Urolithin A production drives the effects of pomegranate on the gut microbial metabolism of bile acids and cholesterol in mild dyslipidaemic overweight and obese individuals.

The metabolism of (poly)phenols and some host metabolites, including bile acids (BAs) and cholesterol, varies among individuals depending on their gut microbiota. The gut microbial metabolism of ellagitannins (ETs) and ellagic acid (EA) produces urolithins (Uros), yielding three metabotypes with quantitative and qualitative differences based on dissimilar Uro-producing profiles (UM-A, UM-B, and UM-0, i.e., non-producers). Previous animal studies demonstrated that polyphenols impact BAs and cholesterol microbial metabolism, but data on their effects in humans and data regarding the inter-individual variability of these metabolic conversions are scant. We evaluated whether UMs, as distinctive functional gut-microbiome signatures, could determine the potential effect of a pomegranate extract (PE) rich in ET-EA on the metabolism of BAs and cholesterol in mild dyslipidaemic overweight-obese individuals, with possible consequences on host-lipid homeostasis and gut health. At the baseline, UM-B presented the highest levels of faecal total and secondary BAs and coprostanol, suggesting that the lipid absorption capacity and gut cytotoxic risk could be augmented in UM-B. PE intake significantly reduced faecal coprostanol and BA production, especially secondary BAs, and modulated the gut microbiome, reducing the gut cytotoxic risk, especially in UM-B individuals. The lowering of faecal microbial coprostanol and BAs and some BA-metabolising bacteria was quantitatively correlated with Uro concentrations, mainly faecal Uro-A. This suggests that PE consumption could exert cardiovascular and gut protection through Uro-A production as a direct driver of the effects and indirectly by reducing the Coriobacteriaceae family and BA pool, known factors involved in the gut absorption of lipids.

Unveiling metabotype clustering in resveratrol, daidzein, and ellagic acid metabolism: Prevalence, associated gut microbiomes, and their distinctive microbial networks.

The gut microbiota (GM) produces different polyphenol-derived metabolites, yielding high interindividual variability and hampering consistent health effects. GM metabotypes associated with ellagic acid (urolithin metabotypes A (UMA), B (UMB), and 0 (UM0)), resveratrol (lunularin -producers (LP) and non-producers (LNP)), and daidzein (equol-producers (EP) and non-producers (ENP)) are known. However, individual polyphenol-related metabotypes do not occur individually. In contrast, different combinations coexist (i.e., metabotype clusters, MCs). We report here for the first time these MCs, their distribution, and their associated GM in adult humans (n = 127) after consuming for 7 days a nutraceutical (pomegranate, Polygonum cuspidatum, and red clover extracts) containing ellagitannins + ellagic acid, resveratrol, and isoflavones. Urine metabolites (UHPLC-QTOF-MS) and fecal microbiota (16S rRNA sequencing) were analyzed. Ten MCs were identified: LP + UMB + ENP (22.7%), LP + UMA + ENP (21.3%), LP + UMA + EP (16.7%), LP + UMB + EP (16%), LNP + UMA + ENP (11.3%), LNP + UMB + ENP (5.3%), LNP + UMA + EP (3.3%), LNP + UMB + EP (2%), LNP + UM0 + EP (0.7%), and LNP + UM0 + ENP (0.7%). Sex, BMI, and age did not affect the distribution of metabotypes or MCs. Multivariate analysis (MaAslin2) revealed genera differentially present in individual metabotypes and MCs. Network analysis (MENA) showed the taxa acting as module hubs and connectors. Compositional and functional profiling, alpha and beta diversities, topological network features, and GM modulation by the nutraceutical differed depending on whether the entire cohort or each MC was considered. The nutraceutical did not change the composition of LP + UMA + EP (the most robust GM with the most associated functions) but increased its network connectors. This pioneering approach, joining GM's compositional, functional, and network features in polyphenol metabolism, paves the way for identifying personalized GM-targeted strategies to improve polyphenol health benefits.

Effects of inorganic and compost tea fertilizers application on the taxonomic and functional microbial diversity of the purslane rhizosphere.

