Microbial SCFAs as epigenetic mediators: fine-tuning the gut-brain axis in neurodegenerative disorders

Highlights

• •SCFAs function as gut-derived epigenetic regulators, bridging dietary fiber metabolism to brain-wide chromatin remodeling in neurodegenerative diseases.
• •Butyrate acts as a potent HDAC inhibitor, enhancing histone acetylation to suppress neuroinflammation and promote synaptic plasticity in AD and PD models.
• •SCFAs modulate DNA methylation dynamics via TET-DNMT balance, correcting aberrant gene expression linked to Aβ and α-synuclein pathologies.
• •Emerging evidence positions histone lactylation as a novel SCFA-sensitive mechanism linking microglial metabolism to neuroinflammatory loops in neurodegeneration.

Abstract

The gut-brain axis is a bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS). Short-chain fatty acids (SCFAs) are microbial metabolites produced through the anaerobic fermentation of dietary fiber. Growing evidence positions SCFAs as critical signaling molecules within this axis, capable of modulating key neurobiological processes relevant to neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). SCFAs exert neuroprotective effects by mitigating neuroinflammation, promoting neurogenesis, enhancing synaptic plasticity, and preserving blood–brain barrier integrity. These actions are largely mediated through epigenetic mechanisms. Butyrate functions as a histone deacetylase inhibitor to alter gene expression related to neuronal survival, inflammation, and metabolism. SCFAs also influence DNA methylation dynamics via modulation of DNA methyltransferases and ten-eleven translocation (TET) enzymes. Emerging findings suggest their involvement in novel histone modifications, such as lactylation. This review synthesizes current understanding of SCFA production, metabolic fate, and their multifaceted epigenetic actions in the brain, while evaluating their translational and therapeutic potential. Gut-derived SCFAs represent promising modulators of the brain’s epigenetic landscape. Elucidating their mechanisms offers a foundation for developing novel interventions, including dietary, probiotic, and epigenetics-based strategies, for the prevention and treatment of NDs.

Graphical abstract

Introduction

Neurodegenerative diseases (NDs) are characterized by the progressive and irreversible loss of neuronal structure and function, leading to severe neurological decline. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are among the most common and debilitating NDs. AD is defined by the accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, which trigger neuroinflammation, synaptic loss, and cognitive decline (Jin et al., 2025). In contrast, PD involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies containing α-synuclein, leading to motor symptoms such as tremors and rigidity, as well as non-motor symptoms like depression and cognitive impairment. The global impact of these diseases is profound. Currently, AD affects more than 50 million people worldwide, and this number is projected to rise to 152 million by 2050, largely due to aging populations (Liu and Geng, 2025, Khan et al., 2023). Similarly, PD affects over 8.5 million individuals globally, with a worldwide prevalence of 315 per 100,000 people (Ben-Shlomo et al., 2024; Pringsheim et al., 2014). These escalating figures highlight the urgent need to elucidate the underlying mechanisms of neurodegeneration and to develop effective strategies for prevention and treatment.

Despite decades of intensive investigation, the precise pathogenic mechanisms underlying NDs remain unclear. Although gene–environment interactions are known to contribute significantly, a substantial proportion of disease risk, termed “missing heritability”, cannot be attributed to known genetic variants alone. For example, in AD, the APOEε4 allele represents the strongest known genetic risk factor, yet it accounts for only a fraction of overall heritability (Yang et al., 2025a). Similarly, in PD, mutations in genes such as LRRK2 (e.g., G2019S) and SNCA contribute to pathogenesis but account for only a minority of cases (He et al., 2023a). Environmental factors such as limited education and pesticide exposure have also been linked to NDs, but their interaction with genetic factors is not well understood. Recently, gut microbiota dysbiosis, an imbalance in gut microbial communities, has emerged as a key factor in ND pathogenesis, highlighting the importance of the gut–brain axis (GBA) (Pan et al., 2024). The GBA is a bidirectional communication system connecting the gut and the brain through neural, immune, endocrine, and metabolic pathways (Suchiita et al., 2025). The gut microbiota, composed of over 100 trillion microorganisms from more than 1000 species (Bäckhed et al., 2005), functions as a metabolically active organ that releases numerous bioactive molecules, including SCFAs. These microbial metabolites, particularly acetate, propionate, and butyrate, are produced from dietary fiber fermentation in the colon and have attracted attention as important signaling molecules (Mukhopadhya and Louis, 2025). Beyond their local roles in the gut, such as providing energy for colonocytes, supporting gut barrier function, and regulating immune responses, SCFAs can enter systemic circulation, cross the blood–brain barrier (BBB), and directly influence the central nervous system (CNS) function. This positions SCFAs as crucial mediators linking gut microbial activity to brain health and neurodegeneration (Seethaler et al., 2022, Sun et al., 2021a).

