Biology subjects

Laye, S.

Publications and source records attributed to Laye, S..

7 recordsLinked to original sources

bioRxiv2026

Dietary fructose promotes anxiety through impairment of microglia physiology

Excessive dietary fructose has been linked to metabolic and mood disorders but the underlying brain mechanisms remain unclear. In this study, we tested whether microglia, the brain resident immune cells, mediate fructose-induced anxiety. Adult C57BL/6J mice and mice knock-down for the fructose transporter Glut5 selectively in microglia (Slc2a5flox/flox:Tmem119-Cre-positive mice) were exposed to 25% fructose in drinking water for 8 weeks. We assessed metabolic parameters, anxiety- and depression-like behaviors using a battery of behavioral tests. We then performed RNA sequencing in several brain regions, including the hippocampus to characterize fructose-induced transcriptional changes. Microglial responsiveness to lipopolysaccharide (LPS) treatment was assessed in vitro and in vivo using immunohistochemistry (microglia morphology) and RT-qPCR (cytokine gene expression). Fructose feeding induced marked metabolic alterations and robust anxiety-like behavior in male mice, together with memory deficits, whereas females showed milder metabolic changes and memory impairment without clear emotional disturbances. RNA sequencing revealed that fructose alters microglial gene-expression profiles in the hippocampus. Microglial Glut5 knockdown prevented fructose-induced anxiety-like behavior in the novelty-suppressed feeding test, indicating that microglial fructose uptake is required for this effect. At the molecular level, physiological fructose exposure did not markedly increase microglial cytokine expression but blunted the cytokine response to lipopolysaccharide, consistent with a hypo-reactive microglial state. Overall, these findings identify microglia as a critical mediator of fructose-induced anxiety and suggest that chronic fructose exposure promotes a maladaptive microglial phenotype that disrupts brain circuit function, with potential implications for diet-related mental health risk.

neuroscience↗

bioRxiv2026

Standardized brain and plasma EV enrichment pipeline validated for Single sample multi-Omic and fatty acids applications in Mouse and Human

Extracellular vesicles (EVs) are key mediators of intercellular communication, yet their molecular profiles across tissues and species remain poorly characterized, particularly due to currently available methods requiring a large amount of biological material (tissue or biofluids). Here, we established a workflow allowing the deep phenotyping of EV cargos starting from single samples of human and mouse origin. We took advantage of standardised EV isolation procedures and multi-omic techniques for the isolation and analysis of EVs from brain and plasma of human and mouse, integrating flow cytometric profiling, proteomics, miRNA sequencing, and fatty acid profiling. Here we report specific brain-derived EVs proteome, enriched in neuronal and glial proteins, polyunsaturated fatty acids profiles, and distinct miRNAs. At the periphery, we also report plasma-derived EVs signatures reflecting immune, metabolic, and systemic transport functions. Despite these expected material-specific differences, EVs from the same source displayed greater similarity across species than EVs from different material, supporting the translational relevance of mouse models. Importantly, using state-of-the-art miRNA profiling approach, we identified novel EV-specific miRNAs in human and mouse brain EVs, potentially allowing the exploration of new roles in neuronal signalling. Overall, we report here a method enabling deep multi-omic characterization from minimal starting material, offering a practical approach for studies with limited biological samples. These findings also demonstrate that the origin strongly shapes EV composition, highlighting conserved and species-specific molecular features, and provide a scalable framework for multi-omic investigations of EV biology. Summary StatementWe present a standardised workflow allowing multi-omic profiling of brain and plasma-derived EVs from minimal human and mouse material. Our findings reveal both tissue-specific and species specific EV molecular signatures.

neuroscience↗

bioRxiv2025

Maternal n-3 PUFA deficiency alters brain fatty acid and oxylipin profiles across perinatal development in offspring

Long-chain polyunsaturated fatty acids (LC-PUFAs), particularly arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), are essential for optimal neurodevelopment through their effect on neuronal proliferation, neurite outgrowth and synaptogenesis. Emerging evidence highlights that brain PUFAs are metabolized in oxylipins, the bioactive oxidized PUFA metabolites known to regulate inflammatory processes. Recent data highlighted that both PUFA and oxylipin profiles are modulated in the adult male brain by dietary PUFA content. However, little is known on the impact of maternal dietary n-3 PUFA intake during the perinatal period and the neurodevelopmental profile of brain fatty acids and associated oxylipins in offspring, and whether these effects differ between sexes. To address this question, we first measured fatty acid levels in the placenta and embryonic brain of male and female offspring of mothers fed a sufficient or deficient diet in n-3 PUFAs at embryonic day (E)17.5. Then, fatty acids and oxylipins were measured at different post-natal stages, in the brain at P0 and P7, and in the hippocampus at P14 and P21, in both male and female offspring. Our results show that maternal n-3 PUFA dietary deficiency alters fatty acid profiles as early as E17.5 in both the placenta and the brain. Furthermore, dietary intervention affects both fatty acid and oxylipin profiles throughout postnatal brain development, with notable sex-specific differences. These findings underscore the critical importance of adequate maternal n-3 PUFA intake during the perinatal period for maintaining an optimal PUFA and oxylipin profiles, with potential implications for fetal and postnatal brain development.

neuroscience↗

bioRxiv2025

Fructose malabsorption induces dysbiosis and increases anxiety in Human and animal models

