Intestinal epithelial cells (IECs) are central regulators of intestinal homeostasis and organismal well-being. In response to infection or injury, intestinal epithelial stem cells (ISCs) alter their differentiation to promote host-protective inflammation in the epithelium. However, intestinal epithelial inflammation must be tightly regulated to prevent pathology. Type 2 intestinal inflammation occurs during food allergy and parasitic helminth infection that together cause substantial morbidity worldwide. In this context, bioactive lipids are released locally and lipid receptor expression is dynamically regulated, perfectly positioning lipids to fine tune IEC activities. However, how lipids regulate Type 2 epithelial inflammation is poorly defined, representing a gap in our understanding of how intestinal homeostasis is restored following allergy or worm infection. In intestinal Type 2 inflammation, IECs sense stimuli and release alarmins that activate immune cells to secrete the cytokine IL-13, which acts on ISCs to promote their differentiation to secretory goblet and tuft cells. Studies from our laboratory have recently shown that CRTH2, a receptor for the bioactive lipid prostaglandin D2 (PGD2), is expressed in murine and human IECs and enriched in ISCs. CRTH2-deficient ISCs were more likely to differentiate into goblet cells in vitro. PGD2, dependent on CRTH2, counteracted effects of IL-13 on murine small intestine IECs in vitro and in vivo, suppressing goblet cell differentiation during infection with a parasitic helminth. Finally, CRTH2-deficient mice retained goblet cell hyperplasia and increased barrier permeability after the resolution of Type 2 immune activation. Based on these data, we hypothesize that PGD2 acts on CRTH2+ ISCs to return the intestine to homeostasis after a Type 2 inflammatory event and to shape the IEC response to new stimuli. To test this idea, we propose 2 Aims. Aim 1 includes mechanistic studies that will test if PGD2 suppresses ISC differentiation to secretory lineages in response to Type 2 cytokines. Aim 1 will use a novel CRTH2-reporter mouse to identify PGD2-responsive IECs and will test how the PGD2-CRTH2 pathway affects murine and human ISC biology. Aim 2 includes studies that assess the biological significance of PGD2-CRTH2-mediated suppression of IEC responses. Aim 2 will test how PGD2 and CRTH2 affect barrier function and homeostasis and epigenetically program ISCs after Type 2 inflammation and how IEC CRTH2 deficiency during Type 2 inflammation impacts intestinal repair and pathology during a subsequent, acute or chronic inflammatory event. These studies are essential for understanding how PGD2 and CRTH2 aid in restoring gut homeostasis after Type 2 inflammation and will inform the use of existing CRTH2 modulators and other drugs that target lipids in the treatment of intestinal inflammatory disorders.