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. The goals of this application are to investigate how MP induce cellular changes in both intestinal epithelial cells and macrophages and to determine how these MP-induced changes in cellular pathways can lead to intestinal permeability, dysbiosis and an inflammatory state. Our preliminary data challenges the current stance of WHO that is not possible to draw any firm conclusions on MP toxicity to humans. To challenge this statement, we will utilize human intestinal organoids, primary human macrophages and animal models to understand the consequence of MP ingestion. Based on our preliminary studies, we advance a novel hypothesis that MP ingestion indeed pose a human health hazard by disrupting oxidative metabolism in both epithelial cells and macrophages 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. In aim 1, we will establish how MP contribute to intestinal permeability through cellular metabolic changes in the epithelium and gut metabolome. In Aim 2, we will determine the effects of MP on the GI tract of a susceptible host. Aim 3 will delineate the mechanism of MP modulation of human macrophage metabolism and its impact on the intestinal barrier. 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 and macrophage function and overall human health. Project Summary Page