Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3

Microbiome, Год журнала: 2024, Номер 12(1)

Опубликована: Фев. 20, 2024

Abstract Background Remodeling eubiosis of the gut microenvironment may contribute to preventing occurrence and development depression. Mounting experimental evidence has shown that complement C3 signaling is associated with pathogenesis depression, disruption microbiota be an underlying cause system activation. However, mechanism by which participates in gut-brain crosstalk depression remains unknown. Results In present study, we found chronic unpredictable mild stress (CUMS)-induced mice exhibited obvious depression-like behavior as well cognitive impairment, was significant dysbiosis, especially enrichment Proteobacteria elevation microbiota-derived lipopolysaccharides (LPS). addition, peripheral central activation C3/CR3-mediated aberrant synaptic pruning microglia have also been observed. Transplantation from CUMS-induced model into specific pathogen-free germ-free induced concomitant impairment recipient mice, accompanied increased C3/CR3 pathway prefrontal cortex abnormalities microglia-mediated pruning. Conversely, antidepressants fecal transplantation antidepressant-treated donors improved behaviors restored microbiome disturbances depressed mice. Concurrently, inhibition pathway, amelioration abnormal pruning, expression synapsin postsynaptic density protein 95 were Collectively, our results revealed dysbiosis induces through synapse C3, key targeting microbes treat Conclusions Our findings provide novel insights involvement chemotactic

Язык: Английский

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Reprogramming astrocytic NDRG2/NF-κB/C3 signaling restores the diabetes-associated cognitive dysfunction

EBioMedicine, Год журнала: 2023, Номер 93, С. 104653 - 104653

Опубликована: Июнь 16, 2023

Dementia is a serious complication in patients with diabetes-associated cognitive dysfunction (DACD). In this study, we aim to explore the protective effect of exercise on DACD diabetic mice, and role NDRG2 as potential guarder for reversing pathological structure neuronal synapses.Seven weeks standardized at moderate intensity was carried out using an animal treadmill vehicle + Run STZ groups. Based quantitative transcriptome tandem mass tag (TMT) proteome sequencing, weighted gene co-expression analysis (WGCNA) set enrichment (GSEA) were used investigate activation complement cascades injury synaptic plasticity. Golgi staining, Western blotting, immunofluorescence electrophysiology verify reliability sequencing data. The assessed by overexpressing or inhibiting vivo. Moreover, estimated function normal DSST scores.Exercise reversed plasticity downregulation astrocytic which succeeded attenuating DACD. deficiency aggravated C3 accelerating phosphorylation NF-κB, ultimately leading dysfunction. Conversely, overexpression promoted remodeling C3, thus Meanwhile, C3aR blockade rescued dendritic spines loss deficits mice. average score significantly lower than that non-diabetic peers. Levels human serum elevated compared those patients.Our findings illustrate effectiveness integrative mechanism NDRG2-induced improvement cognition from multi-omics perspective. Additionally, they confirm expression closely related mice accelerated impairment acts regulator astrocytic-neuronal interaction via NF-κB/C3/C3aR signaling restore mice.This study supported National Natural Science Foundation China (No. 81974540, 81801899, 81971290), Key Research Development Program Shaanxi (Program No. 2022ZDLSF02-09) Fundamental Funds Central Universities (Grant xzy022019020).

Язык: Английский

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Dietary long-chain fatty acids promote colitis by regulating palmitoylation of STAT3 through CD36-mediated endocytosis

Cell Death and Disease, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 17, 2024

Abstract The Western diet, characterized by its high content of long-chain fatty acids (LCFAs), is widely recognized as a significant triggering factor for inflammatory bowel disease (IBD). While the link between high-fat diet and colitis has been observed, specific effects mechanisms remain incompletely understood. Our study provides evidence that rich in LCFAs can disrupt integrity intestinal barrier exacerbate experimental mice. Mechanistically, upregulate signal transducer activator transcription-3 (STAT3) pathway model, STAT3 knockout effectively counters pro-inflammatory on colitis. Specifically, palmitic acid (PA), representative LCFA, enters epithelial cells via cluster differentiation 36 (CD36) participates palmitoylation cycle STAT3. Inhibiting this using pharmacological inhibitors like 2-Bromopalmitate (2-BP) ML349, well DHHC7 knockdown, ability to alleviate inflammation induced PA. These findings highlight role dietary LCFAs, especially PA, development progression IBD. Diet adjustments targeted modulation offer potential therapeutic strategies managing condition.

Язык: Английский

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Inhibition of NLRP3 attenuates sodium dextran sulfate-induced inflammatory bowel disease through gut microbiota regulation

Biomedical Journal, Год журнала: 2023, Номер 46(5), С. 100580 - 100580

Опубликована: Фев. 8, 2023

Inflammatory bowel disease (IBD) is a chronic, life-threatening inflammatory of gastrointestinal tissue characterized by inflammation the gut. Recent studies have shown that gut microbiota involved in pathophysiology IBD. However, it unknown whether direct inhibition NLR family pyrin domain containing 3 (NLRP3) inflammasome regulates IBD and alters microbiota.Here, NLRP3 expression was evaluated colon subjects. Then, we investigated effects MCC950 on IBD-like symptoms induced dextran sulfate sodium (DSS).Firstly, IL-1β levels were increased patients with as compared healthy individuals. animal experiment showed significantly attenuated such diarrhea colonic DSS-induced mice. In addition, inhibited NLRP3/ASC/caspase-1/IL-1β signaling pathway colon, which over-activated DSS. Furthermore, abundance phylum Firmicutes, decreased Bacteroidetes, Firmicutes/Bacteroidetes ratio, indicating could regulate intestinal flora. According to correlation analysis, might produce its functional role regulation oxidation indicators changing composition, especially Bacteroidota, genus Lactobacillus species reuteri.This study suggests attenuates regulating microbiota, provides basis for clinical application target treatment

Язык: Английский

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Psychiatric Comorbidities of Inflammatory Bowel Disease: It Is a Matter of Microglia’s Gut Feeling

Cells, Год журнала: 2024, Номер 13(2), С. 177 - 177

Опубликована: Янв. 17, 2024

Inflammatory bowel disease (IBD), a common term for Crohn’s and ulcerative colitis, is chronic, relapse-remitting condition of the gastrointestinal tract that increasing worldwide. Psychiatric comorbidities, including depression anxiety, are more prevalent in IBD patients than healthy individuals. Evidence suggests varying levels neuroinflammation might underlie these states patients. Within this context, microglia crucial non-neural cells brain responsible innate immune responses following inflammatory insults. Alterations microglia’s functions, such as secretory profile, phagocytic activity, synaptic pruning, play significant roles mediating psychiatric manifestations IBD. In review, we discuss role played by IBD-associated comorbidities.

Язык: Английский

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Botulinum neurotoxin A ameliorates depressive-like behavior in a reserpine-induced Parkinson’s disease mouse model via suppressing hippocampal microglial engulfment and neuroinflammation

Acta Pharmacologica Sinica, Год журнала: 2023, Номер unknown

Опубликована: Фев. 10, 2023

Depression is one of the common non-motor symptoms Parkinson's disease (PD). In clinic, botulinum neurotoxin A (BoNT/A) has been used to treat depression. this study, we investigated mechanisms underlying anti-depressive effect BoNT/A in a PD mouse model. Mice were administered reserpine (3 μg/mL drinking water) for 10 weeks. From 10th week, (10 U·kg-1·d-1) was injected into cheek 3 consecutive days. We showed that chronic administration produced behavioral phenotypes depression and neurochemical changes substantia nigra pars compacta (SNpc) striatum. treatment significantly ameliorated depressive-like behaviors, but did not improve TH activity SNpc reserpine-treated mice. demonstrated reversed reserpine-induced complement microglia activation hippocampal CA1 region. Furthermore, attenuated microglial engulfment presynaptic synapses, thus ameliorating apparent synapse spine loss hippocampus Moreover, suppressed microglia-mediated expression pro-inflammatory cytokines TNF-α IL-1β addition, (0.1 U/mL) BV2 cells vitro. conclude ameliorates behavior model through reversing mediated by classical induced-microglial as well alleviating proinflammatory responses. behavior, reverses pathway-initiated alleviates response

Язык: Английский

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A unique inflammation-related mechanism by which high-fat diets induce depression-like behaviors in mice

Journal of Affective Disorders, Год журнала: 2023, Номер 339, С. 180 - 193

Опубликована: Июль 10, 2023

Язык: Английский

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The impact of neuroinflammation on neuronal integrity

Immunological Reviews, Год журнала: 2024, Номер 327(1), С. 8 - 32

Опубликована: Окт. 1, 2024

Neuroinflammation, characterized by a complex interplay among innate and adaptive immune responses within the central nervous system (CNS), is crucial in responding to infections, injuries, disease pathologies. However, dysregulation of neuroinflammatory response could significantly affect neurons terms function structure, leading profound health implications. Although tremendous progress has been made understanding relationship between processes alterations neuronal integrity, specific implications concerning both structure have not extensively covered, with exception perspectives on glial activation neurodegeneration. Thus, this review aims provide comprehensive overview multifaceted interactions key inflammatory players, exploring mechanisms through which inflammation influences functionality structural integrity CNS. Further, it will discuss how these lead impairment functions architecture highlight consequences caused dysregulated functions, such as cognitive dysfunction mood disorders. By integrating insights from recent research findings, enhance our landscape set stage for future interventions that transform current approaches preserve CNS-related conditions.

Язык: Английский

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Role of ginsenoside Rb1 in attenuating depression-like symptoms through astrocytic and microglial complement C3 pathway

Metabolic Brain Disease, Год журнала: 2024, Номер 39(6), С. 1039 - 1050

Опубликована: Июль 22, 2024

Язык: Английский

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C3/C3aR Bridges Spinal Astrocyte‐Microglia Crosstalk and Accelerates Neuroinflammation in Morphine‐Tolerant Rats

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(1)

Опубликована: Янв. 1, 2025

Communication within glial cells acts as a pivotal intermediary factor in modulating neuroimmune pathology. Meanwhile, an increasing awareness has emerged regarding the detrimental role of and neuroinflammation morphine tolerance (MT). This study investigated influence crosstalk between astrocyte microglia on evolution tolerance. Sprague-Dawley rats were intrathecally treated with twice daily for 9 days to establish morphine-tolerant rat model. Tail-flick latency test was performed identify analgesic effect morphine. The microglia, C3-C3aR axis elucidated by real-time quantitative polymerase chain reaction, Western blot, immunofluorescence. Chronic treatment notably promoted activation upregulated production proinflammatory mediators (interleukin-1 alpha (IL-1α), tumor necrosis (TNFα), complement component 1q (C1q)). Simultaneously, it programed astrocytes pro-inflammatory phenotype (A1), which mainly expresses 3 (C3) serping1. PLX3397 (a colony-stimulating 1 receptor (CSF1R) inhibitor), Compstain C3 inhibitor) SB290157(a C3aR antagonist) could reverse above pathological process alleviate different extents. Our findings amplifier microglia-astrocyte crosstalk, node therapeutic intervention

Язык: Английский

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