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Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient’s primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis.

Portion size selection is an indicator of appetite and within younger adults, is predicted by factors such as expected satiety, liking and motivations to achieve an ideal sensation of fullness (i.e., implicit satiety goals). Currently, there is limited research available on the determinants of portion size selection within older adults. Therefore, the current study aimed to examine the relationship between individual differences in implicit satiety goals, food-related expectations, and portion size selection in older adults. Free-living older adult Singaporeans (N = 115; N

SCOPE: Diet is considered an important modulator of cognitive decline and dementia, but the available evidence is, however, still fragmented and often inconsistent.METHODS AND RESULTS: The article studies the long-term prospective Three-City Cohort, which consists of two separate nested case-control sample sets from different geographic regions (Bordeaux, n = 418; Dijon, n = 424). Cognitive decline is evaluated through five neuropsychological tests (Mini-Mental State Examination, Benton Visual Retention Test, Isaac's Set Test, Trail-Making Test part A, and Trail-Making Test part B). The food-related and microbiota-derived circulating metabolome is studied in participants free of dementia at baseline, by subjecting serum samples to large-scale quantitative metabolomics analysis. A protective association is found between metabolites derived from cocoa, coffee, mushrooms, red wine, the microbial metabolism of polyphenol-rich foods, and cognitive decline, as well as a negative association with metabolites related to unhealthy dietary components, such as artificial sweeteners and alcohol.CONCLUSION: These results provide insight into the early metabolic events that are associated with the later risk to develop cognitive decline within the crosstalk between diet, gut microbiota and the endogenous metabolism, which can help identify potential targets for preventive and therapeutic strategies to preserve cognitive health.

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., The authors acknowledge networking support by the European Cooperation in Science and Technology (COST) Action FA 1403 POSITIVe (Interindividual Variation in Response to Consumption of Plant Food Bioactives and Determinants Involved). Dorrain Low has received the support of EU H2020 in the framework of the FP7-Marie Curie-COFUND People Programme, through award of the AgreenSkills+ Fellowship (grant number 609398) and Nanyang Technological University, Singapore, through award of the Presidential Postdoctoral Fellowship (grant number 001991-00001). The MetaboHUB French infrastructure has supported the INRAE platform (PFEM, MetaboHUB-Clermont) involved in this work (grant number ANR-INBS-0010). Kateřina Valentová and Lucie Petrásková acknowledge financial support from the Czech Science Foundation (grant number 19-00043S). The Faculty of Pharmacy of Lisbon University acknowledges FUNDAÇÃO PARA A CIÊNCIA E TECNOLOGIA and PORTUGAL 2020 for financial support of the Portuguese Mass Spectrometry Network (grant number LISBOA-01-0145-FEDER-402-022125). Kati Hanhineva and Ville Koistinen have received funding from the Academy of Finland (grant numbers 277986 and 312550), Lantmännen Foundation and EU H2020 FP7-Marie Curie-COFUND MoRE Programme (grant number 754412). Biocenter Finland has financially supported the LC-MS metabolomics unit of University of Eastern Finland. Cristina Andres-Lacueva and Raúl González-Domínguez thank CIBERFES and ISCIII projects AC19/00111 and AC19/00096 (co-funded by FEDER Program from EU, “A way to make Europe”), Generalitat de Catalunya’s Agency AGAUR (grant number 2017SGR1546), “Juan de la Cierva” program from MINECO (grant number IJC2019-041867-I) and ICREA Academia award 2018. Francisco A. Tomás-Barberán has received financial support from the Spanish National Research program (grant numbers AGL-2015-73107-EXP/AEI, CSIC 201870E014) and Fundación Seneca Región de Murcia (grant number 19900/GERM/15). Gesine Schmidt acknowledges support through the Norwegian Agriculture and Food Industry Research Funds (grant number 262300). Lars Dragsted and Jan Stanstrup thank the Carlsberg Foundation for a Semper Ardens grant to support this work. László Abrankó acknowledges the Hungarian Academy of Sciences for the János Bolyai Scholarship, and support of the EU and ESF co-financed project of SZIU (grant number EFOP-3.6.3-VEKOP-16-2017-00005). Sonia de Pascual-Teresa thanks the Spanish MINECO for financial support (grant number AGL2016-76832-R). Dilip K. Rai acknowledges Teagasc for the financial support through the Walsh Fellowship (grant number 2016038).

