Implications of microbe-derived ɣ-aminobutyric acid (GABA) in gut and brain barrier integrity and GABAergic signaling in Alzheimer’s disease

Gut Microbes, Journal Year: 2024, Volume and Issue: 16(1)

Published: July 15, 2024

The gut microbial ecosystem communicates bidirectionally with the brain in what is known as gut-microbiome-brain axis. Bidirectional signaling occurs through several pathways including via vagus nerve, circulation of metabolites, and immune activation. Alterations microbiota are implicated Alzheimer's disease (AD), a progressive neurodegenerative disease. Perturbations communities may affect within axis altered production metabolites ɣ-aminobutyric acid (GABA), primary inhibitory mammalian neurotransmitter. GABA has been shown to act on integrity modulation mucins tight junction proteins be involved nerve signal inhibition. GABAergic pathway dysregulated AD, responsive interventions. Gut recent interest neurological disorders, AD. Bacteroides Lactic Acid Bacteria (LAB), Lactobacillus, predominant producers GABA. This review highlights how temporal alterations associated AD pathway, intestinal barrier integrity, AD-associated inflammation.

Language: Английский

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Neuropeptide substance P attenuates colitis by suppressing inflammation and ferroptosis via the cGAS-STING signaling pathway

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(7), P. 2507 - 2531

Published: Jan. 1, 2024

Neuropeptide substance P (SP) belongs to a family of bioactive peptides and regulates many human diseases. This study aims investigate the role underlying mechanisms SP in colitis. Here, activated SP-positive neurons increased expression were observed dextran sodium sulfate (DSS)-induced colitis lesions mice. Administration exogenous efficiently ameliorated clinical symptoms, impaired intestinal barrier function, inflammatory response. Mechanistically, protected mitochondria from damage caused by DSS or TNF-α exposure, preventing mitochondrial DNA (mtDNA) leakage into cytoplasm, thereby inhibiting cyclic GMP-AMP synthase-stimulator interferon genes (cGAS-STING) pathway. can also directly prevent STING phosphorylation through neurokinin-1 receptor (NK1R), activation TBK1-IRF3 signaling Further studies revealed that alleviated TNF-α-induced ferroptosis process, which was associated with repressing cGAS-STING Notably, we identified NK1R inhibition reversed effects on inflammation via Collectively, unveil attenuates suppressing mtDNA-cGAS-STING acting pathway, contributing improving an NK1R-dependent manner. These findings provide novel mechanism regulating ulcerative (UC) disease.

Language: Английский

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Alleviating effect of vagus nerve cutting in Salmonella-induced gut infections and anxiety-like behavior via enhancing microbiota-derived GABA

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 119, P. 607 - 620

Published: April 23, 2024

Language: Английский

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cAMP-PKA signaling pathway and anxiety: Where do we go next?

Cellular Signalling, Journal Year: 2024, Volume and Issue: 122, P. 111311 - 111311

Published: July 24, 2024

Language: Английский

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Enteric Nervous System Alterations in Inflammatory Bowel Disease: Perspectives and Implications

Gastrointestinal Disorders, Journal Year: 2024, Volume and Issue: 6(2), P. 368 - 379

Published: March 28, 2024

The enteric nervous system (ENS), consisting of neurons and glial cells, is situated along the gastrointestinal (GI) tract’s wall plays a crucial role in coordinating digestive processes. Recent research suggests that optimal functioning GI relies on intricate connections between ENS, intestinal epithelium, immune system, microbiome, central (CNS). Inflammatory bowel disease (IBD) encompasses group chronic inflammatory disorders, such as Crohn’s (CD) ulcerative colitis (UC), characterized by recurring inflammation damage to tract. This review explores emerging dynamic field IBD sheds light potential ENS alterations both etiology management IBD. Specifically, we delve into IBD-induced cell (EGC) activation its implications for persistent gliosis, elucidating how this disrupts function through gut–brain axis (GBA). Additionally, examine IBD-associated alterations, focusing EGC senescence acquisition senescence-associated secretory phenotype (SASP). We highlight pivotal these changes recurrence Finally, discuss therapeutic interventions involving senotherapeutic agents, providing insights avenues managing targeting ENS-related mechanisms. approach might represent alternative advance treatment multifaceted disease.

Language: Английский

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Alzheimer's disease and gut-brain axis: Drosophila melanogaster as a model

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: Feb. 4, 2025

Research indicates that by 2050, more than 150 million people will be living with Alzheimer's disease (AD), a condition associated neurodegeneration due to the accumulation of amyloid-beta and tau proteins. In addition genetic background, endocrine disruption, cellular senescence, management gut microbiota has emerged as key element in diagnosis, progression, treatment AD, certain bacterial metabolites can travel through bloodstream cross blood-brain barrier. This mini-review explores relationship between protein dysbiosis Drosophila melanogaster . model facilitates investigation how gut-derived contribute neurocognitive impairment dementia. Understanding role direct indirect by-products, such lactate acetate, glial cell activation dynamics may provide insights into mechanisms AD progression effective treatments. Here we discuss simplicity extensive tools make it valuable for studying these interactions testing potential therapeutics, including probiotics. Integrating studies other established models reveal conserved pathways accelerate translation findings clinical applications.

Language: Английский

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NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 10, 2025

Age-related decline in nicotinamide adenine dinucleotide (NAD+)-a central regulator of cellular metabolism, DNA repair, and immune homeostasis-is strongly associated with physiological dysfunction. Nicotinamide mononucleotide (NMN), a potent NAD+ precursor, shows promise counteracting aging-related pathologies, particularly neurodegenerative decline. An aging model was established mice through 8-week D-galactose (D-gal) exposure, followed by NMN oral supplementation. Behavioral outcomes (open field test, Morris water maze) were analyzed alongside oxidative stress markers (SOD, CAT, AGEs), inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10), neurotransmitters (LC-MS/MS). Apoptotic activity (TUNEL, p16/p21), mitochondrial regulators (Sirt1, p-AMPK, PGC-1α), intestinal barrier integrity (HE/AB-PAS staining) evaluated. Sirt1 dependency confirmed using inhibitor Ex527. restored locomotor spatial memory D-gal without altering body weight. Mechanistically, synergistically attenuated systemic inflammation, elevating antioxidant enzymes CAT) IL-10 while suppressing pro-inflammatory IL-6) AGEs. Cortical/hippocampal analyses revealed reduced apoptosis (TUNEL+ cells) senescence (p16, p21), enhanced function via Sirt1/AMPK/PGC-1α activation p-AMPK). concurrently preserved mucosal architecture, mitigating D-gal-induced disruption. Crucially, all benefits abolished inhibition, confirming pathway specificity. Our findings establish as multifaceted therapeutic agent that preserves neurocognitive homeostasis models orchestrating antioxidative, anti-inflammatory, antiapoptotic responses activation. This work provides translational insights into NAD+-boosting strategies for age-related disorders.

Language: Английский

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The Double‐Edged Sword: The Complex Function of Enteric Glial Cells in Neurodegenerative Diseases

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(4)

Published: April 1, 2025

ABSTRACT Over the past two decades, a growing number of studies have been conducted on role bidirectional communication through gut–brain axis in development neurodegenerative diseases. These were driven by curious fact that all these diseases present varying degrees intestinal involvement included their wide range symptoms. A population cells belonging to ENS, called enteric glial (EGCs), appears actively participate this between intestine and brain, but acting dualistic manner, sometimes reactive gliosis releasing inflammatory mediators, promoting homeostasis resilience face injuries. To date, intracellular mechanisms define transcriptional profile expressed EGCs each situation not yet elucidated. This review proposes discussion on: (1) complex distinct phenotypes involved diseases, such as Parkinson's disease (PD), Alzheimer's (AD), amyotrophic lateral sclerosis (ALS), Huntington's (HD) multiple (MS); (2) innovative strategies IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, act potential treat image

Language: Английский

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Activation of GABABR Attenuates Intestinal Inflammation by Reducing Oxidative Stress through Modulating the TLR4/MyD88/NLRP3 Pathway and Gut Microbiota Abundance

Antioxidants, Journal Year: 2024, Volume and Issue: 13(9), P. 1141 - 1141

Published: Sept. 21, 2024

Oxidative stress emerges as a prominent factor in the onset and progression of intestinal inflammation, primarily due to its critical role damaging cells tissues. GABAergic signaling is important occurrence development various disorders, yet effect on oxidative remains unclear. We attempted assess whether participated regulation during enteritis. The results showed that lipopolysaccharide (LPS) significantly decreased γ-aminobutyric acid (GABA) levels ileal tissues mice. Interestingly, application GABA repressed shedding mucosal epithelial inflammatory cell infiltration, inhibited expressions proinflammatory factors, including granulocyte colony-stimulating granulocyte-macrophage colony stimulating factor, enhanced anti-inflammatory cytokines interleukin (IL)-4 IL-10, indicating could alleviate enteritis This observation was further supported by transcriptome sequencing, revealing total 271 differentially expressed genes, which exhibited marked enrichment immune-related pathways, alongside enhancement B receptor (GABA

Language: Английский

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GABAB Modulate NF-κB/NLRP3 Pathways in Electroacupuncture Prevention of Depression in CUMS Rats

Brain Research Bulletin, Journal Year: 2024, Volume and Issue: 218, P. 111108 - 111108

Published: Oct. 22, 2024

Language: Английский

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