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The two bacterial consortia colonized the intestine of rats and converted UM-0 (non-urolithin-producing) animals into urolithin-producing animals mimicking the UM-A and UM-B metabotypes.

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., This research has been supported by the projects AGL2015- 64124-R and PID2019-103914RB-I00 (Spanish Ministry of Science and Innovation), PIE-201570I005 (Spanish National Research Council) and FS/20880/PI/18 (Fundación Séneca, Spain). The authors are grateful to the Murcia Federation of Parkinson’s disease

The maternal-infant transmission of several urolithins through breast milk and the gut colonization of infants by the urolithin-producing bacterium

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).

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.

We recently showed that methylxanthines and conjugated phenolic-derived metabolites reached the mammary tissue (MT) of breast cancer patients after consuming a blend of phenolic-rich extracts. The pre-surgery fasting could prevent the detection of some (including those non-conjugated) metabolites. We investigated here the pharmacokinetics in rat plasma and MT of phenolic-derived metabolites and methylxanthines using the same blend (pomegranate, olive, cocoa, orange, lemon, and grapeseed extracts plus resveratrol; containing 37 phenolics, theobromine, and caffeine). We also compared the pharmacokinetics of resveratrol when administered in the blend or individually. We show for the first time that micromolar levels of methylxanthines and conjugated-derived (but not free) metabolites from resveratrol, dihydroresveratrol, hesperetin, urolithins, and hydroxytyrosol reached the MT. Resveratrol-3-glucuronide and resveratrol-3-sulfate showed shorter Tmax (plasma and MT) and resveratrol-3-sulfate higher Cmax (MT) when resveratrol was administered individually. This study could help to conveniently design preclinical studies using physiologically relevant conditions in (breast) cell models.

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&ndash, electro spray ionization&ndash, quadrupole time of flight&ndash, 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).

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 &lsquo, protective&rsquo, 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 (&ge, 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&rsquo, 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.

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.

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.

Gordonibacter urolithinfaciens DSM 27213 T 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.

The contribution of Gordonibacter to the different abilities, both qualitative and quantitative, of individuals to transform dietary ellagic acid into anti-inflammatory urolithins was investigated. A specific and suitable q-PCR system was developed for the detection and quantification of Gordonibacter . Ellagic acid metabolism in the gut and faecal microbiota of healthy individuals, who consumed walnuts (n = 20) or a pomegranate extract (n = 49), were studied. Urolithin-A was positively correlated to Gordonibacter in faeces, whereas excretion of isourolithin-A and/or urolithin-B was inversely correlated to both. The relationship between Gordonibacter and urolithin-A found in vivo was also confirmed in vitro . This suggests that the beneficial effects attributed to the consumption of foods containing ellagic acid could be mediated by the individuals' Gordonibacter levels. The development of prebiotics, probiotics or synbiotic aimed at increasing Gordonibacter and related species could improve the individual's ability to produce the anti-inflammatory, cardioprotective and anticancer metabolite urolithin-A.

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.

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., Projects AGL2015-64124 and AGL2015-73107-EXP (MINECO, Spain), 19900/GERM/15 (Fundación Séneca, Spain) supported this work. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).

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., This work was funded by the Projects BACCHUS (FP7-KBBE2012-6-single stage, European Commission Grant Agreement 312090), CICYT AGL2011-22447, AGL201564124-R (MINECO, Spain), 201370E068 (CSIC, Spain), and Fundacion Seneca (19900/GERM/15). H.V. is a Ph.D. Fellowship Strategic Basic Researcher of the Research Foundation-Flanders (FWO). We thank the Special Research Fund of Ghent University (BOF 01B04212) for the funding of the TEER equipment., We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).

Background and aims Bifidobacterium pseudocatenulatum CECT 7765 moderates body weight gain and metabolic parameters in high-fat diet-(HFD)-fed mice but, the mechanisms of action are not yet understood. To further understand the effects of this bacterial strain, we have investigated the molecular changes in the liver of mice fed a HFD and supplemented with the bacteria. Methods and results Gene expression and protein levels were measured in the liver of C57BL/6 male mice following sub-chronic consumption of a HFD and B. pseudocatenulatum CECT 7765. Our results show that the consumption of this bacterial strain modulated the expression of key genes involved in the regulation of energy metabolism and transport of lipids that were affected by the HFD. B. pseudocatenulatum CECT 7765 significantly counteracted the effects caused by the HFD on the fatty acid transporter CD36, the transcription regulator of lipid biosynthesis EGR1 and the regulators of glucose metabolism, IGFBP2 and PPP1R3B, both at the mRNA and protein levels. The bacterial strain slightly induced the transcript levels of PNPLA2, a lipase that hydrolyses triglycerides in lipid droplets. In the standard diet (SD)-fed mice, the administration of B. pseudocatenulatum CECT 7765 donwregulated the expression of INSIG1 and HMGCR critically involved in the regulation of cholesterol levels. Conclusion B. pseudocatenulatum CECT 7765 modified the expression of key regulators of fatty acid and cholesterol metabolism and transport, lipid levels and glucose levels in the liver which supports the beneficial metabolic effects of this bacterial strain.

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 massinformationandtheisotopicpatternprovidedbyTOF-MSanalyzer.Themainmetabolites 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 5,6,7,10tetrahydro-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.

