Taken together, untargeted metabolomics revealed that hepcidin deficiency altered portal blood metabolite profiles in mice, and in combination with further screening for specific tryptophan metabolites with gut microbiota depletion and fecal microbiota transplantation strategies, we found that the gut microbiota–derived tryptophan metabolite IPA might be a key gut–liver axis signaling molecule mediating the differences in the antibacterial defense of KCs between Hamp1–/– and WT mice during bloodstream bacterial infection. Here, HAMP is linked to bacterial infectious disease.