Objectives Gordonibacter urolithinfaciens (GUro) is one of the three human bacteria that can convert ellagic acid (EA) to urolithins (Uros). Individuals deficient in Uro-producing bacteria may not benefit from EA-rich diets due to poor bioavailability of EA. Thus, GUro supplementation could be a solution. This work aims to examine 1) the viability of naked and protected GUro after gastrointestinal (GI) digestion; 2) colonization of GUro in vivo and the impact of GUro on gut microbiota; 3) the effect of GUro supplementation on the bioavailability of EA and Uros. Methods In vitro studies: Simulated GI digestion was conducted with GUro in naked (NG), alginate-chitosan encapsulated (ACG) or hydrogel protected (HGG) forms. Bacteria enumeration was performed by plate count. In vivo studies: Male C57BL/6J mice deficient in GUro were divided into 2 groups: Control (Ctrl, vehicle) and Experiment (Exp, GUro at 107 CFU/mouse). Mice received vehicle or GUro on days 1, 2, 3 and 7 by oral gavage, and then 20 mg/kg EA 12 h after the final dose of GUro or vehicle on D8. Feces were collected for gut microbiota analysis. Blood and tissues were collected at 0.5, 12, 24 and 36 h after EA intake. 36 h excretion of urine and feces were collected. The change in the main genera of gut microbiota was measured by qPCR. Colon tissue histology was examined by H&E staining. EA and Uros were extracted from biosamples and analyzed by UHPLC with triple quadrupole mass spectrometry. Results NG showed comparable viability as ACG and HGG after in vitro GI digestion indicating GUro's suitability to be ingested without protection. For in vivo study, the level of GUro increased 8 folds 12 h after the last dose of GUro but returned to baseline in 24–36 h. For Ctrl group, Akkermansia (Akk) increased substantially at all time points. Similarly, Akk bloomed post-gavage of EA but most strikingly at 0.5 h in Exp group. GUro administration significantly enhanced the bioavailability of EA and Uros. Substantial amounts of Uro C, dimethyl Uro C, Uro A and methyl Uro A were excreted in the urine of Exp group, but barely detected in the Ctrl. Conclusions Supplementation of GUro improved the bioavailability of EA and bioactive metabolites. Moreover, the high survival rate of naked GUro after GI digestion indicated its potential to serve as a probiotic. Funding Sources National Natural Science Foundation of China; PolyU Research Institute for Future Food.

Schisandrin B (Sch-B) is a predominant bioactive lignan in the fruit of a traditional Chinese medicinal plant Schisandra Chinensis with widely reported anti-cancer properties. Using a xenograft mouse model of colorectal cancer (CRC), we showed potent anti-tumor effects of Sch-B and synergistic effects when co-treated with the chemotherapy drug, fluorouracil (5-FU). To explore the underlying anti-tumor mechanism of Sch-B, we first compared the bioavailability, metabolism and tissue distribution of Sch-B and its metabolites among healthy and tumor-bearing mice. To understand the drug-phytochemical interactions associated with the synergy between Sch-B and 5-FU, we examined their reciprocal influence on drug metabolism, tissue distribution, and multidrug resistance (MDR) gene expression in tumor-bearing mice. Using a targeted metabolomics approach, three Sch-B metabolites and two bioactive 5-FU metabolites were quantified and found to reach tumor tissue. Generally, Sch-B metabolites were present at higher levels in tumor-bearing than healthy mice, whereas 5-FU metabolite accumulation was remarkably higher in the co-treatment than 5-FU alone group. Moreover, MDR genes were significantly downregulated upon co-treatment, demonstrating the capacity of Sch-B to reverse MDR in chemotherapy. This study showed that Sch-B may serve as a promising adjuvant to chemotherapy drugs via favorably modulating drug metabolism and bioavailability, and attenuating MDR.

Zearalenone (ZEA), a secondary metabolite from Fusarium fungi found in cereal-based foods, promotes the growth of colon, breast, and prostate cancers in vitro. However, the lack of animal studies hinders a deeper mechanistic understanding of the cancer promotive effect of ZEA. The aim of this study was to unveil the effect of ZEA on colon cancer progression and its underlying mechanism. Through integrative analyses of transcriptomics, metabolomics, metagenomics, and host phenotypes, we investigated the impact of a 4-week ZEA intervention on colorectal cancer in xenograft mice. Our results showed that a 4-week ZEA intervention increased the tumor weight twofold. ZEA exposure significantly increased the mRNA and protein levels of BEST4, DGKB and KI67, and the phosphorylation levels of ERK1/2 and AKT. Metabolomics analysis of the serum revealed the levels of amino acids, including histidine, arginine, citrulline and glycine decreased significantly in the ZEA group. Furthermore, ZEA lowered the alpha diversity of the gut microbiota and reduced the abundance of 9 genera, such as Tuzzerella and Rikenella, etc. Further association analysis indicated that Tuzzerella was negatively associated with the expression of BEST4 and DGKB genes, serum uric acid level and tumor weight. In addition, circulatory hippuric acid level was positively correlated with the tumor weight and the expression of oncogenic genes, including ROBO3, JAK3 and BEST4. Altogether, our results indicated that ZEA promoted colon cancer tumor progression through enhancing the BEST4/AKT/ERK1/2 pathway, lowering the circulatory amino acid concentration, alternating the gut microbiota composition, and suppressing the SCFA production.

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