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.

cope The pomegranate lipid-lowering properties remain controversial, probably due to the interindividual variability in polyphenol (ellagitannins) metabolism. Objective We aimed at investigating whether the microbial-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 eighteen cardiovascular risk biomarkers in healthy overweight-obese individuals. Methods and Results A double-blind, cross-over, dose-response, randomised, placebo-controlled trial was conducted. The study (POMEcardio) consisted of 2 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 oxidised-LDL-cholesterol (-24±2.5%) dose-dependently decreased (P

[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 β-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. β-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 β-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., This project was financed by the Spanish Centre for the Development of Industrial Technology (CDTI) as part of the project SENIFOOD, which belongs to the CENIT subvention program (Ref: CEN-20091006). This work was also supported by the Project Consolider Ingenio 2010, CSD2007-00063 (Fun-C-Food) and by the Seneca Foundation of the Region of Murcia, Spain (Group of Excellence GERM 06 04486 and 05556/PI/04).

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/+ )a nd 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-1 (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,theREdecreased adiposephosphorylatedAMP-activatedproteinkinaseanddidnotaffect hepatic peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the Ob rats. Conclusion: OurresultsshowthatanRErichinCAexertsanti-inflammatoryeffectsandaffects 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.

[Background] Rosemary (Rosmarinus officinalis L.) extracts (REs) exhibit hepatoprotective, anti-obesity and anti-inflammatory properties and are widely used in the food industry. REs are rich in carnosic acid (CA) and carnosol which may be responsible for some of the biological activities of REs. The aim of this study was to investigate whether inhibition of lipase activity in the gut may be a mechanism by which a RE enriched in CA (40%) modulates body weight and lipids levels in a rat model of metabolic disorders and obesity., [Methods and Principal Findings] RE was administered for 64 days to lean (fa/+) and obese (fa/fa) female Zucker rats and body weight, food intake, feces weight and blood biochemical parameters were monitored throughout the study. Lipase activity (hydrolysis of p-nitrophenylbutyrate) was measured in the gastrointestinal tract at the end of the study and the contents of CA, carnosol and methyl carnosate were also determined. Sub-chronic administration of RE moderately reduced body weight gain in both lean and obese animals but did not affect food intake. Serum triglycerides, cholesterol and insulin levels were also markedly decreased in the lean animals supplemented with RE. Importantly, lipase activity was significantly inhibited in the stomach of the RE-supplemented animals where the highest content of intact CA and carnosol was detected., [Conclusions] Our results confirm that long-term administration of RE enriched in CA moderates weight gain and improves the plasma lipids profile, primarily in the lean animals. Our data also suggest that these effects may be caused, at least in part, by a significant inhibition of gastric lipase and subsequent reduction in fat absorption., This project was financed by the Spanish Centre for the Development of Industrial Technology (CDTI) as part of the project SENIFOOD, which belongs to the CENIT subvention program (Ref: CEN-20091006).

[ES] Epichloë festucae (Ascomycota) infecta a la gramínea Festuca rubra. La infección a en gramíneas confiere a la planta una serie de beneficios, entre otros ser más resistentes a herbívoros. E. festucae está infectado a su vez por un genoma vírico de 5109bp RNAbc, dicho genoma fue secuenciado, y adicionalmente se estudió su incidencia en poblaciones naturales, al igual que su modo de transmisión. En función a las características que presenta el genoma viral, se ha caracterizado como miembro de la familia Totiviridae. Está formado por dos ORFs que están solapados por un tetranucleótido; el ORF1 codifica para una posible proteína de la cápsida con una longitud de 765 aminoácidos; por su parte el ORF2 (en desfase de lectura de -1 con respecto al ORF1, codifica para una posible proteína RNA polimerasa RNA dependiente de una longitud de 826 aminoácidos. Este virus es denominado Epichloë festucae virus 1 (EfV1), y está relacionado con los miembros del género Victorivirus que infecta a hongos filamentosos, y que es deducido por medio de un análisis filogenético de la CPs y la RdRps. En dos poblaciones naturales de Epichloë festucae, el 36.4% de los aislados están infectados por EfV1. El virus fue transmitido por esporas asexuales (conidios) con una eficiencia del 100%, mientras que no se produce nunca transmisión por ascosporas procedentes del cruce sexual entre individuos con virus y sin virus., [EN] Festucae Epichloë (Ascomycota) infects the grass Festuca rubra. The infection of grasses gives the plant a number of benefits, including more resistant to herbivores. E. festucae turn is infected by a RNAbc 5109bp viral genome, this genome was sequenced, and further studied its effect on natural populations, as well as their mode of transmission. According to the features found in the viral genome has been characterized as Totiviridae family member. It consists of two ORFs which are overlapping by a tetranucleotide, the ORF1 coding for a possible coat protein with a length of 765 amino acids, for its part, the ORF2 (in reading lag of -1 with respect to ORF1, encodes a possible RNA-dependent RNA polymerase protein of 826 amino acids long. This virus is called Epichloë festucae virus 1 (EfV1), and is related to members of the genus Victorivirus infecting filamentous fungi, and is inferred by a phylogenetic analysis of the CPs and RdRps. Two natural populations of Epichloë festucae, 36.4% of isolates are infected EfV1. The virus was transmitted through asexual spores (conidia) with an efficiency of 100%, while transmission never occurs by sexual ascospores from the cross between individuals with and without virus virus.