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

ABSRTACT Klebsiella 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 the gut microbiota affects the host defenses in the respiratory system systematically, however,...

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Autores principales:	Ting Wu, Hongru Li, Cong Su, Fangming Xu, Guangwei Yang, Kaili Sun, Mengran Xu, Na Lv, Bao Meng, Yanyan Liu, Lifen Hu, Yan Liu, Yufeng Gao, Heng Wang, Yanhu Lan, Dexiang Xu, Jiabin Li
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	K. pneumoniae gut microbiota immune responses SCFAs LAMTOR2 mechanisms Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c4284f90add142ebb3e54f0359dc9604
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spelling	oai:doaj.org-article:c4284f90add142ebb3e54f0359dc96042021-12-02T19:46:19ZMicrobiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages10.1128/mSystems.00587-202379-5077https://doaj.org/article/c4284f90add142ebb3e54f0359dc96042020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00587-20https://doaj.org/toc/2379-5077ABSRTACT Klebsiella 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 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 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 43 (GPCR43), enhances a macrophage’s capacity to phagocytose invading K. pneumoniae. 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 Lamtor2 in macrophages decreases their antimicrobial activity, even though mice were pretreated with exogenous SCFA supplementation. IMPORTANCE These observations highlight that SCFAs promote macrophage elimination of K. pneumoniae via a LAMTOR2-dependent signal pathway and suggest that it is possible to intervene in K. pneumoniae pneumonia by targeting the gut microbiota.Ting WuHongru LiCong SuFangming XuGuangwei YangKaili SunMengran XuNa LvBao MengYanyan LiuLifen HuYan LiuYufeng GaoHeng WangYanhu LanDexiang XuJiabin LiAmerican Society for MicrobiologyarticleK. pneumoniaegut microbiotaimmune responsesSCFAsLAMTOR2mechanismsMicrobiologyQR1-502ENmSystems, Vol 5, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	K. pneumoniae gut microbiota immune responses SCFAs LAMTOR2 mechanisms Microbiology QR1-502
spellingShingle	K. pneumoniae gut microbiota immune responses SCFAs LAMTOR2 mechanisms Microbiology QR1-502 Ting Wu Hongru Li Cong Su Fangming Xu Guangwei Yang Kaili Sun Mengran Xu Na Lv Bao Meng Yanyan Liu Lifen Hu Yan Liu Yufeng Gao Heng Wang Yanhu Lan Dexiang Xu Jiabin Li Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages
description	ABSRTACT Klebsiella 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 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 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 43 (GPCR43), enhances a macrophage’s capacity to phagocytose invading K. pneumoniae. 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 Lamtor2 in macrophages decreases their antimicrobial activity, even though mice were pretreated with exogenous SCFA supplementation. IMPORTANCE These observations highlight that SCFAs promote macrophage elimination of K. pneumoniae via a LAMTOR2-dependent signal pathway and suggest that it is possible to intervene in K. pneumoniae pneumonia by targeting the gut microbiota.
format	article
author	Ting Wu Hongru Li Cong Su Fangming Xu Guangwei Yang Kaili Sun Mengran Xu Na Lv Bao Meng Yanyan Liu Lifen Hu Yan Liu Yufeng Gao Heng Wang Yanhu Lan Dexiang Xu Jiabin Li
author_facet	Ting Wu Hongru Li Cong Su Fangming Xu Guangwei Yang Kaili Sun Mengran Xu Na Lv Bao Meng Yanyan Liu Lifen Hu Yan Liu Yufeng Gao Heng Wang Yanhu Lan Dexiang Xu Jiabin Li
author_sort	Ting Wu
title	Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages
title_short	Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages
title_full	Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages
title_fullStr	Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages
title_full_unstemmed	Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages
title_sort	microbiota-derived short-chain fatty acids promote lamtor2-mediated immune responses in macrophages
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/c4284f90add142ebb3e54f0359dc9604
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Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages

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