Systemic inflammation and the inflammatory context of the colonic microenvironment is improved by urolithin A

Abstract Diet affects cancer risk and plant-derived polyphenols exhibit cancer-preventive properties. Walnuts are an exceptional source of polyphenolic ellagitannins, converted into urolithins by gut microflora. This clinical study examines the impact of urolithin metabolism on inflammatory markers in blood and colon polyp tissue. We evaluate the effects of walnut consumption on urinary urolithins, serum inflammatory markers and immune cell markers in polyp tissues obtained from 39 subjects. Together with detailed food frequency data, we perform integrated computational analysis of metabolomics data combined with serum inflammatory markers and spatial imaging of polyp tissues using imaging mass cytometry. LC-MS/MS analyses of urine and fecal samples identifies a widely divergent capacity to form nine urolithin metabolites in this patient population. Subjects with higher urolithin A formation exhibit lower levels of several key serological inflammatory markers, including C-peptide, sICAM 1, sIL6R, Ghrelin, TRAIL, sVEGFR2, PDGF and MCP2, alterations that are more pronounced in obese individuals for siCAM-1, ENA-78, Leptin, GLP-1 and MIP-1D. There is a significant increase in levels of PYY associated with urolithin A formation, whereas TNF-α levels show an opposite trend, recapitulated in an in vitro system with ionomycin/PMA-stimulated PBMCs. Spatial imaging of colon polyp tissues shows altered cell cluster patterns, including a significant reduction of vimentin and CD163 expression associated with urolithin A. The ability to form urolithin A is linked to inflammation, warranting further studies to understand the role of urolithins in cancer prevention.