Accumulating evidence shows that SCFAs affect brain health and neurodegeneration through epigenetic mechanisms, heritable changes in gene expression that do not involve alterations to the DNA sequence itself. Key epigenetic pathways include histone modifications (e.g., acetylation, methylation), DNA methylation, and regulated by long non-coding RNAs (lncRNAs). These mechanisms dynamically control genes involved in neuroinflammation, synaptic plasticity, and neuronal cell death, processes central to NDs pathogenesis (Nayak et al., 2022, Hamidpour et al., 2024). Dysregulation of epigenetic mechanisms has been strongly linked to AD and PD. In AD, for example, abnormal histone acetylation and methylation patterns, as well as altered methylation of genes related to Aβ and tau, have been observed (De Plano et al., 2024). Similarly, PD involves epigenetic changes that affect α-synuclein aggregation and dopaminergic neuron survival (Song et al., 2023). Importantly, SCFAs, especially butyrate, act as natural histone deacetylases (HDACs) inhibitors. By increasing histone acetylation, they directly influence chromatin structure and gene transcription. This supports the idea that gut-derived SCFAs help shape the brain’s epigenetic environment. Thus, gut dysbiosis may contribute to neurodegeneration partly through SCFA-driven epigenetic changes.

A deeper understanding of how SCFAs influence epigenetic regulation in neurodegeneration is essential to decipher the complex interactions among gut microbiota, the GBA, and CNS dysfunction. This review systematically examines the production and metabolism of SCFAs by gut microbes, their epigenetic mechanisms in the brain, and their therapeutic potential. By integrating current evidence, we aim to clarify these mechanisms and support the development of novel interventions, such as dietary changes, probiotics, and epigenetics-based therapies, for the treatment and prevention of NDs.

SCFAs production by gut microbiota

SCFAs are produced in the gastrointestinal tract through the anaerobic fermentation of dietary fiber by gut microbes, as shown in Fig. 1. Dietary fibers, such as cellulose, hemicellulose, pectin, resistant starch, and inulin, are complex carbohydrates that resist human digestion and serve as the main substrates for this process. These fibers are commonly found in plant-based foods like fruits, vegetables, whole grains, and legumes. Specialized bacteria, including Bifidobacterium, Bacteroides, Prevotella, and Faecalibacterium, break down these fibers using enzymes such as glycoside hydrolases and polysaccharide lyases. This hydrolysis produces simpler sugars like glucose, fructose, and xylose, which are then metabolized via glycolysis and the pentose phosphate pathway into intermediates such as pyruvate and acetyl-CoA. SCFAs are finally generated through specific biochemical pathways: acetate from acetyl-CoA reduction, propionate via the succinate or acrylate pathways, and butyrate mainly through the condensation of two acetyl-CoA molecules (Rekha et al., 2024).

Fig. 1.

Schematic of microbial short-chain fatty acids (SCFAs) production.

Dietary fibers (e.g., hemicellulose, resistant starch, inulin) and complex polysaccharides (e.g., cellulose, pectin) are initially degraded by primary fermenting bacteria (e.g., Bifidobacterium, Bacteroides) via microbiota-derived enzymes. This hydrolysis yields oligosaccharides and monosaccharides, which are further metabolized through glycolysis or the pentose phosphate pathway to generate phosphoenolpyruvate (PEP) and other intermediates (e.g., pyruvate, lactate, succinate). Terminal fermentation by specialized bacterial consortia then converts these intermediates into the major SCFAs: acetate (via the Wood-Ljungdahl pathway by bacteria like Akkermansia muciniphila), propionate (via the succinate or acrylate pathways by bacteria such as Phocaeicola), and butyrate (via the butyryl-CoA pathway by bacteria including Faecalibacterium and Roseburia). Key bacterial taxa involved in each pathway are color-coded for clarity. Dashed lines indicate simplified or omitted metabolic steps.

