trans-Resveratrol can be catabolized by the gut microbiota to dihydroresveratrol, 3,4′-dihydroxy-trans-stilbene, lunularin, and 4-hydroxydibenzyl. These metabolites can reach relevant concentrations in the colon. However, not all individuals metabolize RSV equally, as it depends on their RSV gut microbiota metabotype (i.e., lunularin producers vs. non-producers). However, how this microbial metabolism affects the cancer chemopreventive activity of stilbenes and their microbial metabolites is poorly known. We investigated the structure–antiproliferative activity relationship of dietary stilbenes, their gut microbial metabolites, and various analogs in human cancer (Caco-2 and HT-29) and non-tumorigenic (CCD18-Co) colon cells. The antiproliferative IC₅₀ values of pterostilbene, oxy-resveratrol, piceatannol, resveratrol, dihydroresveratrol, lunularin, 3,4′-dihydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 4-hydroxy-trans-stilbene, 4-hydroxydibenzyl, 3-hydroxydibenzyl, and 4-trans-stilbenemethanol were calculated. IC₅₀ values were correlated with 34 molecular characteristics by bi- and multivariate analysis. Little or no activity on CCD18-Co was observed, while Caco-2 was more sensitive than HT-29, which was explained by their different capacities to metabolize the compounds. Caco-2 IC₅₀ values ranged from 11.4 ± 10.1 μM (4-hydroxy-trans-stilbene) to 73.9 ± 13.8 μM (dihydropinosylvin). In HT-29, the values ranged from 24.4 ± 11.3 μM (4-hydroxy-trans-stilbene) to 96.7 ± 6.7 μM (4-hydroxydibenzyl). At their IC₅₀, most compounds induced apoptosis and arrested the cell cycle at the S phase, pterostilbene at G₂/M, while 4-hydroxy-trans-stilbene and 3,4′-dihydroxy-trans-stilbene arrested at both phases. Higher Connolly values (larger size) hindered the antiproliferative activity, while a lower pKa1 enhanced the activity in Caco-2, and higher LogP values (more hydrophobicity) increased the activity in HT-29. Reducing the styrene double bond in stilbenes was the most critical feature in decreasing the antiproliferative activity. These results (i) suggest that gut microbiota metabolism determines the antiproliferative effects of dietary stilbenes. Therefore, RSV consumption might exert different effects in individuals depending on their gut microbiota metabotypes associated with RSV metabolism, and (ii) could help design customized drugs with a stilbenoid and (or) dibenzyl core against colorectal cancer.

Echinacea purpurea L. (EP) preparations are globally popular herbal supplements known for their medicinal benefits, including anti-inflammatory activities, partly related to their phenolic composition. However, regarding their use for the management of inflammation-related intestinal diseases, the knowledge about the fate of orally ingested constituents throughout the human gastrointestinal tract and the exposition of in vitro digested extracts in relevant inflammatory models are unknown. This study investigated for the first time the impact of in vitro gastrointestinal digestion (INFOGEST) on the phenolic composition and anti-inflammatory properties of EP extracts from flowers (EF), leaves (EL), and roots (ER) on IL-1β-treated human colon-derived CCD-18Co cells. Among the seven hydroxycinnamic acids identified using HPLC-UV-MS/MS, chicoric and caftaric acids showed the highest concentrations in EL, followed by EF and ER, and all extracts exerted significant reductions in IL-6, IL-8, and PGE₂ levels. After digestion, despite reducing the bioaccessibility of their phenolics, the anti-inflammatory effects were preserved for digested EL and, to a lesser extent, for EF, but not for digested ER. The lower phenolic content in digested EF and ER could explain these findings. Overall, this study emphasizes the potential of EP in alleviating intestinal inflammatory conditions and related disorders.