Insights From Liver-Humanized Mice on Cholesterol Lipoprotein Metabolism and LXR-Agonist Pharmacodynamics in Humans

Background and Aims Genetically modified mice have been used extensively to study human disease. However, the data gained are not always translatable to humans because of major species differences. Liver-humanized mice (LHM) are considered a promising model to study human hepatic and systemic metabolism. Therefore, we aimed to further explore their lipoprotein metabolism and to characterize key hepatic species-related, physiological differences. Approach and Results Fah(-/-), Rag2(-/-), and Il2rg(-/-) knockout mice on the nonobese diabetic (FRGN) background were repopulated with primary human hepatocytes from different donors. Cholesterol lipoprotein profiles of LHM showed a human-like pattern, characterized by a high ratio of low-density lipoprotein to high-density lipoprotein, and dependency on the human donor. This pattern was determined by a higher level of apolipoprotein B100 in circulation, as a result of lower hepatic mRNA editing and low-density lipoprotein receptor expression, and higher levels of circulating proprotein convertase subtilisin/kexin type 9. As a consequence, LHM lipoproteins bind to human aortic proteoglycans in a pattern similar to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein was not required to determine the human-like cholesterol lipoprotein profile. Moreover, LHM treated with GW3965 mimicked the negative lipid outcomes of the first human trial of liver X receptor stimulation (i.e., a dramatic increase of cholesterol and triglycerides in circulation). Innovatively, LHM allowed the characterization of these effects at a molecular level. Conclusions LHM represent an interesting translatable model of human hepatic and lipoprotein metabolism. Because several metabolic parameters displayed donor dependency, LHM may also be used in studies for personalized medicine.Peer reviewe

Ecological and aromatic impact of two Gram-negative bacteria ( Psychrobacter celer and Hafnia alvei) inoculated as part of the whole microbial community of an experimental smear soft cheese

The impact of the growth of two Gram-negative bacteria, Psychrobacter celer and Hafnia alvei, inoculated at 10(2) and 10(6) cfu/g, on the dynamics of a multispecies community as well as on volatile aroma compound production during cheese ripening was investigated. Results showed that P. celer was able to successfully implant itself in cheese, regardless of its inoculation level. However, when it was inoculated at a high level, the bacterial biodiversity was drastically lowered from day 25 to the end of ripening. Overall, the presence of P. celer led to the higher production of volatile aroma compounds such as aldehydes, ketones and sulfur compounds. Regardless of its inoculation level, H. alvei barely affected the growth of the bacterial community and was subdominant at the end of ripening. It influenced total volatile aroma compound production with volatile sulfur compounds being the most abundant. Overall, these two bacteria were able to implant themselves in a cheese community and significantly contributed to the aromatic properties of the cheese. Their role in flavoring and their interactions with the technological microorganisms must be considered during cheese ripening and should be further investigated

How to design an efficient and robust pipeline for 16S rRNA-gene sequence analysis to improve our understanding on microbial communities?

Voici la composition du Comité d'Organisation (CO) de JOBIM 2015Le Comité Logistique (CL) est présidé par : Philippe LEROY (UMR 1095 INRA/UBP, Unité Génétique, Diversité et Ecophysiologie des Céréales - GDEC, Clermont-Ferrand) Eric PEYRETAILLADE (Université d'Auvergne, Unité EA-CIDAM, Clermont-Ferrand)Trois personnes clefs: Secrétariat JOBIM2015 - Manon MARTINET (LB2MN-EA.CIDAM 4678, Université d'Auvergne) Gestion Administrative - Cathy RESSOT (Direction de la Recherche de l’Innovation et de la valorisation, Université d'Auvergne) Gestion Financière - Isabelle DELPIT (Direction de la Recherche de l’Innovation et de la valorisation, Université d'Auvergne) Le Comité Scientifique (CS) est présidé par : Pierre PEYRET (Université d'Auvergne, Unité EA-CIDAM, Clermont-Ferrand) Jérôme SALSE (MR 1095 INRA/UBP, Unité Génétique, Diversité et Ecophysiologie des Céréales - GDEC, Clermont-Ferrand)Microorganisms are considered one of the most important players involved in different environmental processes and services including nutrient cycling, pollutants attenuation as well as plant, animal and human health. In order to understand the functioning of microbial ecosystems and their impact on ecosystem processes we need to accurately assess their composition and response to environmental constraints. The application of high-throughput sequencing technologies to the study of 16S/18S rRNA-genes has revolutionized the characterization of complex microbial ecosystems. However, although it is now possible to generate hundreds of thousands of sequence reads at low costs, the analysis of the obtained data is still challenging: potential source errors including amplification biases, technical contamination, sequencing artifacts and taxonomical affiliation mistakes can lead to misinterpretations of microbial community diversity. Furthermore, progresses in sequencing technologies produce larger number of sequences at lower cost, but many tools are not scalable and pipelines have to be adapted for huge dataset. With the objective of defining best practices to analyze 16S/18S rRNA-gene sequence data, the Metagenomics, species identification, phylogeny pole of INRA was created to put together experience of biologist, bioinformaticians and statisticians of different laboratories

