Arginine-mediated gut microbiome remodeling promotes host pulmonary immune defense against nontuberculous mycobacterial infection

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 .

Characterizing microbiota and metabolomics analysis to identify candidate biomarkers in lung cancer

“…Arginine is present in the precursors of various organic compounds such as nitric oxide (NO), ornithine and myosine, which have huge impacts on immune cell biology, especially macrophage, dendritic cell and T cell immunobiology (32,33). Kim et al reported that arginineinduced changes in gut microbiota enhanced host lung immunity to nontuberculous mycobacterial infection, and that indicated that arginine might plays a protective role in lungs (34). Taurine, as conditionally essential amino acid of human, has multiple physiological functions, including the regulation of neural conduction, participating in endocrine activities, immunity enhancement, and strengthening the antioxidant capacity of cytomembrane (35).…”

Inosine: A bioactive metabolite with multimodal actions in human diseases

“…In addition, several recent studies have suggested a link between inosine and antimicrobial function during bacterial infection. Our recent study showed that inosine, as a metabolite of B. pseudolongum , contributes to antimicrobial responses in mouse models with Mycobacteroides abscessus (Mabc) infection ( Kim et al, 2022 ). Interestingly, ʟ-arginine administration of Mabc-infected mice led to gut microbiota remodeling toward enrichment of B. pseudolongum , which promoted effector T-cell responses with IFN-γ activation and inducible nitric oxide synthase (iNOS) expression, indicating a Th1-mediated M1 shift ( Kim et al, 2022 ).…”

“…Our recent study showed that inosine, as a metabolite of B. pseudolongum , contributes to antimicrobial responses in mouse models with Mycobacteroides abscessus (Mabc) infection ( Kim et al, 2022 ). Interestingly, ʟ-arginine administration of Mabc-infected mice led to gut microbiota remodeling toward enrichment of B. pseudolongum , which promoted effector T-cell responses with IFN-γ activation and inducible nitric oxide synthase (iNOS) expression, indicating a Th1-mediated M1 shift ( Kim et al, 2022 ). Importantly, ʟ-arginine administration upregulated the serum level of inosine in mice infected with Mabc, and inosine treatment exhibited a similar protective phenotype as observed in ʟ-arginine-treated conditions in the context of NTM infections ( Sun et al, 2020 ; Kim et al, 2022 ).…”

“…Interestingly, ʟ-arginine administration of Mabc-infected mice led to gut microbiota remodeling toward enrichment of B. pseudolongum , which promoted effector T-cell responses with IFN-γ activation and inducible nitric oxide synthase (iNOS) expression, indicating a Th1-mediated M1 shift ( Kim et al, 2022 ). Importantly, ʟ-arginine administration upregulated the serum level of inosine in mice infected with Mabc, and inosine treatment exhibited a similar protective phenotype as observed in ʟ-arginine-treated conditions in the context of NTM infections ( Sun et al, 2020 ; Kim et al, 2022 ). It was previously reported suberic acid is produced by B. pseudolongum ( Sun et al, 2020 ); however, treatment of Mabc-infected mice with suberic acid did not show any protective immune responses during Mabc infection.…”

Central carbon metabolism remodeling as a mechanism to develop drug tolerance and drug resistance in Mycobacterium tuberculosis

“…Recently, Kim et al. integrated metabolomics and transcriptomics profiles of sera from nontuberculous mycobacterial (NTM) disease patients and identified the NTM infection-mediated impact on the host gut microbiome, serum metabolome, and immune defense against NTM infection ( Kim et al., 2022 ). Overlaying the data from other omics studies onto the metabolic landscape is extremely useful to build a quantitative and integrative model of a target biological system.…”