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• Chestnut shells extract valorized as a promising nutraceutical ingredient. • Total phenolics improved during in-vitro digestion. • Hydroxybenzoic, phenylpropanoic, and phenylacetic acids identified upon digestion. • Proven bioactivity on α-amylase, acetylcholinesterase, and antioxidant enzymes. • Multivariate analysis predicted the role of phenolics in extract bioactivity. Chestnut (Castanea sativa) shells (CS) are an undervalued antioxidant-rich by-product. This study explores the impact of in-vitro digestion on the bioaccessibility, bioactivity, and metabolic profile of CS extract prepared by Supercritical Fluid Extraction, aiming its valorization for nutraceutical applications. The results demonstrated significantly (p < 0.05) lower phenolic concentrations retained after digestion (38.57 µg gallic acid equivalents/mg dry weight (DW)), reaching 30% of bioaccessibility. The CS extract showed antioxidant/antiradical, hypoglycemic, and neuroprotective properties after in-vitro digestion, along with upmodulating effects on antioxidant enzymes activities and protection against lipid peroxidation. The metabolic profile screened by LC-ESI-LTQ-Orbitrap-MS proved the biotransformation of complex phenolic acids, flavonoids, and tannins present in the undigested extract (45.78 µg/mg DW of total phenolic concentration) into hydroxybenzoic, phenylpropanoic, and phenylacetic acids upon digestion (35.54 µg/mg DW). These findings sustain the valorization of CS extract as a promising nutraceutical ingredient, delivering polyphenols with proven bioactivity even after in-vitro digestion. [ABSTRACT FROM AUTHOR]

[Display omitted] • Chestnut shells extracted by SFE valorized as a potential nutraceutical ingredient. • Neuroprotective, hypoglycemic, and hypolipidemic effects proved. • Untargeted metabolic profile revealed 60 % lipids and 30 % phenolics in permeates. • Ellagic acid and caffeic acid metabolites quantified after intestinal permeation. • Enrichment analysis identified 29 metabolic pathways. The health benefits of chestnut (Castanea sativa) shells (CSs) have been ascribed to phytochemicals, mainly phenolic compounds. Nevertheless, an exhaustive assessment of their intestinal absorption is vital considering a possible nutraceutical application. This study evaluated the bioactivity of CSs extract prepared by Supercritical Fluid Extraction and untargeted metabolomic profile upon in-vitro intestinal permeation across a Caco-2/HT29-MTX co-culture model. The results demonstrated the neuroprotective, hypoglycemic, and hypolipidemic properties of CSs extract by inhibition of acetylcholinesterase, α-amylase, and lipase activities. The untargeted metabolic profiling by LC-ESI-LTQ-Orbitrap-MS unveiled almost 60 % of lipids and 30 % of phenolic compounds, with 29 metabolic pathways indicated by enrichment analysis. Among phenolics, mostly phenolic acids, flavonoids, and coumarins permeated the intestinal barrier with most metabolites arising from phase I reactions (reduction, hydrolysis, and hydrogenation) and a minor fraction from phase II reactions (methylation). The permeation rates enhanced in the following order: ellagic acid < o -coumaric acid < p -coumaric acid < ferulaldehyde ≤ hydroxyferulic acid ≤ dihydroferulic acid < ferulic acid < trans -caffeic acid < trans -cinnamic acid < dihydrocaffeic acid, with better outcomes for 1000 µg/mL of extract concentration and after 4 h of permeation. Taken together, these findings sustained a considerable in-vitro intestinal absorption of phenolic compounds from CSs extract, enabling them to reach target sites and exert their biological effects. [ABSTRACT FROM AUTHOR]