabolic disturbances, and epithelial damage. Our study is the first to establish a mechanistic link between <i>E. coli</i> K99 infection and intestinal dysfunction <i>via</i> a microbiota-bile acid-host signaling cascade. These findings uncover a previously unrecognized pathophysiological pathway in bacterial diarrhea and suggest that modulation of gut microbiota and bile acid metabolism represents a promising therapeutic strategy for managing enteric infections in veterinary and potentially human medicine.