Biology subjects

Cryan, J. F.

Publications and source records attributed to Cryan, J. F..

9 recordsLinked to original sources

bioRxiv2026

CD11c+ microglia promote dysfunctional T cell activation in diffuse midline glioma

Paediatric diffuse midline glioma (DMG) remains refractory to immunotherapy despite T-cell infiltration, indicating that local mechanisms actively suppress anti-tumour immunity. Using complementary genetic and orthotopic mouse models, we performed lineage-resolved profiling of the DMG immune microenvironment, resolving myeloid ontogeny and microglial states by distinguishing resident microglia from infiltrating bone marrow-derived macrophages. We identified microglia as the predominant tumour-associated myeloid population and discovered selective expansion of CD11c positive; microglia exhibiting enriched antigen-presentation and immune-regulatory transcriptional programs. Tumour-infiltrating CD4+; and CD8+; T cells exhibited chronic activation and exhaustion, while ligand receptor analysis predicted inhibitory microglia T cell communication. Pharmacological CSF1R inhibition depleted CD11c positive; microglia, attenuated antigen-presentation and immune-regulatory programs, and shifted tumour-infiltrating T cells toward a less exhausted phenotype. Together, these findings identify a previously unrecognised CD11 positive; microglia T-cell axis that establishes immune dysfunction in DMG and provide a rationale for combining myeloid- and T cell-targeted immunotherapies.

cell biology↗

bioRxiv2026

Gut Microbial Signals Influence Motivational Responses in the Male Mouse

Mammalian motivation to obtain natural rewards is regulated by internal biological and external environmental factors. Increasing evidence suggests the gut microbiota may represent one such factor. Here, we observed that antibiotic (ABX)-induced disruption of the gut microbiota increased the motivation to obtain palatable rewards, elevated inflammatory cytokine levels and elicited significant alterations in synaptic plasticity-related gene pathways in the mouse nucleus accumbens (NAc). We also observed that the dynamic state of the gut microbiota partially impacts motivational responses and identified several gut microbial metabolites that could be driving this phenotype. Finally, surgical ablation of vagal signalling via subdiaphragmatic vagotomy partially rescued transcriptomic signatures in the NAc and elevations in inflammatory markers but was not enough to prevent the increase in motivational responses. Overall, our results highlight an important new role for the gut microbiota in regulating the cascade of metabolic, neurochemical and immunological events necessary for reward processing and motivation.

neuroscience↗

bioRxiv2026

Microbiota-sensitive glial and metabolic programs define a critical window in early postnatal brainstem development

Paediatric brain tumours are increasingly recognised as diseases of disrupted development, arising when lineage progression programs, that normally govern neural and glial maturation, become stalled or dysregulated. Diffuse midline glioma (DMG), a highly aggressive paediatric brainstem tumour, emerges during early childhood in the pons, a region undergoing rapid postnatal growth characterized by oligodendrocyte precursor cell (OPC) proliferation and differentiation. However, the environmental factors that shape these developmental trajectories remain poorly defined. Here, using germ-free and conventionally colonized mice, we investigated whether early-life microbiota influences transcriptional and metabolic programs in the developing brainstem during this critical developmental window. Bulk RNA sequencing revealed pronounced microbiota-associated transcriptional differences at postnatal day 2 (P2), but not at P8, identifying a temporally restricted period during which microbial colonization is associated with pathways linked to oligodendrocyte lineage progression, myelination, and neuroimmune signalling. Transcriptional analyses further identified altered expression of genes associated with CD11c microglia, a developmental microglial subtype implicated in regulating oligodendrocyte maturation. Untargeted metabolomic profiling revealed parallel microbiota-associated differences in pathways related to mitochondrial function, redox balance, and methyl-donor metabolism. Integrated multi-omics analyses identified coordinated networks linking glial lineage programs with metabolites involved in cellular metabolism and epigenetic regulation. Notably, several of these transcriptional and metabolic programs overlap with gene signatures reported in diffuse midline glioma, suggesting that microbiota-sensitive developmental pathways intersect with cellular states relevant to paediatric brainstem tumour biology.

neuroscience↗

bioRxiv2026

Birth by Cesarean Section Remodels Neonatal Brain Barriers and Associated Immune and Metabolic Pathways in Mice

