l-aspartic acid promotes fish survival against Vibrio alginolyticus infection through nitric oxide-induced phagocytosis.

Bacterial infection severely impairs aquaculture development throughout the world. Despite the use of antibiotics to control bacterial infection, few other options are available especially in the area of complex ecosystem and various types of fish. In search for novel approaches in controlling bacterial infection, we adopt zebrafish, Danio reiro, as infection host and the bacteria, Vibrio alginolyticus, as pathogen to explore potential metabolites that boost host's capability to eliminate bacterial infection. By comparing the metabolome of dying fish, l-aspartic acid is a metabolite of differential abundance between the dying fish and surviving fish upon Vibrio alginolyticus infection. Exogenous l-aspartic acid increases fish survival rate from 46.67% to 76.67%. We further demonstrated that l-aspartic acid drives the production of nitrogen oxide that promotes phagocytosis. Whereas the inhibition of nitrogen oxide synthase would abolish l-aspartic acid-triggered phagocytosis as well as in vivo protective ability to V. alginolyticus. The importance of nitrogen oxide production in fish survival is also consistent with the observation in the dying fish that showed increased urea production but not nitrogen oxide. Thus, our results exemplify a novel approach in promoting fish survival in an eco-friendly way.