Dietary isoflavones differentially induce gene expression changes in lymphocytes from postmenopausal women who form equol as compared with those who do not

Abstract

Human and animal studies suggest that dietary soy isoflavones reduce cancer risk, ameliorate postmenopausal syndrome and decrease bone resorption in postmenopausal women. The capacity to form the metabolite equol from daidzein is suggested as an important modulator of response to isoflavones; this capacity depends on gut colonization with appropriate bacteria. We administered a dietary supplement containing high-dose purified soy isoflavones (genistein, 558 mg/day; daidzein, 296 mg/day; and glycitein, 44 mg/day) to 30 postmenopausal women for 84 days and collected peripheral lymphocytes at timed intervals. Using microarray analysis, we determined whether changes in gene expression associated with this treatment support existing hypotheses as to isoflavones' mechanisms of action. Expression of a large number of genes was altered by isoflavone treatment, including induction of genes associated with cyclic adenosine 3′,5′-monophosphate (cAMP) signaling and cell differentiation and decreased expression of genes associated with cyclindependent kinase activity and cell division. We report that isoflavone treatment in subjects who have the capacity to produce equol differentially affects gene expression as compared with nonproducers, supporting the plausibility of the importance of equol production. In general, isoflavones had a stronger effect on some putative estrogen-responsive genes in equol producers than in nonproducers. Our study suggests that, in humans, isoflavone changes are related to increased cell differentiation, increased cAMP signaling and G-protein-coupled protein metabolism and increased steroid hormone receptor activity and have some estrogen agonist effects; equol-production status is likely to be an important modulator of responses to isoflavones.

Metabolic fate of polyphenols in the human superorganism

“…A recent attempt in this area associated circulation levels of a single microbial polyphenol metabolite with differences in long-term bioactivity as defined by transcriptomics of leukocytes (111). We envisage that the introduction of nutrikinetic phenotypes will allow for stronger associations between nutritional phenotypes and bioactivity of polyphenols.…”

Does equol production determine soy endocrine effects?

“…To determine the selectivity of the genes regulated by S-equol, gene profiling of genes that contain oestrogenresponse elements was carried out in lymphocytes isolated from postmenopausal women who were either equol producers or not [90]. In the equol producers, oestrogenrelated receptor beta and four orphan nuclear receptors (BROB2, NR2C1, NR2F2 and NR113) were the most overexpressed genes which demonstrating status as an equol producer is associated with selective changes in gene expression [90].…”

A risk assessment-driven quantitative comparison of gene expression profiles in PBMCs and white adipose tissue of humans and rats after isoflavone supplementation

“…Another important issue is that rats are known to be equol producers (Setchell et al, 2005), while this is only the case for 20-30% of Western populations (Setchell & Clerici, 2010). In previous studies, differences in gene expression were observed between equol-producers and non-producers (Niculescu et al, 2007;van der Velpen et al, 2014), which also applies to estrogen responsive genes (7.0% in producers, 4.4% in nonproducers). However, this difference is not always addressed in extrapolation of findings from isoflavone animal studies to humans.…”