Gut microbiota dysbiosis correlates with reduced drug exposure in patients with multidrug-resistant tuberculosis

Although systemic exposure to anti-tuberculosis agents is critical for therapeutic efficacy, substantial inter-individual variability of drug exposure persists despite standardized dosing. Emerging studies suggest that the gut microbiota may influence drug metabolism and host pharmacokinetics, yet the role of the gut microbiota in driving pharmacokinetic variability in the context of multidrug-resistant tuberculosis (MDR-TB) remains unclear. In this prospective cohort study, we aimed to examine whether pre-treatment gut microbial composition and functional capacity shape drug exposure in patients with MDR-TB. We enrolled patients with MDR-TB at designated TB medical institutions in Suzhou, Jiangsu Province. Fecal samples were collected prior to anti-tuberculosis treatment for metagenomic sequencing, and blood samples were obtained after two weeks of treatment to estimate the drug exposure levels of levofloxacin, linezolid, bedaquiline, clofazimine, and cycloserine. The relationship between gut microbiota features and drug exposure was assessed using MaAsLin2 to identify microbial species, metabolic pathways, and enzymes associated with drug metabolism. Pronounced dysbiosis, characterized by reduced alpha diversity and a decrease in anaerobic bacteria abundance accompanied by an increase in facultative anaerobes, was associated with lower plasma exposure to levofloxacin, linezolid, bedaquiline, clofazimine, and cycloserine. Metagenomic functional profiling indicated that biosynthesis pathways for amino acid and peptidoglycan were enriched in individuals with higher drug exposure, while degradation pathways for these compounds were more prevalent in those with lower exposure. Specific species positively associated with drug exposure encoded genes for the enzymes involved in the biosynthesis pathways for amino acid and peptidoglycan. Analyses demonstrate that pre-treatment dysbiosis is associated with lower systemic exposure to anti-TB drugs. These findings suggest a potential link between gut microbiota composition and drug exposure variability, though causality remains to be established. Further research is needed to determine whether microbiota-targeted strategies could influence pharmacokinetics and improve MDR-TB treatment outcomes.