Background Evidence has accumulated to demonstrate that intestinal microbiome can inhibit viral infection. However, our knowledge of the signaling pathways and identity of specific commensal microbes that mediate the antiviral response is limited. Zebrafish have emerged as a powerful animal model for study of vertebrate-microbiota interactions. Here, a rhabdoviral infection model in zebrafish allows us to investigate the modes of action of microbiome-mediated antiviral effect. Results We observed that oral antibiotics-treated and germ-free zebrafish exhibited greater spring viremia of carp virus (SVCV) infection. Mechanistically, depletion of the intestinal microbiome alters TLR2-Myd88 signaling and blunts neutrophil response and type I interferon (IFN) antiviral innate immunity. Through 16S rRNA sequencing of the intestinal contents from control and antibiotic(s)-treated fish, we identified a single commensal bacterial species, Cetobacterium somerae, that can restore the TLR2- and neu