Intestinal inflammation induces glymphatic remodeling, priming early neurodegenerative signals in male mice

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-10-09 DOI:10.1002/alz.70640

Clara Ciampi, Francesca Fagiani, Valentina Murtaj, Federica Comella, Veronica Torre, Marta Filibian, Annapaola Andolfo, Clarissa Braccia, Nicola Opallo, Maria Grazia Bottone, Edoardo Pedrini, Elena Lucarini, Maria Bove, Stefano Govoni, Carla Ghelardini, Rosaria Meli, Luigia Trabace, Anna Pittaluga, Giuseppina Mattace Raso, Lorenzo Di Cesare Mannelli, Cristina Lanni

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Abstract

INTRODUCTION

Inflammatory bowel disease triggers extraintestinal manifestations, including in the central nervous system (CNS). However, the direct impact of peripheral inflammation on the CNS is largely unknown.

METHODS

Using a mouse model of colitis with pain and anxiety-like behavior, we investigated the intricate pathogenic link between colonic inflammation, disruptions in circadian rhythmicity and impaired glymphatic circulation.

RESULTS

By in vivo magnetic resonance imaging, we observed a derangement of brain fluid dynamics, with a significant enlargement of the cerebral lateral ventricles and waste deposition within the brain parenchyma. Proteomics revealed changes in cerebrospinal fluid (CSF) composition, enriched in proteins related to inflammation, immune response, complement, neuronal, and lipid metabolic pathways. Alterations in brain metabolite concentrations and in inhibitory control mechanisms and excitatory transmission were detected.

DISCUSSION

Colonic inflammation induces remodeling in CSF volume distribution, clearance, and metabolism, with derangement of the crosstalk between neurons and astrocytes, priming synaptopathy.

HIGHLIGHTS

An acute peripheral inflammatory trigger affects the central level by remodeling central nervous system (CNS) fluid distribution and priming early signals of synaptopathy.
A single dextran sulfate sodium (DSS) challenge disrupts the circadian clock machinery and alters CNS fluid distribution, a so far neglected system, thereby impairing glymphatic clearance of waste products and indirectly altering neurotransmitter release dynamics.
These combined effects ultimately impact brain function, extending to the regulation of behavior.
Understanding how an intestinal inflammatory insult may derange the daily rhythm of the mechanisms controlling brain waste disposal may help identify specific groups of subjects at high risk of developing neurological disorders.

Abstract Image

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肠道炎症诱导淋巴重塑，引发雄性小鼠早期神经退行性信号

炎症性肠病可引发肠外表现，包括中枢神经系统（CNS）。然而，外周炎症对中枢神经系统的直接影响在很大程度上是未知的。方法使用具有疼痛和焦虑样行为的结肠炎小鼠模型，我们研究了结肠炎症、昼夜节律紊乱和淋巴循环受损之间复杂的致病联系。结果通过体内磁共振成像，我们观察到脑流体动力学紊乱，脑侧脑室明显增大，脑实质内有废物沉积。蛋白质组学揭示了脑脊液（CSF）组成的变化，其中富含与炎症、免疫反应、补体、神经元和脂质代谢途径相关的蛋白质。检测到脑代谢物浓度、抑制控制机制和兴奋传递的变化。结肠炎症引起脑脊液体积分布、清除和代谢的重塑，神经元和星形胶质细胞之间的串扰紊乱，引发突触病。急性外周炎症触发器通过重塑中枢神经系统（CNS）流体分布和启动突触病的早期信号来影响中枢水平。单次葡聚糖硫酸钠（DSS）刺激破坏生物钟机制，改变中枢神经系统液体分布，从而损害淋巴废物的清除，间接改变神经递质释放动力学，这是一个迄今为止被忽视的系统。这些综合影响最终影响大脑功能，延伸到行为调节。了解肠道炎症性损伤如何扰乱控制脑废物处理机制的日常节律，可能有助于识别神经系统疾病高风险的特定人群。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.