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

ABSRTACT<i>Klebsiella pneumoniae</i> 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 the gut microbiota affects the host defenses in the respiratory system systematically, however, remain poorly understood. Here, we show that gut microbiota depletion increases susceptibility to extracellular <i>K. pneumoniae</i> 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 43 (GPCR43), enhances a macrophage's capacity to phagocytose invading <i>K. pneumoniae</i> Furthermore, SCFAs and GPR43 increase macrophage bacterial clearance by upregulating 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 <i>Lamtor2</i> in macrophages decreases their antimicrobial activity, even though mice were pretreated with exogenous SCFA supplementation.<b>IMPORTANCE</b> These observations highlight that SCFAs promote macrophage elimination of <i>K. pneumoniae</i> via a LAMTOR2-dependent signal pathway and suggest that it is possible to intervene in <i>K. pneumoniae</i> pneumonia by targeting the gut microbiota.