Mycobacterium tuberculosis infection disrupts gut and respiratory microbial communities and networks with incomplete restoration after two months of treatment.

Pulmonary tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a major global health concern. Respiratory infections can influence the gut microbiome, and vice versa, through communication between the gut and respiratory microbiome—the gut–lung axis. Yet how TB infection and treatment relate to this connection remains unclear. To investigate the associations between TB and gut–respiratory microbiome interactions, we analyzed paired gut and respiratory samples from patients with TB at baseline (TB-0) and two months after treatment (TB-trt), along with matched healthy controls (HC). Microbial communities were profiled at the species level, and integrated gut–respiratory microbial networks were constructed and compared. MTB infection altered both microbial composition and network structure. Patients with TB showed lower levels of short-chain fatty acid (SCFA)–producing species and higher levels of inflammation-associated taxa. Consistent trends emerged in the gut–respiratory networks: SCFA-producing species were central in the networks of HC and persisted in TB-trt, whereas inflammation-associated species occupied influential positions in TB-0 and remained, though less prominently, after treatment. The size and complexity of the networks also differed across groups. TB infection was accompanied by broad disruptions of the gut–respiratory microbiome, and treatment resulted in only partial restoration. Species associated with these shifts, including Bifidobacterium spp. and Sutterella wadsworthensis, have the potential to serve as TB biomarkers or as adjuncts to improve treatment outcomes, with further experimental validation required.