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Discovery and Biological Signatures of Diet-Derived Microbial Metabolites

Council Date: October 6, 2017

Program Directors: D. Craig Hopp, Ph.D.; Linda Duffy, Ph.D. 


Many dietary phytochemicals have poor oral bioavailability. Consequently, there has always been doubt about their ability to impart biological activity at a systemic level. There is an established and growing evidence base to support the hypothesis that the gut microflora can metabolize these compounds into metabolites possessing improved bioavailability and important biological activity. Frequently, these low-molecular-weight compounds are phenolic acids that may be derived from a wide range of precursors. These small gut-derived metabolites may ultimately be the missing link that explains the widely acknowledged health benefit of a diet high in fruits and vegetables. 
A handful of investigators are conducting research in this area and have provided a proof of concept to support this hypothesized interaction between the microbiome, dietary phytochemicals, and improved health outcomes. A concerted effort is now needed to more systematically identify the variety of microbial metabolites produced and the commensal bacteria responsible for their production, as well as their beneficial biological activities. Importantly, many of the studies to date suggest that these metabolites are effective anxiolytic, antidepressant, and anti-inflammatory agents, but the mechanisms by which they impart these biological activities are poorly understood. This initiative could provide much-needed data to fill current gaps in our understanding regarding the abundance and variety of these gut-derived metabolites and how they individually and collectively might improve measures of psychological and immunological resilience. Various omics technologies, particularly metabolomics, are well suited to detect and validate correlations between the chemical profile of gut-derived metabolites and their biological profile of activities (i.e., biological signature) in phenotypic models of interest to the National Center for Complementary and Integrative Health.

Purpose of Proposed Initiative

Evidence is building that low-molecular-weight compounds, derived from interactions of dietary constituents and other natural products with the microbiome, have important biological activity in animal models. This initiative seeks to characterize the compounds produced by microbial metabolism of dietary phytochemicals, identify the commensal bacteria responsible for their production, establish the biological signatures that define their interaction with a biological system, and coordinate and oversee the sharing of the relevant omic data generated.


The objectives to be met by this concept include but are not limited to the following:

  • Use multiomics approaches to discover new diet-derived microbial metabolites, establish their relationship with specific commensal gut bacteria, and determine their biological activity in models of psychological or immunological stress.
  • Use multiomics approaches to identify phenotypic-level biological signatures (i.e., mechanism of action) of new or known diet-derived microbial metabolites in models of psychological or immunological stress.
  • Use metabolomic approaches to establish pharmacokinetic properties (i.e., absorption, distribution, metabolism, excretion, and toxicity) of diet-derived microbial metabolites. 
  • Where certain dietary natural products have been shown to be associated with improved resilience to psychological or immunological stress, use metabolic phenotyping to identify microbial metabolites that might mediate that effect.
  • Where certain commensal bacteria have been shown to be associated with improved resilience to psychological or immunological stress, use metabolic phenotyping to identify dietary phytochemicals that might mediate that effect.
  • Use multiomics approaches for discovery of sex-specific differences in production and/or biological activity of diet-derived microbial metabolites. 
  • Develop resources to harmonize activities of microbiome researchers and coordinate data generation and sharing.