A Screening of native (poly)phenols and gut-related metabolites on 3D HCT116 spheroids reveals gut health benefits of a flavan-3-ol metabolite

Scope: Epidemiological evidence suggests that a reduced risk of colorectalcancer (CRC) is correlated with high consumption of fruits and vegetables,which are major sources of fiber and phytochemicals, such as flavan-3-ols.However, it remains unknown how these phytochemicals and their specificgut-related metabolites may alter cancer cell behavior.Methods and results: A focused screening using native (poly)phenols and gutmicrobial metabolites (GMMs) on 3D HCT116 spheroids is carried out usinga high-throughput imaging approach. Dose–responses, IC50, and long-termexposure are calculated for the most promising native (poly)phenols andGMMs. As a result, this research shows that (poly)phenol catabolites mayplay a key role in preventing cancer propagation. Indeed, μM concentrationlevels of (4R)-5-(3ʹ,4ʹ-dihydroxyphenyl)--valerolactone significantly decreasespheroid size at early stages of spheroid aggregation and gene expression ofmatrix metalloproteinases.Conclusion: A chronic exposure to (4R)-5-(3ʹ,4ʹ-dihydroxyphenyl)--valerolactone may lead to a reduced CRC risk. Daily intake of monomeric,oligomeric, and polymeric flavan-3-ols may increase the colonicconcentrations of this metabolite, and, in turn, this compound may act locallyinteracting with intestinal epithelial cells, precancerous and cancer cells.