The production of SCFAs is influenced by several factors, with diet playing a central role. High-fiber diets promote the growth of SCFA-producing bacteria and increase SCFA levels, whereas diets high in fat and sugar shift the gut microbiota toward less fermentative taxa, reducing SCFA output (Rinninella et al., 2023). Antibiotic use also disrupts this balance by reducing microbial diversity and depleting SCFA-producing bacteria. Aging is associated with decreased SCFA concentrations, likely due to dietary changes, reduced gastrointestinal motility, and impaired immune function, all of which alter the gut microbiota’s structure and activity (Ling et al., 2022).

The major SCFAs, including acetate, propionate, and butyrate, are each synthesized by specific groups of gut microbes and serve distinct metabolic roles in the host. Acetate, the most abundant SCFA, is produced by a variety of bacteria, including Bifidobacterium and Lactobacillus, through the fermentation of substrates such as glucose, lactate, and amino acids. Propionate, by contrast, is mainly generated by specialized taxa including Akkermansia muciniphila, which metabolizes mucin from the intestinal mucus layer, as well as Megasphaera spp. and Coprococcus catus, which employ the acrylate pathway (He et al., 2023b). These bacteria are especially prevalent in the distal colon, where they account for roughly 20–25% of total SCFA production. Butyrate production, on the other hand, is dominated by members of the Firmicutes phylum, including Clostridium, Eubacterium, Faecalibacterium, Roseburia, and Butyrivibrio (Sasaki et al., 2022). Among these, F. prausnitzii is particularly notable, accounting for up to 10% of the gut microbiota in healthy individuals and playing a key role in gut health through butyrate production (Geng et al., 2025, Wang et al., 2024a).

The distinct physiological roles of acetate, propionate, and butyrate underscore their importance in host metabolism. Acetate is efficiently taken up in the colon via monocarboxylate transporters (MCT1, MCT4) and sodium-coupled monocarboxylate transporters (SMCT1) (Llibre et al., 2025). Once in circulation, it contributes to energy production by entering the tricarboxylic acid (TCA) cycle and serves as a substrate for hepatic synthesis of lipids and cholesterol, thereby supplying energy to peripheral tissues such as skeletal and cardiac muscle. It also crosses the BBB, influencing CNS function by regulating neurotransmitter release and microglial activity (Ahmed et al., 2022). Propionate is absorbed by colonocytes and transported to the liver via the portal vein. Within enterocytes and hepatocytes, it is converted to succinyl-CoA and fed into the TCA cycle to support ATP generation. It also acts as a precursor for gluconeogenesis in the liver and aids in glutamine production in peripheral tissues (Pettinato et al., 2022). Additionally, propionate helps regulate satiety and energy balance through interactions with enteroendocrine cells and CNS pathways (Bastings et al., 2023). Butyrate, though present at lower systemic concentrations, is vital for gut homeostasis. It serves as the principal energy source for colonocytes, undergoing β-oxidation to acetyl-CoA before entering the TCA cycle (Fagundes et al., 2024). Butyrate also strengthens the intestinal barrier by upregulating tight junction proteins such as zonula occludens-1 (ZO-1) and occludin (Huang et al., 2021, Fu et al., 2024), and exerts anti-inflammatory effects by suppressing pro-inflammatory cytokine production in gut mucosal immune cells (Mohamed Elfadil et al., 2023). Butyrate also enters systemic circulation, influences energy metabolism in muscle and adipose tissue, and crosses the BBB to provide neuroprotection via epigenetic mechanisms (Zhang et al., 2021a).

Notably, NDs are associated with gut microbiota alterations and reduced SCFA production. In AD, fecal microbial profiles show marked dysbiosis, with decreased abundance of SCFA-producing genera such as Odoribacter, Anaerobacterium, and Papillibacter, and an increase in potentially pro-inflammatory taxa like Bifidobacterium, Sphingomonas, Lactobacillus, and Blautia, correlating with lower fecal butyrate and propionate (Zhou et al., 2021a). Similarly, PD patients exhibit a decline in butyrate-producing bacteria likeFaecalibacterium and Roseburia, alongside a rise in pro-inflammatory bacteria (Nishiwaki et al., 2020). These findings highlight the importance of SCFA metabolism in NDs and point to the gut microbiota–SCFA axis as a promising therapeutic target.

