Integrative analysis of the intestinal metabolome of childhood asthma

Background: The intestinal metabolome reflects the biological consequences of diverse exposures and might provide insight into asthma pathophysiology. Objective: We sought to perform an untargeted integrative analysis of the intestinal metabolome of childhood asthma in this ancillary study of the Vitamin D Antenatal Asthma Reduction Trial. Methods: Metabolomic profiling was performed by using mass spectrometry on fecal samples collected from 361 three-year-old subjects. Adjusted logistic regression analyses identified metabolites and modules of highly correlated metabolites associated with asthma diagnosis by age 3 years. Sparse canonical correlation analysis identified associations relevant to asthma between the intestinal metabolome and other omics'': the intestinal microbiome as measured by using 16S rRNA sequencing, the plasma metabolome as measured by using mass spectrometry, and diet as measured by using food frequency questionnaires. Results: Several intestinal metabolites were associated with asthma at age 3 years, including inverse associations between asthma and polyunsaturated fatty acids (adjusted logistic regression beta = -6.3; 95% CI, -11.3 to -1.4; P = .01) and other lipids. Asthma-associated intestinal metabolites were significant mediators of the inverse relationship between exclusive breast-feeding for the first 4 months of life and asthma (P for indirect association = .04) and the positive association between a diet rich in meats and asthma (P = .03). Specific intestinal bacterial taxa, including the family Christensenellaceae, and plasma metabolites, including gamma-tocopherol/beta-tocopherol, were positively associated with asthma and asthma-associated intestinal metabolites. Conclusion: Integrative analyses revealed significant interrelationships between the intestinal metabolome and the intestinal microbiome, plasma metabolome, and diet in association with childhood asthma. These findings require replication in future studies.