Aspartate induces metabolic changes and improves the host's ability to fight against Aeromonas hydrophila infection in Cyprinus carpio

Abstract

Host innate immunity modulated by metabolites is a powerful strategy that can be used to defend against microbial infections. However, the mechanisms underlying the metabolic processes in controlling bacterial infections remain unexplored. Here, a GC-MS based metabolomics approach was adopted to investigate the metabolic characteristics between the surviving and dying Cyprinus carpio upon Aeromonas hydrophila infection. Aspartate was identified as an essential biomarker whose abundance significantly decreased in the dying group while increasing in the surviving group when compared to the control. Exogenous aspartate increased fish survival rate in a dose-dependent manner. Concurrently, we also found that aspartate regulated the expressions of inflammatory and anti-inflammatory factors, and alleviated oxidative damage based on the evaluations of the activities of antioxidant enzymes and histopathology. Interestingly, the results revealed that exogenous aspartate promoted arginine and proline metabolism and arginine biosynthesis, but attenuated the TCA cycle, thereby enhancing the disease resistance against A. hydrophila. We further demonstrated that aspartate induced iNOS expression and NO production, and L-NAME treatment inhibited iNOS expression and blocked NO production, which significantly increased the cumulative mortality of infecting A. hydrophila. These findings indicated that exogenous aspartate could reprogram C. carpio metabolome and improve the host's ability to fight against A. hydrophila infection by inducing of NO release, and demonstrated the metabolite-mediated immunomodulatory as a therapeutic intervention for A. hydrophila infection.