People living with HIV display increased anti-apolipoprotein A1 auto-antibodies, inflammation, and kynurenine metabolites: a case–control study

ObjectiveThis study aimed to study the relationship between auto-antibodies against apolipoprotein A1 (anti-apoA1 IgG), human immunodeficiency virus (HIV) infection, anti-retroviral therapy (ART), and the tryptophan pathways in HIV-related cardiovascular disease.DesignThis case–control study conducted in South Africa consisted of control volunteers (n = 50), people living with HIV (PLWH) on ART (n = 50), and untreated PLWH (n = 44). Cardiovascular risk scores were determined, vascular measures were performed, and an extensive biochemical characterisation (routine, metabolomic, and inflammatory systemic profiles) was performed.MethodsAnti-apoA1 IgG levels were assessed by an in-house ELISA. Inflammatory biomarkers were measured with the Meso Scale Discovery® platform, and kynurenine pathway metabolites were assessed using targeted metabolomic profiling conducted by liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS).ResultsCardiovascular risk scores and vascular measures exhibited similarities across the three groups, while important differences were observed in systemic inflammatory and tryptophan pathways. Anti-apoA1 IgG seropositivity rates were 15%, 40%, and 70% in control volunteers, PLWH ART-treated, and PLWH ART-naïve, respectively. Circulating anti-apoA1 IgG levels were significantly negatively associated with CD4+ cell counts and positively associated with viremia and pro-inflammatory biomarkers (IFNγ, TNFα, MIPα, ICAM-1, VCAM-1). While circulating anti-apoA1 IgG levels were associated with increased levels of kynurenine in both control volunteers and PLWH, the kynurenine/tryptophan ratio was significantly increased in PLWH ART-treated.ConclusionHIV infection increases the humoral response against apoA1, which is associated with established HIV severity criteria and kynurenine pathway activation

Metabolomics reveals the role of endocannabinoid system in modulating obesity-associated inflammation in adipose tissue

As a powerful phenotyping technology, metabolomics provides new opportunities in biomarker discovery through metabolome-wide association studies (MWAS) and identification of metabolites having a regulatory effect in various biological processes. In this research program, multiple efforts were devoted to the development and improvement of analytical conditions for comprehensive metabolome study in different research projects. Notably, the focus was laid on the optimization of different experimental settings and the development of new bioinformatic tools for processing and mining of metabolome data. To exemplify such process, in this manuscript, we present in detail the application of untargeted metabolomics into a research project called InflaWAT, focused on improving our molecular understanding of the development of inflammation in adipose tissue in obesity. Obesity is a major public health concern due to its association with multiple metabolic disorders. A pattern of low grade and chronic inflammation is known to develop in obesity, starting from visceral adipose tissue and propagating to other peripheral metabolic tissues and in the circulation, but the mechanisms underlying its onset and need to be clarified. To identify molecular pathways potentially involved in the onset of obesity-associated inflammation, one aim of this project was to compare the metabolome of mouse visceral (vAT) and subcutaneous (scAT) adipose tissue, two fat depots characterized by a different susceptibility to inflammation in response to a high fat diet (HFD). Untargeted metabolomics was set up for application on adipose tissue matrix, along with the optimization of an analytical pipeline for data mining. Notably, we implemented “dbnorm”, a new package in R, developed for removing analytical heterogeneity from metabolome data. Our untargeted metabolomics on scAT and vAT, revealed only a mild effect of HFD after 1 week of HFD, while an extensive regulation of vAT metabolome, but not of scAT, was observed after 8 weeks of HFD. This time point was also characterized by a strong induction of inflammation in vAT upon HFD, as assessed by histological and gene expression analyses. The metabolome profiling revealed 2-arachidonoylglycerol (2-AG) and then endocannabinoid system (ECS), respectively, as one of the top-ranked metabolites and biological functions activated in vAT, as opposed to scAT, in response to HFD. These observations were further confirmed and validated by targeted metabolomics, gene expression and epigenetic measurements. To systematically explore the differential regulation and the role of ECS in vAT and scAT, we isolated mature adipocytes from the stromal vascular fraction in mice fed with a HFD for 8 weeks. Our results suggested that adipocytes are the main source of increased production of 2-AG in vAT, while the ligands can act on both infiltrating immune cells and adipocytes, both expressing CB receptors. We next explored the functional role of ECS in obese AT, by separately stimulating macrophages and adipocytes with cannabinoids and found that, only in activated macrophages, cannabinoids dampen the inflammatory response. Collectively our results depict the fine regulation of ECS in AT in response to HFD, suggesting a coordinate system in which the production of EC in adipocytes might signal on both infiltrating immune cells and adipocytes with cell-specific effects. Future studies will further dissect the paracrine communication mediated by ECS in adipose tissue. -- En tant que puissante technologie de phénotypage, la métabolomique offre de nouvelles possibilités dans la découverte de biomarqueurs grâce à des études d'association à l'échelle du métabolome (MWAS) et à l'identification des métabolites ayant un effet régulateur dans divers processus biologiques. Dans le cadre de ce programme de recherche, de nombreux efforts ont été consacrés au développement et à l'amélioration des conditions analytiques pour l'étude complète du métabolome dans différents projets de recherche. Pour illustrer ce processus, dans ce manuscrit, nous présentons en détail l'application de la métabolomique non ciblée dans un projet de recherche appelé InflaWAT, axé sur l'amélioration de notre compréhension moléculaire du développement de l'inflammation dans le tissu adipeux lié à l'obésité. On sait qu'une inflammation chronique de faible intensité se développe avec l'obésité, partant du tissu adipeux viscéral et se propageant à d'autres tissus métaboliques périphériques et dans la circulation, mais les mécanismes qui sous-tendent son apparition doivent être clarifiés. Afin d'identifier les voies moléculaires potentiellement impliquées dans l'apparition de l'inflammation associée à l'obésité, l'un des objectifs de ce projet était de comparer le métabolome du tissu adipeux viscéral (vAT) et sous-cutané (scAT) de la souris, deux dépôts de graisse caractérisés par une sensibilité différente à l'inflammation en réponse à un régime alimentaire riche en graisses (HFD). La métabolomique non ciblée a été mise en place pour une application sur la matrice du tissu adipeux, ainsi que l'optimisation d'un pipeline analytique pour l'exploration de données. Nous avons notamment mis en œuvre "dbnorm", un nouveau progiciel en R, développé pour éliminer l'hétérogénéité analytique des données métabolomiques. Notre métabolomique non ciblée sur le scAT et le vAT n'a révélé qu'un léger effet du régime HFD après une semaine , tandis qu'une dérégulation complexe du métabolome du vAT, mais pas du scAT, a été observée après huit semaines de HFD. Cette période a également été caractérisée par une forte induction de l'inflammation du vAT après un régime HFD, comme l'ont montré les analyses histologiques et les analyses de l'expression génétique. Le profilage du métabolome a révélé que le 2-arachidonoylglycérol (2-AG) et plus largement le système endocannabinoïde (ECS) étaient parmi les fonctions biologiques les plus activés dans le vAT en réponse à l'HFD. Ces observations ont été confirmées et validées par la métabolomique ciblée, l'expression des gènes et des mesures épigénétiques. Pour explorer systématiquement la régulation différentielle et le rôle de l'ECS dans le vAT et le scAT, nous avons isolé des adipocytes matures de la fraction vasculaire du stroma chez des souris nourries avec un HFD pendant 8 semaines. Nos résultats suggèrent que les adipocytes sont la principale source de production accrue de 2-AG dans la vAT, tandis que les ligands peuvent agir à la fois sur les cellules immunitaires infiltrantes et sur les adipocytes, les deux exprimant les récepteurs CB. Nous avons ensuite exploré le rôle fonctionnel de l'ECS dans l'AT obèse, en stimulant séparément les macrophages et les adipocytes avec des cannabinoïdes et avons constaté que, seulement dans les macrophages activés, les cannabinoïdes réduisaient la réponse inflammatoire. Collectivement, nos résultats décrivent la régulation fine de l'ECS dans l'AT en réponse au HFD, suggérant un système de coordination dans lequel la production d'EC dans les adipocytes pourrait signaler à la fois les cellules immunitaires infiltrantes et les adipocytes avec des effets spécifiques aux cellules. Des études futures permettront de disséquer davantage la communication paracrine médiée par l'ECS dans le tissu adipeux

