UCLA

It is estimated that air pollution kills 7 million people every year, and an estimated 90% of the global population live in areas with high levels of pollutants exceeding the WHO recommendations. There is a strong body of literature demonstrating the adverse effects of ambient air pollution on human health. Air pollution is a varied mix of toxic gaseous and particulate compounds, but clinical and epidemiological evidence support the particulate phase compounds as main contributors to adverse health outcomes. Our studies investigate a novel, potential mechanism linking ultrafine particles (UFPs) with intestinal inflammation. This study would be first to report not only the kinetics of microbiome effects, but also regional and longitudinal microbiome differences caused by UFP inhalation, a more physiologically relevant route of administration. We have assessed both the small intestine and colon, as well as both the mucosal and luminal microbiome. We combined controlled exposure using UFPs, the purportedly toxic component of PM, and inhalation to investigate the impact of air pollution on the gut microflora. Furthermore, our use of controlled chambers and re-aerosolization of PM selecting for UFP-range particulate matter represents significant advances in PM toxicity research. The present study leverages physiologically relevant UFP inhalation exposure, metabolic mouse models, acute and chronic IBD models, as well as microbiome bioinformatics analysis. In this dissertation, Chapter 1 discusses the basis for the need to study toxicological effects of ultrafine air particulates and lay the foundation for the relationship between air pollution, the microbiome, and inflammatory bowel disease. Chapter 2 describes microbiome effects from UFP exposure on hyperlipidemic and normolipidemic mice as well as in-vitro confirmation of UFP bioactivity. Chapter 3 characterizes the effect of UFP exposure on two acute chemically-induced mouse models of colitis. Chapter 4 discusses microbiome and inflammatory effects of UFP exposure in a genetically-modified, spontaneous chronic IBD mouse model, IL-10-/-. The work is a collaborative effort between both the Jacobs and Araujo labs at UCLA, with the assistance of the Engineering students from USC led by Dr. Constantinos Sioutas. Our studies offer insight into a potential mechanism that may explain the role of air pollution as an environmental factor contributing to rising incidence of IBD. This study is significant because we evaluate for the first time to our knowledge the effects of pulmonary UFP exposure on gut microbiome composition in IBD murine models.