Role of walnut-derived urolithins in reducing colonic inflammation in a patient cohort elucidated by an integrated omics analysis

Abstract Diet can directly affect colon health and cancer risk. For example, the polyphenolic ellagitannins (punicigalin) that are present in walnuts are converted by the microbiome to a panel of bioactive urolithin metabolites. In particular, urolithin A has been studied for its anti-inflammatory and anti-cancer properties. In this pilot clinical trial, we evaluate the effects of walnut consumption (2-oz per day) on urinary urolithins and blood serum inflammatory markers, as well as on the transcriptome of normal colon and polyp tissue in 38 healthy obese and non-obese subjects. Our in-depth computational analysis of metabolomics and proteomics data suggests that subjects with higher urolithin A formation show significantly lower levels of several key serological markers of inflammation, including C-Peptide, sICAM-1, sIL6-R, Ghrelin, TRAIL, sVEGFR2, MCP2, and Haptoglobin. Furthermore, RNA-Seq transcriptomic analysis of colon tissue taken from proximal and distal colon shows reduced inflammatory programs and activation of the KICSTOR complex in subjects with higher urolithin A formation. These studies indicate that higher urolithin A formation is linked to an anti-inflammatory response, warranting further studies to better understand the role of urolithins in the inflammatory process. Supported by grants from American Institute for Cancer Research, California Walnut Commission, and National Cancer Institute (R01 CA252045).