Saturday, December 21, 2024
12/21/2024
PROJECT SUMMARY: In the context of the gut barrier, Vitamin A metabolite retinoic acid (RA) is central to immune homeostasis in the gut, coordinating both innate and adaptive immunity. Vitamin A directly regulates proliferation and differentiation in the intestinal epithelium, which is crucial for maintaining optimal gut barrier. Our work in the last funding cycle revealed that gut bacteria are crucial in regulating how dietary vitamin A is processed in the intestinal mucosa. Specifically, we showed for the first time that commensal bacteria suppress RA synthesis in the gut by modulating the intestinal epithelium’s vitamin A metabolic gene rdh7. Our findings delineated the previously unknown impact of commensal bacteria on the vitamin A homeostasis, thus opening up questions regarding the role of microbially regulated RA synthesis on mucosal immunity and epithelial regeneration. Using a mouse model that constitutively expresses rdh7 gene in IECs we now show that dysregulated epithelium intrinsic RA synthesis is detrimental to host and results in increased number of IFNγ producing T-cells and enhanced susceptibility to experimental colitis. We find that overexpressing Rdh7 gene in IECs results in decreased proliferation and repair upon damage compared to control mice. Additionally, our work establishes that commensal bacteria in the gut possess vitamin A metabolic activity and significantly increase RA concentration in the gut lumen. Precise role of bacteria derived RA on epithelial barrier and intestinal immune homeostasis remains to be discovered. We hypothesize that the host and bacteria collaborate to generate an RA gradient that supports optimal intestinal epithelium renewal and immune homeostasis. In this grant proposal we will:1) determine the mechanism by which IEC intrinsic RA regulates T-cell effector responses and whether impact of IEC intrinsic RA is restricted to T-cells residing in close proximity to IECs. Additionally, we will evaluate the role of IEC intrinsic rdh7 expression in regulating IFNγ dependent immunity against intestinal pathogens and infection burden (Aim1), 2) delineate the mechanism by which RA regulates stem cells and assess the role of rdh7 expression in remodeling stem cell niche during infection via interactions with underlying immune cells (Aim2), and 3) metabolic difference in ability of gut bacteria to produce RA from pro-form vs pre-form vitamin A to probe the exclusive role of gut-bacteria sourced RA on host physiology(Aim3). Our work will deliver an unprecedented and comprehensive understanding of the role of bacterially regulated vitamin A homeostasis in the host. Our Aims will generate new paradigms for investigating and understanding vitamin A-mediated ISC remodeling. Our work will provide microbial and dietary interventions that could be therapeutic for diseases with an underlying defect in ISC regeneration and mucosal immunity.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).