Intestinal Dysbiosis and Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) affects 20–30% of the population, with an increased prevalence in industrialized regions. Some patients with NAFLD develop an inflammatory condition termed non-alcoholic steatohepatitis (NASH) that is characterized by hepatocellular injury, innate immune cell-mediated inflammation, and progressive liver fibrosis. In clinical practice, abdominal imaging, which reveals hepatic steatosis, is sufficient for NAFLD diagnosis if other diseases have been rejected. However, a liver biopsy is needed to differentiate NASH from simple steatosis. Therapeutic strategies used to treat obesity and metabolic syndrome improve NAFLD, but there is no specific treatment effective for NASH. The gut microbiota (GM) is composed of millions of microorganisms. Changes in the GM have a significant impact on host health. Intestinal dysbiosis is an imbalance in the GM that can induce increased permeability of the epithelial barrier, with migration of GM-derived mediators through portal vein to the liver. These mediators, such as lipopolysaccharides, short-chain fatty acids, bile acids (BAs), choline, and endogenous ethanol, seem to be involved in NAFLD pathogenesis. Given this evidence, it would be interesting to consider GM-derived mediator determination through omics techniques as a noninvasive diagnostic tool for NASH and to focus research on microbiota modulation as a possible treatment for NASH

Uso de la adrenalina autoinyectable (AAI) en pacientes con antecedentes de anafilaxia

La adrenalina autoinyectable (AAI) es un tratamiento que debe prescribirse a aquellos pacientes que han sufrido una reacción anafiláctica y son susceptibles de sufrir otra. En nuestro estudio, mediante una encuesta, valoramos el uso y el manejo de la AAI en pacientes a los que se les prescribió AAI y que siguen controles en nuestras consultas.L'adrenalina autoinjectable (AAI) és un tractament que s'ha de prescriure a aquells pacients que han patit una reacció anafilàctica i que són susceptibles de patir-ne una altra. Al nostre estudi, mitjançant una enquesta, valorem l'ús i el maneig de l'AAI en pacients als que se'ls ha prescrit AAI i que segueixen controls a les nostres consultes

Retinol binding Protein-4 circulating levels were higher in nonalcoholic fatty liver disease vs. histologically normal liver from morbidly obese women.

We aimed to analyze the retinol binding protein-4 (RBP4) messenger RNA (mRNA) expression profiles in adipose tissues and liver of morbidly obese (MO) women with or without nonalcoholic fatty liver disease (NAFLD), and to study the relationships with other pro- and anti-inflammatory adipokines in vivo and in vitro. We performed a cross-sectional analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and liver samples from four lean and 45 MO women with or without NAFLD by enzyme-linked immunosorbent assay and real-time reverse transcription-PCR. We also studied RBP4 expression in HepG2 hepatocytes under various inflammatory stimuli. Circulating RBP4 levels were higher in MO women, and specifically, in MO subjects with NAFLD compared with normal liver controls (lean and MO). RBP4 liver expression was higher in nonalcoholic steatohepatitis (NASH)-moderate/severe than in NASHmild. Overall RBP4 gene expression was higher in liver than in adipose tissues. Among them, the higher expression corresponded to SAT. VAT expression was lower in the MO cohort. In HepG2, RBP4 mRNA expression was reduced by tumor necrosis factor (TNF)-α and increased by adiponectin treatment. In conclusion, the results obtained in MO women with NAFLD, brings up the use of RBP4 and other adipokines as a panel of noninvasive molecular biomarkers when NAFLD is suspected. Further studies are needed with other obesity groups.Fil: Terra, Ximena. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; EspañaFil: Auguet, Teresa. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; España. Hospital Universitari Joan XXIII. Servei Medicina Interna,; EspañaFil: Broch, Montserrat. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; EspañaFil: Sabench, Fátima. Hospital Sant Joan de Reus. Servei de Cirurgia,; EspañaFil: Hernandez, Mercè. Hospital Sant Joan de Reus. Servei de Cirurgia,; EspañaFil: Pastor, Rosa M.. Hospital Universitari Joan XXIII. Laboratori de Bioquímica; EspañaFil: Quesada, Isabel María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; EspañaFil: Lunna, Ana. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; EspañaFil: Aguilar, Carmen. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; EspañaFil: Del Castillo, Daniel. Hospital Sant Joan de Reus. Servei de Cirurgia, ; EspañaFil: Richard, Cristobal. Universitat Rovira i Virgil. Departament de Medicina i Cirurgia; España. Hospital Universitari Joan XXIII. Servei Medicina Interna,; Españ