Introduction: Soil fertility is a major determinant of plant-microbial interactions, thus, directly and indirectly affecting crop productivity and ecosystem functions. In this study, we analysed for the first time the effects of fertilizer addition on the cropping of purslane (Portulaca oleracea) with particular attention to the taxonomic and functional characteristics of their associated soil microbiota. Methods: We tested the effects of different doses of inorganic fertilization differing in the amount of N:P:K namely IT1 (300:100:100); IT2 (300:200:100); IT3 (300:200:200); and IT4 (600:100:100) (ppm N:P:K ratio) and organic fertilization (compost tea) which reached at the end of the assay the dose of 300 ppm N. Results and discussion: Purslane growth and soil quality parameters and their microbial community structure, abundance of fungal functional groups and prevailing bacterial metabolic functions were monitored. The application of compost tea and inorganic fertilizers significantly increased the purslane shoot biomass, and some soil chemical properties such as pH and soil enzymatic activities related to C, N and P biogeochemical cycles. The bacterial and fungal community compositions were significantly affected by the organic and chemical fertilizers input. The majority of inorganic fertilization treatments decreased the fungal and bacterial diversity as well as some predictive bacterial functional pathways. Conclusions: These findings suggest that the inorganic fertilization might lead to a change of microbial functioning. However, in order to get stronger evidence that supports the found pattern, longer time-frame experiments that ideally include sampling across different seasons are needed. Thus, further research is still needed to investigate the effects of fertilizations on purslane productivity under commercial field conditions.

In vivo administration of gut bacterial consortia replicates urolithin metabotypes A and B in a non-urolithin-producing rat model.

Urolithin (Uro) production capacity and, consequently, at least partly, the health effects attributed to ellagitannin and ellagic acid consumption vary among individuals. The reason is that not all individuals have the gut bacterial ecology needed to produce the different Uro metabolites. Three human urolithin metabotypes (UM-A, UM-B, and UM-0) based on dissimilar Uro production profiles have been described in populations worldwide. Recently, the gut bacterial consortia involved in ellagic acid metabolism to yield the urolithin-producing metabotypes (UM-A and UM-B) in vitro have been identified. However, the ability of these bacterial consortia to customize urolithin production to mimic UM-A and UM-B in vivo is still unknown. In the present study, two bacterial consortia were assessed for their capacity to colonize the intestine of rats and convert UM-0 (Uro non-producers) animals into Uro-producers that mimic UM-A and UM-B, respectively. Two consortia of Uro-producing bacteria were orally administered to non-urolithin-producing Wistar rats for 4 weeks. Uro-producing bacterial strains effectively colonized the rats' gut, and the ability to produce Uros was also effectively transferred. Bacterial strains were well tolerated. No changes in other gut bacteria, except Streptococcus reduction, or adverse effects on haematological and biochemical parameters were observed. Besides, two novel qPCR procedures were designed and successfully optimized to detect and quantify Ellagibacter and Enterocloster genera in faecal samples. These results suggest that the bacterial consortia are safe and could be potential probiotics for human trials, which is especially relevant for UM-0 individuals, who cannot produce bioactive Uros.

Urolithins: potential biomarkers of gut dysbiosis and disease stage in Parkinson's patients.

Gut microbiota alteration (gut dysbiosis) occurs during the onset and progression of Parkinson's disease. Gut dysbiosis biomarkers could be relevant to prodromal disease. Urolithins, anti-inflammatory metabolites produced from some dietary polyphenols by specific gut microbial ecologies (urolithin metabotypes), have been proposed as biomarkers of gut microbiota composition and functionality. However, this has not been explored in Parkinson's disease patients. The current study aimed to assess associations between urolithin metabotypes, gut dysbiosis and disease severity in Parkinson's disease patients. Participants (52 patients and 117 healthy controls) provided stool samples for microbiota sequencing and urine samples for urolithin profiling before and after consuming 30 g of walnuts for three days. Data on demographics, medication, disease duration and Hoehn and Yahr disease stage were collected. We observed a significant gradual increase of urolithin non-producers (metabotype-0) as the disease severity increased. The gut microbiome of metabotype-0 patients and patients with the greatest severity was characterized by a more altered bacterial composition, i.e., increased pro-inflammatory Enterobacteriaceae and reduced protective bacteria against autoimmune and inflammatory processes, including butyrate and urolithin-producing bacteria (Lachnospiraceae members and Gordonibacter). Besides, their microbiome was characterized by predictive functions of lipopolysaccharide biosynthesis and metabolism of glutathione, cysteine and methionine that could indirectly reflect the gut pro-inflammatory status. Urolithin detection in urine is a feasible, non-invasive and fast approach that can reflect gut microbiome dysbiosis and intestinal inflammation in Parkinson's disease patients. Our current study could provide novel strategies for improving diagnostics, and for preventing and treating disease progression in microbiota-based interventions.

