Selenium Supplementation for Moderate-Severe Ulcerative Colitis Flares - Selenium deficiency is common in ulcerative colitis (UC), even during periods of quiescent disease, and deficiency of selenium in UC is associated with an increased risk for disease flares and need for colectomy. Recent evidence demonstrates that coloncytes can directly uptake selenium and use it to synthesize selenoprotein-P (SELENOP), which is secreted basolaterally into the colonic microenvironment. Myeloid specific loss of SELENOP, but not epithelial specific loss of SELENOP, results in increased susceptibility to induction of colitis. Through large integrated human single-cell and spatial transcriptomics datasets, we observed an inverse association between myeloid SELENOP expression and disease activity in UC. In a prospectively recruited cohort of biologic treated moderate-severe UC patients, non-responders to IL23 blockade had significantly lower myeloid SELENOP expression and increased myeloid ferroptosis. These myeloid transcriptional changes for SELENOP and ferroptosis were not seen for non-responders to anti-TNF or anti-trafficking therapy. In-vitro data confirmed effects of selenium exposure for increasing anti-ferroptosis pathways in myeloid cells. Trace element profiling of human tissue and blood confirmed selenium deficiency in active UC patients in colonic tissue biopsies, but not blood, demonstrating a need for colonic microenvironmental selenium supplementation. A small prior placebo-controlled clinical trial in mild-moderate UC demonstrated improved symptom activity with selenium supplementation, but proof-of-concept data is lacking in moderate-severe UC. We aim to complete a proof-of- concept clinical trial for selenium supplementation in moderate-severe UC patients starting advanced biologic or small molecule therapy. Using human biospecimens from this trial, we aim to develop an exposure-response model for selenium and study changes in myeloid ferroptosis with selenium supplementation in UC. The data generated from this proposal will be used to design and power a larger multi-center clinical trial to confirm clinical effects of selenium supplementation in moderate-severe UC and establish whether this clinical effect is greater for patients being treated with anti-IL23 biologics.
