The gut-lung axis and microbiome dysbiosis in non-tuberculous mycobacterial infections: immune mechanisms, clinical implications, and therapeutic frontiers.

Non-tuberculous mycobacteria (NTM) are emerging pathogens of global concern, particularly in regions with declining tuberculosis rates. This review synthesizes current evidence on the epidemiology, immune pathogenesis, and microbiome interactions underlying NTM infections. The rising incidence of NTM is driven by environmental factors, immunocompromised populations, and advanced diagnostics. Clinically, NTM manifests as pulmonary, lymphatic, skin/soft tissue, or disseminated disease, with Mycobacterium avium complex (MAC) and M. abscessus being predominant pathogens. Host immunity, particularly Th1 responses mediated by IL-12/IFN-γ and TLR2 signaling, is critical for controlling NTM, while dysregulated immunity (e.g., elevated Th2 cytokines, PD-1/IL-10 pathways) exacerbates susceptibility. Emerging research highlights the gut-lung axis as a pivotal mediator of disease, where microbiome dysbiosis-marked by reduced Prevotella and Bifidobacterium-impairs systemic immunity and promotes NTM progression. Short-chain fatty acids (SCFAs) and microbial metabolites like inosine modulate macrophage and T-cell responses, offering therapeutic potential. Studies reveal distinct airway microbiome signatures in NTM patients, characterized by enriched Streptococcus and Prevotella, and reduced diversity linked to worse outcomes. Despite advances, treatment remains challenging due to biofilm formation, antibiotic resistance, and relapse rates. This review underscores the need for microbiome-targeted therapies, personalized medicine, and longitudinal studies to unravel causal relationships between microbial ecology and NTM pathogenesis.