Urolithins in Human Breast Milk after Walnut Intake and Kinetics of Gordonibacter Colonization in Newly Born: The Role of Mothers' Urolithin Metabotypes.

The maternal-infant transmission of several urolithins through breast milk and the gut colonization of infants by the urolithin-producing bacterium Gordonibacter during their first year of life were explored. Two trials (proof-of-concept study: n = 11; validation study: n = 30) were conducted, where breastfeeding mothers consumed walnuts as a dietary source of urolithin precursors. An analytical method was developed and validated to characterize the urolithin profile in breast milk. Total urolithins ranged from 8.5 to 176.9 nM, while they were not detected in breast milk of three mothers. The mothers' urolithin metabotypes governed the urolithin profile in breast milk, which might have biological significance on infants. A specific quantitative polymerase chain reaction method allowed monitoring the gut colonization of infants by Gordonibacter during their first year of life, and neither breastfeeding nor vaginal delivery was essential for this. The pattern of Gordonibacter establishment in babies was conditioned by their mother's urolithin metabotype, probably because of mother-baby close contact.

Urolithin Metabotypes Can Determine the Modulation of Gut Microbiota in Healthy Individuals by Tracking Walnuts Consumption over Three Days.

Walnuts are rich in polyphenols ellagitannins, modulate gut microbiota (GM), and exert health benefits after long-term consumption. The metabolism of ellagitannins to urolithins via GM depends on urolithin metabotypes (UM-A, -B, or -0), which have been reported to predict host responsiveness to a polyphenol-rich intervention. This study aims to assess whether UMs were associated with differential GM modulation after short-term walnut consumption. In this study, 27 healthy individuals consumed 33 g of peeled raw walnuts over three days. GM profiling was determined using 16S rRNA illumina sequencing and specific real-time quantitative polymerase chain reactions (qPCRs), as well as microbial activity using short-chain fatty acids analysis in stool samples. UMs stratification of volunteers was assessed using ultra performance liquid chromatography-electro spray ionization-quadrupole time of flight-mass spectrometry (UPLC-ESI-QTOF-MS) analysis of urolithins in urine samples. The gut microbiota associated with UM-B was more sensitive to the walnut intervention. Blautia, Bifidobacterium, and members of the Coriobacteriaceae family, including Gordonibacter, increased exclusively in UM-B subjects, while some members of the Lachnospiraceae family decreased in UM-A individuals. Coprococcus and Collinsella increased in both UMs and higher acetate and propionate production resulted after walnuts intake. Our results show that walnuts consumption after only three days modulates GM in a urolithin metabotype-depending manner and increases the production of short-chain fatty acids (SCFA).

Urolithin Metabotypes can Anticipate the Different Restoration of the Gut Microbiota and Anthropometric Profiles during the First Year Postpartum.

The metabolism of dietary polyphenols ellagitannins by the gut-microbiota allows the human stratification in urolithin metabotypes depending on the final urolithins produced. Metabotype-A only produces urolithin-A, metabotype-B yields urolithin-B and isourolithin-A in addition to urolithin-A, and metabotype 0 does not produce urolithins. Metabotype-A has been suggested to be 'protective', and metabotype-B dysbiotic-prone to cardiometabolic impairments. We analyzed the gut-microbiome of 40 healthy women and determined their metabotypes and enterotypes, and their associations with anthropometric and gut-microbial changes after 3 weeks, 4, 6, and 12 months postpartum. Metabotype-A was predominant in mothers who lost weight (≥2 kg) (75%) versus metabotype-B (54%). After delivery, the microbiota of metabotype-A mothers changed, unlike metabotype-B, which barely changed over 1 year. The metabotype-A discriminating bacteria correlated to the decrease of the women's waist while some metabotype-B bacteria were inversely associated with a reduction of body mass index (BMI), waist, and waist-to-hip ratio. Metabotype-B was associated with a more robust and less modulating microbial and anthropometric profiles versus metabotype-A, in which these profiles were normalized through the 1-year follow-up postpartum. Consequently, urolithin metabotypes assessment could be a tool to anticipate the predisposition of women to normalize their anthropometric values and gut-microbiota, significantly altered during pregnancy and after childbirth.

Deciphering the Human Gut Microbiome of Urolithin Metabotypes: Association with Enterotypes and Potential Cardiometabolic Health Implications.

