Flavonoid metabolites reduce tumor necrosis factor‐α secretion to a greater extent than their precursor compounds in human THP‐1 monocytes

Abstract

ScopeFlavonoids are generally studied in vitro, in isolation, and as unmetabolized precursor structures. However, in the habitual diet, multiple flavonoids are consumed together and found present in the circulation as complex mixtures of metabolites. Using a unique study design, we investigated the potential for singular or additive anti‐inflammatory effects of flavonoid metabolites relative to their precursor structures.Methods and resultsSix flavonoids, 14 flavonoid metabolites, and 29 combinations of flavonoids and their metabolites (0.1–10 μM) were screened for their ability to reduce LPS‐induced tumor necrosis factor‐α (TNF‐α) secretion in THP‐1 monocytes. One micromolar peonidin‐3‐glucoside, cyanidin‐3‐glucoside, and the metabolites isovanillic acid (IVA), IVA‐glucuronide, vanillic acid‐glucuronide, protocatechuic acid‐3‐sulfate, and benzoic acid‐sulfate significantly reduced TNF‐α secretion when in isolation, while there was no effect on TNF‐α mRNA expression. Four combinations of metabolites that included 4‐hydroxybenzoic acid (4HBA) and/or protocatechuic acid also significantly reduced TNF‐α secretion to a greater extent than the precursors or metabolites alone. The effects on LPS‐induced IL‐1β and IL‐10 secretion and mRNA expression were also examined. 4HBA significantly reduced IL‐1β secretion but none of the flavonoids or metabolites significantly modified IL‐10 secretion.ConclusionThis study provides novel evidence suggesting flavonoid bioactivity results from cumulative or additive effects of circulating metabolites.

Signatures of anthocyanin metabolites identified in humans inhibit biomarkers of vascular inflammation in human endothelial cells

“…Peak metabolite signatures appeared to have biological activity, despite the extremely low concentrations of their individual constitutes. Here responses were often greater then activities previously reported by our group for the same metabolites in isolation or in mixtures at equal molar concentrations . Previous studies have explored this concept of physiologically relevant concentrations of metabolite profiles by applying extracted serum/plasma to cell culture models.…”

“…Traditionally, in vitro studies have explored the activity of parent anthocyanins mechanistically, however their low plasma concentrations and rapid clearance kinetics suggests they are not the bioactive forms responsible for in vivo activity. It is therefore probable that anthocyanin bioactivity in vivo results from the lesser studied, though more bioavailable, phenolic metabolites, and we have recently demonstrated they are more active on inflammatory biomarkers than their precursor structures .…”

Phytochemical and Antinociceptive, Anti‐Inflammatory, and Antioxidant Studies of Smilax larvata (Smilacaceae)

“…Previous studies have already observed an antinociceptive activity of other glycosides of this flavonol, mainly over the inflammatory pain [48, 49]. The antioxidant and anti-inflammatory activities of the p -hydroxybenzoic acid have already been described previously [50, 51]. In relation to its potential antinociceptive effect, it is interesting to note that the p -hydroxybenzoic acid is an isomer of the salicylic acid, a molecule widely used for pain treatment [52].…”

Berry anthocyanin intake and cardiovascular health

“…Microbial metabolites are more bioactive than the parent compounds in in vitro models exerting greater vascular and antiinflammatory activity than the metabolites formed and absorbed in the small intestine (Amin et al 2015;de Ferrars et al 2014;di Gesso et al 2015;Krga et al 2016). Together, these data provide further evidence that the bioactivity of anthocyanins is highly likely attributed to their microbially-derived metabolites, which are present in the circulation significantly longer and at much higher levels than the parent anthocyanins (Czank et al 2013;de Ferrars et al 2014).…”