Neuromodulatory potential of SCFAs

As key microbial metabolites, SCFAs exert broad physiological effects beyond the gut. Systemically, they help maintain intestinal barrier function, modulate immune activity, and regulate metabolism, creating an environment that supports neural health. SCFAs also directly influence the nervous system by crossing biological barriers, interacting with neural cells, and modulating signaling pathways. Among SCFAs, butyrate is particularly notable for its ability to cross the BBB via monocarboxylate transporters, enabling direct CNS interaction. Acetate and propionate also contribute to neural regulation, often through indirect systemic or neural signaling. Together, SCFAs affect several key brain functions, including BBB integrity, neuroimmune activity, and neurotransmitter regulation (Dalile et al., 2019), as summarized in Fig. 2.

Fig. 2.

Systemic and neural functions of short-chain fatty acids (SCFAs) mediated via the gut-brain axis.

SCFAs produced in the colon are absorbed by colonic epithelial cells via monocarboxylate transporters (MCT1/2, SMCT1). A portion of these SCFAs is metabolized in mitochondria to generate ATP through oxidative phosphorylation, providing energy to peripheral tissues such as skeletal and cardiac muscle via systemic circulation. In the liver, SCFAs serve as metabolic precursors—acetate contributes to cholesterol synthesis, while propionate supports gluconeogenesis. Butyrate exerts anti-inflammatory effects by inhibiting histone deacetylases (HDACs) and signaling through the GPR109A–NF-κB pathway. SCFAs that enter the brain via the bloodstream help maintain blood–brain barrier integrity, suppress microglial activation, support the astrocyte-mediated glutamate–glutamine cycle, and activate neuronal GPR41/43 receptors. Together, these actions promote neuroprotection and support mitochondrial function.

Maintaining BBB homeostasis

The BBB is a protective interface that regulates molecule passage between the blood and the brain. Composed of specialized endothelial cells, pericytes, and astrocytes, the BBB prevents harmful substances from entering the brain while allowing essential nutrients through (Xiang et al., 2025). In AD and PD, BBB dysfunction allows inflammatory molecules to infiltrate the CNS, worsening neural damage. SCFAs, especially butyrate, help maintain BBB integrity.

Animal studies support this protective role. In a mouse model of traumatic brain injury (TBI), sodium butyrate reduced brain swelling, enhanced endothelial cell survival, and increased levels of the tight junction protein ZO-1 by inhibiting HDAC3. Similarly, administration of the butyrate-producing bacterium C. butyricum improved neurological function and increased occludin expression in brain endothelial cells (Li et al., 2018). In an AD mouse model, butyrate supplementation reduced BBB leakage and limited Aβ plaque accumulation (Wang et al., 2022). Other SCFAs also contribute: in a cerebral ischemia model, propionate reduced BBB leakage by increasing the water channel AQP4 in astrocytes via GPR43 activation (Harijan et al., 2024). In a neuroinflammation model, acetate protected endothelial cells and increased claudin-5, another tight junction protein (Fock and Parnova, 2023). SCFAs also support the BBB indirectly by strengthening the intestinal barrier and reducing systemic inflammation. In a PD mouse model, a mixture of SCFAs activated GPR109A, reduced gut leakage, and lowered inflammation in brain endothelial cells (Yassin et al., 2025). By reducing both peripheral and central inflammation, SCFAs help preserve the functional integrity of the BBB. Clinically, higher fecal butyrate levels in AD patients were associated with lower blood levels of S100β, a marker of BBB damage (Guo et al., 2025). These findings highlight the potential of SCFAs as biomarkers and therapeutic agents for BBB protection.

Overall, SCFAs help maintain BBB homeostasis through direct effects on brain endothelial cells and indirect modulation of the GBA. By enhancing tight junction expression, reducing inflammation, and supporting endothelial survival, SCFAs represent a promising therapeutic approach for preserving BBB function in NDs.

Neuroimmune modulation

Microglia, the primary immune cells of the CNS, display significant functional plasticity. They can adopt either a pro-inflammatory (M1) state, releasing cytokines such as IL-1β and TNF-α, or an anti-inflammatory (M2) state, which supports tissue repair and resolution of inflammation. In AD and PD, chronic exposure to pathological proteins like Aβ and α-synuclein drives microglia toward sustained M1 activation, perpetuating neuroinflammation and disrupting synaptic function (Awogbindin et al., 2024). SCFAs help rebalance microglial activity through multiple pathways. Among SCFAs, butyrate has shown particularly strong anti-inflammatory properties. In a mouse model of alcohol-induced neuroinflammation, butyrate reduced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and increased the anti-inflammatory cytokine IL-10, partly through GPR109A activation and nuclear factor kappa-B (NF-κB) inhibition (Awogbindin et al., 2024, Wei et al., 2023). Butyrate also promotes the M2 phenotype; in AD model mice, it enhanced Aβ clearance and increased M2 microglia near plaques (Sun et al., 2020a). Additionally, butyrate acts as an epigenetic modulator by inhibiting HDACs, increasing acetylation at the IL-10 promoter and reinforcing anti-inflammatory gene expression (Senarath et al., 2024).

