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Bone marrow mesenchymal stem/stromal cells (BM-MSCs) have immunoregulatory capacity; therefore, they have been used in different clinical protocols in which it is necessary to decrease the immune response. This capacity is mainly regulated by TNF-α and IFN-γ, and it has been observed that cell-cell contact, mainly mediated by ICAM-1, is important for MSCs to carry out efficient immunoregulation. Therefore, in the present work, we analyzed the effect of TNF-α alone or in combination with IFN-γ on the expression of ICAM-1. Besides, given the importance of cell contact in the immunoregulatory function of MSCs, we analyzed whether these cells release ICAM-1+ microvesicles (MVs). Our results show for the first time that TNF-α is capable of increasing the early expression of ICAM-1 in human BM-MSCs. Also, we observed that TNF-α and IFN-γ have a synergistic effect on the increase in the expression of ICAM-1. Furthermore, we found that BM-MSCs exposed to an inflammatory environment release MVs enriched in ICAM-1 (MVs-ICAM-1high). The knowledge generated in this study will contribute to the improvement of in vitro conditioning protocols that favor the therapeutic effect of these cells or their products.

© 2020 by the authors., The gut microbiota (GM) has attracted attention as a new target to combat several diseases, including metabolic syndrome (MetS), a pathological condition with many factors (diabetes, obesity, dyslipidemia, hypertension, etc.) that increase cardiovascular disease (CVD) risk. However, the existence of a characteristic taxonomic signature associated with obesity-related metabolic dysfunctions is under debate. To investigate the contribution of the CVD risk factors and(or) their associated drug treatments in the composition and functionality of GM in MetS patients, we compared the GM of obese individuals (n = 69) vs. MetS patients (n = 50), as well as within patients, depending on their treatments. We also explored associations between medication, GM, clinical variables, endotoxemia, and short-chain fatty acids. Poly-drug treatments, conventional in MetS patients, prevented the accurate association between medication and GM profiles. Our results highlight the heterogeneity of taxonomic signatures in MetS patients, which mainly depend on the CVD risk factors. Hypertension and(or) its associated medication was the primary trait involved in the shaping of GM, with an overabundance of lipopolysaccharide-producing microbial groups from the Proteobacteria phylum. In the context of precision medicine, our results highlight that targeting GM to prevent and(or) treat MetS should consider MetS patients more individually, according to their CVD risk factors and associated medication., This research was funded by MINECO (Spain), grant number AGL2015-64124-R, and Fundación Séneca de la Región de Murcia (Spain), grant number 20880/PI/18. A.C.M. is the holder of a predoctoral grant from MINECO (Spain).

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.

Environmental and genetic factors are associated with pandemic obesity since childhood. However, the association of overweight-obesity with these factors, acting as a consortium, has been scarcely studied in children. We aimed here to assess the probabilities of being overweighed-obese in a randomly recruited cohort of Spanish children and adolescents (n = 415, 5−17 years-old) by estimating the odds ratios for different predictor variables, and their relative importance in the prediction. The predictor variables were ethnicity, age, sex, adherence to the Mediterranean diet (KIDMED), physical activity, urolithin metabotypes (UM-A, UM-B and UM-0) as biomarkers of the gut microbiota, and 53 single-nucleotide polymorphisms (SNPs) from 43 genes mainly related to obesity and cardiometabolic diseases. A proportional-odds logistic ordinal regression, validated through bootstrap, was used to model the data. While every variable was not independently associated with overweight-obesity, however, the ordinal logistic model revealed that overweight-obesity prevalence was related to being a young boy with either UM-B or UM-0, low KIDMED score and high contribution of a consortium of 24 SNPs, being rs1801253-ADRB1, rs4343-ACE, rs8061518-FTO, rs1130864-CRP, rs659366-UCP2, rs6131-SELP, rs12535708-LEP, rs1501299-ADIPOQ, rs708272-CETP and rs2241766-ADIPOQ the top-ten contributing SNPs. Additional research should confirm and complete this model by including dietary interventions and the individuals’ gut microbiota composition., This research was funded by the Project AGL2015-64124-R (MINECO, Spain). A.C.-M. is the holder of a FPI predoctoral grant from MINECO (Spain).

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: Poly-pharmacological therapy shapes the gut microbiota (GM) in metabolic syndrome (MetS) patients. The effects of polyphenols in poly-medicated MetS patients are unknown. Methods and results: A randomized, placebo-controlled, double-blinded, and crossover trial in poly-medicated MetS patients (n=50) explored whether the effects of a pomegranate extract nutraceutical (PE, 320 mg phenolics/day for 1 month) are affected by the drug therapy. Considering the lipid-lowering (LL-), anti-hypertensive (HP-) and(or) anti-diabetic (AD-) treatments: GM (16S rRNA sequencing), short-chain fatty acids, 40 inflammatory-metabolic and endotoxemia-related biomarkers, associations between biomarkers and GM with 53 cardiometabolic dysfunctions-related single-nucleotide polymorphisms (SNPs), and urolithin metabotypes (UMs) influence are evaluated. Representative SNPs-GM associations after PE include Lactococcus and ClostridiumXIVa with rs5443-GNB3 (G-protein-β-polypeptide-3) and ClostridiumXIVa with rs7903146-TCF7L2 (transcription-factor-7-like-2) and rs1137101-LEPR (leptin-receptor). PE decreases sICAM-1 in LL-patients and the lipopolysaccharide-binding protein in all the patients. PE does not affect the other patients’ markers as a group or stratifying by UMs. After PE, Lactococcus increases in AD-, LL-, and HP-patients, Bifidobacterium increases in LL- and AD-, while Clostridium XIVa decreases in non-LL- and non-HP-patients. Conclusion: The prebiotic effect of PE depends on the medication, mainly on HP-treatments. Targeting GM can complement MetS therapy, but the patients’ drug therapy should be considered individually., Ministerio de Economía y Competitividad. Grant Number: AGL2015-94124-R Fundación Séneca. Grant Number: 20880/PI/18 Ministerio de Ciencia e Innovación. Grant Number: PID2019-103914RB-I00

