The relevance of environmental triggers in Crohn's disease remains poorly explored, despite the well‐known association between industrialization and disease onset/progression. We have aimed at ...evaluating the influence of endocrine disrupting chemicals in CD patients. We performed a prospective observational study on consecutive patients diagnosed of CD. Serum levels of endocrine disruptors, short‐chain fatty acids, tryptophan and cytokines were measured. Bacterial‐DNA and serum endotoxin levels were also evaluated. Gene expression of ER‐α, ER‐β and GPER was measured in PBMCs. All patients were genotyped for NOD2 and ATG16L1 polymorphisms. A series of 200 CD patients (140 in remission, 60 with active disease) was included in the study. Bisphenol A was significantly higher in patients with active disease versus remission and in colonic versus ileal disease. GPER was significantly increased in active patients and correlated with BPA levels. BPA was significantly increased in patients with bacterial‐DNA and correlated with serum endotoxin levels, (r = 0.417; P = .003). Serum butyrate and tryptophan levels were significantly lower in patients with bacterial‐DNA and an inverse relationship was present between them and BPA levels (r = −0.491; P = .001) (r = −0.611; P = .001). Serum BPA levels correlated with IL‐23 (r = 0.807; P = .001) and IL‐17A (r = 0.743; P = .001). The multivariate analysis revealed an independent significant contribution of BPA and bacterial‐DNA to serum levels of IL‐23 and IL‐17A. In conclusion, bisphenol A significantly affects systemic inflammatory response in CD patients with gut barrier disruption and dysbiotic microbiota secretory products in blood. These results provide evidence of an endocrine disruptor playing an actual pathogenic role on CD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Urolithins (dibenzo-pyran-b,d-6 one derivatives) are human gut microbiota metabolites produced from the natural food antioxidant ellagic acid. Urolithins are better absorbed than ellagic acid and ...demonstrate biological activities that suggest that they are responsible for the health effects observed after consuming ellagitannin- and ellagic acid-containing foods. Urolithins occur in the systemic circulation as glucuronide conjugates following phase II metabolism. These phase II conjugates are essential for testing the urolithin mechanisms of action in human cell line bioassays. Urolithin glucuronides are not commercially available, and their biosynthesis leads to mixtures of regional isomers. This study describes a novel and regioselective synthesis of urolithin A (3,8-dihydroxy urolithin) 3- and 8-glucuronides and isourolithin A (3,9-dihydroxy urolithin) 3- and 9-glucuronides. The metabolites were characterized using 1H and 13C NMR spectroscopy and UV spectrophotometry. The presence of these metabolites in human subjects belonging to different urolithin metabotypes was also investigated.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Orange juice is a very rich source of dietary flavanones. The effect of flavanone concentration and solubility of orange beverages on their bioavailability has been studied in a crossover study with ...10 healthy volunteers. Five different beverages with different flavanone concentrations were evaluated. Commercial orange juices (29.2−70.3 mg of flavanones/100 mL) were compared with experimental orange beverages in which the flavanone concentration was enhanced (110.2 mg/100 mL). Hesperetin and naringenin glucuronides and sulfates were detected and quantified in plasma and urine. The study shows that the solubility of the flavanones, and particularly that of hesperidin, in the juice is a key factor for the bioavailability as flavanone excretion and the C max in plasma correlate well with the soluble flavanone concentration in the juice, whereas it has no correlation with the total flavanone intake. In addition, a large interindividual variation was observed, this being consistent for each individual after the intake of the different beverages, suggesting that flavanone bioavailability is also dependent on the occurrence of specific microbiota that is able to remove the rutinosides from the juice glycosides, which results in aglycones that are then absorbed from the gut.
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•Identifying food bioactive compounds in untargeted metabolomics is challenging.•Predicted retention time is valuable towards effort in metabolite identification.•24 Chromatographic ...systems obtained predicted retention times from PredRet database.•High accuracy and coverage of retention time predictions for new compounds obtained.•We recommend extensive retention time data sharing in open access PredRet database.
