Program Director/Principal Investigator: Castillo, Eliseo, F PROJECT SUMMARY Plastic pollution and the breakdown of plastic materials primarily into micron-sized microplastic particles (MP) have contaminated our food and water sources, raising public health concerns. MP ingestion by humans is now an inevitable consequence of global plastic pollution and there is a critical gap in knowledge as to how MP impact human health (WHO). There is also an important gap in knowledge regarding how MP affect the major direct organ of contact, the gastrointestinal (GI) tract. The studies proposed in this grant application seek to bridge this gap in environmental health knowledge and provide insight into how MP pose a significant health risk to the general population as well as susceptible (i.e. Inflammatory Bowel Disease; IBD) individuals. Our preliminary data provides evidence chronic MP exposure affects the GI tract specifically causing gut dysbiosis, low-level intestinal inflammation, and alterations in cellular metabolism. Based on our preliminary studies, we advance a novel hypothesis that MP ingestion indeed pose a human health hazard by disrupting oxidative metabolism in epithelial cells subsequently causing intestinal permeability, dysbiosis, and an immunometabolic active state which could lead to intestinal inflammation. Additionally, we hypothesize MP ingestion pose a significant health risk to individuals that have an underlying condition such as intestinal inflammation as seen in IBD patients. The goals of this application are to investigate how MP induce cellular changes in intestinal epithelial cells and to determine how these MP-induced changes in cellular pathways can lead to intestinal permeability, dysbiosis and an inflammatory state. In aim 1, we will investigate the effects of varying doses and types of MP on intestinal permeability in a zebrafish model. In Aim 2, we will determine the mechanism behind MP induced dysbiosis and intestinal permeability. Aim 3 will delineate how an intact human intestinal tract responds to microplastics through the use of human colonoids derived from health patients as well as IBD patients. The information generated from this project would be a ground-breaking step with important long-term implications in understanding how MP can affect intestinal homeostasis through modulation of epithelial barrier function and overall human health.