Our results pave the way for future studies aimed at shedding light on the relevance of estrogens in the protection of fish by natural antibodies, the signaling mechanism involved, including classical nuclear ERs, the impact of natural antibodies and estrogens in the crosstalk between natural antibodies, both IgM and IgT, and microbiota, and the therapeutic potential of estrogen administration to protect fish against infections in aquaculture. This evidence concerns the gene CD40LG and infection.