Prediction of retention times (RTs) is increasingly considered in untargeted metabolomics to complement MS/MS matching for annotation of unidentified peaks. We tested the performance of PredRet (http://predret.org/) to predict RTs for plant food bioactive metabolites in a data sharing initiative containing entry sets of 29–103 compounds (totalling 467 compounds, >30 families) across 24 chromatographic systems (CSs). Between 27 and 667 predictions were obtained with a median prediction error of 0.03–0.76 min and interval width of 0.33–8.78 min. An external validation test of eight CSs showed high prediction accuracy. RT prediction was dependent on shape and type of LC gradient, and number of commonly measured compounds. Our study highlights PredRet’s accuracy and ability to transpose RT data acquired from one CS to another CS. We recommend extensive RT data sharing in PredRet by the community interested in plant food bioactive metabolites to achieve a powerful community-driven open-access tool for metabolomics annotation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The effect of two technological treatments on orange juice flavanone bioavailability in humans was assessed. Processing affected flavanone solubility and particle size of the cloud. Volunteers were ...stratified in high, medium, and low urinary excretion capabilities. Flavanones from high-pressure homogenized juice showed better absorption than those of conventional pasteurized juice in high excretors. These differences were not observed in medium and low excretors. High flavanone excretors took advantage of the high-pressure homogenization juice attributes (smaller cloud particle size) and showed an improved absorption/excretion. Stratification of the individuals by their excretion capability is more relevant than technological treatments in terms of flavanone bioavailability. This stratification should be considered in clinical studies with citrus juices and extracts as it could explain the large interindividual variability that is often observed.
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Ellagitannin and ellagic acid metabolism to urolithins in the gut shows a large human interindividual variability and this has been associated with differences in the colon microbiota. In the present ...study we describe the isolation of one urolithin-producing strain from the human faeces of a healthy volunteer and the ellagic acid transformation to different urolithin metabolites by two species of intestinal bacteria. The isolate belongs to a new species described as Gordonibacter urolithinfaciens, sp. nov. The type strain of the Gordonibacter genus, Gordonibacter pamelaeae DSM 19378(T), was also demonstrated to produce urolithins. Both human intestinal bacteria grew similarly in the presence and absence of ellagic acid at 30 μM concentration. Ellagic acid catabolism and urolithin formation occurred during the stationary phase of the growth of the bacteria under anaerobic conditions. The HPLC-MS analyses showed the sequential production of pentahydroxy-urolithin (urolithin M-5), tetrahydroxy-urolithin (urolithin M-6) and trihydroxy-urolithin (urolithin C), while dihydroxy-urolithins (urolithin A and isourolithin A), and monohydroxy-urolithin (urolithin B) were not produced in pure cultures. Consequently, either other bacteria from the gut or the physiological conditions found in vivo are necessary for completing metabolism until the final urolithins (dihydroxy and monohydroxy urolithins) are produced. This is the first time that the urolithin production capacity of pure strains has been demonstrated. The identification of the urolithin-producing bacteria is a relevant outcome as urolithin implication in health (cardiovascular protection, anti-inflammatory and anticarcinogenic properties) has been supported by different bioassays and urolithins can be used in the development of functional foods and nutraceuticals. This study represents an initial work that opens interesting possibilities of describing enzymatic activities involved in urolithin production that can help in understanding both the human interindividual differences in polyphenol metabolism, the microbial pathways involved, and the role of polyphenols in human health. The presence of urolithin producing bacteria can indirectly affect the health benefits of ellagitannin consumption.
Scope: trans‐Resveratrol (RES) and/(or) its metabolites exert many effects in vivo. Our aim was to study the metabolism and tissue distribution of RES using the pig, a mammal physiologically close to ...humans.
Methods and results: Forty‐seven tissues, organs and fluids were analyzed 6 h after intragastric RES administration (5.9 mg/kg body weight) using HPLC‐MS/MS. Twelve RES and seven dihydroresveratrol (DH‐RES) metabolites were detected. DH‐RES was the main metabolite in cecum, colon and rectum, whereas RES‐3‐O‐glucuronide was the most abundant one in fluids and organs. Approximately 74.5% of the total RES administered was recovered in the form of RES, DH‐RES and derived metabolites (65.1% along the gastrointestinal tract, 7.7% in urine, 1.2% in bile and 0.5% in organs). We report here, for the first time, the occurrence of RES ribosyl‐sulfate derivative, DH‐RES diglucuronide, DH‐RES sulfoglucuronide and DH‐RES disulfate as well as the metabolic profile of RES and DH‐RES in the aorta, lymph, lymph node, ovaries, uterus, cerebellum, pancreas, urinary bladder tissue, fat and muscle.
