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Nontuberculous mycobacterial pulmonary diseases (NTM-PDs) are emerging as global health threats with issues of antibiotic resistance. Accumulating evidence suggests that the gut–lung axis may provide novel candidates for host-directed therapeutics against various infectious diseases. However, little is known about the gut–lung axis in the context of host protective immunity to identify new therapeutics for NTM-PDs. This study was performed to identify gut microbes and metabolites capable of conferring pulmonary immunity to NTM-PDs. Using metabolomics analysis of sera from NTM-PD patients and mouse models, we showed that the levels of l-arginine were decreased in sera from NTM-PD patients and NTM-infected mice. Oral administration of l-arginine significantly enhanced pulmonary antimicrobial activities with the expansion of IFN-γ-producing effector T cells and a shift to microbicidal (M1) macrophages in the lungs of NTM-PD model mice. Mice that received fecal microbiota transplants from l-arginine-treated mice showed increased protective host defense in the lungs against NTM-PD, whereas l-arginine-induced pulmonary host defense was attenuated in mice treated with antibiotics. Using 16S rRNA sequencing, we further showed that l-arginine administration resulted in enrichment of the gut microbiota composition with Bifidobacterium species. Notably, oral treatment with either Bifidobacterium pseudolongum or inosine enhanced antimicrobial pulmonary immune defense against NTM infection, even with multidrug-resistant clinical NTM strains. Our findings indicate that l-arginine-induced gut microbiota remodeling with enrichment of B. pseudolongum boosts pulmonary immune defense against NTM infection by driving the protective gut–lung axis in vivo.
Young Jae Kim,June-Young Lee,Jae Jin Lee,Sang Min Jeon
Hyungjin Eoh,Jin-Woo Bae,Eun-Kyeong Jo
Young Jae Kim,June-Young Lee,Jae Jin Lee,Sang Min Jeon,Prashanta Silwal,In Soo Kim,Hyeon Ji Kim,Cho Rong Park,Chaeuk Chung,Jeong Eun Han,Jee-Won Choi,Euon Jung Tak,Ji-Ho Yoo,Su-Won Jeong,Do-Yeon Kim,Warisa Ketphan,Su-Young Kim,Byung Woo Jhun,Jake Whang,Jin-Man Kim,Hyungjin Eoh,Jin-Woo Bae,Eun-Kyeong Jo