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This study aims to investigate how urolithin A, a compound produced when gut bacteria metabolize ellagitannins (naturally occurring plant polyphenols found in foods such as walnuts, pomegranates, and berries), modulates immune cytokine production in human peripheral blood mononuclear cells (PBMCs). Findings from our prior NIH-funded walnut supplementation study (UConn Health IRB #21-167JS-1) demonstrated decreased circulating pro-inflammatory cytokines (IL-21, IL-17A, GM-CSF) following walnut consumption. While these results suggest that walnut intake and urolithin A production reduce inflammatory signaling in vivo, the underlying cellular and molecular mechanisms remain unclear. To address this knowledge gap, we will enroll 3-10 healthy adult volunteers and collect a single fasting blood sample from each participant. PBMCs will be isolated and stimulated in vitro under different conditions: unstimulated, PMA/ionomycin-stimulated, and PMA/ionomycin with urolithin A exposure. Cytokine production will be quantified by ELISA, and flow cytometry will be used to identify immune cell subsets (CD4 , CD8 , etc.) responsible for cytokine secretion. This study will be conducted independently of our NIH-funded work and will not recontact or re-enroll prior participants. The results will establish baseline PBMC cytokine responses in individuals naïve to walnut supplementation, providing a control comparison for prior findings. Additionally, exploratory analyses will compare these results to de-identified data from previously identified high urolithin A producers to assess variability in cytokine modulation. Ultimately, this research will clarify how urolithin A influences inflammatory pathways in human immune cells, providing critical mechanistic insight into the immunomodulatory effects of dietary walnut-derived metabolites.
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