SCOPE: The gut microbiota ellagitannin-metabolizing phenotypes (i.e., urolithin metabotypes [UMs]) are proposed as potential cardiovascular disease (CVD) risk biomarkers because the host blood lipid profile is reported to be associated with specific UMs. However, the link for this association remains unknown so far. METHODS AND RESULTS: The gut microbiome of 249 healthy individuals is analyzed using 16S rDNA sequencing analysis. Individuals are also stratified by UMs (UM-A, UM-B, and UM-0) and enterotypes (Bacteroides, Prevotella, and Ruminococcus). Associations of UMs discriminating bacteria with CVD risk markers are investigated. Distribution and gut microbiota composition of UMs and enterotypes are not coincident. Almost half of the discriminating genera between UM-A and UM-B belongs to the Coriobacteriaceae family. UM-B individuals present higher blood cholesterol levels and higher alpha-diversity, including Coriobacteriaceae family, than those of UM-A. Coriobacteriaceae, whose abundance is the highest in UM-B, is positively correlated with total cholesterol, LDL cholesterol, and body mass index. CONCLUSIONS: Results herein suggest that the family Coriobacteriaceae could be a link between individuals' UMs and their blood cholesterol levels. Further research is needed to explore the mechanisms of the host metabolic phenotype, including cholesterol excretion products, to modulate this bacterial family.

The Endotoxemia Marker Lipopolysaccharide-Binding Protein is Reduced in Overweight-Obese Subjects Consuming Pomegranate Extract by Modulating the Gut Microbiota: A Randomized Clinical Trial.

SCOPE: Gut microbiota dysbiosis, intestinal barrier failure, obesity, metabolic endotoxemia, and pro-inflammatory status promote cardiovascular risk. However, the modulation of the gut microbiome to prevent endotoxemia in obesity has been scarcely studied. We investigated the association between gut microbiota modulation and plasma lipopolysaccharide-binding protein (LBP), a surrogate marker of endotoxemia, in overweight-obese individuals. METHODS AND RESULTS: In a randomized trial, 49 overweight-obese subjects (body mass index> 27 kg m-2 ) with mild hypelipidemia daily consumed, in a cross-over fashion, two doses (D1 and D2, lasting 3 weeks each) of pomegranate extract (PE) or placebo alternating with 3 weeks of wash-out periods. A significant decrease (p < 0.05) of plasma LBP and a marginal decrease (p = 0.054) of high-sensitivity C-reactive protein were observed, but only after PE-D2 administration (656 mg phenolics). 16S rDNA sequencing analyses revealed the increase of microorganisms important for maintaining normal balance of gut microbiota and gut barrier function, particularly Bacteroides, Faecalibacterium, Butyricicoccus, Odoribacter, and Butyricimonas. PE-D2 also decreased pro-inflammatory microorganisms including Parvimonas, Methanobrevibacter, and Methanosphaera. Remarkably, plasma LBP reduction was significantly associated (p < 0.05) with both Faecalibacterium and Odoribacter increase and Parvimonas decrease. CONCLUSIONS: Consumption of PE decreased endotoxemia in overweight-obese individuals by reshaping the gut microbiota, mainly through the modulation of Faecalibacterium, Odoribacter, and Parvimonas.

Ellagibacter isourolithinifaciens gen. nov., sp. nov., a new member of the family Eggerthellaceae, isolated from human gut.

Urolithins are gut microbial metabolites that exert health benefits in vivo and are generated from ellagic acid (EA) and ellagitannin-containing foods such as strawberries, pomegranates and walnuts. Gordonibacter species produce some intermediary urolithins but the micro-organisms responsible for the transformation of EA into the final and more bioactive urolithins, such as urolithin A and isourolithin A, are unknown. We report here a new bacterium, capable of metabolizing EA into isourolithin A, isolated from healthy human faeces and characterized by determining phenotypic, biochemical and molecular methods. Strain CEBAS 4A belongs to the Eggerthellaceae family and differed from other genera of this family, both phylogenetically and phenotypically. Based on 16S rRNA gene sequence similarity, the strain was related to Enterorhabdus musicola DSM 19490T (92.9 % similarity), Enterorhabdus caecimuris DSM 21839T (92.7 % similarity), Adlercreutzia equolifaciens DSM 19450T (92.5 % similarity), Asaccharobacter celatus DSM 18785T (92.5 % similarity) and Parvibacter caecicola DSM 22242T (91.2 % similarity). This strain was strictly anaerobic and Gram-stain-positive. The whole-cell fatty acids were saturated (98.3 %), a very high percentage that differs from the nearest genera ranging from 62 to 73 %. The major respiratory lipoquinone was menaquinone-7 and the diamino acid in the peptidoglycan was meso-diaminopimelic acid. Diphosphatidylglycerol and phosphatidylglycerol comprised the main polar lipid profile in addition to several phosphoglycolipids (PGL1-2), phospholipids (PL1-4), glycolipids (GL1-6) and lipids. Based on these data, a new genus, Ellagibacter gen. nov. is proposed with one species, Ellagibacter isourolithinifaciens sp. nov. The type strain of Ellagibacter isourolithinifaciens is CEBAS 4AT (=DSM 104140T=CCUG 70284T).

