Abstract
Plant lignans and their microbial metabolites, e.g., enterolactone (ENL), may affect bile acid (BA) metabolism through interaction with hepatic receptors. We evaluated the effects of a flaxseed lignan extract (50 mg/day secoisolariciresinol diglucoside) compared to a placebo for 60 days each on plasma BA concentrations in 46 healthy men and women (20-45 years) using samples from a completed randomized, crossover intervention. Twenty BA species were measured in fasting plasma using LC-MS. ENL was measured in 24-h urines by GC-MS. We tested for (a) effects of the intervention on BA concentrations overall and stratified by ENL excretion; and (b) cross-sectional associations between plasma BA and ENL. We also explored the overlap in bacterial metabolism at the genus level and conducted in vitro anaerobic incubations of stool with lignan substrate to identify genes that are enriched in response to lignan metabolism. There were no intervention effects, overall or stratified by ENL at FDR < 0.05. In the cross-sectional analysis, irrespective of treatment, five secondary BAs were associated with ENL excretion (FDR < 0.05). In vitro analyses showed positive associations between ENL production and bacterial gene expression of the bile acid-inducible gene cluster and hydroxysteroid dehydrogenases. These data suggest overlap in community bacterial metabolism of secondary BA and ENL.
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Key Points
Diets higher in fiber are associated with reduced risk of several chronic diseases, including many cancers, cardiovascular disease, and obesity and related metabolic diseases. Health benefits of high-fiber foods may be attributed, in part, to microbial metabolites of plant lignans. Lignans are polyphenols found in a variety of plant foods. They can be converted to enterolignans (enterolactone (ENL) and enterodiol (END)) through gut microbial metabolism. 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.
There is growing recognition that both primary and secondary bile acids are strong signaling molecules involved in metabolism. In the liver, intestine, and other tissues, bile acids interact with the farnesoid-X receptor (FXR) and G-protein-coupled bile acid receptor, more commonly known as TGR5, which contribute to glucose homeostasis and immune regulation. ENL interacts with nuclear receptors involved in bile acid metabolism and therefore may mediate bile acid synthesis and metabolism. These interactions between ENL and hepatic receptors, and subsequent microbial activity, lead to a variety of secondary bile acid species, and contribute to changes in bile acid pool size and composition. Given the observation that ENL may affect synthesis and metabolism of bile acids, thereby regulating downstream metabolic effects of bile acids, the primary goal of this analysis was to examine the effects of a lignan intervention on plasma bile acid concentrations.
In this ancillary study using data from a randomized, crossover trial, a modest intervention effects of a flaxseed lignan extract as compared to the placebo on circulating bile acids, mainly CA, overall and by ENL excreter status was found. However, these effects did not remain significant after controlled for multiple testing. In the cross-sectional analysis, irrespective of treatment, robust associations between ENL excretion and certain circulating secondary bile acids, particularly secondary CA-derived species were observed. These results likely reflect lower liver-derived CA available as substrate.
In conclusion, this in vitro approach supports the application of metagenomic and metatranscriptomics to reveal the gene abundance and expression of species and genes involved in ENL and bile acid metabolism. Analysis of these microbial pathways within a larger controlled dietary intervention can provide the analytical rigor needed to unravel the impact of ENL on bile acid metabolism and host health.