Biology subjects

De Santis, S.

Publications and source records attributed to De Santis, S..

9 recordsLinked to original sources

bioRxiv2026

Multimodal neuroimaging-microbiota integration identifies Akkermansia as a modulator of alcohol-induced gut-liver-brain pathology

Alcohol use disorder (AUD) disrupts the gut-liver-brain axis, yet mechanistically grounded and therapeutically actionable targets within this network remain poorly defined. To identify microbial modulators of alcohol-induced tissue pathology, longitudinal advanced diffusion MRI and fecal 16S rRNA profiling were integrated across Marchigian Sardinian alcohol-preferring rats evaluated at baseline, after four weeks of voluntary alcohol intake, and following six weeks of abstinence. Machine learning, specifically random forest models combining neuroimaging and microbiota data, improved phase classification and identified Akkermansia as the microbial feature most strongly associated with alcohol-related white matter microstructural abnormalities. Alcohol exposure induced widespread white matter alterations alongside gut dysbiosis characterized by reduced microbial diversity. To evaluate functional relevance, Akkermansia muciniphila was administered during the abstinence phase. Supplementation with A. muciniphila restored intestinal mucus, reduced liver injury markers, and elevated myelin basic protein levels within affected white matter regions. Collectively, these findings highlight Akkermansia as a critical modulator of alcohol-induced gut-liver-brain pathology and provide experimental support for a causal contribution of specific gut bacteria to persistent white matter damage in AUD. More broadly, this work establishes a robust multimodal framework for microbiome-based target discovery with clear translational relevance for disorders characterized by dysfunction along the gut-liver-brain axis. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAlcohol use disorder (AUD) is associated with gut dysbiosis, impaired intestinal barrier function, liver injury, and persistent white matter abnormalities. Previous studies in patients and animal models have linked alcohol exposure to reduced microbial diversity, altered gut permeability, and white matter microstructural damage, particularly during abstinence. Other work has shown that microbiota-derived interventions can ameliorate peripheral consequences of alcohol exposure, especially in the gut and liver. However, the specific microbial features linked to alcohol-induced brain pathology remain poorly defined, and no prior study has integrated longitudinal microbiota and neuroimaging data to identify candidate microbial modulators of alcohol-related white matter damage and then functionally test them in vivo across the gut-liver-brain axis. Added value of this studyWe developed a multimodal framework that integrates longitudinal advanced diffusion MRI with fecal microbiota profiling and machine learning in alcohol-preferring rats. This approach identified Akkermansia as the microbial feature most strongly associated with alcohol-induced white matter abnormalities. Guided by this result, we administered Akkermansia muciniphila during abstinence and observed coordinated beneficial effects across multiple organs, including restoration of intestinal mucus, reduction of liver injury markers, and recovery of myelin basic protein in affected white matter regions. To our knowledge, this is the first study to combine longitudinal microbiota-MRI integration with experimental validation of a microbiota-based intervention that mitigates alcohol-induced pathology across the gut-liver-brain axis while restoring central white matter integrity. Implications of all the available evidenceOur findings support a mechanistic contribution of specific gut bacteria to persistent alcohol-induced tissue damage and identify Akkermansia as a candidate modulator of gut-liver-brain axis dysfunction in AUD. More broadly, this study establishes a generalizable strategy for integrating microbiota and neuroimaging data to discover biologically meaningful and therapeutically actionable targets in complex disorders involving coordinated peripheral and central pathology.

neuroscience↗

bioRxiv2026

Longitudinal MRI reveals hormone-dependent brain remodeling supporting preserved cognition in aged females

Adaptive plasticity, the brains capacity to counteract structural decline and preserve performance with age, is a hallmark of successful aging, yet its biological underpinnings remain poorly understood. Here, we combined longitudinal magnetic resonance imaging (MRI) spanning the entire lifespan with electrophysiology, immunohistochemistry, and behavioral assays in female and male rats to identify key region- and systems-level mechanisms underlying this process. Resting-state functional MRI revealed a striking sex-specific pattern of connectivity reorganization in anterior brain regions, emerging in midlife and more pronounced in females. Microstructural MRI and histological analyses linked increased connectivity to prolonged white matter preservation and downstream maintenance of neuronal function in the female prefrontal cortex, while electrophysiological recordings demonstrated enhanced effective connectivity in the same region in aged females. Behaviorally, enhanced anterior connectivity was associated with superior memory performance. Ovariectomy at a critical time point for white matter maturation compromised this female-specific neuroprotection, disrupting microstructural integrity and functional reorganization, thereby highlighting the role of sex hormones in shaping these trajectories. Together, these findings identify a novel sexually dimorphic pattern of functional reorganization in anterior brain regions and point to estrogen availability during critical periods as a key modulator of brain aging.

neuroscience↗

bioRxiv2025

A missense mutation in Muc2 promotes gut microbiome- and metabolome-dependent colitis-associated tumorigenesis.

