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Polyphenols’ Gut Microbiota Metabolites: Bioactives or Biomarkers? Francisco A. Tomas-Barberan,* Maria V. Selma, and Juan C. Espín* Laboratory of Food & Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, CEBAS-CSIC, P.O. Box 164, Espinardo, Murcia 30100, Spain Gut microbiota (poly)phenol metabolites have shown a range of biological effects on in vitro human cell line bioassays and less frequently in studies with animal models (rats, mice, C. elegans).1,2 These assays show mild anti-inflammatory, cardioprotective, neuroprotective, “prebiotic-like”, antioxidant, antidiabetic, antiobesity, and chemopreventive activity and enhancement of the muscular performance. The number of published clinical studies, however, is rather limited, and only a few studies have reported biological effects upon oral administration of gut microbiota metabolites.3 Indirect studies to correlate the production of a specific gut microbiota metabolite with health biomarkers have also been elusive, particularly for phytoestrogens such as soybean isoflavones and flaxseed lignans, although equol producers responded better to soybean intake than the nonproducers. For soy isoflavones, the active metabolite is thought to be Sequol, the gut microbiota metabolite of daidzein. When S-equol was given orally to individuals of the equol-producing ecause (poly)phenols present in foods are poorly phenotype, the response was improvement of some cardiovasabsorbed, they are transferred during digestion to the cular risk biomarkers.3 This improvement, however, was not colon where they encounter the gut microbes. Colonic observed when S-equol was given to individuals of the equol microbiota degrades the unabsorbed (poly)phenols leading to nonproducing phenotype, therefore leading to questioning its biological effects in vivo and suggesting an effect mediated metabolites that are better absorbed than their food precursors. through gut microbiota.4 (Poly)phenol gut microbiota metabolites have been considAlthough this is the only example showing the interindividual ered as bioactive compounds, whose activity has been primarily variability of effects unequivocally attributed to a (poly)phenol demonstrated using in vitro assays involving human cell lines, gut microbiota metabolite, another recent study showed similar and in some preclinical studies with animal models. The clinical results with pomegranate ellagitannin-derived urolithins.4 In trials in which the gut microbiota metabolites are orally this study, individuals belonging to metabotype B, from the administered are, however, very limited. three different urolithin-producing metabotypes previously The unambiguous determination of the health effects of described (A, B, and 0),5 responded better to the treatment (poly)phenols has been revealed to be a very difficult task. This with pomegranate ellagitannins.4 This might suggest that the is mainly due to the large interindividual variation in the gut microbiota metabolites produced in metabotype B biological response to (poly)phenols for which determinants individuals would be more active than those of metabotype have been highlighted by the European COST action A. This could be in disagreement with a number of in vitro POSITIVe (https://www6.inra.fr/cost-positive). This study studies where urolithin A (the main metabolite in metabotype has identified the gut microbiota as a key determinant of the A) is usually more active than isourolithin A and urolithin B, interindividual variability observed when studying the cardiocharacteristic metabolites of metaboptype B.6,7 This indicates vascular health effects of dietary polyphenols. that the health effects observed for metabotype B could be due It has been hypothesized that differences in the health effects to other factors other than the direct biological activity of potentially observed after the intake of (poly)phenols could be urolithins. It is true, however, that the individuals of associated with differences in the production of bioactive metabotype B have been reported to have higher levels of compounds by the gut microbiota, which depends on the cardiovascular risk biomarkers than those of metabotype A.4 variations in microbial ecology that colonizes the colon of each This could be due to either the inability of metabotype B individual. This means that a given (poly)phenol can lead to individuals to produce relevant levels of urolithin A before the intervention with pomegranate or to different indirect effects different metabolites depending on each individual (i.e., on through interactions with the gut microbiota modulating its their specific gut microbiota composition), and therefore to composition and/or functionality. different biological effects (differences in potentially bioactive compounds). These differences can also reflect the composition and/or function of the gut microbiota (biomarkers of gut Received: February 14, 2018 microbiota).
