Objectives: The role of gut microbiota in host defense against nontuberculous mycobacterial lung disease (NTM-LD) was poorly understood.

Methods: Microbiota compositions of feces samples from patients with NTM-LD and healthy controls were compared and validated. To characterize the relationship between gut microbiota dysbiosis, compromised immunity, and NTM-LD susceptibility, mice receiving four antibiotics followed by NTM infection were used as a study model.

Results: Significant gut microbiota dysbiosis was identified in patients with NTM-LD compared with the controls. Reduced abundance of Prevotella was significantly associated with NTM-LD and its disease severity. Compromised TLR2 activation activity in feces and plasma in the NTM-LD patients was highlighted. In the antibiotics-treated mice, gut microbiota dysbiosis with reduction of TLR2 activation activity in feces, sera, and lung tissue occurred.. Transcriptomic analysis demonstrated that expressions of genes involved in immunocompromised activity[u1]  in both intestine and lung were closely associated with increased NTM-LD susceptibility. Oral administration of Prevotella enhanced TLR2 signaling, restored immune response, and ameliorated NTM-LD susceptibility. Subsequently, delivery using capsular polysaccharides from Prevotella that enhanced TLR2 activation also reduced NTM-LD susceptibility.

Conclusions: Our data highlighted the causal effect of gut microbiota dysbiosis in association with systematically compromised immunity and NTM-LD development. TLR2 activation by Prevotella or its capsular polysaccharides might help prevent NTM-LD.