Colitis-associated cancer (CAC) arises from a complex interplay between host and environmental factors, including the gut microbiome. Since ulcerative colitis (UC), a significant risk factor for CAC, is rising in prevalence worldwide, an integrative approach is essential to identify potential triggers linking inflammation to cancer. In the present study, we investigated the role of the gut microbiome using Winnie mice, a UC-like model with a relevant missense mutation in the Muc2 gene. Upon transfer from a conventional (CONV) to a specific-pathogen-free (SPF) facility, Winnie mice exhibited a more severe colitis phenotype, and notably, spontaneous CAC as early as four weeks of age, which progressively worsened over time. In contrast, CONV Winnie developed only mild colitis but with no overt signs of tumorigenesis. Notably, when rederived into germ-free (GF) conditions, SPF Winnie mice were protected from colitis or colon tumor development, indicating an essential role for the gut microbiome in the initiation and progression of CAC in these mice. Using shotgun metagenomics, metabolomics, and lipidomics, we identified a distinct pro-inflammatory microbial and metabolic signature that potentially drives the transition from colitis to CAC. Fecal microbiota transplantation (FMT), using either SPF Winnie or WT (Bl/6) donors into GF Winnie recipients, demonstrated that while colitis developed regardless of donor, only FMT from SPF Winnie donors resulted in CAC, revealing a microbiota-driven, host-specific susceptibility to tumorigenesis in Winnie mice. Our studies present a novel and relevant model of CAC, providing further evidence that the microbiome plays a key role in the pathogenesis of CAC, thereby challenging the concept of colon cancer as a strictly non-transmissible disease. Lay summaryThis study reveals a distinct metagenomic, metabolomic, and lipidomic profile associated with tumorigenesis in a murine model of ulcerative colitis, highlighting the risks of specific intestinal dysbiosis in genetically predisposed subjects. What you need to knowO_ST_ABSBackground and contextC_ST_ABSColitis-associated colorectal cancer arises from complex host-environment interactions, including gut microbiome influences, driving chronic inflammation, with the intestinal lumen environment remaining a largely unexplored potential risk factor in cancer development. New findingsWinnie mice in specific pathogen-free conditions developed severe colitis, and a novel juvenile colon dysplasia and cancer, with gut microbiome changes driving colitis-associated cancer initiation and progression. LimitationsWe identified a pro-inflammatory microbial/metabolic signature promoting colitis-to-CAC transition in Winnie mice, with FMT confirming microbiota-driven tumor susceptibility. However, further research is needed to pinpoint the key bacteria-metabolite-lipid combination driving CAC. Clinical research relevanceThis newly characterized microbiota-metabolome-based model of CAC, challenges the dogma of cancer as a non-transmittable disease, providing a foundation for developing microbiota-based strategies for CAC prevention and treatment. Basic research relevanceUnlike genetic or chemically induced models, the Winnie mouse model uniquely serves as a dual model for spontaneous colitis and juvenile CAC, offering a fast, 100% penetrant phenotype that enhances reliability, accelerates research, and provides valuable insights into IBD and CAC.

cancer biology↗

bioRxiv2024

More with less: Simulation-based inference enables accurate diffusion-weighted MRI with minimal acquisition time

Diffusion-weighted magnetic resonance imaging (dMRI) is an essential tool in neuro-science, providing non-invasive insights into brain microstructure. However, obtaining accurate maps demands long acquisitions, due to oversampling of the parameter space. Leveraging simulation-based inference (SBI) with neural networks, we directly approximate posterior distributions of diffusion parameters from experimental measurements without requiring real-data training. SBI achieves accurate parameter estimation using up to 90% fewer acquisitions and outperforms standard nonlinear least squares under noisy, sparse sampling. We demonstrate improvements across diffusion tensor imaging, diffusion kurtosis imaging, and biophysical models estimating axonal density and calibre. Validation on simulated and real datasets from healthy and pathological brains shows SBIs robustness and generalizability. This approach can expand dMRI access, e.g. for paediatric and other time-sensitive patients, enable advanced microstructure-sensitive protocols, and rescue legacy data with suboptimal quality. By reducing scan times and preserving privacy, SBI-integrated dMRI workflows promise faster, more comfortable exams, MRI-based virtual tissue biopsy, and have potential to substantially impact radiology workflows.

neuroscience↗

bioRxiv2024

SAMson: an automated brain extraction tool for rodents using SAM

Accurate brain extraction is a critical step in the analysis of rodent head magnetic resonance imaging (MRI) data. However, current methods often encounter difficulties in handling the diverse range of imaging setups, resolutions, and experimental conditions that are commonly found in this field. Based on the Segment Anything Model (SAM), we introduce here SAMson (SAM for Segmentation Of Neuroimages), an automated tool for robust rodent brain extraction. SAMson integrates a bounding box generator and a mask prediction pipeline, offering fully automated and semi-automated modes to address varying experimental complexities. The performance of SAMson was evaluated using three multi-centre rodent MRI datasets annotated at the pixel level, which differed in terms of acquisition parameters, resolution, and animal age groups. SAMson demonstrates superior performance to existing methods, including BET, RBM, and BEN, in terms of segmentation accuracy, with Jaccard indices exceeding 90% across datasets. The semi-automated mode demonstrates particular efficacy in challenging scenarios, including low-resolution images and cases requiring refined mask precision. In contrast to conventional volumetric techniques, SAMson identifies errors at the level of individual slices, thereby enabling rapid and targeted correction when needed. By providing open-source access, SAMson aims to support large-scale research workflows and advance translational neuroscience. The curated data can be downloaded from https://doi.org/10.20350/digitalCSIC/17000, and the code is available at https://github.com/CanalsLab/SAMson.

