Through treatment of zebrafish with selective pharmacological inhibitors and by using germ-free (GF) larvae, we demonstrate that acute HCD-induced myeloid cell accumulation is primarily and directly dependent on cholesterol uptake by NPC1L1 and secondarily dependent on constitutive PRR and nuclear factor-κB (NF-κB) activation by the commensal microbiota. This evidence concerns the gene NPC1L1 and heavy chain disease.