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Knowledge about the fate of beebread bioactive compounds throughout the human gastrointestinal tract are scarce. The present study aimed at assessing the effects of gastrointestinal digestion followed by intestinal permeability in vitro on phenolic profile and anti-inflammatory activity of Baccharis beebread. Palynological analysis confirmed the beebread is predominantly composed by pollen grains from Baccharis species, which are endemic in south and southeast Brazil. Flavonols and phenylamides were found in beebread hydroalcoholic extract by HPLC-ESI-QTOF-MS analysis. Moreover, simulated digestion lead to compounds' breakage, releasing both aglycones from glycosylated flavonols and p-coumaric acid, but not caffeic acid from phenylamides. Only spermidines crossed the Caco-2 cell monolayer, possibly due to spermine oxidation. Free p-coumaric acid was released after digestion, and epithelial transport. Concomitantly, NF-κΒ activation and TNF-α level was decreased by beebread even after Caco-2 transport, which indicates spermidines conjugated with p-coumaric acid may be bioavailable compounds with anti-inflammatory activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)