Complete Genome Sequence of the New Urolithin-Producing Bacterium Gordonibacter urolithinfaciens DSM 27213T.

Gordonibacter urolithinfaciens DSM 27213T was isolated from human feces and is able to metabolize ellagic acid (a dietary phenolic compound present in various fruits) to urolithins. Here, we report the finished and annotated genome sequence of this organism.

Isolation of Human Intestinal Bacteria Capable of Producing the Bioactive Metabolite Isourolithin A from Ellagic Acid.

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.

Gastrointestinal Simulation Model TWIN-SHIME Shows Differences between Human Urolithin-Metabotypes in Gut Microbiota Composition, Pomegranate Polyphenol Metabolism, and Transport along the Intestinal Tract.

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.

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.

SCOPE: The pomegranate lipid-lowering properties remain controversial, probably due to the interindividual variability in polyphenol (ellagitannins) metabolism. OBJECTIVE: We aimed at investigating whether the microbially derived ellagitannin-metabolizing phenotypes, i.e. urolithin metabotypes A, (UM-A), B (UM-B), and 0 (UM-0), influence the effects of pomegranate extract (PE) consumption on 18 cardiovascular risk biomarkers in healthy overweight-obese individuals. METHODS AND RESULTS: A double-blind, crossover, dose-response, randomized, placebo-controlled trial was conducted. The study (POMEcardio) consisted of two test phases (dose-1 and dose-2, lasting 3 weeks each) and a 3-week washout period between each phase. Forty-nine participants (BMI > 27 kg/m2 ) daily consumed one (dose-1, 160 mg phenolics/day) or four (dose-2, 640 mg phenolics/day) PE or placebo capsules. Notably, UM-B individuals showed the highest baseline cardiovascular risk. After dose-2, total cholesterol (-15.5 ± 3.7%), LDL-cholesterol (-14.9 ± 2.1%), small LDL-cholesterol (-47 ± 7%), non-HDL-cholesterol (-11.3 ± 2.5%), apolipoprotein-B (-12 ± 2.2%), and oxidized LDL-cholesterol -24 ± 2.5%) dose dependently decreased (P < 0.05) but only in UM-B subjects. These effects were partially correlated with urolithin production and the increase in Gordonibacter levels. Three (50%) nonproducers (UM-0) became producers following PE consumption. CONCLUSIONS: UM clustering suggests a personalized effect of ellagitannin-containing foods and could explain the controversial pomegranate benefits. Research on the specific role of urolithins and the microbiota associated with each UM is warranted.

The human gut microbial ecology associated with overweight and obesity determines ellagic acid metabolism.

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.

Dietary phenolics against colorectal cancer--From promising preclinical results to poor translation into clinical trials: Pitfalls and future needs.

Colorectal cancer (CRC) remains a major cause of cancer death worldwide. Over 70% of CRC cases are sporadic and related to lifestyle. Epidemiological studies inversely correlate CRC incidence with the intake of fruits and vegetables but not with their phenolic content. Preclinical studies using in vitro (cell lines) and animal models of CRC have reported anticancer effects for dietary phenolics through the regulation of different markers and signaling pathways. Herein, we review and contrast the evidence between preclinical studies and clinical trials (patients with CRC or at risk, familial adenopolyposis or aberrant crypt foci) investigating the protective effects of curcumin, resveratrol, isoflavones, green tea extracts (epigallocatechin gallate), black raspberry powder (anthocyanins and ellagitannins), bilberry extract (anthocyanins), ginger extracts (gingerol derivatives), and pomegranate extracts (ellagitannins and ellagic acid). To date, curcumin is the most promising polyphenol as possible future adjuvant in CRC management. Overall, the clinical evidence of dietary phenolics against CRC is still weak and the amounts needed to exert some effects largely exceed common dietary doses. We discuss here the possible reasons behind the gap between preclinical and clinical research (inconsistence of results, lack of clinical endpoints, etc.), and provide an outlook and a roadmap to approach this topic.