Human mesenchymal stem cells (MSCs) are good candidates for brain cell replacement strategies and have already been used as adjuvant treatments in neurological disorders. MSCs can be obtained from many different sources, and the present study compares the potential of neuronal transdifferentiation in MSCs from adult and neonatal sources (Wharton’s jelly (WhJ), dental pulp (DP), periodontal ligament (PDL), gingival tissue (GT), dermis (SK), placenta (PLAC), and umbilical cord blood (UCB)) with a protocol previously tested in bone marrow- (BM-) MSCs consisting of a cocktail of six small molecules: I-BET151, CHIR99021, forskolin, RepSox, Y-27632, and dbcAMP (ICFRYA). Neuronal morphology and the presence of cells positive for neuronal markers (TUJ1 and MAP2) were considered attributes of neuronal induction. The ICFRYA cocktail did not induce neuronal features in WhJ-MSCs, and these features were only partial in the MSCs from dental tissues, SK-MSCs, and PLAC-MSCs. The best response was found in UCB-MSCs, which was comparable to the response of BM-MSCs. The addition of neurotrophic factors to the ICFRYA cocktail significantly increased the number of cells with complex neuron-like morphology and increased the number of cells positive for mature neuronal markers in BM- and UCB-MSCs. The neuronal cells generated from UCB-MSCs and BM-MSCs showed increased reactivity of the neuronal genes TUJ1, MAP2, NF-H, NCAM, ND1, TAU, ENO2, GABA, and NeuN as well as down- and upregulation of MSC and neuronal genes, respectively. The present study showed marked differences between the MSCs from different sources in response to the transdifferentiation protocol used here. These results may contribute to identifying the best source of MSCs for potential cell replacement therapies.

The full consensus on the role of dietary polyphenols as human-health-promoting compounds remains elusive. The two-way interaction between polyphenols and gut microbiota (GM) (i.e., modulation of GM by polyphenols and their catabolism by the GM) is determinant in polyphenols' effects. The identification of human metabotypes associated with a differential gut microbial metabolism of polyphenols has opened new research scenarios to explain the inter-individual variability upon polyphenols consumption. The metabotypes unequivocally identified so far are those involved in the metabolism of isoflavones (equol and(or) O-desmethylangolesin producers versus non-producers) and ellagic acid (urolithin metabotypes, including producers of only urolithin-A (UM-A), producers of urolithin-A, isourolithin-A, and urolithin-B (UM-B), and non-producers (UM-0)). In addition, the microbial metabolites (phenolic-derived postbiotics) such as equol, urolithins, valerolactones, enterolactone, and enterodiol, and 8-prenylnaringenin, among others, can exert differential health effects. The knowledge is updated and position is taken here on i) the two-way interaction between GM and polyphenols, ii) the evidence between phenolic-derived postbiotics and health, iii) the role of metabotypes as biomarkers of GM and the clustering of individuals depending on their metabotypes (metabotyping) to explain polyphenols' effects, and iv) the gut microbial metabolism of catecholamines to illustrate the intersection between personalized nutrition and precision medicine.

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: The stratification of individuals according to their gut microbiota metabotypes is crucial to understand the polyphenols health effects as reported for isoflavones and ellagitannins. To date, the existence of human gut microbiota metabotypes associated with proanthocyanidins (PAs) catabolism remains unclear. METHODS & RESULTS: Sixty‐eight healthy volunteers (40 adolescents and 28 adults) consumed a mixture of walnuts, almonds, and hazelnuts for 3 days, providing 163.65 ± 11.74 mg of PAs. Urine samples were analyzed by ultra‐performance LC–ESI‐quadrupole time‐of‐flight. Twenty‐one isomers of conjugated valerolactones and valeric acids were identified, which derived from six valerolactone and valeric acid precursors after analysis of hydrolyzed urine. This combined approach allowed discrimination between the inter‐individual variability related to phase‐II enzymes polymorphisms and the metabolism of PAs by the gut microbiota. No associations of PAs metabolism with gender, age, BMI, or ellagitannin metabotypes were found. Different quantitative excretion was observed after multivariate analysis but not true gut microbiota metabotypes associated with PAs catabolism. CONCLUSIONS: The metabolism of PAs does not reveal urinary metabolites consistent with distinctive gut microbiota metabotypes. The quantitative excretion of metabolites is inadequate to stratify individuals due to the strong influence of external factors (source, quantity, and time of the last intake of PAs, etc.).

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.