neuroscience↗

bioRxiv2023

Sleep loss impairs myelin function by altering cholesterol metabolism in oligodendroglia

The increasing prevalence of sleep deprivation in modern society demands comprehension of the biological consequences of sleep loss on brain functioning. Our study reveals significant effects of sleep deprivation on myelin integrity. As a result, we identify increased conduction delays in nerve signal propagation, hindered interhemispheric synchronization, and impaired motor performance associated with sleep loss. By profiling oligodendrocyte transcriptome and lipidome, we observe sleep loss-induced endoplasmic reticulum stress and lipid metabolism disruption, particularly affecting cholesterol homeostasis. This shift in cholesterol levels alters myelin physical properties. Boosting cholesterol transport to myelin sheaths prevents sleep loss effects on nerve signal propagation and behavior. Our findings highlight the critical role of oligodendrocyte cholesterol regulation in behavioral deficits associated with sleep loss and unveil a novel target for intervention.

neuroscience↗

bioRxiv2023

Sex matters: the MouseX DW-ALLEN Atlas for mice diffusion-weighted MR imaging

Overcoming sex bias in preclinical research requires not only including animals of both sexes in the experiments, but also developing proper tools to handle such data. Recent work revealed sensitivity of diffusion-weighted MRI to glia morphological changes in response to inflammatory stimuli, opening up exciting possibilities to characterize inflammation in a variety of preclinical models of pathologies, the great majority of them available in mice. However, there are limited resources dedicated to mouse imaging, like those required for the data processing and analysis. To fill this gap, we build a mouse MRI template of both structural and diffusion contrasts, with anatomical annotation according to the Allen Mouse Brain Atlas, the most detailed public resource for mouse brain investigation. To achieve a standardized resource, we use a large cohort of animals in vivo, and include animals of both sexes. To prove the utility of this resource to integrate imaging and molecular data, we demonstrate significant association between the mean diffusivity from MRI and gene expression-based glial counting. To demonstrate the need of equitable sex representation, we compared across sexes the warp fields needed to match a male-based template, and our template built with both sexes. Then, we use both templates for analysing mice imaging data obtained in animals of different ages, demonstrating that using a male-based template creates spurious significant sex effects, not present otherwise. All in all, our MouseX DW-ALLEN Atlas will be a widely useful resource getting us one step closer to equitable healthcare. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/568800v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@b3a616org.highwire.dtl.DTLVardef@5d2b3corg.highwire.dtl.DTLVardef@c1767borg.highwire.dtl.DTLVardef@149a259_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

A translational MRI approach to validate acute axonal damage detection in multiple sclerosis

Axonal degeneration is a central pathological feature of neurodegenerative pathologies and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in vivo are limited in their specificity, clinical applicability, and lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion-weighted signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the whole brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls, a pathology associated with a neurodegenerative component. AxCaliber is sensitive to microstructural axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the target tract, which correlated with the neurotoxin neurofilament staining. In humans, we uncovered a diffuse increase in mean axonal caliber in multiple sclerosis lesions and, importantly, in most areas of the normal-appearing white matter. Our results demonstrate that axonal diameter mapping is a sensitive and specific imaging biomarker able to link noninvasive imaging contrasts with the underlying biological substrate, supporting the key role of generalized axonal damage useful in diseases such as multiple sclerosis.

neuroscience↗

bioRxiv2020

Imaging Microglia and Astrocytes non-invasively using Diffusion MRI

Glia, and particularly microglia, are increasingly implicated in the pathophysiology of psychiatric and neurodegenerative disorders. However, to date the only methods for imaging these cells in vivo involve either invasive procedures (e.g. multi-photon imaging in rodents) or TSPO-PET radiotracers, which afford low resolution and specificity, since TSPO expresses across multiple cell types. Here, we present a non-invasive diffusion-weighted MRI method to image changes in glia morphometry in vivo. Using two rat models of neuroinflammation, with and without neurodegeneration, we demonstrate that diffusion-weighted MRI carries the fingerprint of microglia and astrocytes activation, and that specific signatures from each population can be quantified non-invasively. We demonstrate that the method can further detect glia proliferation, and provide a quantitative account of neuroinflammation regardless of the existence of a concomitant neuronal loss. We prove the translational value of the approach showing significant correlations between MRI and histological microglia markers measured across different brain regions in humans. This framework holds the potential to transform basic and clinical research by providing a tool to clarify the role of inflammation in health and disease across the lifespan.

neuroscience↗