Peripheral tryptophan, serotonin, kynurenine, and their metabolites in major depression: A case–control study

International audienceAim: Tryptophan is the sole precursor of both peripherally and centrally produced serotonin and kynurenine. In depressed patients, tryptophan, serotonin, kynurenine, and their metabolite levels remain unclear. Therefore, peripheral tryptophan and metabolites of serotonin and kynurenine were investigated extensively in 173 patients suffering from a current major depressive episode (MDE) and compared to 214 healthy controls (HC).Methods: Fasting plasma levels of 11 peripheral metabolites were quantified: tryptophan, serotonin pathway (serotonin, its precursor 5-hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid), and kynurenine pathway (kynurenine and six of its metabolites: anthranilic acid, kynurenic acid, nicotinamide, picolinic acid, xanthurenic acid, and 3-hydroxyanthranilic acid).Results: Sixty (34.7%) patients were antidepressant-drug free. Tryptophan levels did not differ between MDE patients and HC. Serotonin and its precursor (5-hydroxytryptophan) levels were lower in MDE patients than in HC, whereas, its metabolite (5-hydroxyindoleacetic acid) levels were within the standard range. Kynurenine and four of its metabolites (kynurenic acid, nicotinamide, picolinic acid, and xanthurenic acid) were lower in MDE patients.Conclusion: Whilst the results of this study demonstrate an association between the metabolites studied and depression, conclusions about causality cannot be made. This study uses the largest ever sample of MDE patients, with an extensive assessment of peripheral tryptophan metabolism in plasma. These findings provide new insights into the peripheral signature of MDE. The reasons for these changes should be further investigated. These results might suggest new antidepressant therapeutic strategies

Peripheral tryptophan, serotonin, kynurenine, and their metabolites in major depression: A case–control study

International audienceAim: Tryptophan is the sole precursor of both peripherally and centrally produced serotonin and kynurenine. In depressed patients, tryptophan, serotonin, kynurenine, and their metabolite levels remain unclear. Therefore, peripheral tryptophan and metabolites of serotonin and kynurenine were investigated extensively in 173 patients suffering from a current major depressive episode (MDE) and compared to 214 healthy controls (HC).Methods: Fasting plasma levels of 11 peripheral metabolites were quantified: tryptophan, serotonin pathway (serotonin, its precursor 5-hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid), and kynurenine pathway (kynurenine and six of its metabolites: anthranilic acid, kynurenic acid, nicotinamide, picolinic acid, xanthurenic acid, and 3-hydroxyanthranilic acid).Results: Sixty (34.7%) patients were antidepressant-drug free. Tryptophan levels did not differ between MDE patients and HC. Serotonin and its precursor (5-hydroxytryptophan) levels were lower in MDE patients than in HC, whereas, its metabolite (5-hydroxyindoleacetic acid) levels were within the standard range. Kynurenine and four of its metabolites (kynurenic acid, nicotinamide, picolinic acid, and xanthurenic acid) were lower in MDE patients.Conclusion: Whilst the results of this study demonstrate an association between the metabolites studied and depression, conclusions about causality cannot be made. This study uses the largest ever sample of MDE patients, with an extensive assessment of peripheral tryptophan metabolism in plasma. These findings provide new insights into the peripheral signature of MDE. The reasons for these changes should be further investigated. These results might suggest new antidepressant therapeutic strategies

The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age

Activation of thermogenic beige adipocytes has recently emerged as a promising therapeutic target in obesity and diabetes. Relevant human models for beige adipocyte differentiation are essential to implement such therapeutic strategies. We report a straightforward and efficient protocol to generate functional human beige adipocytes from human induced pluripotent stem cells (hiPSCs). Without overexpression of exogenous adipogenic genes, our method recapitulates an adipogenic developmental pathway through successive mesodermal and adipogenic progenitor stages. hiPSC-derived adipocytes are insulin sensitive and display beige-specific markers and functional properties, including upregulation of thermogenic genes, increased mitochondrial content, and increased oxygen consumption upon activation with cAMP analogs. Engraftment of hiPSC-derived adipocytes in mice produces well-organized and vascularized adipose tissue, capable of β-adrenergic–responsive glucose uptake. Our model of human beige adipocyte development provides a new and scalable tool for disease modeling and therapeutic screening

