BACKGROUND: Symbiotic microbiota in vertebrates play critical roles in establishing and enhancing host resistance to pathogenic infections as well as maintaining host homeostasis. The interactions and mechanisms of commensal microbiota-mediated mucosal immune systems have been extensively studied in mammals and, to a lesser extent, in birds. However, despite several studies emphasizing the role of mucosal microbiota in controlling pathogen infections in teleost fish, limited knowledge exists regarding the core microbiota and the mechanisms by which they contribute to resistance against viral infections. RESULTS: Our findings suggest that viral infections shape clinical manifestations of varying severity in infected fish. An increased abundance of Bacillus spp. in the mild phenotype indicates its crucial role in influencing fish immunity during viral infections. To confirm that Bacillus spp. act as a core contributor against viral infection in fish, we isolated a representative strain of Bacillus spp. from largemouth bass (Micropterus salmoides), which was identified as Bacillus velezensis (Bv), and subsequently conducted feeding trials. Our study demonstrated that dietary supplementation with Bv significantly reduced mortality from largemouth bass virus (LMBV) infection in bass by enhancing host immunity and metabolism as well as by regulating the microbial community. Furthermore, multi-omics analysis elucidated the mechanism by which Bacillus spp. confer resistance to viral infections by regulating the production of diglyceride (DG) during lipid metabolism. CONCLUSIONS: Our study provides the first evidence that Bacillus spp. are a core microbiota for combating viral infections in teleost fish, shedding light on the conserved functions of probiotics as a core microbiota in regulating microbial homeostasis and mucosal immunity across the vertebrate lineage.