Propionate influences neuroimmunity by restraining inflammasome activation and reducing oxidative stress (ROS). Propionate reduced NLRP3 inflammasome activity and IL-1β release by binding to GPR43 and suppressing mitochondrial ROS production (Abarca et al., 2025). It also aids microglial metabolic reprogramming: in PD models, propionate enhanced mitochondrial respiration and supported an anti-inflammatory microglial phenotype, correlating with improved dopamine neuron survival and motor function (Hou et al., 2021). Acetate, though less potent, contributes to neuroimmune balance by modulating astrocyte-microglia communication. In LPS-induced neuroinflammation, acetate reduced astrocyte activation and subsequent microglial M1 polarization via GPR41 signaling (Liu et al., 2020). It also promotes brain-derived neurotrophic factor (BDNF) production in astrocytes through epigenetic mechanisms, supporting a restorative microenvironment (Lin et al., 2023).

The efficacy of SCFAs depends on an individual’s gut microbiome. For example, PD patients with low microbial diversity and reduced SCFA levels show greater microglial activation, reflecting a more pronounced shift toward the pro-inflammatory M1 phenotype. Restoring propionate levels using specific probiotics reduced brain inflammation and improved motor symptoms (Krueger et al., 2025). Together, these findings show that SCFAs fine-tune microglial behavior through multiple pathways, positioning them as promising candidates for treating neuroinflammation in NDs.

Neurotransmitter regulation

SCFAs significantly influence CNS function by regulating the synthesis, metabolism, and signaling of key neurotransmitters. These effects help maintain neuronal excitability, synaptic transmission, and plasticity, which often disrupted in NDs. SCFAs act directly on brain enzymes and receptors and indirectly through the GBA, offering a potential way to restore neurotransmitter balance in AD and PD. One key pathway influenced by SCFAs is the glutamate–glutamine cycle, which maintains excitatory neurotransmitter homeostasis. In AD, Aβ impairs astrocytic glutamine synthetase (GS), leading to glutamate accumulation and excitotoxicity. SCFAs restored GS activity in neuron–astrocyte co-cultures, increasing glutamine levels and reducing oxidative stress (Sun et al., 2023). In AD model mice, SCFA supplementation raised hippocampal GS expression, lowered extracellular glutamate, and improved synaptic plasticity (Sun et al., 2023). SCFAs also modulate GABA, the major inhibitory neurotransmitter. In a mouse model of metabolic dysfunction, sodium butyrate increased plasma and hippocampal GABA levels, elevated expression of the GABA-synthesizing enzyme GAD67, and enhanced histone acetylation at the GAD67 promoter. Similarly, in a PD model, propionate restored striatal GABA, rebalancing excitatory–inhibitory transmission and improving motor function (Chen et al., 2024a). Beyond direct neuromodulation, SCFAs stimulate serotonin (5-HT) release in the gut via FFAR3 receptors on enteroendocrine cells. This triggers vagal signaling to the brain and supports hippocampal neurogenesis. In AD models, SCFA treatment increased hippocampal 5-HT and neurogenesis, underscoring the role of gut–brain communication in maintaining neurotransmitter and cognitive health (Liu et al., 2020). Thus, SCFAs regulate multiple neurotransmitter systems through direct, indirect, and epigenetically mediated pathways.

