for the CANONIC Study Investigators of the EASL Clif Consortium, Grifols Chair and the European Foundation for the Study of Chronic Liver Failure (EF Clif), Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF,

Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.

The metabolome is the set of small molecular mass compounds found in biological media, and metabolomics, which refers to as the analysis of metabolome in a given biological condition, deals with the large scale detection and quantification of metabolites in biological media. It is a data driven and multidisciplinary approach combining analytical chemistry for data acquisition, and biostatistics, informatics and biochemistry for mining and interpretation of these data. Since the middle of the 2000s, high resolution mass spectrometry is widely used in metabolomics, mainly because the detection and identification of metabolites are improved compared to low resolution instruments. As the field of HRMS is quickly and permanently evolving, the aim of this work is to review its use in different aspects of metabolomics, including data acquisition, metabolite annotation, identification and quantification. At last, we would like to show that, thanks to their versatility, HRMS instruments are the most appropriate to achieve optimal metabolome coverage, at the border of other omics fields such as lipidomics and glycomics.

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In this study, we describe a simple and efficient method for mapping the distribution and localization of all sialylated sphingoglycolipids present in coronal mouse brain sections using a conventional axial matrix-assisted laser desorption/ionization time of flight. A single scan of a histological tissue section gives a complete profile of ganglioside species without derivatization or labeling. We have developed and tested a new matrix preparation (2,6-dihydroxyacetophenone [DHA]/ammonium sulfate/heptafluorobutyric acid [HFBA]) to maximize the detection of all ganglioside species; the ammonium sulfate limits the formation of salt adducts, while the addition of HFBA increases the stability of DHA in a vacuum, thus facilitating imaging applications. Our results, in both extracted samples and whole tissue sections using negative ion reflectron and linear modes, show differences in localization in several brain regions depending on the sialic acids and the ceramide-associated core gangliosides.

Gangliosides are amphiphilic molecules found in the outer layer of plasma membranes of all vertebrate cells. They play a major role in cell recognition and signaling and are involved in diseases affecting the central nervous system (CNS). We are reporting the differential distribution of ganglioside species in the rat brain’s cerebrum, based on their ceramide associated core, and for the first time the presence of acetylation detected by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, which was used to map and image gangliosides with detailed structural information and histological accuracy. In the hippocampus, localization of the major species GM1, GD1, O-acetylGD1, GT1, and O-acetylGT1 depends on the sphingoïd base (d18:1 sphingosine or d20:1 eïcosasphingosine) in the molecular layer of the dentate gyrus (ML), which is made up of three distinct layers, the inner molecular layer (IML), which contains sphingosine exclusively, and the middle molecular layer (MML) and the outer molecular layer (OML) where eïcosasphingosine is the only sphingoïd base. These results demonstrate that there is a different distribution of gangliosides in neuronal axons and dendrites depending on the ceramide core of each layer. GM3, GM2, GD3, and GD2 contain sphingosine predominantly and are mainly present in body cell layers, which are made up of the pyramidal cell layer (Py) and the granular layer of the dentate gyrus (GL), in contrast with GQ1 and the O-acetylated forms of GD1, GT1, and GQ1 gangliosides, which contain both sphingoïd bases. However their distribution is based on the sialylated and acetylated oligosaccharide chains in the neuronal cell bodies.

Explosive detonations generate atmospheric pressure changes that produce nonpenetrating blast induced "mild" traumatic brain injury (bTBI). The structural basis for mild bTBI has been extremely controversial. The present study applies matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging to track the distribution of gangliosides in mouse brain tissue that were exposed to very low level of explosive detonations (2.5−5.5 psi peak overpressure). We observed major increases of the ganglioside GM2 in the hippocampus, thalamus, and hypothalamus after a single blast exposure. Moreover, these changes were accompanied by depletion of ceramides. No neurological or brain structural signs of injury could be inferred using standard light microscopic techniques. The first source of variability is generated by the Latency between blast and tissue sampling (peak intensity of the blast wave). These findings suggest that subtle molecular changes in intracellular membranes and plasmalemma compartments may be biomarkers for biological responses to mild bTBI. This is also the first report of a GM2 increase in the brains of mature mice from a nongenetic etiology. E xplosive devices used in conflicts have increased the prevalence of blast-induced mild traumatic brain injuries (bTBI) in the U.S. military. It has been estimated that about 20% of deployed personnel have been exposed to at least one episode of bTBI. 1,2 Explosive detonations produce shock waves, blast wind and electromagnetic pulses. Primary injury is due to distortion of tissue by propagation of atmospheric pressure (AP) differential between blast overpressure and normal AP, thus compressing soft tissues (lung, GI, ear, brain), followed by reverse negative pressure leading to tearing and shearing of tissue, including veins. 3 These AP changes result in nonpenetrating mild bTBI, with physical and psychological consequences. However, behavioral manifestations of mild bTBI are often not associated with discernible structural changes in brain tissue or neurological signs, in either animal models or humans. 4−9 Diagnosis is problematic and indeed even the existence of a bTBI syndrome has been debated. 10 Ceramide and derived glycosphingolipids form 20% of total lipids of plasmalemma and intracellular organelle membranes. 11Gangliosides constitute 6% by weight of total brain lipids and include four major structural series of species, constructed on a ceramide scaffold with an oligosaccharide chain containing at least one sialic acid moiety. Their formation is catalyzed by membrane-bound glycosyltransfersases in the Golgi apparatus and endoplasmic reticulum. GM1, accounts for approximately 21% of total gangliosides, while GM2, a very minor ganglioside species, constitutes less than 0.5% of total gangliosides or 0.08% of all brain lipids. Concentration ratios of ganglioside species in intracellular membranes (e.g., Golgi apparatus and endoplasmic reticulum) and plasmalemma compartments (components of lipid rafts) appear to be tightly regulated i...

Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute‐on‐chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28‐day follow‐up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short‐term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow‐up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow‐up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow‐up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.