Microbiota-Derived Short Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages

Klebsiella (K.) pneumoniae is a common cause of human pneumonia-derived sepsis with high morbidity and mortality. The microbiota promotes and maintains host immune homeostasis. The mechanisms by which gut microbiota affects the host defenses in respiratory system systematically, however, still remain poorly understood. Here, we show that gut microbiota-depletion increases susceptibility to extracellular K. pneumoniae infections in terms of increased bacterial burdens in lung and decreased survival rates. Oral supplementation with gut microbiota-derived short chain fatty acids (SCFAs), subsequently activating G-protein-coupled receptor GPCR43, enhances macrophages capacity of phagocytosis of invading K. pneumoniae. Furthermore, SCFAs/GPR43 increases macrophages bacterial clearance by up-regulating LAMTOR2, which is further identified as an antibacterial effector and elucidated to facilitate phagosome-lysosome fusion and extracellular signal- regulated kinase (ERK) phosphorylation. Lastly, conditional ablation of Lamtor2 in macrophages decreases the antimicrobial activity although mice are pre-treated with exogenous SCFAs supplementation.