Neurogenesis, synaptic plasticity, and mitochondrial function regulation

SCFAs play a vital role in maintaining neuronal health by modulating neurogenesis, synaptic plasticity, and mitochondrial function, processes often impaired in NDs. Through epigenetic, metabolic, and receptor-mediated mechanisms, SCFAs help preserve neuronal integrity and support cognitive and motor functions. SCFAs promote neurogenesis by enhancing the proliferation and differentiation of neural progenitor cells. Physiological levels of acetate, propionate, and butyrate accelerate the proliferation of human neural progenitor cells by upregulating genes involved in neurogenesis, cell-cycle progression, and apoptosis (Yang et al., 2020). Butyrate, as an HDAC inhibitor, promotes hippocampal neurogenesis and synaptic plasticity by upregulating genes involved in neuronal survival and synapse formation (Jaworska et al., 2019). Synaptic plasticity, essential for learning and memory, is also enhanced by SCFAs. Butyrate increases synaptic protein expression and dendritic spine density, improving long-term potentiation (McClarty et al., 2024). Acetate supports astrocyte function and glutamate recycling, reducing excitotoxicity and preserving synaptic integrity (Sun et al., 2023). Propionate, signaling through neuronal GPR43 receptors, stabilizes glutamate receptors at the synaptic membrane, supporting synaptic transmission (Grüter et al., 2023). Mitochondrial function, often impaired in NDs, is supported by SCFAs through metabolic and signaling mechanisms. SCFAs enter the mitochondrial matrix, where they participate in β-oxidation and the TCA cycle, supplying energy and reducing equivalents. SCFAs also act as ligands for GPR41 and GPR43, influencing neuronal proliferation, differentiation, and survival (Dalile et al., 2019, Qian et al., 2022). As metabolic substrates, SCFAs like butyrate cross the BBB, support neuronal energy metabolism, and enhance antioxidative defenses, collectively promoting neuroplasticity and reducing oxidative stress (Harijan et al., 2024, Lan et al., 2024). Otherwise, SCFAs modulate the heme oxygenase-2 (HO-2) signaling pathway, which protects cerebral microvascular endothelial cells against oxidative stress-induced mitochondrial dysfunction. Under oxidative stress conditions, SCFAs restore HO-2 expression and enzymatic activity, improve mitochondrial calcium homeostasis, and reduce the production of mitochondrial ROS and hydrogen peroxide, thereby enhancing mitochondrial function, a critical factor for maintaining neuronal viability and function, especially in the context of neurodegeneration (Kassan et al., 2023).

These regulatory axes are interdependent: neurogenesis relies on mitochondrial energy supply, and synaptic activity depends on efficient metabolism. Recent studies in PD models show that propionate enhances mitochondrial biogenesis and dopaminergic neuron survival, highlighting the integrative effects of SCFAs (Cao et al., 2025a). Together, these findings position SCFAs as multi-level regulators of neuronal and metabolic homeostasis, offering therapeutic opportunities for NDs.

Linking energy metabolism to neural function

SCFAs act as key metabolic integrators, bridging peripheral energy homeostasis and the high energy demands of neural function. In the periphery, SCFAs help maintain a stable supply of energy substrates to the brain. Propionate enhances insulin sensitivity and gluconeogenesis to support neuronal glucose supply (Portincasa et al., 2022); acetate supports lipoprotein-mediated fatty acid delivery, critical for myelin and synaptic membranes (Guo et al., 2018); and butyrate reduces adipose inflammation and improves leptin signaling, ensuring energy is available for neural needs (Zhang et al., 2021b). Within the CNS, SCFAs directly modulate cellular energy pathways. Astrocytes use SCFAs to boost glycolysis and lactate production, sustaining synaptic activity in energy-constrained regions like the hippocampus (Drougard et al., 2024). SCFAs also enhance neuronal mitochondrial function by upregulating respiratory chain complexes, countering age-related declines in efficiency (Sutherland et al., 2021). Central metabolic sensing is coordinated through the hypothalamus, where acetate activates AMPK and propionate signals via vagal afferents to prioritize energy allocation to neural processes (Grüter et al., 2023, Wada et al., 2025). In neurodegeneration, this coupling is critical: butyrate upregulates SIRT3 to restore mitochondrial function in AD models, reducing ROS and pathology (Wang et al., 2022, Kim et al., 2020); propionate enhances mitochondrial biogenesis in PD, protecting dopaminergic neurons (Wang et al., 2024b). SCFAs also shift microglia from pro-inflammatory glycolysis to anti-inflammatory oxidative phosphorylation, reducing neurotoxicity (Guo et al., 2025, Cao et al., 2025b). Overall, by maintaining energy substrate availability, enhancing central metabolic efficiency, and supporting hypothalamic regulation, SCFAs help preserve synaptic function, neurogenesis, and neuronal health, highlighting their therapeutic potential in countering energy failure in NDs.

In summary, SCFAs have extensive and multifaceted neural regulatory roles, encompassing BBB integrity, CNS immune responses, neurotransmitter systems, neurogenesis, mitochondrial function, and energy metabolism. These diverse mechanisms underscore the potential of SCFAs as key regulators of CNS function and promising therapeutic targets for NDs. The specific neuroregulatory mechanisms mediated by epigenetic modifications, which are critical for long-term neural changes, are explored in the following sections.