International audience; The age-associated reduction in the proliferation of neural stem cells (NSCs) has been associated with cognitive decline. Numerous factors have been shown to modulate this process, including dietary components. Frequent consumption of caffeine has been correlated with an increased risk of cognitive decline, but further evidence of a negative effect on hippocampal progenitor proliferation is limited to animal models. Here, we used a human hippocampal progenitor cell line to investigate the effects of caffeine on hippocampal progenitor integrity and proliferation specifically. The effects of five caffeine concentrations (0 mM = control, 0.1 mM ∼ 150 mg, 0.25 mM ∼ 400 mg, 0.5 mM ∼ 750 mg, and 1.0 mM ∼ 1500 mg) were measured following acute (1 day) and repeated (3 days) exposure. Immunocytochemistry was used to quantify hippocampal progenitor integrity (i.e., SOX2- and Nestin-positive cells), proliferation (i.e., Ki67-positive cells), cell count (i.e., DAPI-positive cells), and apoptosis (i.e., CC3-positive cells). We found that progenitor integrity was significantly reduced in supraphysiological caffeine conditions (i.e., 1.0 mM ∼ 1500 mg), but relative to the lowest caffeine condition (i.e., 0.1 mM ∼ 150 mg) only. Moreover, repeated exposure to supraphysiological caffeine concentrations (i.e., 1.0 mM ∼ 1500 mg) was found to affect proliferation, significantly reducing % Ki67-positive cells relative to control and lower caffeine dose conditions (i.e., 0.1 mM ∼ 150 mg and 0.25 mM ∼ 400 mg). Caffeine treatment did not influence apoptosis and there were no significant differences in any measure between lower doses of caffeine (i.e., 0.1 mM, 0.25 mM, 0.5 mM) - representative of daily human caffeine intake - and control conditions. Our study demonstrates that dietary components such as caffeine can influence NSC integrity and proliferation and may be indicative of a mechanism by which diet affects cognitive outcomes.

Scope Coffee and tea are among the most popular beverages in the world. However, the association between habitual coffee, green tea, and black tea consumption with metabolomics profiles in Asian populations remain largely unknown. Methods and results 158 metabolites (14 amino acids, 45 acylcarnitines, and 99 sphingolipids) in the blood plasma of participants are measured from the population-based Singapore Prospective Study Program cohort using mass spectrometry (MS). Linear regression models are used to obtain the estimates for the association between coffee and tea consumption with metabolite levels, adjusted for potential confounders and false discovery rate (FDR). Coffee consumption is significantly associated with higher levels of 63 sphingolipids (29 sphingomyelins, 32 ceramides, a sphingosine-1-phosphate, and a sphingosine) and lower levels of 13 acylcarnitines and alanine. Black tea consumption is significantly associated with higher levels of eight sphingolipids, and lower levels of an amino acid, whereas green tea is significantly inversely associated with four metabolites (C8:1-OH acylcarnitine, ganglioside GM3 d18:1/16:0, sphingomyelins d18:2/18:0 and d18:1/14:0). Conclusions Coffee, black tea, and green tea consumption are associated with plasma levels of certain classes of sphingolipids and acylcarnitines in an Asian population, particularly sphingomyelins, which may mediate the health benefits of these beverages.

Addition of fibre hydrocolloids to diets is expected to result in altered rates of digesta passage due to structuring effects, and the localised production of short chain fatty acids (SCFA) as fermentation products. However, it is not known whether these effects are similar for extracted and intrinsic plant cell wall fibre types. The purpose of this study was to determine the effect of isolated (apple) pectin and fruit (mango) pulp on gastric emptying (GE), passage rate, and SCFA production along the porcine gastrointestinal (GI) tract. Thirty pigs were fed a starch-based diet with or without addition of either pectin or mango pulp over a 21-day intervention trial. Indigestible solid phase constant markers as well as solid and liquid phase pulse markers (fed 2, 4 or 6 h prior to sampling) were fed to measure apparent mean retention time (aMRT) and GE, respectively. The GI tract was divided into nine sections and analysed for digesta contents, marker recovery and SCFA production. The control diet showed significantly faster GE of the liquid digesta phase compared to solid phase, while the addition of pectin significantly delayed GE of the solid phase. The addition of pectin and mango pulp each increased digesta water content, and the pectin diet significantly decreased aMRT along the small intestine. SCFA content was increased significantly in both isolated pectin and mango pulp diets, particularly in the caecum and large intestine, with the isolated pectin diet favouring butyrate production and the mango pulp diet favouring propionate production.

Nutrient digestion kinetics are determined by gastric emptying (GE) in the stomach and apparent mean retention time (aMRT) along the small and large intestine. This study aimed to evaluate the effects of cereal dietary fibres (DF), either as intrinsic components of plant foods or added ingredients, on the retention of solid and liquid phases of digesta along the gastrointestinal (GI) tract. Thirty pigs were fed one of five diets containing whole wheat (WW), wheat starch (WS) or wheat starch partially replaced by wheat arabinoxylan (AX) or oat β-glucan (βG), or in combination (WSAXβG). Indigestible solid and liquid phase markers were added to each diet and fed at i) constant and ii) pulse dose intervals. Constant markers (acid insoluble ash and chromium) provided aMRT along 11 sections of the GI tract, while pulse dose markers (cerium, ytterbium and cobalt), fed 2–6 h before anaesthesia, provided a GE time. aMRT was slowest in the caecum and large intestine (LI, 15.4h), followed by the small intestine (SI, 3.4h) and stomach (2.6h) with liquid phases moving faster compared to solid phases. Between DF, AX but not βG, delayed GE of solid and liquid contents and showed longer retention time in SI and LI. In the absence of isolated soluble fibres, WS and WW diets showed similar flow characteristics of solid and liquid phases. The aMRT was shown to be dependent on the structure and swellability of added DF.