People living with HIV display increased anti-apolipoprotein A1 auto-antibodies, inflammation, and kynurenine metabolites : a case–control study

Objective This study aimed to study the relationship between auto-antibodies against apolipoprotein A1 (anti-apoA1 IgG), human immunodeficiency virus (HIV) infection, anti-retroviral therapy (ART), and the tryptophan pathways in HIV-related cardiovascular disease. Design This case–control study conducted in South Africa consisted of control volunteers ( n  = 50), people living with HIV (PLWH) on ART ( n  = 50), and untreated PLWH ( n  = 44). Cardiovascular risk scores were determined, vascular measures were performed, and an extensive biochemical characterisation (routine, metabolomic, and inflammatory systemic profiles) was performed. Methods Anti-apoA1 IgG levels were assessed by an in-house ELISA. Inflammatory biomarkers were measured with the Meso Scale Discovery® platform, and kynurenine pathway metabolites were assessed using targeted metabolomic profiling conducted by liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS). Results Cardiovascular risk scores and vascular measures exhibited similarities across the three groups, while important differences were observed in systemic inflammatory and tryptophan pathways. Anti-apoA1 IgG seropositivity rates were 15%, 40%, and 70% in control volunteers, PLWH ART-treated, and PLWH ART-naïve, respectively. Circulating anti-apoA1 IgG levels were significantly negatively associated with CD4+ cell counts and positively associated with viremia and pro-inflammatory biomarkers (IFNγ, TNFα, MIPα, ICAM-1, VCAM-1). While circulating anti-apoA1 IgG levels were associated with increased levels of kynurenine in both control volunteers and PLWH, the kynurenine/tryptophan ratio was significantly increased in PLWH ART-treated. Conclusion HIV infection increases the humoral response against apoA1, which is associated with established HIV severity criteria and kynurenine pathway activation.</p

Dynamic lipidome alterations associated with human health, disease and ageing.

Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report &gt;800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed &gt;1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies

Temporal dynamics of the multi-omic response to endurance exercise training

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ )