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

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.

Enterolignan Production in a Flaxseed Intervention Study in Postmenopausal US Women of African Ancestry and European Ancestry

“…Given that ENL production is also affected by microbial conversion efficiency of different lignans to enterolignans [ 42 , 43 , 44 , 45 ], the gut microbiota may contribute to inter-individual and population-specific variation in enterolignan exposures. Gut microbial diversity may be responsive to the variety of dietary components resulting from cultural and ethnic differences in dietary patterns [ 33 ], although in our study, alpha diversity did not differ in the AA or EA at baseline or in response to FS.…”

“…Our data suggest that observed differences in ENL production and microbiome composition between AA and EA could be relevant to population-specific differences in chronic disease prevalence. For example, cross-sectional studies have reported an inverse relationship between ENL excretion and circulating secondary bile acids [ 63 , 64 ], bacterial metabolites associated with increased risk of CVD, cirrhosis [ 65 ], and CRC [ 45 , 64 ]. In our study, Lachnoclostridium was inversely associated with ENL production in EA.…”

Novel ι-Carrageenan Tetrasaccharide Alleviates Liver Lipid Accumulation via the Bile Acid–FXR–SHP/PXR Pathway to Regulate Cholesterol Conversion and Fatty Acid Metabolism in Insulin-Resistant Mice

“…Bile acids, which were essential metabolic regulators, have gained more and more attention for their potential functions in lipid disorder therapeutics as specific targets. Bile acids, converted from hepatic cholesterol, are secreted into the intestinal tract in response to extrinsic stimulation, in which primary bile acids will develop into secondary bile acids by microbial biotransformation . Bile acids consist of various molecular species, which were reported in association with a variety of chronic diseases, such as nonalcoholic fatty liver disease .…”

Personalized Nutrition Using Microbial Metabolite Phenotype to Stratify Participants and Non-Invasive Host Exfoliomics Reveal the Effects of Flaxseed Lignan Supplementation in a Placebo-Controlled Crossover Trial

“…In our study population, there were no baseline differences in demographic and lifestyle factors between individuals classified as low-and high-ENL excreters [6,24]. Generally, in cross-sectional, observational studies, factors that affect ENL measures include intake of lignan-rich foods, antibiotic use, body mass index, smoking, sex and age [7].…”