Bioactive compounds present in plant-based foods, and their metabolites derived from gut microbiota and endogenous metabolism, represent thousands of chemical structures of potential interest for human nutrition and health. State-of-the-art analytical methodologies, including untargeted metabolomics based on high-resolution mass spectrometry, are required for the profiling of these compounds in complex matrices, including plant food materials and biofluids. The aim of this project was to compare the analytical coverage of untargeted metabolomics methods independently developed and employed in various European platforms. In total, 56 chemical standards representing the most common classes of bioactive compounds spread over a wide chemical space were selected and analyzed by the participating platforms (n = 13) using their preferred untargeted method. The results were used to define analytical criteria for a successful analysis of plant food bioactives. Furthermore, they will serve as a basis for an optimized consensus method., This research was funded by the Generalitat de Catalunya’s Agency AGAUR (grant number 2017 SGR 1546), the Spanish MINECO´s “Juan de la Cierva” programme (grant number FJCI-2015-26590), Spanish National Programme for Research Aimed at the Challenges of Society (AGL2016-76832-R), the Czech Science Foundation (grant number 18-00132S), the European Structural and Investment Funds (grant agreement No. VEKOP-2.3.3-15-2017-00022), and Fundação para a Ciência e Tecnologia (grant number LISBOA-01-0145-FEDER-402-022125). Networking support was provided by the COST Action FA1403 POSITIVe (Inter-individual variation in response to consumption of plant food bioactives and determinants involved), supported by COST (European Cooperation in Science and Technology).

The release of carotenoids from fresh fruits or vegetables is determined by the encapsulating plant tissue matrix, intracellular carotenoid location within the cell, and the mastication process. The objectives of this study were to assess the particle sizes obtained after mastication of mango fruit tissue, and how the resulting degree of plant tissue rupture affects carotenoid bioaccessibility. A fine and a coarse chewer were selected after screening 20 healthy volunteers for in vivo human mastication, and the collected chewed boluses were subjected to wet sieving fractionation, followed by an in vitro gastric and small intestinal digestion model. Confocal micrographs show that the smallest particle size fraction (0.075 mm) consists mostly of fragmented cells and the largest size fraction (2.8 mm) contains bulky clusters of whole cells and vascular fibers. Higher amounts of total carotenoids (211–320 μg/100 g) were observed in the larger particle size fraction (2.8 mm) relative to the 1 mm (192–249 μg/100 g) and 0.075 mm fractions (136–199 μg/100 g). Smaller particles showed a greater % release of total carotenoids after in vitro digestion. Xanthophyll derivatives are more bioaccessible than β-carotene for all particle sizes. The effects of particle size or degree of fine vs coarse chewing are unexpectedly small (p > 0.05), but the process of chewing substantially reduced the release of β-carotene and xanthophylls by 34% and 18%, respectively. While there is a (small) particle size effect, this appears to not be the primary factor controlling bioaccessibility for soft tissues such as mango, in contrast to previous reports that a single cell wall appears to be enough to prevent bioaccessibility of carotenoids in more robust carrot tissues.

Mango and banana cell structures, which survived in vivo mastication and in vitro gastrointestinal digestion, were fermented in vitro for 48h. For both fruits, flavonoids and phenolic acids were liberated and underwent microbial metabolism involving ring fission, dehydroxylation and decarboxylation. UHPLC-PDA/Q-ToF-MS profiles revealed rapid degradation (72-78%) of most intact precursors (epicatechin and several unidentified compounds) within 10h, before the exponential phase of the cumulative gas production. Concomitant formation of catabolites (e.g. 4-hydroxyphenylacetic acid) occurred within 4-8h, while metabolism of catechin derivative and 3-(4-hydroxyphenyl)propanoic acid continued slowly for at least 48h, suggesting intact plant cell walls can be a controlling factor in microbial susceptibility. Untargeted PCA and OPLS-DA demonstrated clear classifications in the compositional fruit type and compound profiles as a function of time. Clusters and distinct discriminating compounds were recognised, which could lead to subsequent biomarker identification for establishing differences in polyphenol microbial metabolism of various fruit matrices.

Fruits (and vegetables) contain cellular structures that are not degraded by human digestive enzymes. Therefore, the structure of the insoluble fraction of swallowed fruits is mostly retained until intestinal microbial fermentation. In vitro fermentation of mango and banana cell structures, which survived in vivo mastication and in vitro gastrointestinal digestion, were incubated with porcine faecal inoculum and showed intensive metabolic activity. This included degradation of cell walls, leading to the release of encapsulated cell contents for further microbial metabolism. Production of cumulative gas, short chain fatty acids and ammonia were greater for mango than for banana. Microscopic and spectroscopic analyses showed this was due to a major fermentation-resistant starch fraction present in banana, that was absent in mango. This study demonstrated distinctive differences in the fermentability of banana and mango, reflecting a preferential degradation of (parenchyma) fleshy cell walls over resistant starch in banana, and the thick cellulosic vascular fibres in mango.