A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model

Symbiotic gut microorganisms (microbiome) interact closely with the mammalian host's metabolism and are important determinants of human health. Here, we decipher the complex metabolic effects of microbial manipulation, by comparing germfree mice colonized by a human baby flora (HBF) or a normal flora to conventional mice. We perform parallel microbiological profiling, metabolic profiling by 1H nuclear magnetic resonance of liver, plasma, urine and ileal flushes, and targeted profiling of bile acids by ultra performance liquid chromatography–mass spectrometry and short-chain fatty acids in cecum by GC-FID. Top-down multivariate analysis of metabolic profiles reveals a significant association of specific metabotypes with the resident microbiome. We derive a transgenomic graph model showing that HBF flora has a remarkably simple microbiome/metabolome correlation network, impacting directly on the host's ability to metabolize lipids: HBF mice present higher ileal concentrations of tauro-conjugated bile acids, reduced plasma levels of lipoproteins but higher hepatic triglyceride content associated with depletion of glutathione. These data indicate that the microbiome modulates absorption, storage and the energy harvest from the diet at the systems level

CRMP5 Regulates Generation and Survival of Newborn Neurons in Olfactory and Hippocampal Neurogenic Areas of the Adult Mouse Brain

The Collapsin Response Mediator Proteins (CRMPs) are highly expressed in the developing brain, and in adult brain areas that retain neurogenesis, ie: the olfactory bulb (OB) and the dentate gyrus (DG). During brain development, CRMPs are essentially involved in signaling of axon guidance and neurite outgrowth, but their functions in the adult brain remain largely unknown. CRMP5 has been initially identified as the target of auto-antibodies involved in paraneoplasic neurological diseases and further implicated in a neurite outgrowth inhibition mediated by tubulin binding. Interestingly, CRMP5 is also highly expressed in adult brain neurogenic areas where its functions have not yet been elucidated. Here we observed in both neurogenic areas of the adult mouse brain that CRMP5 was present in proliferating and post-mitotic neuroblasts, while they migrate and differentiate into mature neurons. In CRMP5−/− mice, the lack of CRMP5 resulted in a significant increase of proliferation and neurogenesis, but also in an excess of apoptotic death of granule cells in the OB and DG. These findings provide the first evidence that CRMP5 is involved in the generation and survival of newly generated neurons in areas of the adult brain with a high level of activity-dependent neuronal plasticity

Consolidation of an Olfactory Memory Trace in the Olfactory Bulb Is Required for Learning-Induced Survival of Adult-Born Neurons and Long-Term Memory

Background: It has recently been proposed that adult-born neurons in the olfactory bulb, whose survival is modulated by learning, support long-term olfactory memory. However, the mechanism used to select which adult-born neurons following learning will participate in the long-term retention of olfactory information is unknown. We addressed this question by investigating the effect of bulbar consolidation of olfactory learning on memory and neurogenesis. Methodology/Principal Findings: Initially, we used a behavioral ecological approach using adult mice to assess the impact of consolidation on neurogenesis. Using learning paradigms in which consolidation time was varied, we showed that a spaced (across days), but not a massed (within day), learning paradigm increased survival of adult-born neurons and allowed long-term retention of the task. Subsequently, we used a pharmacological approach to block consolidation in the olfactory bulb, consisting in intrabulbar infusion of the protein synthesis inhibitor anisomycin, and found impaired learning and no increase in neurogenesis, while basic olfactory processing and the basal rate of adult-born neuron survival remained unaffected. Taken together these data indicate that survival of adult-born neurons during learning depends on consolidation processes taking place in the olfactory bulb. Conclusion/Significance: We can thus propose a model in which consolidation processes in the olfactory bulb determine both survival of adult-born neurons and long-term olfactory memory. The finding that adult-born neuron survival durin

ACTION DE LA FLORE BACTÉRIENNE SUR LA MORPHOLOGIE ET LA SURFACE DE LA MUQUEUSE DE L'INTESTIN GRÊLE DU RAT

International audienc

ACTION D'UNE FLORE MICROBIENNE QUI NE DÉCONJUGUE PAS LES SELS BILIAIRES SUR LA MORPHOLOGIE ET LE RENOUVELLEMENT CELLULAIRE DE LA MUQUEUSE DE L'INTESTIN GRÊLE DU RAT

