Lung microbial dysregulation and TNF inhibition are associated with worsened nontuberculous mycobacterial lung disease

Introduction Nontuberculous mycobacteria (NTM) are ubiquitous bacteria that cause a spectrum of diseases, most notably pulmonary disease (NTMPD). The host factors contributing to the heightened susceptibility and severity of NTMPD in elderly individuals are poorly understood. Prior studies have reported increased incidence of NTMPD in individuals receiving immune modulatory biologics such as anti-TNF and JAK-STAT inhibitors. Moreover, we recently described that age-related changes in the lung microbiome, notably the loss of a main commensal Tropheryma species, may contribute to increased severity. Therefore, in this study we explore the hypothesis that TNF-inhibition and a disrupted lung microbiome are key factors associated with poor NTMPD outcomes. Methods Young (4–7 years old) rhesus macaques were either pretreated with: (1) nebulized amikacin and vancomycin to disrupt the lung microbiome; (2) the TNF inhibitor Inflectra to suppress Th1 responses; or (3) left untreated. Animals were subsequently inoculated with M. avium subsp. hominissuis (MAH) in the right lung. Bacterial load, radiographic changes, immune responses, and microbiome composition were monitored longitudinally. Results and discussion Antibiotic-treated animals experienced significant microbiome compositional shifts including the depletion of Tropheryma from the lung microbiome. One antibiotic-treated animal developed and resolved cavitary disease after the lung microbiome returned to homeostasis. One Inflectra-treated animal developed chronic granulomatous disease. No control animals showed granulomas. These data suggest that lung microbiome disruption and TNF inhibition are associated with increased susceptibility to NTM granulomatous disease.