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© XXXX American Chemical Society
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DOI: 10.1021/acs.jafc.8b00827 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry
(6) González-Sarrías, A.; Núñez-Sánchez, M. A.; García-Villalba, R.; Tomás-Barberán, F. A.; Espín, J. C. Antiproliferative activity of the ellagic acid-derived gut microbiota isourolithin A and comparison with its urolithin A isomer: the role of cell metabolism. Eur. J. Nutr. 2017, 56, 831−841. (7) Kang, I.; Espin, J. C.; Tomas-Barberan, F. A.; Kim, Y. E.; Chung, S. Urolithin A, C and D, but not iso-Urolithin A and Urolithin B, attenuate triglyceride accumulation in human cultures of adipocytes and hepatocytes. Mol. Nutr. Food Res. 2016, 60, 1129−1138.
Therefore, (poly)phenol gut microbiota metabolites could be considered a priori either as bioactives or as biomarkers. As bioactives, it would involve the production of a powerful mixture of different bioavailable metabolites (multimetabolites/ muti-target effect) but with rather mild bioactivity. As biomarkers, they would act as a metabolic signature reflecting the catabolic capacity of the microbiome of each individual, and therefore indirectly be a marker of the individual gut microbiota composition, richness, diversity, and functionality. They could also be both and act as mild bioactive metabolites and biomarkers regarding gut microbiota composition and functionality, which is related to the health and potential response to dietary interventions. With the current evidence available in humans, the metabolites produced by the microbiota from (poly) phenols are closer to being biomarkers than to being bioactives. To move forward beyond this position, the correlations between gut microbiota composition and the metabolic signature produced for different (poly)phenols should be further studied and defined in both health and illness states.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Francisco A. Tomas-Barberan: 0000-0002-0790-1739 Juan C. Espín: 0000-0002-1068-8692 Funding
Projects AGL2015-64124-R and AGL2015-73107-EXP (MINEICO, Spain), 201870E014 (CSIC, Spain), Fundación Séneca (19900/GERM/15) and by the European COST Action FA1403 POSITIVe. Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Larrosa, M.; González-Sarrías, A.; Yáñez-Gascón, M. J.; Selma, M. V.; Azorín-Ortuño, M.; Toti, S.; Tomás-Barberán, F. A.; Dolara, P.; Espín, J. C. Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin A in a colitis rat model and the effect of colon inflammation on the phenolic metabolism. J. Nutr. Biochem. 2010, 21, 717−725. (2) Ryu, D.; Mouchiroud, L.; Andreux, P. P.; Katsyuba, E.; Moullan, N.; Nicolet-dit-Félix, A. A.; Williams, E. S.; Jha, P.; Lo Sasso, G.; Huzard, D.; Aebischer, P.; Sandi, C.; Rinsch, C.; Auwerx, J. Urolithin A induced mitophagy nd prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 2016, 22, 879−888. (3) Hazim, S.; Curtis, P. J.; Schär, M. Y.; Ostertag, L. M.; Kay, C. D.; Minihane, A. M.; Cassidy, A. Acute benefits of the microbial-derived isoflavone metabolite equol on arterial stiffness in men prospectively recruited according to equol producer phenotype: a double-blind randomized controlled trial. Am. J. Clin. Nutr. 2016, 103, 694−702. (4) González-Sarrías, A.; García-Villalba, R.; Romo-Vaquero, M.; Alasalvar, C.; Ö rem, A.; Zafrilla, P.; Tomás-Barberán, F. A.; Selma, M. V.; Espin, J. C. Clustering according to urolithin metabotype explains the interindividual variability in the improvement of cardiovascular risk biomarkers in overweight-obese individuals consuming pomegranate: A randomized clinical trial. Mol. Nutr. Food Res. 2017, 61, 1600830. (5) Tomás-Barberán, F. A.; García-Villalba, R.; González-Sarrías, A.; Selma, M. V.; Espín, J. C. Ellagic acid metabolism by human gut microbiota: Consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J. Agric. Food Chem. 2014, 62, 6535−6538. B
DOI: 10.1021/acs.jafc.8b00827 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
