EVALUATING THE ROLE OF THE HUMAN RESPIRATORY MICROBIOME AND METABOLOME IN THE RESPONSE TO WOOD SMOKE EXPOSURE

The increasing global exposure to wildfire smoke, consistently linked to adverse respiratory outcomes, poses a significant and growing public health concern affecting both healthy and vulnerable populations. Therefore, understanding the mechanisms underlying the respiratory response to wildfire smoke is imperative for protecting respiratory health and developing novel therapeutic strategies against the adverse effects induced by smoke inhalation.In this study, we evaluated the microbiome and metabolome response of healthy individuals (n = 54) subjected to controlled exposure to wood smoke (500 µ/m3 for 2 hours). Induced sputum samples were collected at baseline and at two post-exposure time points (6 hours post-exposure (hpe) and 24 hpe). Microbiome analysis involved sequencing the bacterial 16S rRNA gene, while metabolomics analysis employed a non-targeted approach using a liquid chromatography-mass spectrometry (LC-MS/MS) workflow. Finally, microbiome and metabolome data were integrated with paired inflammatory cell and proteomic data following a multi-omics approach.Our findings revealed that short-term exposure to wood smoke causes respiratory dysbiosis and dynamic metabolic changes. Microbiome analysis revealed the enrichment of pathogenic bacteria (Haemophilus influenzae and Selenomonas) and a decrease in commensals (Neisseria cinerea and Porphyromonas catoniae). Furthermore, metabolomics analysis revealed a dynamic response to wood smoke, as well as the presence of bacteria-derived metabolites, including D-alanyl-alanine and various acyl-homoserine lactones. Metabolomics analysis also uncovered a differential response based on baseline levels of 8-hydroxy-2’-deoxyguanosine, a marker of oxidative damage. Multi-omics integration revealed that at 24 hpe, airways undergo an overall anti-inflammatory or immune resolution response, driven by macrophages that are strongly correlated with proteins associated with an M2-like phenotype and commensal bacterial species (Neisseria oralis). This analysis also detected core and smoke-resilient bacteria-metabolite interactions, which could be characteristic of respiratory health.Together, these findings provide novel insights into the role of the respiratory microbiome in the host response to wood smoke. This study emphasizes the significance of considering the respiratory microbiome in inhalational toxicology studies, as well as the benefits of employing integrative approaches to gain a more comprehensive understanding of complex systems.