Gut microbial dysbiosis has been associated with alterations in production of immune and inflammatory
cytokines and other circulating metabolites contributing to inflammation. Gut microbial composition and
function are amenable to modification by diet. Flaxseed (FS), a whole food commonly consumed as a dietary
adjuvant for several purported health effects, is a rich source of the polyphenolic lignans. Structurally similar to
endogenous estrogens, lignans have been most widely studied for phytoestrogen effects; however, anti-
inflammatory, immunomodulatory, and antioxidant effects have also been reported, primarily in animal and cell
models. Importantly, to become physiologically available to humans, plant lignans require metabolism to
enterolignans by a consortium of gut microbial community members, but not all individuals are enterolactone
producers. Plant lignans are converted by the gut bacteria to the primary circulating enterolignan
enterolactone (ENL) which can be measured in most body fluids. ENL has been inversely associated with
several inflammation-related chronic diseases and, as a bacterial metabolite, has significant potential to impact
health. Using existing data and specimens from a completed flaxseed intervention study in healthy,
postmenopausal African American (AA) and non-Hispanic White (NHW) women that investigated the impact of
the intervention on gut microbial communities, lignan metabolism, and steroid hormone metabolism, we will
accomplish the following Aims: 1) In the overall study sample, determine associations between gut microbial
community profiles, circulating metabolic profiles, and circulating inflammation-related cytokines for women
who are high vs low ENL producers; 2) In a subset of women (n=80; 40 high producers [20 AA, 20 NHW], 40
low producers [20 AA, 20 NHW]), utilize metatranscriptomics to a) characterize the impact of the FS
intervention on pre- and postintervention microbial gene expression, b) determine associations between
microbial gene expression and circulating metabolites and inflammation-related cytokines, and c) how these
associations differ by producer status and race; and 3) In the subset of women in Aim 2, utilize fecal
metabolomics to characterize microbial metabolic profiles pre- and post-intervention, and determine
associations with microbial gene expression (metatranscriptomics), circulating metabolites, and inflammation-
related cytokines. We hypothesize that the FS intervention will modify microbial gene expression and
metabolic pathways related to chronic low grade inflammation and these pathways will differ by producer
status and for AA and NHW women. The proposed study offers a unique opportunity to characterize changes
in microbial function and subsequent modification of circulating metabolic profiles related to chronic low grade
inflammation in a generous sample of AA and NHW white women. Given the higher incidence of inflammation
related chronic disease in AA, this study will contribute significantly to our understanding of the role of the
microbiome in inflammatory metabolic processes.