The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age

<div><p>Metabolomic approaches are increasingly used to identify new disease biomarkers, yet normal values of many plasma metabolites remain poorly defined. The aim of this study was to define the “normal” metabolome in healthy volunteers. We included 800 French volunteers aged between 18 and 86, equally distributed according to sex, free of any medication and considered healthy on the basis of their medical history, clinical examination and standard laboratory tests. We quantified 185 plasma metabolites, including amino acids, biogenic amines, acylcarnitines, phosphatidylcholines, sphingomyelins and hexose, using tandem mass spectrometry with the Biocrates AbsoluteIDQ p180 kit. Principal components analysis was applied to identify the main factors responsible for metabolome variability and orthogonal projection to latent structures analysis was employed to confirm the observed patterns and identify pattern-related metabolites. We established a plasma metabolite reference dataset for 144/185 metabolites. Total blood cholesterol, gender and age were identified as the principal factors explaining metabolome variability. High total blood cholesterol levels were associated with higher plasma sphingomyelins and phosphatidylcholines concentrations. Compared to women, men had higher concentrations of creatinine, branched-chain amino acids and lysophosphatidylcholines, and lower concentrations of sphingomyelins and phosphatidylcholines. Elderly healthy subjects had higher sphingomyelins and phosphatidylcholines plasma levels than young subjects. We established reference human metabolome values in a large and well-defined population of French healthy volunteers. This study provides an essential baseline for defining the “normal” metabolome and its main sources of variation.</p></div

Main characteristics of the healthy volunteers according to sex.

<p>Main characteristics of the healthy volunteers according to sex.</p

Age effect on the metabolite profile of healthy volunteers.

<p><b>(A) Scores plot from OPLS multivariate analysis, cross-validated score plot resulting from OPLS modeling of age.</b> Each age group is represented in different colors, from blue to red. <b>(B) Age S-plot.</b> Metabolites in the upper-right corner correlate positively with age, while those in the bottom-left corner correlate negatively with age. The p axis describes the contribution of each variable to the model. (<b>C) Total sphingomyelins concentration according to the age group. (D) Total phosphatidylcholines concentration according to the age group. (E) Phospholipase activity according to the age group.</b> *p<0.05; ** p<0.01; ***p<0.001.</p

Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial.

Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown.Comparative StudyJournal ArticleMulticenter StudyRandomized Controlled TrialResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Correlation of TBC with metabolome values in healthy volunteers.

<p><b>(A) Scores plot from OPLS multivariate analysis, cross-validated score plot resulting from OPLS modeling of Total Blood Cholesterol.</b> Clinically relevant limits have been set on the TBC concentrations; the red dots represent HVs with TBC above 6.2 mmol/L, the green dots, HVs with TBC below 5.1 mmol/L, and the yellow dots are in-between. <b>(B) TBC S-plot.</b> Metabolites in the upper right corner correlate positively with total blood cholesterol. The p axis describes the contribution of each variable to the model. <b>(C) Total phosphatidylcholines concentration according to total blood cholesterol.</b> TBC below 5.1 mmol/L (green), between 5.11 and 6.2 mmol/L (orange) and above 6.21 mmol/L (red). <b>(D) Total sphingomyelins concentration according to total blood cholesterol. (E) Phospholipase activity according to total blood cholesterol.</b> ** p<0.01;***p<0.001.</p

Gender effect on the metabolic profile of healthy volunteers.

<p><b>(A) Scores plot from OPLS multivariate analysis, cross-validated score plot resulting from OPLS modeling of gender.</b> Females are represented with red dots, males with blue dots. <b>(B) Gender S-Plot.</b> Metabolites in the upper-right corner are higher in women; those in the lower-left corner are higher in males. The p axis describes the contribution of each variable to the model. <b>(C) Total sphingomyelins concentration according to sex. (D) Total lysophosphatidylcholines concentration according to sex. (E) Phospholipase activity according to sex.</b> ***p<0.001.</p

Management of alcohol-related liver disease: the French Association for the Study of the Liver and the French Alcohol Society clinical guidelines

International audienceExcessive alcohol consumption is the leading cause of liver diseases in Western countries, especially in France. Alcohol-related liver disease (ARLD) is an extremely broad context and there remains much to accomplish in terms of identifying patients, improving prognosis and treatment, and standardising practices. The French Association for the Study of the Liver wished to organise guidelines together with the French Alcohol Society in order to summarise the best evidence available about several key clinical points in ARLD. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe how patients with ARLD should be managed nowadays and discuss the main unsettled issues in the field