Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells

Abstract

Oligomers and polymers of flavan-3-ols (proanthocyanidins) are very abundant in the Mediterranean diet, but are poorly absorbed. However, when these polyphenols reach the colon, they are metabolised by the intestinal microbiota into various phenolic acids, including phenylpropionic, phenylacetic and benzoic acid derivatives. Since the biological properties of these metabolites are not completely known, in the present study, we investigated the effect of the following microbial phenolic metabolites: 3,4-dihydroxyphenylpropionic acid (3,4-DHPPA), 3-hydroxyphenylpropionic acid, 3,4-dihydroxyphenylacetic acid (3,4-DHPAA), 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid and 4-hydroxyhippuric acid (4-HHA), on modulation of the production of the main pro-inflammatory cytokines (TNF-a, IL-1b and IL-6). The production of these cytokines by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) pre-treated with the phenolic metabolites was studied in six healthy volunteers. With the exception of 4-HHA for TNF-a secretion, only the dihydroxylated compounds, 3,4-DHPPA and 3,4-DHPAA, significantly inhibited the secretion of these pro-inflammatory cytokines in LPS-stimulated PBMC. Mean inhibition of the secretion of TNF-a by 3,4-DHPPA and 3,4-DHPAA was 84·9 and 86·4 %, respectively. The concentrations of IL-6 in the culture supernatant were reduced by 88·8 and 92·3 % with 3,4-DHPPA and 3,4-DHPAA pre-treatment, respectively. Finally, inhibition was slightly higher for IL-1b, 93·1 % by 3,4-DHPPA and 97·9 % by 3,4-DHPAA. These results indicate that dihydroxylated phenolic acids derived from microbial metabolism present marked anti-inflammatory properties, providing additional information about the health benefits of dietary polyphenols and their potential value as therapeutic agents.

The urinary phenolic acid profile varies between younger and older adults after a polyphenol-rich meal despite limited differences in in vitro colonic catabolism

“…The bioactivity of specific phenolic acids is less well defined, with examples including 3,4diOHPAA an inhibitor of enzymes involved in detoxification (GSTT2), inflammation (COX-2) and anti-proliferative activity in HCT-116 colon cancer cells [67,70]; 3,4-diOHPPA (3 µM) and 3,4-diOHPAA (3 µM), inhibitors of the pro-inflammatory cytokines such as TNF-a, IL-1b and IL-6 in lipopolysaccharide-stimulated peripheral blood mononuclear cells [70,71]; and gallic acid (882 µM) inhibitor of Clostridium histolyticum in in vitro faecal fermentation [65,72].…”

Metabolic fate of polyphenols in the human superorganism

“…In a bottomup approach, potential bioactivity of gut microbiota-mediated metabolites needs to be screened in relevant in vitro and animal models. In a recent screening exercise, gut-microbial polyphenol metabolites were indeed able to reduce the ex vivo response of peripheral blood mononuclear cells to an inflammatory challenge (108). When screening gut-mediated metabolites for biological activity, one should however take into account the different conjugation routes once they have entered systemic circulation (109).…”

Cocoa Polyphenols and Inflammatory Markers of Cardiovascular Disease

“…, TNF-α, IL-1β and IL-6, in LPS-stimulated PBMC [225]. The phenolic acids used were at a biological concentration level (1 mM) within the range (0.1–10 mM) found in plasma samples after cocoa polyphenol intake [227].…”

“…The concentrations of IL-6 were reduced with 3,4-DHPPA and 3,4-DHPAA pretreatment. This study demonstrated that dihydroxylated phenolic acids derived from colonic microbial metabolites could probably act as an anti-inflammatory agent, providing favourable effects on CVD [225]. …”