Density functional theory (DFT) is undergoing a shift from a descriptive to a predictive tool in the field of solid state physics, with undertakings like the Materials Project, OQMD, and AFLOW leading the way in utilizing high-throughput data to predict and seek novel materials properties. However, methods to rigorously evaluate the validity and accuracy of these studies is lacking in both the availability and utilization of techniques. The natural disconnect between simulated and experimental length-scales and temperatures, combined with this lack of validation, raises serious questions when simulation and experiment disagree. In this thesis, we analyze several transition metal systems where simulations and experiments present unusual disagreements, and develop a new formalism for comparing high-temperature measurements to ab-initio calculations. Our work aims to broaden the understanding not only of the specific systems discussed, but of how presently available ab-initio methods perform for transition metal alloys across all systems. Recent high-throughput ab-initio studies of transition metal binaries have suggested a great number of undiscovered stable phases present in well-studied systems. Co-Pt alloys, especially, have a long experimental history demonstrating three stable mixed phases: L10 CoPt and L12 Co 3Pt and CoPt3, but density functional theory suggests a set of yet-unobserved long-period β2-like superstructures at Pt-rich compositions. We analyze the Co-Pt system in-depth, calculating the energy of over 1,400 structures to thoroughly explore the series of unusual superstructures suggested by DFT. Simulated diffraction patterns, analysis of magnetic behavior, and investigation of the density-of-states emphasize the stark differences between measured behaviors and ab-initio predictions. By moving up the Jacob's Ladder of functionals, we show that we only replace one set of discrepancies for another, and even the introduction of vibrational degrees of freedom fails to solve the massive differences in predicted phase stability. By fitting the ab-initio results to a cluster expansion Hamiltonian and performing Monte Carlo calculations, we show that the resulting high-temperature phase diagram is wholly incompatible with experimental results. Like Co-Pt, Heusler compounds have unique magnetic properties, resulting in interest for their potential applications as spintronic materials. The pseudo-binary (Mn,Fe)Ru2Sn, formed as a solid solution of the full Heuslers (Mn, Fe)Ru2Sn, has been recently shown to exhibit exchange-hardening implicative of two magnetic phases, despite the presence of only one chemical phase. Using ab-initio calculations we show that the magnetic behavior of this alloy arises from a competition between AFM-favoring Sn-mediated superexchange and FM-favoring RKKY exchange mediated by spin-polarized conduction electrons. Changes in valency upon replacement of Mn with Fe shifts the balance from superexchange-dominated interactions to RKKY-dominated interactions. Using our electronic structure calculations, we parameterize a mixed-basis chemical-and-magnetic cluster expansion, and use Monte Carlo simulations to demonstrate a ferromagnetic (FM) to antiferromagnetic (AFM) behavior dependent on composition with the experimental study. By examining the low-temperature ensemble averages of magnetic and chemical correlations, we identify the mechanism behind magnetic hardening in the solid solution. Our multiple successes in utilizing cluster expansions, both to deeply analyze failures and successfully describe complex chemical-magnetic interactions, motivates an experiments-driven approach to lattice Hamiltonians. For alloys, cluster expansion Hamiltonians reduce the complex, many-body electron problem of density functional theory to a series of simple site-wise basis functions (e.g., products of site occupancy variables) on an atomic scale. The resulting energy polynomial is computationally inexpensive, and hence suitable for the (tens of) thousands of calculations of large systems required by stochastic methods. We present a new method to run the statistical mechanics problem “in reverse”, using high-temperature observations and thermodynamic connections to construct an effective Hamiltonian and thereby predict the 0 Kelvin energy spectrum and associated ground states. By re-examining the cluster expansion coefficients as thermodynamic state variables and utilizing entropy-maximization approaches, we develop an algorithm to select clusters and determine cluster interactions using only a few, hightemperature experiments on disordered phases. We demonstrate that our approach can recover not only the stable ground states at 0 Kelvin, but also the full phase behavior for three realistic two-dimensional and three-dimensional alloy test-cases

ACTION D'UNE FLORE MICROBIENNE QUI NE DÉCONJUGUE PAS LES SELS BILIAIRES SUR LA MORPHOLOGIE ET LE RENOUVELLEMENT CELLULAIRE DE LA MUQUEUSE DE L'INTESTIN GRÊLE DU RAT

International audienc

Effects of microflora on the dimensions of enterocyte microvilli in the rat

International audienc