Epidemiological evidence has clarified circulating metabolite-respiratory pathology associations, but their fundamental causal mechanisms remain unclear.

A systematic two-sample Mendelian randomization analysis was performed to explore causal relationships between 1400 plasma metabolites and three major respiratory disorders ((chronic obstructive pulmonary disease (COPD), pulmonary tuberculosis (PTB), and asthma)) using genome-wide association studies (GWASs) data. Inverse variance-weighted (IVW) regression was the primary method, with MR-Egger and weighted median as supplements. Rigorous sensitivity analyses were performed using Cochrane's Q test, MR-Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test, leave-one-out analysis.

27 plasma metabolites showed significant causal associations with the three diseases. Notably, O-cresol sulfate levels were positively associated with an increased risk of asthma in both adults and children. In contrast, elevated levels of α-ketoglutarate were linked to a reduced asthma risk. O-cresol sulfate increased asthma risk while α-ketoglutarate reduced it; 3-hydroxy-2-methylpyridine sulfate elevated COPD risk, and 16α-hydroxy-DHEA-3-sulfate exerted a protective effect on both COPD and PTB, with N-methylhydroxyproline increasing PTB risk. Sensitivity analyses confirmed no bias from weak instruments, horizontal pleiotropy or reverse causality.Conclusion: Our study provides robust evidence supporting causal associations between 27 plasma metabolites and respiratory disease risk. The identified metabolites and their related metabolic pathways may serve as clinically actionable biomarkers for disease screening and prevention.