Plasma metabolite abundances are associated with urinary enterolactone excretion in healthy participants on controlled diets

Abstract

Enterolignans, products of gut bacterial metabolism of plant lignans, have been associated with reduced risk of chronic diseases, but their association with other plasma metabolites is unknown. We examined plasma metabolite profiles according to urinary enterolignan excretion in a cross-sectional analysis using data from a randomized crossover, controlled feeding study. Eighty healthy adult males and females completed two 28-day feeding periods differing by glycemic load, refined carbohydrate, and fiber content. Lignan intake was calculated from food records using a polyphenol database. Targeted metabolomics was performed by LC-MS on plasma from fasting blood samples collected at the end of each feeding period. Enterolactone (ENL) and enterodiol (END), were measured in 24-h urine samples collected on the penultimate day of each study period using GC-MS. Linear mixed models were used to test the association between enterolignan excretion and metabolite abundances. Pathway analyses were conducted using the Global Test. Benjamini-Hochberg false discovery rate (FDR) was used to control for multiple testing. Of the metabolites assayed, 121 were detected in all samples. ENL excretion was associated positively with plasma hippuric acid and melatonin, and inversely with epinephrine, creatine, glycochenodeoxycholate, and glyceraldehyde (P <0.05). Hippuric acid only satisfied the FDR of q < 0.1. END excretion was associated with myristic acid and glycine (q <0.5). Two of 57 pathways tested were associated significantly with ENL, ubiquinone and terpenoid-quinone biosynthesis, and inositol phosphate metabolism. These results suggest a potential role for ENL or ENL-metabolizing gut bacteria in regulating plasma metabolites.

Lignans and Gut Microbiota: An Interplay Revealing Potential Health Implications

“…There are particularly rich dietary sources of lignans, such as oilseeds (flaxseed, sesame, linseed, and sunflower), whilst other foods present moderate to low amounts [7]. Nevertheless, dietary surveys have observed that whole grains (especially rye), legumes, fruits, vegetables, nuts, and some beverages such as tea and coffee, can be considered good dietary sources of these compounds [8,9]. Starting from the previous considerations, it seems clear that the characteristics of the diet will define the degree of exposition to plant lignans.…”

Effect of a Flaxseed Lignan Intervention on Circulating Bile Acids in a Placebo-Controlled Randomized, Crossover Trial

“…The enterolignans, and ENL in particular, possess a range of biologic activities including anti-proliferative and anti-inflammatory effects, and modulation of estrogen signaling, lipid metabolism, and bile acid regulation [ 7 ]. High inter-individual variation in metabolism of lignans has been observed under controlled conditions [ 8 , 9 ], and may influence the level of exposure to the bioactive microbial metabolites and subsequent health-related outcomes.…”

Anticancer and antimetastatic potential of enterolactone: Clinical, preclinical and mechanistic perspectives

“…PIN is first metabolized to LAR, which is further converted to SECO, and then to ED and EL while MAT is directly converted to EL. Detection of both enterolignans and dietary lignans in human serum and urine indicates that both types of lignans are absorbed from the gut (Clavel et al, 2006a;Miles et al, 2017). A recent study in humans has shown that, following single-bolus oral administration of SDG, the SECO appeared rapidly in serum with peak concentrations reaching after 5-7 h independent of the dose ingested or the extent of purity of the extract while the peak serum ED and EL concentrations appeared at 19.2 ± 2.6 h and 26.7 ± 2.5 h, respectively (Setchell et al, 2014).…”

“…Once produced by intestinal bacteria, ED and EL are absorbed, conjugated in the gut epithelium or liver with sulfate or glucuronic acid, and excreted in the urine and bile. Since EL (~11.6 h) has a longer half-life than ED (~9 h), it constitutes the majority of enterolignans in circulation or in urine excretion (Kuijsten et al, 2005;Miles et al, 2017;Setchell et al, 2014). In order to get a better understanding of the oral absorption characteristics of SDG, SECO, ED & EL, a systematic evaluation of the intestinal permeation and conjugative metabolism was conducted using the polarized Caco-2 cell system in recent study.…”