Abstract: Although diet and gut microbial composition have been linked to chronic respiratory diseases, these associations remain difficult to interpret because of confounding and reverse causation. The gut-lung axis provides a plausible framework for this interaction, yet direct genetic evidence is limited. Using a two-step, two-sample Mendelian randomization (MR) framework, supplemented by multivariable MR (MVMR) to adjust for pleiotropic effects and Benjamini-Hochberg false discovery rate (FDR) correction for multiple testing, we assessed the causal contributions of dietary habits and gut microbial taxa to major chronic respiratory diseases. We identified 22 dietary factors with causal effects on disease risk and 225 microbial taxa that acted as independent risk or protective contributors. Mediation analyses further showed that the effects of 12 dietary habits were transmitted through 32 specific microbial taxa. Notably, genetically predicted pork intake increased the risk of chronic obstructive pulmonary disease (COPD) (OR=10.53, 95% CI [8.54, 13.00]), an effect partly mediated by elevated abundance of CAG-485 sp002404675. In contrast, bread consumption conferred protection against asthma (OR=0.68, 95% CI [0.64, 0.72]), whereas this benefit was offset by approximately 45% through a pathway involving reduced Veillonella abundance. Collectively, these findings provide genetic support for the gut-lung axis and demonstrate that the gut microbiome functions as a causal mediator linking diet to chronic respiratory disease risk. However, since this study was based on individuals of European ancestry, caution is warranted when generalizing these causal estimates to non-European populations, such as East Asian groups. This work suggests new opportunities for microbiota-targeted prevention and therapeutic strategies.
Key words: Mendelian randomization; gut microbiome; respiratory disease; dietary; European descent populations
CLC number: R56                 Document code: A        DOI: 10.3969/j. issn.1007-7146.2026.01.005