Delivery mode shapes early-life physiology through multiple pathways, including stress and hormonal signalling, neonatal oxygenation, and exposure to maternal microbes. Cesarean section (CS) bypasses several of these processes and has been associated with altered immune maturation and neurodevelopmental outcomes in humans and animal models. Given that CS is known to disrupt gut barrier integrity and that gut and brain barriers operate as a coordinated network, we investigated whether CS affects early postnatal brain barriers. Using a mouse model, we compared CS-delivered pups to vaginally born (VB) controls at postnatal days 8-9. Brain barrier permeability and structure were assessed using tracer extravasation and vascular and tight junction analyses, choroid plexus immune populations were profiled, and metabolomics was performed in cortex and plasma. The blood-brain barrier in the medial prefrontal cortex was mostly preserved. In contrast, the blood-cerebrospinal fluid barrier (BCSFB) exhibited structural alterations in vascular and epithelial tight junction compartments. These changes were accompanied by immune remodelling, including expansion of antigen-presenting border-associated macrophages and reduced parenchymal microglia density. CS delivery increased brain tracer accumulation, consistent with altered barrier function during this developmental window. Metabolomic analyses revealed lower levels of key brain metabolites, including N-acetylaspartate, a marker of neuronal metabolic state. Together, these findings demonstrate that CS delivery induces early alterations in brain barrier function, BCSFB structure, the immune landscape, and metabolic profiles in mice. This identifies delivery mode as a key perinatal variable shaping neonatal brain physiology and establishes a framework for dissecting how birth context may influence long-term neurodevelopmental trajectories. HIGHLIGHTSO_LICesarean section (CS) reveals the neonatal BCSFB as a vulnerable interface shaped by birth mode C_LIO_LICS increases brain tracer accumulation despite largely preserved BBB structural markers at the mPFC C_LIO_LICS induces region-specific vascular, epithelial, and immune remodeling in the choroid plexus C_LIO_LICesarean birth increases the proportion of antigen-presenting choroid plexus macrophages C_LIO_LICS shifts mPFC metabolic profiles, including reduced N-acetylaspartate and malate C_LI

neuroscience↗

bioRxiv2025

Faecal transplantation from exuberant toddlers increases exploratory behaviour in rats

BackgroundBehavioural phenotypes have previously been transferred via faecal microbiota transplantation (FMT) from patients with psychiatric disorders to rodents. Studies indicate that the gut microbiota composition may be linked to certain temperament traits, defined as biologically-based differences in emotional reactivity and self-regulation. Here, we aimed to determine if the gut microbiota plays a role in temperament using an FMT approach. We focused on the temperament traits of exuberance, defined as positive reactivity, decreased behavioural inhibition, and high behavioural approach tendencies. MethodsFaeces from 2.5-year-old toddlers from FinnBrain Birth Cohort Study with high exuberance/approach or high behavioural inhibition in the LabTAB bubbles-episode was transferred to juvenile male Sprague Dawley rats (age 22/23 days). Behaviour of the rat recipients (n=53) was assessed using the novel non-social arena, novel social arena, hole board test for exploratory behaviour, social approach-avoidance test, and forced swim test. The faecal pellets collected from the rodents were analyzed with 16s rRNA sequencing and faecal samples from the sample of toddlers (which included the donors, n=176) were analysed using short-read metagenomic sequencing. The striatum and prefrontal cortex from the rodents brains were analysed post-mortem using RNAseq. ResultsMicrobiome from toddlers with high exuberance traits induced increased exploratory behaviour compared to vehicle-controls and rats receiving faeces from inhibited toddlers. Locomotor activity, social, and depressive-like behaviour remained unaffected. We noted a downregulation of the dopamine synapse pathway within the striatum of the rats that received faeces from the inhibited trait donors compared with vehicle-controls. Faecal microbiota of rats receiving faeces from the same donor resembled more each other than rats from a different cage. Clostridium species AM29 11AC in toddler microbiome was positively related to exuberance, but there were no cross-sectional associations between faecal metabolites in the human sample. ConclusionsFMT from exuberant toddlers lead to altered exploratory-related behaviour in rats.

microbiology↗

bioRxiv2025

The South American MicroBiome Archive (saMBA): Enriching the healthy microbiome concept by evaluating uniqueness and biodiversity of neglected populations

The composition and function of the human gut microbiome has been linked to multiple health outcomes across all world regions, often with region-specific associations. Unfortunately, the extent to which microbiomes from different populations are characterised is limited by their economic resources. Over 70% of the sequenced human microbiomes come from analyses of European and North American populations, skewing our understanding by focusing excessively on just 15% of the global population. Thus, entire continents rely on results from research conducted in wealthier countries whose main findings are unlikely to generalize across other world regions. Moreover, statistical models perform poorly when applied to minorities, a blind spot with serious consequences in biomedicine, and which can only be addressed by analysing microbiome data from currently neglected areas. To address this problem, we created saMBA-- the largest archive of gut microbiomes from South America, one of the worlds most biodiverse regions in terms of the gut microbiome of its inhabitants, yet the one with the fewest samples. saMBA includes 33 gut microbiome studies, [~]73% of which were incorporated in a microbiome archive for the first time. By leveraging this resource, we uncovered a high biodiversity within --and uniqueness between-- gut microbiomes across the continent, expanding the concept of the healthy microbiome to be more globally representative. Additionally, our results highlight that the gut microbiome biodiversity of this region remains far from fully characterized. We demonstrate how saMBA can guide new sampling efforts to better capture this diversity. Finally, the code deployed to build saMBA is compatible with that of a previous global compendium and is openly available to researchers from other underrepresented regions, fostering the inclusion of other neglected populations to accelerate microbiome research globally.

bioinformatics↗

bioRxiv2024

The Neuroactive Potential of the Elderly Human Gut Microbiome is Associated with Mental Health Status

Ageing is usually associated with physiological decline, increased mental health issues, and cognitive deterioration, alongside specific changes in the gut microbiome. However, the relationship between the neuroactive potential of the gut microbiome and mental health and cognition among the elderly remains less explored. This study examines a cohort of 153 older Chilean adults with cognitive complaints, assessing anthropometric data, mental health via five distinct tests, and gut microbiome composition through 16SV4 sequencing. Our findings reveal associations between anthropometric factors and depression scores in mental tests of participants with their gut microbiome composition. Notably, depression was associated with changes in the abundance of Lachnospiraceae Eubacterium xylanophilum group and Fusobacteriaceae Fusobacterium. Additionally, bacterial pathways involved in metabolising neuroactive compounds such as tryptophan, short-chain fatty acids, p-cresol, glutamate, and nitric oxide were associated with participant age, sex, and cognitive performance. Moreover, participants sex was associated with the neuroactive potential of specific bacteria, suggesting a role of the gut microbiome in sex-related mental health differences in the elderly. Together, to the best of our knowledge, this study demonstrates for the first time the association between the neuroactive potential of the human gut microbiome and mental health status in older individuals with cognitive complaints.

animal behavior and cognition↗

bioRxiv2024

Distinct Dendritic Morphological Changes in the Nucleus Accumbens of Microbiota-deficient Male Mice

The gut microbiota has been shown to be an important regulator of brain and behaviour. Germ-free rodents are a key model to study the microbiome-gut-brain axis to reveal the microbial underpinnings of diseases, including those related to psychiatric illnesses. The present study evaluated whether the absence of gut microbiota could alter the morphological development of the nucleus accumbens, a brain region located in the ventral striatum involved in stress, mood and addiction. In germ-free mice, there was dendritic hypertrophy of medium spiny neurons in the shell and dendritic elongation in the core. This led to an increase in the number of stubby dendritic spines within the shell and an increase in both stubby and thin spines in the core. Taken together, these results indicate that the gut microbiota is essential for the normal development of the dendritic structure of medium spiny neurons in the nucleus accumbens and that altered remodelling may contribute to maladaptive psychiatric disorders.

neuroscience↗

bioRxiv2023

Kronos: A computational tool to facilitate biological rhythmicity analysis

MotivationCircadian rhythms, or 24-hour biological cycles, are key in maintaining health in almost all living organisms and synchronize important physiological and behavioural processes daily. Interest in circadian rhythm research is expanding as our urban environments have increased exposure to factors that can disrupt the normal physiological rhythm of our body, such as delayed bedtimes, shift work, jet-lag, increased screen-time, and exposure to artificial light. Discovering how oscillatory signals respond to both external and internal factors can lead to important biological breakthroughs, but assessing rhythmicity can be both limited by the complexity of statistical models and demanding in terms of coding and statistical expertise. ImplementationHere, we describe the development of a novel easy-to-use R-based tool, Kronos, to assess circadian rhythms in biological data sets. Kronos provides the user with new functionalities not currently available, including the analysis of two or more groups in complex study designs, handling both independent and repeated-measures data, as well as ranging from single variables to high dimensional omics data sets. Kronos is a novel tool to facilitate the analysis of rhythmicity in simple and complex experimental designs and enables researchers from diverse scientific fields to interrogate rhythmicity. Availabilityhttps://github.com/thomazbastiaanssen/kronos

bioinformatics↗