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 colorectal cancer (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 specific gut‐related metabolites may alter cancer cell behavior. Methods and results A focused screening using native (poly)phenols and gut microbial metabolites (GMMs) on 3D HCT116 spheroids is carried out using a high‐throughput imaging approach. Dose–responses, IC50, and long‐term exposure are calculated for the most promising native (poly)phenols and GMMs. As a result, this research shows that (poly)phenol catabolites may play a key role in preventing cancer propagation. Indeed, µM concentration levels of (4R)‐5‐(3′,4′‐dihydroxyphenyl)‐γ‐valerolactone significantly decrease spheroid size at early stages of spheroid aggregation and gene expression of matrix metalloproteinases. Conclusion A chronic exposure to (4R)‐5‐(3′,4′‐dihydroxyphenyl)‐γ‐valerolactone may lead to a reduced CRC risk. Daily intake of monomeric, oligomeric, and polymeric flavan‐3‐ols may increase the colonic concentrations of this metabolite, and, in turn, this compound may act locally interacting with intestinal epithelial cells, precancerous and cancer cells. This work explores the potential of native phytochemicals and gut microbial metabolites in promoting gut health. 3D HCT116 spheroids are first exposed to (poly)phenols and (poly)phenols metabolized by the gut microbiota. Secondly, by combining high‐throughput imaging techniques and transcriptional profiling, this research shows that a flavan‐3‐ol metabolite may play a pivotal role in promoting gut health.