Pharmacogenetics of efficacy and safety of HCV treatment in HCV-HIV coinfected patients: significant associations with IL28B and SOCS3 gene variants.

Background and Aims This was a safety and efficacy pharmacogenetic study of a previously performed randomized trial which compared the effectiveness of treatment of hepatitis C virus infection with pegylated interferon alpha (pegIFNα) 2a vs. 2b, both with ribavirin, for 48 weeks, in HCV-HIV coinfected patients. Methods The study groups were made of 99 patients (efficacy pharmacogenetic substudy) and of 114 patients (safety pharmacogenetic substudy). Polymorphisms in the following candidate genes IL28B, IL6, IL10, TNFα, IFNγ, CCL5, MxA, OAS1, SOCS3, CTLA4 and ITPA were assessed. Genotyping was carried out using Sequenom iPLEX-Gold, a single-base extension polymerase chain reaction. Efficacy end-points assessed were: rapid, early and sustained virological response (RVR, EVR and SVR, respectively). Safety end-points assessed were: anemia, neutropenia, thrombocytopenia, flu-like syndrome, gastrointestinal disturbances and depression. Chi square test, Student's T test, Mann-Whitney U test and logistic regression were used for statistic analyses. Results As efficacy is concerned, IL28B and CTLA4 gene polymorphisms were associated with RVR (p<0.05 for both comparisons). Nevertheless, only polymorphism in the IL28B gene was associated with SVR (p = 0.004). In the multivariate analysis, the only gene independently associated with SVR was IL28B (OR 2.61, 95%CI 1.2-5.6, p = 0.01). With respect to safety, there were no significant associations between flu-like syndrome or depression and the genetic variants studied. Gastrointestinal disturbances were associated with ITPA gene polymorphism (p = 0.04). Anemia was associated with OAS1 and CTLA4 gene polymorphisms (p = 0.049 and p = 0.045, respectively), neutropenia and thromobocytopenia were associated with SOCS3 gene polymorphism (p = 0.02 and p = 0.002, respectively). In the multivariate analysis, the associations of the SOCS3 gene polymorphism with neutropenia (OR 0.26, 95%CI 0.09-0.75, p = 0.01) and thrombocytopenia (OR 0.07, 95%CI 0.008-0.57, p = 0.01) remained significant. Conclusions In HCV-HIV coinfected patients treated with PegIFNα and ribavirin, SVR is associated with IL28B rs8099917 polymorphism. HCV treatment-induced neutropenia and thrombocytopenia are associated with SOCS3 rs4969170 polymorphism

The bacterial community composition of the surface microlayer in a high mountain lake

The existence of bacterioneuston in aquatic ecosystems is well established, but little is known about its composition and dynamics, particularly in lakes. The bacterioneuston underlies extreme conditions at the air–water boundary, which may influence its dynamics in a different way compared with the bacterioplankton. In this study, we assessed quantitative changes in major bacterial groups of the surface microlayer (SML) (upper 900 μm) and the underlying water (ULW) (0.2–0.5 m depth) of an alpine lake during two consecutive ice-free seasons. Analysis of the bacterial community composition was done using catalyzed reporter deposition FISH with oligonucleotide probes. In addition, several physicochemical parameters were measured to characterize these two water layers. Dissolved organic carbon was consistently enriched in the SML and the dissolved organic matter pool presented clear signals of photodegradation and photobleaching. The water temperature was generally colder in the SML than in the subsurface. The bacterial community of the SML and the ULW was dominated by Betaproteobacteria and Actinobacteria. The bacterial community composition was associated with different combinations of physicochemical factors in these two layers, but temporal changes showed similar trends in both layers over the two seasons. Our results identify the SML of alpine lakes as a microhabitat where specific bacterial members such as of Betaproteobacteria seem to be efficient colonizers

