The respiratory microbiome in pulmonary tuberculosis: a meta-analysis reveals niche-specific microbial and functional signatures

Tuberculosis (TB) remains a major global health challenge. The close relationship between the microbiome and the host is becoming increasingly notable. While studies on the respiratory microbiome in pulmonary tuberculosis (PTB) exist, a comprehensive understanding of microbial characteristics across the entire respiratory tract is still lacking. To address this, we conducted a meta-analysis by integrating data from common and representative respiratory samples. We integrated 16S rRNA data from 11 public datasets encompassing upper respiratory tract specimens (URTs), sputum, and bronchoalveolar lavage fluid (BALF). Ecological patterns were investigated through co-occurrence networks and neutral community modeling, while taxonomic and functional analyses were conducted with QIIME2 and PICRUSt2. The respiratory microbiota in PTB exhibited dynamic variations while sharing common genera, such as Streptococcus , Prevotella , Veillonella , and Neisseria . Alpha diversity was consistently higher in PTB than in healthy controls, with BALF exhibiting the greatest microbial diversity. Several differentially abundant genera were identified among the three sample types, Serratia being almost exclusively detected in BALF. Notably, the microbial interaction network in sputum was more complex and demonstrated the best fit to the neutral community model. Functional predictions highlighted enriched pathways such as peptidoglycan maturation and ABC transporters, and Bacillus was linked to multiple metabolic pathways. Several KO functions were predicted to be more active in URTs and sputum than in BALF. Our multi-scale analysis delineates a niche-specific biogeography of the respiratory microbiome in PTB. By elucidating community assembly and microbe interplay, we position the respiratory microbiota as an active contributor to TB. This work paves the way for novel microbiota-based diagnostics and ecologically informed therapies. Importance Pulmonary tuberculosis (PTB) remains a leading cause of global mortality, yet the ecological principles shaping its respiratory microbiome are poorly understood. By integrating 16S rRNA datasets from upper and lower airway specimens, this study provides the first comprehensive meta-analysis of respiratory microbial diversity and function in PTB. We reveal distinct community structures and functional potentials among upper airways, sputum, and bronchoalveolar lavage fluid, driven by niche-specific ecological processes rather than stochastic assembly. These findings establish a baseline framework for interpreting microbial biogeography across the respiratory tract and highlight potential microbial biomarkers for site-specific monitoring and therapeutic targeting in PTB.