Understanding individuals’ response to dietary bioactives is crucial for personalized nutrition. We report here for the first time in a Caucasian cohort (5–90 years, n = 839) that aging is the main factor that determines the gut microbiota involved in the ellagic acid–ellagitannin metabolism (urolithin metabotypes), with potential consequences for human health.

Urolithins are intestinal microbial metabolites produced from ellagitannin- and ellagic acid-containing foods such as walnuts, strawberries, and pomegranates. These metabolites, better absorbed than their precursors, can contribute significantly to the beneficial properties attributed to the polyphenols ellagitannins and ellagic acid (EA). However, both the ability of producing the final metabolites in this catabolism (urolithins A, B and isourolithin A) and the health benefits associated with ellagitannin consumption differ considerably among individuals depending on their gut microbiota composition. Three human urolithin metabotypes have been previously described, i.e., metabotype 0 (urolithin non-producers), metabotype A (production of urolithin A as unique final urolithin) and metabotype B (urolithin B and/or isourolithin A are produced besides urolithin A). Although production of some intermediary urolithins has been recently attributed to intestinal species from Eggerthellaceae family named Gordonibacter urolithinfaciens and Gordonibacter pamelaeae, the identification of the microorganisms responsible for the complete transformation of EA into the final urolithins, especially those related to metabotype B, are still unknown. In the present research we illustrate the isolation of urolithin-producing strains from human feces of a healthy adult and their ability to transform EA into different urolithin metabolites, including isourolithin A. The isolates belong to a new genus from Eggerthellaceae family. EA transformation and urolithin production arisen during the stationary phase of the growth of the bacteria under anaerobic conditions. The HPLC-DAD-MS analyses demonstrated the sequential appearance of 3,8,9,10-tetrahydroxy-urolithin (urolithin M6), 3,8,9-trihydroxy-urolithin (urolithin C) and 3,9-dihydroxy-urolithin (isourolithin A) while 3,8-dihydroxy-urolithin (urolithin A) and 3-hydroxy-urolithin (urolithin B) were not detected. For the first time isourolithin A production capacity of pure strains has been described. The biological activity attributed to urolithins A and B and isourolithin A (anti-inflammatory, anti-carcinogenic, cardioprotective and neuroprotective properties) explains the relevance of identifying these urolithin-producing bacteria as potential novel probiotics with applications in the development of functional foods and nutraceuticals. Their human administration could improve the health benefits upon ellagitannin consumption, especially in metabotype 0 individuals. However, further research is necessary to probe well established beneficial effects on the host and safety requirements before being considered among the next-generation probiotics.

We recently identified three metabotypes (0, A and B) that depend on the metabolic profile of urolithins produced from polyphenol ellagic acid (EA). The gut microbiota and Gordonibacter spp. recently were identified as species able to produce urolithins. A higher percentage of metabotype B was found in patients with metabolic syndrome or colorectal cancer in comparison with healthy individuals. The aim of the present study was to analyse differences in EA metabolism between healthy overweight-obese and normoweight individuals and evaluate the role of gut microbial composition including Gordonibacter. Although the three metabotypes were confirmed in both groups, metabotype B prevailed in overweight-obese (31%) versus normoweight (20%) individuals while metabotype A was higher in normoweight (70%) than the overweight-obese group (57%). This suggests that weight gain favours the growth of bacteria capable of producing urolithin B and/or isourolithin A with respect to urolithin A-producing bacteria. Gordonibacter spp. levels were not significantly different between normoweight and overweight-obese groups but higher Gordonibacter levels were found in metabotype A individuals than in those with metabotype B. Other bacterial species have been reported to show a much closer relationship to obesity and dysbiosis than Gordonibacter. However, Gordonibacter levels are negatively correlated with metabotype B, which prevails in metabolic syndrome and colorectal cancer. This is the first report that links overweight and obesity with an alteration in the catabolism of EA, and where the correlation of Gordonibacter to this alteration is shown. Future investigation of Gordonibacter and urolithin metabotypes as potential biomarkers or therapeutic targets of obesity-related diseases is warranted.

A TWIN-SHIME system was used to compare the metabolism of pomegranate polyphenols by the gut microbiota from two individuals with different urolithin metabotypes. Gut microbiota, ellagitannin metabolism, short-chain fatty acids (SCFA), transport of metabolites, and phase II metabolism using Caco-2 cells were explored. The simulation reproduced the in vivo metabolic profiles for each metabotype. The study shows for the first time that microbial composition, metabolism of ellagitannins, and SCFA differ between metabotypes and along the large intestine. The assay also showed that pomegranate phenolics preserved intestinal cell integrity. Pomegranate polyphenols enhanced urolithin and propionate production, as well as Akkermansia and Gordonibacter prevalence with the highest effect in the descending colon. The system provides an insight into the mechanisms of pomegranate polyphenol gut microbiota metabolism and absorption through intestinal cells. The results obtained by the combined SHIME/Caco-2 cell system are consistent with previous human and animal studies and show that although urolithin metabolites are present along the gastrointestinal tract due to enterohepatic circulation, they are predominantly produced in the distal colon region.