Circulating pyruvate is a potent prognostic marker for critical COVID-19 outcomes

Background: Coronavirus-19 (COVID-19) disease is driven by an unchecked immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which alters host mitochondrial-associated mechanisms. Compromised mitochondrial health results in abnormal reprogramming of glucose metabolism, which can disrupt extracellular signalling. We hypothesized that examining mitochondrial energy-related signalling metabolites implicated in host immune response to SARS-CoV-2 infection would provide potential biomarkers for predicting the risk of severe COVID-19 illness. Methods: We used a semi-targeted serum metabolomics approach in 273 patients with different severity grades of COVID-19 recruited at the acute phase of the infection to determine the relative abundance of tricarboxylic acid (Krebs) cycle-related metabolites with known extracellular signaling properties (pyruvate, lactate, succinate and α-ketoglutarate). Abundance levels of energy-related metabolites were evaluated in a validation cohort (n=398) using quantitative fluorimetric assays. Results: Increased levels of four energy-related metabolites (pyruvate, lactate, a-ketoglutarate and succinate) were found in critically ill COVID-19 patients using semi-targeted and targeted approaches (p<0.05). The combined strategy proposed herein enabled us to establish that circulating pyruvate levels (p<0.001) together with body mass index (p=0.025), C-reactive protein (p=0.039), D-Dimer (p<0.001) and creatinine (p=0.043) levels, are independent predictors of critical COVID-19. Furthermore, classification and regression tree (CART) analysis provided a cut-off value of pyruvate in serum (24.54 µM; p<0.001) as an early criterion to accurately classify patients with critical outcomes. Conclusion: Our findings support the link between COVID-19 pathogenesis and immunometabolic dysregulation, and show that fluorometric quantification of circulating pyruvate is a cost-effective clinical decision support tool to improve patient stratification and prognosis prediction.This work has been developed in the framework of the COVIDOMICS’ project supported by Direcció General de Recerca i Innovació en Salut (DGRIS), Departament de Salut, Generalitat de Catalunya (PoC-6-17 and PoC1-5). The research was also funded by the Programa de Suport als Grups de Recerca AGAUR (2017SGR948), the SPANISH AIDS Research Network [RD16/0025/0006]-ISCIII-FEDER (Spain) and the Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII [CB21/13/00020], Madrid, Spain. LR is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CD20/00105” through the program “Contratos Sara Borrell”. FV is supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII and by “Premi a la Trajectòria Investigadora dels Hospitals de l’ICS 2018”. AR is supported by a grant from IISPV through the project “2019/IISPV/05” (Boosting Young Talent), by GeSIDA through the “III Premio para Jóvenes Investigadores 2019” and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00146” through the Miguel Servet Program. This study was also supported by grants SAF2015–65019-R and RTI2018–093919-B-100 (to SF-V.) funded by MCIN/AEI and by “ERFD A way of making Europe”; PI19/01337 to FV, PI20/00095 to VC.-M, PI20/00326 to AR and PI20/00338 to JV funded by ISCIII, cofinanced by the European Regional Development Fund (ERDF), and from Fundación Bancaria Caixa d’Estalvis i Pensions de Barcelona (HR20-00051 to SF-V). The Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) (CB07708/0012) is an initiative of the Instituto de Salud Carlos III. SF-V acknowledges support from the Miguel Servet tenure-track program (CP10/00438 and CPII16/00008) from the Fondo de Investigación Sanitaria, cofinanced by the ERDF. VC-M acknowledges support from the Ramón y Cajal program (RYC2019-026490-I) from the Spanish Ministry of Science and Innovation, cofinanced by the ERDF. The work was also supported by Consejeria de Salud y Familia (COVID-0005-2020), Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades Junta de Andalucia (CV20-85418to ER-M) and Instituto de Salud Carlos III (ISCIII) under grant agreement CP19/00159 to AGV “a way to make Europe”. ER-M was supported by the Spanish Research Council (CSIC). The funders have no roles in study design, data collection, data analysis, interpretation or the writing of this research.Peer reviewe

