Lower Airway Microbial Sulfur Metabolism and Oxidative Stress in Inflammatory Lung Disease

About This Grant

Abstract. Oxidative stress is a key factor in many inflammatory airway diseases, driven by redox dysregulation. Cigarette smoke, a major contributor, induces reactive oxygen species (ROS) accumulation, disrupting redoex homeostasis and upregulating pro-inflammatory pathways. While the gut microbiome’s influence on host redox status and antioxidant capacity is well documented, the role of the lung microbiome in oxidative stress has been less clear, despite observed lower airway dysbiosis in many inflammatory diseases. Recent research, including data from us, indicates that the lung microbiome is functionally active and can directly influence the metabolic landscape of the lower airways. Enrichment of anaerobic bacteria such as Veillonella and Actinobacteria, along with metabolites like glutathione disulfide, is associated with worsening pulmonary function and symptoms in inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD). This suggests that microbial metabolites contribute to disease pathophysiology. Many oral commensal bacteria utilize sulfur-containing compounds, and their enrichment in the lower airways, observed in early-stage COPD patients, may impact the local sulfur pool. This can alter crucial sulfur compounds, including sulfur-containing amino acids, reactive sulfur species, and thiol antioxidants, which are vital for redox signaling and oxidative stress modulation. Our central hypothesis is that the aspiration of oral commensals alters sulfur metabolism and shifts sulfur compound abundance in the lungs, contributing to redox dysregulation and increased susceptibility to oxidative stress, leading to inflammation. To investigate this, we propose two specific aims: 1.) Assess if altered sulfur metabolism is associated with the enrichment of oral commensals and increased oxidative stress in the lower airways, using samples already collected from a human cohort; and 2.) Evaluate the microbial contribution to lower airway sulfur compounds and oxidative stress in a preclinical mouse model. We hypothesize that introducing these bacteria will decrease lower airway abundance of sulfate, increase total sulfide, and cause heightened oxidative stress and subsequent inflammation. This research aims to provide proof of concept for the role of the lower airway microbiome in oxidative stress injury, potentially present in early inflammatory airway diseases. Our findings will support larger prospective and longitudinal studies, which will be key to proving that these microbial metabolic pathways are active in the lower airways and amenable to targeted interventions.