Metabolic regulation protects mice against Klebsiella pneumoniae lung infection

Abstract

Purpose: Klebsiella pneumoniae-caused pneumonia is a risk factor for development of lung injury. However, the current clinical isolates of K. pneumoniae are mostly multidrug-resistance and thus must be addressed with new treatments. One ideal approach is to enhance the innate immunity of the infected host through metabolic modulators. Materials and Methods: We used GC/MS-based metabolomics to profile the metabolomes among Control, Dead and Survival groups. The key metabolites were administrated in mice, and the bacterial loads in lung and survival were measured. The effect of the key metabolites on macrophage phagocytosis was determined by flow cytometry. Results: Compared with the mice that compromised from K. pneumoniae lung infection, mice that survived the infection displayed the varied metabolomic profile. The differential analysis of metabolome showed D-Glucose, Glutamine, L-Serine, Myo-inositol, Ethanedioic acid and Lactic acid related to the host surviving a K. pneumoniae lung infection. Further pathway enrichment analysis proposed that valine, leucine and isoleucine biosynthesis involved in outcome of lung infection. The follow-up data showed that exogenous L-Serine, L-Valine and L-Leucine could decline the load of K. pneumoniae in infected lung and increases the mouse survival. More interestingly, L-Serine, L-Valine and L-Leucine also were able to promote macrophage phagocytosis that is the natural way to promote hosts to clear lung pathogens.Conclusions: Our study establishes a novel strategy of identifying metabolic modulator from surviving host and emphasizes the feasibility of employing the metabolic modulator as a therapy for K. pneumoniae lung infection.