New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women

<p>Abstract</p> <p>Background</p> <p>Vaspin and omentin are recently described molecules that belong to the adipokine family and seem to be related to metabolic risk factors. The objectives of this study were twofold: to evaluate vaspin and omentin circulating levels and mRNA expression in subcutaneous and visceral adipose tissues in non-diabetic morbidly obese women; and to assess the relationship of vaspin and omentin with anthropometric and metabolic parameters, and other adipo/cytokines.</p> <p>Design</p> <p>We analysed vaspin and omentin circulating levels in 71 women of European descent (40 morbidly obese [BMI ≥ 40 kg/m²] and 31 lean [BMI ≤ 25]). We assessed vaspin and omentin gene expression in paired samples of visceral and subcutaneous abdominal adipose tissue from 46 women: 40 morbidly obese and 6 lean. We determined serum vaspin and plasma omentin levels with an Enzyme-Linked Immunosorbent Assay and adipose tissue mRNA expression by real time RT-PCR.</p> <p>Results</p> <p>Serum vaspin levels in the morbidly obese were not significantly different from those in controls. They correlated inversely with levels of lipocalin 2 and interleukin 6. Vaspin mRNA expression was significantly higher in the morbidly obese, in both subcutaneous and visceral adipose tissue.</p> <p>Plasma omentin levels were significantly lower in the morbidly obese and they correlated inversely with glucidic metabolism parameters. Omentin circulating levels, then, correlated inversely with the metabolic syndrome (MS). Omentin expression in visceral adipose tissue was significantly lower in morbidly obese women than in controls.</p> <p>Conclusions</p> <p>The present study indicates that vaspin may have a compensatory role in the underlying inflammation of obesity. Decreased omentin circulating levels have a close association with MS in morbidly obese women.</p

Gut Microbiota-Derived Mediators as Potential Markers in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a common, multifactorial, and poorly understood liver disease whose incidence is globally rising. During the past decade, several lines of evidence suggest that dysbiosis of intestinal microbiome represents an important factor contributing to NAFLD occurrence and its progression into NASH. The mechanisms that associate dysbiosis with NAFLD include changes in microbiota-derived mediators, deregulation of the gut endothelial barrier, translocation of mediators of dysbiosis, and hepatic inflammation. Changes in short chain fatty acids, bile acids, bacterial components, choline, and ethanol are the result of altered intestinal microbiota. We perform a narrative review of the previously published evidence and discuss the use of gut microbiota-derived mediators as potential markers in NAFLD

Are Ingested or Inhaled Microplastics Involved in Nonalcoholic Fatty Liver Disease?

Nonalcoholic fatty liver disease (NAFLD) has emerged as the predominant cause of chronic liver injury; however, the mechanisms underlying its progression have not been fully elucidated. Pathophysiological studies have stated that NAFLD is significantly influenced by dietary and environmental factors that could participate in the development of NAFLD through different mechanisms. Currently, &ldquo;plastic pollution&rdquo; is one of the most challenging environmental problems worldwide since several plastics have potential toxic or endocrine disputing properties. Specifically, the intake of microplastics (MPs) and nanoplastics (NPs) in water or diet and/or the inhalation from suspended particles is well established, and these particles have been found in human samples. Laboratory animals exposed to MPs develop inflammation, immunological responses, endocrine disruptions, and alterations in lipid and energy metabolism, among other disorders. MPs additives also demonstrated adverse reactions. There is evidence that MPs and their additives are potential &ldquo;obesogens&rdquo; and could participate in NAFLD pathogenesis by modifying gut microbiota composition or even worsen liver fibrosis. Although human exposure to MPs seems clear, their relationship with NAFLD requires further study, since its prevention could be a possible personalized therapeutic strategy. Adequate mitigation strategies worldwide, reducing environmental pollution and human exposure levels of MPs, could reduce the risk of NAFLD