A rosemary extract rich in carnosic acid selectively modulates caecum microbiota and inhibits ß-glucosidase activity, altering fiber and short chain fatty acids fecal excretion in lean and obese female rats.

BACKGROUND: Carnosic acid (CA) and rosemary extracts (RE) show body-weight, energy metabolism and inflammation regulatory properties in animal models but the mechanisms are not yet understood. Gut microbiota plays an important role in the host metabolism and inflammatory status and is modulated by the diet. The aim of this research was to investigate whether a RE enriched in CA affected caecum microbiota composition and activity in a rat model of genetic obesity. METHODS AND PRINCIPAL FINDINGS: A RE (40% CA) was administered with the diet (0.5% w/w) to lean (fa/+) and obese (fa/fa) female Zucker rats for 64 days. Changes in the microbiota composition and ß-glucosidase activity in the caecum and in the levels of macronutrients and short chain fatty acids (SCFA) in feces were examined. The RE increased the Blautia coccoides and Bacteroides/Prevotella groups and reduced the Lactobacillus/Leuconostoc/Pediococccus group in both types of animals. Clostridium leptum was significantly decreased and Bifidobacterium increased only in the lean rats. ß-Glucosidase activity was significantly reduced and fecal fiber excretion increased in the two genotypes. The RE also increased the main SCFA excreted in the feces of the obese rats but decreased them in the lean rats reflecting important differences in the uptake and metabolism of these molecules between the two genotypes. CONCLUSIONS: Our results indicate that the consumption of a RE enriched in CA modifies microbiota composition and decreases ß-glucosidase activity in the caecum of female Zucker rats while it increases fiber fecal elimination. These results may contribute to explain the body weight gain reducing effects of the RE. The mutated leptin receptor of the obese animals significantly affects the microbiota composition, the SCFA fecal excretion and the host response to the RE intake.

A rosemary extract enriched in carnosic acid improves circulating adipocytokines and modulates key metabolic sensors in lean Zucker rats: Critical and contrasting differences in the obese genotype.

SCOPE: Carnosic acid (CA) and rosemary extracts (REs) have antiobesity effects but the mechanisms are not understood. We investigated some of the potential mechanisms contributing to the metabolic effects of an RE enriched in CA. METHODS AND RESULTS: An RE (∼40% CA) was administered to lean (Le, fa/+) and obese (Ob, fa/fa) female Zucker rats for 64 days. Several adipocytokines, brain-derived neurotrophic factor, phosphorylated AMP-activated protein kinase, and hepatic gene expression changes were investigated. The RE significantly decreased circulating tumor necrosis factor alpha (RE/CT = 0.36, p < 0.0003), IL-1ß (0.48, p < 0.032), and leptin (0.48, p < 0.002), and upregulated adiponectin (1.47, p < 0.045) in the Le rats. The RE also induced phase I and phase II gene expression and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Notably, the RE decreased adipose phosphorylated AMP-activated protein kinase and did not affect hepatic peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the Ob rats. CONCLUSION: Our results show that an RE rich in CA exerts anti-inflammatory effects and affects hepatic metabolism in normal Le rats. We report significant differences in the expression and regulation of key metabolic sensors between Le and Ob rats that may contribute to explain the different ability of the two genotypes to respond to the RE.

Bioavailability of the major bioactive diterpenoids in a rosemary extract: metabolic profile in the intestine, liver, plasma, and brain of Zucker rats.

SCOPE: Carnosic acid (CA) and derived diterpenes abundant in rosemary extracts (REs) exert anti-obesity effects. The aim of this study was to investigate the bioavailability of these compounds in a rat model of obesity. METHODS AND RESULTS: A total of 26 compounds were tentatively identified based on accurate mass information and the isotopic pattern provided by TOF-MS analyzer. The main metabolites detected in the gut content, liver, and plasma were the glucuronide conjugates of CA, carnosol, and rosmanol. Two other metabolites were also identified: CA 12-methyl ether and 5,6,7,10-tetrahydro-7-hydroxyrosmariquinone. All the metabolites were detected as early as 25 min following oral administration. Most of the compounds remained in the intestine, liver, and (or) plasma at substantial concentrations for several hours supporting their potential health benefits in these tissues. We also corroborated the presence of small quantities of CA and detected trace quantities of the main CA metabolites in the brain. Notably, we did not find significant differences in the metabolic profile between lean and obese rats. CONCLUSION: We report for the first time a comprehensive profile of metabolites in various organs following the oral consumption of an RE enriched in CA and contribute to establish the potential bioactive molecules.