[Erratum for] "Palatability Can Drive Feeding Independent of AgRP Neurons"

Erratum for "Palatability Can Drive Feeding Independent of AgRP Neurons." [Cell Metab. 2015] hal-02067347International audienc

Palatability Can Drive Feeding Independent of AgRP Neurons

International audienceFeeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical because of the ubiquitous source of energy-dense foods and the consequent obesity epidemic. Hypothalamic agouti-related peptide-secreting neurons (AgRP neurons) provide the primary orexigenic drive of homeostatic feeding. Using models of neuronal inhibition or ablation, we demonstrate that the feeding response to a fast ghrelin or serotonin receptor agonist relies on AgRP neurons. However, when palatable food is provided, AgRP neurons are dispensable for an appropriate feeding response. In addition, AgRP-ablated mice present exacerbated stress-induced anorexia and palatable food intake--a hallmark of comfort feeding. These results suggest that, when AgRP neuron activity is impaired, neural circuits sensitive to emotion and stress are engaged and modulated by food palatability and dopamine signaling

Florilege : a database gathering microbial phenotypes of food interest

Food fermentation and biopreservation processes involve the use of various species and strains of bacteria and yeast. These strains are responsible for the targeted qualities of the food products that are sanitary, organoleptic (aroma and texture) and healthy qualities. The Florilege database project aims at (i) gathering bacterial and yeast phenotypes of food product of interest that are automatically extracted from PubMed-referenced full-text litterature by using a text mining approach (ii) managing the information in a relational database (iii) enabling multi-criteria requests via a Web user-friendly interface. To date 368 phenotypes, 260 synthetised or degraded molecules, 1076 medium or food products, 1181 bacterial taxons have been acquired by a combinaison of automatic and manual annotations of text, used for training the text-mining method.Food products are automatically categorized in Florilege according to the OntoBiotope ontology that we have extended with dairy and bakery products definitions. Taxa are categorized by the NCBI taxonomy. An ontology of microbial characteristics has been specifically enriched by the Florilege project. This ontology defines microbial phenotypes (Ontobiotope-Phenotype), including intracellular characteristics of cells (such as shape, antibiotic resistance...) and microbial uses (Ontobiotope-Use) that express the microbial alteration of the external environment, food or matrix, such as aroma, vitamin or other molecule production, degradation or food coloring.A preliminary Web interface is available for querying taxa, culture medium and food products at http://genome.jouy.inra.fr/Florilege/. The public availability of Florilege database is planned for the end of 2017 with a user-friendly interface for multi-criteria requests and access to various phenotypes.Florilege will be a highly valuable tool to (i) assess phenotypic biodiversity of food microbes (ii) assign biochemical functions to each strain/species from fermented or biopreserved food products (iii) help into the development of innovative food products in particular those that involve fermentation or biopreservation processes

Florilège: a database gathering microbial phenotypes of food interest

International audienceFlorilège: a database gathering microbial phenotypes of food interest. 2017 Scientific MEM days: Journées scientifiques MEM (Métaomiques et écosystèmes microbiens

Florilège: a database gathering microbial phenotypes of food interest

International audienceFlorilège: a database gathering microbial phenotypes of food interest. 2017 Scientific MEM days: Journées scientifiques MEM (Métaomiques et écosystèmes microbiens

Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

International audienceThe aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed