Promising Therapy in Alzheimer’s Disease

Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, emerge as promising therapeutic agents in Alzheimer’s disease (AD).
Short-chain fatty acids are produced by gut microbiota fermentation of dietary fibers.
These SCFAs play a complex role in Alzheimer’s disease (AD) through the microbiota-gut-brain axis.
AD patients exhibit gut dysbiosis with reduced SCFA-producing bacteria (e.g., Faecalibacterium prausnitzii, Roseburia spp.), leading to altered circulating SCFA levels—typically elevated acetate and valerate but decreased butyrate—which correlate with amyloid-β (Aβ) deposition, tau pathology, neuroinflammation, and cognitive decline.
SCFAs modulate AD progression by influencing microglial activation, blood-brain barrier(BBB) integrity, and synaptic plasticity, though effects can be beneficial (e.g., anti-inflammatory) or detrimental (e.g., impaired Aβ phagocytosis) depending on concentration, disease stage, and context.Recent 2024–2025 studies emphasize the SCFAs-microglia pathway as a therapeutic target, with preclinical evidence supporting microbiome modulation to restore SCFA homeostasis and slow neurodegeneration.

Key Mechanisms
SCFAs exert dual effects in AD via epigenetic, signaling, and metabolic pathways, primarily targeting microglia—the brain’s resident immune cells that drive neuroinflammation and Aβ/tau pathology.

• Epigenetic Regulation:
  Butyrate and propionate inhibit histone deacetylases (HDACs), promoting hyperacetylation (e.g., H3K9, H3K18) that suppresses NF-κB translocation and pro-inflammatory genes (IL-1β, TNF-α, COX-2), shifting microglia from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotypes.
  In APP/PS1 mice, oral acetate administration for 4 weeks upregulated GPR41 in Aβ-stimulated BV-2 microglia, inhibiting HDAC-related pathways and reducing inflammatory markers.
  Sodium butyrate induced hyperacetylation at H3K9 and H3K18 sites in LPS-stimulated BV-2 microglia. In AD mouse models, sodium butyrate ameliorates synaptic plasticity impairment by inhibiting neuroinflammation via HDAC inhibition.
• Receptor-Mediated Signaling: SCFAs bind G-protein-coupled receptors (FFAR2/3, GPR109A) on microglia, inhibiting TLR4/NF-κB and ERK/JNK pathways, reducing ROS/NO production, and enhancing phagocytosis or autophagy for Aβ clearance. Over 60% of hippocampal FFAR3 expression co-localizes with activated microglia. In APP/PS1 mice, acetate upregulated GPR41 in BV-2 microglia, inhibiting phosphorylation of NF-κB p65, ERK, and JNK, and reducing COX-2 and IL-1β levels. Butyrate reduced Aβ-induced CD11b and COX-2 in BV-2 microglia and inhibited NF-κB p65 phosphorylation. Knockout of GPR41/43 accelerated cognitive decline and impaired hippocampal neurogenesis in 5×FAD mice, but SCFAs intake reversed this by upregulating defensive genes (e.g., B2m, Fgl2, H2-K1) and antigen presentation pathways.
• Metabolic Reprogramming: SCFAs restore tricarboxylic acid (TCA) cycle flux and mitochondrial function in microglia, balancing energy and curbing inflammasome (NLRP3) activation, which exacerbates synaptic loss in AD.
  Gut-derived 13C-acetate can reach the brain and be metabolized by microglia into TCA cycle intermediates (e.g., citrate, α-ketoglutarate, fumarate, malate, succinate), thereby restoring the mitochondrial dysfunction observed in germ-free mice. In 5×FAD mice, acetate inhibited phagocytosis by inducing cytokine expression, exacerbating Aβ burden, and increased mitochondrial activity, ROS production, oxidative phosphorylation, and membrane potential in Aβ-phagocytosing microglia. Acetate improved TCA cycle flux by stimulating short-chain CoA metabolism and increasing acetyl-CoA levels, reducing microglial reactivity. Butyrate reversed FXN depletion-induced mitochondrial oxidative capacity loss via GPR109A, stimulating the itaconate-Nrf2-GSH pathway and reducing ROS.
• Indirect Effects via Gut-Brain Axis: Circulating SCFAs influence peripheral immunity (e.g., Treg/Th17 balance) and vagal signaling, reducing gut permeability and systemic translocation of inflammatory signals to the brain. Propionate pre-treatment reduced peripheral Th17 infiltration and IL-17A levels, decreasing microglial activation in perioperative cognitive dysfunction models relevant to AD. FFAR2 knockout in myeloid cells downregulated microglial inflammatory genes.
  SCFAs promoted Treg generation in the spleen, affecting microglial cytokine release. In 5×FAD mice, peripheral immune pathways mediated SCFAs’ effects on microglial transcriptome and neurogenesis. Elevated acetate may worsen Aβ burden by impairing microglial metabolism, while butyrate supports barrier integrity and BDNF expression.
  SCFAs suppress pro-inflammatory cytokines (IL-1β, MCP-1, TNF-α) and reduce THP-1 phagocytosis; acetate reverses LPS-induced phospholipase C β1/COX-1/COX-2 and reduces TNF-α/IL-6 in astrocytes via p38 MAPK/NF-κB downregulation, increasing IL-4 via TGF-β1/H3K9 acetylation;
  Butyrate inhibits COX-2 in Aβ-microglia via NF-κB.

Evidence from Preclinical and Clinical Studies

Studies reveal context-dependent SCFA effects, with 2025 cross-sectional data confirming AD-specific plasma signatures.
Below is a summary of key 2024–2025 findings:

 

Human evidence is emerging:
Salivary acetate/propionate ↑ in AD, correlating with periodontal risk; plasma SCFAs associate with brain acetate uptake in MCI.

Therapeutic Applications
SCFAs offer adjunctive strategies to target early AD dysbiosis, with 2025 reviews advocating precision interventions to leverage beneficial effects while mitigating risks like impaired phagocytosis.

• Supplementation: Sodium butyrate (500–2000 mg/day) or prodrugs (e.g., tributyrin) restore levels, inhibit HDACs, and improve cognition in models;
  Clinical pilots explore oral dosing for MCI (Mild Cognitive Impairment)
• Prebiotics/Probiotics: Inulin or galacto-oligosaccharides (5–10 g/day) enrich SCFA-producers, reducing microglial senescence and plaques (e.g., 20–30% inflammation ↓ in aged models).
  Strains like Bifidobacterium breve or Roseburia hominis via psychobiotics enhance butyrate, supporting synaptic repair.
• FMT and Diet: Fecal transplants from healthy donors ↑ SCFAs, alleviate neuroinflammation in AD models; high-fiber Mediterranean diets elevate circulating levels, correlating with slower progression.
• Novel Targets: Microglia-specific FFAR2/3 agonists or colon-targeted delivery (e.g., acylated starch) optimize brain penetration; combined with anti-Aβ therapies for amyloid-positive patients.

Doses are safe (up to 4 g/day), but variability from microbiome baseline requires multi-omics personalization.
Challenges include dual effects and BBB (blood-brain barrier) crossing;
Ongoing 2025 trials (e.g., prebiotic RCTs in MCI) aim to validate 15–25% cognitive gains.
SCFAs hold transformative potential for AD prevention, bridging gut modulation to neuroprotection.

Source Grok X AI
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