Epigenetic mechanisms of SCFAs in the brain

SCFAs influence brain function through interconnected epigenetic pathways that link gut microbiota activity to neural processes. As summarized in Table 1, multiple epigenetic alterations occur in NDs, implicating mechanisms central to disease progression. Table 2 illustrates how SCFAs modulate several key epigenetic processes, such as histone deacetylation, DNA methylation, histone lactylation and lncRNA activity. Through these mechanisms, SCFAs dynamically influence gene expression in neural cells, thereby affecting neuroinflammation, synaptic plasticity, and neuronal survival, each of which plays a critical role in neurodegeneration.

Table 1.

Summary of epigenetic alterations in neurodegenerative diseases and associated pathological mechanisms.

Disease	Subjects	Assays	Sample type	Epigenetic change	Pathological outcome	Refs.
AD	AD patients	ELISA	CSF	p300/CBP↓	Regulates TAU secretion and propagation	(Chen et al., 2020)
	AD patients (clinical progression)	Semi-quantitative WB & IHC	CBF	HDAC2↓	Associated with cholinergic nbM neuronal dysfunction, NFT pathology, and cognitive decline	(Mahady et al., 2019)
	AD post-mortem	IHC & WB	Inferior & middle temporal gyrus	H3ac↑, H4ac↑	Correlated with tau load (AD) or amyloid load (Con)	(Narayan et al., 2015)
	MCI patients	Acetyl Histone H4K12 Quantification Kit	Monocytes	H4K12ac↑	AD-pathology	(Plagg et al., 2015)
	APP/PS1 mice (3-, 12-, 18-month-old)	ChIP	Hippocampus, PFC	H3K9ac↑	Modulation of synapse-related gene expression	(McClarty et al., 2024)
	AD patients	IHC	Hippocampus	5-mC↓, 5-hmC↓	Showed negative correlations	(Chouliaras et al., 2013)
	5 × FAD mice	WB	Hippocampus	H4K12la↑ H4K12la↑	Glycolysis/H4K12la/PKM2 positive feedback loop exacerbating microglial activation and dysfunction	(Pan et al., 2022)
	AD patients	WB	Postmortem brain
PD	Idiopathic PD	Immunoblotting, ChIP-seq	Fresh-frozen brain	H3K27ac↓	Transcriptional dysregulation of PD-associated genes	(Toker et al., 2021)
	PD post-mortem	WB	Primary motor cortex	H3K14ac↑, H3K18ac↑, H3K9ac↓	Altered gene transcription	(Gebremedhin and Rademacher, 2016)
	TG-SIRT1 mice	WB	Microglia	SIRT1↑, HSPA4ac↑	Exerts anti-inflammatory effects in glial cells	(Yang et al., 2022)
	Sporadic PD patients	RT-PCR	Venous peripheral blood	SNCAme↓	Associated with susceptibility to sporadic PD	(Ai et al., 2014)
HD	HdhQ7/Q111 mice	IP, WB	Hippocampal tissue	CBP↓, H3ac↓	Improves cognitive impairment	(Giralt et al., 2012)
	HD patients, R6/2 mice	WB	Striatum, superior frontal cortex	H3K9me↑	Involved in neuronal survival	(Ryu et al., 2006)

Abbreviations: 5-hmC, 5-hydroxymethylcytidine; 5-mC, 5-methylcytidine; AD, Alzheimer’s disease; CBF, cholinergic basal forebrain; CBP, CREB-binding protein; ChIP, chromatin immunoprecipitation; ChIP-seq, chromatin immunoprecipitation sequencing; Con, control; CSF, cerebrospinal fluid; HD, Huntington’s disease; HDAC2, histone deacetylase 2; H3ac, histone H3 acetylation; H4ac, histone H4 acetylation; H3K9ac, histone H3 lysine 9 acetylation; H3K9me, histone H3 lysine 9 methylation; H3K14ac, histone H3 lysine 14 acetylation; H3K18ac, histone H3 lysine 18 acetylation; H3K27ac, histone H3 lysine 27 acetylation; H4K12ac, histone H4 lysine 12 acetylation; H4K12la, histone H4 lysine 12 lactylation; HSPA4ac, heat shock protein 4 acetylation; IHC, immunohistochemistry; IP, immunoprecipitation; MCI, mild cognitive impairment; nbM, nucleus basalis of Meynert; NFT, neurofibrillary tangles; PD, Parkinson’s disease; PFC, prefrontal cortex; PKM2, pyruvate kinase M2; p300, E1A-binding protein p300; RT-PCR, reverse transcription polymerase chain reaction; SIRT1, sirtuin 1; SNCAme, α-synuclein gene methylation; TG, transgenic; WB, western blot.