Conclusion: This study contributes to the clarification of the metabolism and tissue distribution of RES and could help to further understand the mechanisms underlying its effects.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, ...also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.
Urolithins are dibenzopyranone metabolites that exert anti-inflammatory activity in vivo and are produced by the gut microbiota from the dietary polyphenols ellagic acid (EA) and ellagitannins. ...However, the bacteria involved in this process remain unknown. We report here a novel bacterium, strain CEBAS 1/15P(T), capable of metabolizing EA to urolithins, that was isolated from healthy human faeces and characterized by determining phenotypic, biochemical and molecular methods. The strain was related to Gordonibacter pamelaeae 7-10-1-b(T), the type and only reported strain of the only species of the genus Gordonibacter, with about 97% 16S rRNA gene sequence similarity; they were both obligately anaerobic, non-spore-forming, Gram-stain-positive, short-rods/coccobacilli and metabolized only small numbers of carbon sources. L-Fucose, D-fructose, turanose, D-galacturonic acid and α-ketobutyric acid were metabolized by strain CEBAS 1/15P(T), while G. pamelaeae was negative for metabolism of these compounds. The whole-cell fatty acids consisted predominantly of saturated fatty acids (70%); strain CEBAS 1/15P(T) differed significantly from G. pamelaeae in the major fatty acid, which was C18 : 1ω9c, while anteiso-C15 : 0 was the major component for G. pamelaeae. The presence of a number of different fatty acid peaks, especially C19 : 0 cyclo and C18 : 1ω6c, was also indicative of distinct species. Six glycolipids (GL1-6) were recognized, while, in G. pamelaeae, only four glycolipids were described. On the basis of these data, the novel species Gordonibacter urolithinfaciens sp. nov. is described, with strain CEBAS 1/15P(T) ( = DSM 27213(T) = CCUG 64261(T)) as the type strain.
•LC, UV and MS (QQQ and QTOF) characteristics of urolithin standards were studied.•Relative response factors in UV at 305nm respect to Uro-A or EA were calculated.•We provide useful data for ...urolithin analysis when standards are not available.•Methods were validated for their application in urine, feces and plasma samples.•Biological samples were analyzed after the intake of ellagitannin-containing foods.
Ellagitannins and ellagic acid (EA) are metabolized by the gut microbiota to produce urolithins that could be responsible for the health effects attributed to ellagitannin-containing food products. Several urolithin aglycones could be present in fecal samples while glucuronide and sulphate conjugates are mainly found in plasma and urine. So far, the lack of available standards has made difficult their correct identification and quantification. In the present study, UV and MS spectra characteristics of urolithins and their phase II metabolites have been determined using different systems based on liquid chromatography (LC) coupled with diode-array or mass spectrometer detectors with different analyzers (triple quadrupole (QqQ) and quadrupole time-of-flight (QTOF)). Chromatographic separation was achieved on a reversed-phase Poroshell C18 column (3×100mm, 2.7μm). Elution order, characteristic UV spectra, and relative response factors (RRFs) with respect to their parental compound (EA) and the most common metabolite urolithin A (Uro-A) were determined. This contribution, along with the most important mass spectra characteristics (MRM transitions, qualifier/quantifier ratio, accurate mass and fragmentation pattern) will allow the determination of urolithin metabolites in different biological samples and their quantification even if not all metabolites are commercially available. The methods developed in the three systems have been fully validated in terms of linearity, sensitivity, precision, recovery, matrix effect, selectivity and stability. After that, they were successfully applied to complex biological matrices (urine, feces and plasma) from two human studies in which volunteers consumed ellagitannin-containing foods, such as walnuts and pomegranate extracts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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