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Importance and Bioactivity of the Microbial trans-Resveratrol Metabolites Dihydroresveratrol and Lunularin

Project

Food and consumer protection

This project contributes to the research aim 'Food and consumer protection'. Which funding institutions are active for this aim? What are the sub-aims? Take a look:
Food and consumer protection


Project code: MRI-OG-08-KA-125-1060ResMet, 274521263
Contract period: 01.10.2015 - 30.06.2019
Purpose of research: Experimental development

The stilbene trans-Resveratrol (t-RES) is considered to mimic the positive effects of calorie restriction (CR), which may prevent or reverse the detrimental effects of obesity, type 2 diabetes, hypertension, chronic inflammation and other age-associated metabolic diseases. It is widely sold as a dietary supplement. Orally ingested t-RES is effectively absorbed in the small intestine and strongly metabolized by phase-II-enzymes and by the gut microbiota. In own preliminary studies, next to dihydroresveratrol (DH-RES), two previously unknown microbial t-RES metabolites, i.e. 3,4´-dihydroxy-trans-stilbene and lunularin, were identified in vitro and in vivo. However, strong inter-individual differences in the profile of microbial metabolites occurred (‘lunularin-producers’ vs. ‘non-lunularin-producers’). However, bacterial lunularin producers are currently unknown. The preliminary human intervention study was performed with a limited number of volunteers (n=12). In addition, little is known about the bioactivity of the microbial metabolites. Our results in HCT116 cells indicate that DH-RES and lunularin differ in their effects on various molecular targets. We therefore hypothesize that conflicting results reported with regard to the beneficial effects of t-RES on lifespan could be caused (at least in part) by the microbial metabolism of t-RES. The objectives of this project are 1.) elucidation of the importance of the microbial t-RES metabolites dihydroresveratrol and lunularin in human adults by means of a human intervention study that is based on a larger cohort (n=100; LC-DAD-MS-analysis of 48 h-urine); 2.) identification of bacterial species which are associated with the formation of lunularin using 16S rRNA high-throughput sequencing, DGGE and qRT-PCR. In addition, lunularin-producing bacteria will be isolated from human faecal samples and subsequently identified; 3.) identification of differences in biological properties of t-RES, DH-RES and lunularin in a mouse model (intraperitoneal injection and feeding, 10 groups à 10 animals). The following CR-related parameters will be investigated in vivo: energy expenditure by indirect calorimetry and body composition by magnet NMR minispec. Murine plasma and urine samples will be analysed as follows: insulin-like growth factor and insulin by ELISA; cholesterol and triglyceride levels by photometry; the expression of Nrf2 target genes GPx, HO-1, GST and NQO1 by Western blotting and qRT-PCR; the activity of AMPK by Western blotting, the Sirt1 activity by fluorimetry and autophagy-markers by Western blotting anti-LC3; comprehensive GCxGC-MS based metabolomics. The investigations described here are anticipated to provide powerful new data to elucidate the importance of lunularin and DH-RES as microbial t-RES metabolites in humans and to assess the impact of microbial t RES metabolism on the CR-mimetic properties of this stilbene.

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Subjects

Framework programme

BMEL Frameworkprogramme 2008

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