ABSTRACT

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.

摘要

非结核分枝杆菌肺病 (NTM-PD) 正在成为全球健康威胁，并伴有抗生素耐药性问题。越来越多的证据表明，肠肺轴可能为针对各种传染病的宿主导向疗法提供新的候选者。然而，人们对宿主保护性免疫背景下的肠肺轴知之甚少，无法确定 NTM-PD 的新疗法。本研究旨在鉴定能够赋予 NTM-PD 肺部免疫力的肠道微生物和代谢物。通过对 NTM-PD 患者和小鼠模型血清的代谢组学分析，我们发现 NTM-PD 患者和 NTM 感染小鼠的血清中l -精氨酸水平降低。口服L-精氨酸可显着增强 NTM-PD 模型小鼠肺中产生 IFN-γ 的效应 T 细胞的扩增以及向杀菌 (M1) 巨噬细胞的转变，从而显着增强肺部抗菌活性。接受L-精氨酸处理的小鼠粪便微生物群移植的小鼠表现出增强的肺部针对 NTM-PD 的保护性宿主防御，而在用抗生素处理的小鼠中， L-精氨酸诱导的肺部宿主防御减弱。使用 16S rRNA 测序，我们进一步表明，L-精氨酸的施用导致肠道微生物群组成中双歧杆菌的富集。值得注意的是，口服假长双歧杆菌或肌苷可增强针对 NTM 感染的抗菌肺免疫防御，即使是多重耐药的临床 NTM 菌株也是如此。我们的研究结果表明，L-精氨酸诱导的肠道微生物群重塑以及假长双歧杆菌的富集，通过驱动体内保护性肠肺轴，增强了针对 NTM 感染的肺部免疫防御。