PROJECT SUMMARY This grant proposal, Microbiome Targeted Treatment of WTC- Lung Injury, builds upon the success of the Food Intake Restriction for Health Outcome Support and Education (FIREHOUSE) trial, a groundbreaking dietary intervention targeting improved lung health in firefighters exposed to World Trade Center dust. Preliminary findings identified a correlation between weight loss and elevated levels of bacteroides ovatus, associated with enhanced pulmonary function. This proposal aims to delve deeper into the potential of bacteriotherapy by investigating antimicrobial peptides and inflammatory proteins in sera collected during the FIREHOUSE trial. Additionally, a murine model will be developed to further explore the therapeutic potential of bacteriotherapy using bacteroides ovatus (b. ovatus). We propose 2 AIMs to explore the hypothesis that b. ovatus can be potentially used as bacteriotherapy to ameliorate the persistent lung disease in WTC-exposed firefighters. AIM1 will identify the inflammatory and health profile changes in those with higher abundance of b. ovatus compared to those with lower abundance. AIM2 will explore the potential of B. ovatus as a therapeutic supplement for PM-induced lung disease using a murine model. Through meticulous analysis of collected specimens and innovative murine models, we aspire to unravel the intricate mechanisms of the microbiome and its role in promoting pulmonary health. We will assay for IL-17 and RAGE, key mediators in particulate matter-related disease, and inflammation in pulmonary and gastrointestinal disease. This research is significant in contributing to the burgeoning field of microbiome studies and may provide crucial insights for developing targeted interventions and therapeutic strategies. By elucidating these pathways, we aim to mitigate the impact of World Trade Center-lung injury on firefighters and similarly exposed populations. The proposed K01 funding not only supports the investigation of this vital health condition but also facilitates the continued professional development of the principal investigator, ensuring the longevity and impact of WTC research. Data generated by this proposal will provide novel insights into central mediators that control the interactions between PM, microbiome, and metabolomic health. We will focus on b. ovatus, but will generate data that can be generalized to identify other related pathways that may be important in other exposed cohorts. These studies will bring us closer to development of bacteriotherapy for lung health. Woven throughout this proposal is a continued training component of advanced bioinformatics and translational techniques that will allow me to seek further independent funding to study the potential of bacteriotherapy in lung disease, a topic of considerable and urgent importance.