Background & AimsExcessive fructose intake is a growing public health concern, yet many individuals have a lower absorption capacity than the average intake, leading to widespread chronic fructose malabsorption. This results in intestinal fructose spillover, disrupting gut microbiota and triggering peripheral inflammation, which, along with neuroinflammation, plays a key role in mood disorders. This study investigates the connection between fructose malabsorption and mood disorders by examining gut microbiota changes in a human cohort and exploring their links with neuroinflammation in a GLUT5-KO mouse model. MethodsIn a human cohort, fructose malabsorption was assessed using a breath hydrogen test, while plasma lipopolysaccharide (LPS) levels and anxiety traits (measured using the State-Trait Anxiety Inventory, STAI) were analyzed. Gut microbiota composition was characterized through 16S rRNA sequencing, and dietary fructose intake was recorded. In the preclinical study, Glut5-KO mice, which lack intestinal fructose transport, were fed a 5% fructose diet for four weeks. Behavioral assays assessed anxiety- and depressive-like behaviors, while gut microbiota composition and microglia-associated gene expression were analyzed. ResultsAmong the recruited healthy volunteers, 60% exhibited fructose malabsorption, along with elevated plasma LPS levels, increased anxiety traits on the STAI, and distinct gut microbiota alterations, partially linked to fructose intake patterns. The average daily fructose intake was 30 g per individual, with significant variability in dietary sources. In the preclinical model, Glut5-KO mice on a 5% fructose diet displayed increased anxiety- and depressive-like behaviors, pronounced gut microbiota shifts, and altered expression of microglia-associated genes. ConclusionsThese findings highlight the complex interplay between dietary fructose, gut microbiota, and neuroinflammation in shaping mental health. Chronic fructose malabsorption may contribute to mood disorders through gut dysbiosis and microglia-dependent neuroinflammation, warranting further investigation into dietary interventions. HIGHLIGHTSO_LIFructose malabsorption is associated with anxiety traits in healthy volunteers. C_LIO_LIFructose malabsorption enhances anxiety-like behaviors in malabsorptive Glut5-KO mice. C_LIO_LIFructose malabsorption is associated with gut microbiota dysbiosis in human and preclinical mouse model of fructose malabsorption in association with fructose intake C_LIO_LIFructose malabsorption increases neuroinflammation and alters microglia functions in malabsorptive Glut5-KO mice. C_LI

microbiology↗

bioRxiv2024

Blood metabolomic profiling reveals new targets in the management of psychological symptoms associated with alcohol use disorder

Alcohol use disorder (AUD) is a global health problem with limited therapeutic options. The biochemical mechanisms that lead to this disorder are not yet fully understood, and in this respect, metabolomics represents a promising approach to decipher metabolic events related to AUD. The plasma metabolome contains a plethora of bioactive molecules that reflects the functional changes in host metabolism but also the impact of the gut microbiome and nutritional habits. In this study, we investigated the impact of severe AUD (sAUD), and of a three-week period of alcohol abstinence, on the blood metabolome (non-targeted LC-MS metabolomics analysis) in 96 sAUD patients hospitalized for alcohol withdrawal. We found that the plasma levels of different lipids ((lyso)phosphatidylcholines, long-chain fatty acids), short-chain fatty acids (i.e. 3-hydroxyvaleric acid) and bile acids were altered in sAUD patients. In addition, several microbial metabolites, including indole-3-propionic acid, p-cresol sulfate, hippuric acid, pyrocatechol sulfate, and metabolites belonging to xanthine class (paraxanthine, theobromine and theophylline) were sensitive to alcohol exposure and alcohol withdrawal. 3-Hydroxyvaleric acid, caffeine metabolites (theobromine, paraxanthine and theophylline) and microbial metabolites (hippuric acid and pyrocatechol sulfate) were correlated with anxiety, depression and alcohol craving. Metabolomics analysis in post-mortem samples of frontal cortex and cerebrospinal fluid of those consuming a high level of alcohol revealed that those metabolites can be found also in brain tissue. Our data allow to for the identification of neuroactive metabolites, from interactions between food components and microbiota, which may represent new targets in the management of neuropsychiatric diseases such as sAUD.

neuroscience↗

bioRxiv2023

Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS

Adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral tissues. ATGL has been associated with both pro- and anti-inflammatory responses in different tissues suggesting its actions are dependent on cell type. Recent studies in microglia and macrophages suggest that lipid droplets (LD), a triglyceride storing organelle, and LD lipolysis via ATGL are important components of inflammatory responses. Here, we determined the impact of ATGL inhibition and microglia-specific ATGL loss-of-function on inflammatory and behavioural responses to acute pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines in mouse primary microglia cultures. LPS led to LD accumulation in microglia and altered the expression of lipolysis regulators. The pan-lipase inhibitor ORlistat alleviated LPS-induced expression of IL-1{beta} and IL-6. Specific inhibition of ATGL by ATGListatin had similar anti-inflammatory action on cytokines expression and secretion in both neonatal and adult microglia cultures. Second, targeted and untargeted lipidomic studies revealed that ATGL inhibition reduced LPS-induced generation of pro-inflammatory prostanoids and affected ceramide profile. Finally, the role of ATGL in neuroinflammation was assessed in a novel mouse model with inducible ATGL deletion specifically in microglia. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and reduced LPS-induced sickness behaviour. Together, our results demonstrate that pharmacological inhibition or loss of ATGL-mediated triglyceride lipolysis reduces LPS-induced inflammation to suggest that inhibition of lipolysis plays a beneficial role in neuroinflammation.

neuroscience↗

bioRxiv2019

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, through the activation of 12/15- lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.\n\nOne Sentence SummaryLow maternal omega-3 fatty acids intake impairs microglia-mediated synaptic refinement via 12-HETE pathway in the developing brain.

neuroscience↗