Table 2.

Regulatory mechanisms of SCFAs on epigenetic modifications in neuroprotection.

SCFAs	Enzyme	Model	Tissues	Epigenetic modification site	Target genes/protein	Function	Refs.
Acetate	↑ACSS2	5 × FAD mice	Hippocampus and PFC	↑H3K9ac, ↑H4K12ac	↑NMDARs, ↑AMPARs	Improves synaptic plasticity	(Lin et al., 2023)
	↓HDAC2	Male SD rats	Brain tissue	↑H3K9ac, ↑H4K8ac, ↑H4K16ac	–	Increases brain histone acetylation state	(Soliman and Rosenberger, 2011)
	↑HAT	Male SD rats	Brain tissue	↑H3K9ac, ↑H4K8ac, ↑H4K16ac	↓IL-1β	Downregulates neuroinflammation	(Soliman et al., 2012)
Butyrate	↑ACSS2	Male C57BL/6 J mice	Hippocampus	↑H3K9ac	↑BDNF	Improves cognitive memory impairment and anxiety symptoms	(Li et al., 2024)
	↓HDAC	Wistar rats	Brain tissue	↑H3ac	↑BDNF	Prevents HI-induced loss of neural progenitor cells, oligodendrocyte precursor cells, and neuroinflammation	(Ziemka-Nalecz et al., 2017)
	↓HDAC1	SH-SY5Y, NB7 cell lines	–	↑H4K8ac, ↑H4K16ac	↑NEP	Accelerates Aβ degradation	(Belyaev et al., 2009)
		GF rats	Microglia	↑H3K9ac	↓IL-1α, ↓INF-γ, ↓MCP-1	Reduces neuroinflammation	(Song et al., 2022)
	↓HDAC3	Male BABL/c mice	Skin tissues	–	↑STAT1, ↓NF-κB	Inhibits inflammatory mediators	(Hu et al., 2024)
		APP/PS1 mice	Hippocampus	–	↓PS1, ↓Aβ, ↑p-CREB, ↑BDNF	Decreases Aβ1–40 and Aβ1–42 levels and amyloid plaques; downregulates microglial activation; attenuates spatial memory deficits	(Zhu et al., 2017)
	↓HDAC4	SD rats	Hippocampus	–	↑GPR43, ↑mtDNA	Increases mitochondrial functions	(Wu et al., 2024)
	↓HDAC4, ↓HAT	SD rats	Serum, hippocampal tissue	↑H4K8ac, ↑H4K12ac, ↑H4K16ac	↓Bax, ↓Caspase 3, ↑Bcl-2	Inhibits apoptosis of hippocampal neurons	(Xu et al., 2023)
	↓HDAC5	SD rats	Hippocampus	↑H3K9ac, ↑H3K14ac, ↑H4K12ac	TH, TPH	Relieves anxiety- and depression-like behaviors	(Qiao et al., 2019)
	↓HDAC6	APP/PS1 mouse	Brain tissue	–	↓APP, ↓BACE1, ↓PSEN1, ↓ADAM10	Reduces Aβ deposition	(Zhang et al., 2024b)
	↓HDAC9	APP/PS1 mice, HEK293 cells	Cortex, hippocampus	↓CaMK22ac, ↓CaMK95ac, ↓CaMK116ac	–	Activates CaMKIIα; attenuates hippocampal short-term memory deficits	(Zhang et al., 2024a)
	↑SIRT1	SH-SY5Y cell lines	–	↓PKM2K135ac, ↓PKM2K206ac	↓PKM2	Improves lactate homeostasis	(Yi et al., 2025, Lian et al., 2024)
	↓SIRT2	Male C57BL/6 mice	Hippocampus	–	–	Regulates memory formation, cell proliferation, and neuroblast differentiation in dentate gyrus	(Yoo et al., 2015)
	↑TET1	Male FRL, FSL rats	Prefrontal cortex	↑5hmC	↑BDNF	Exerts antidepressant-like effects	(Wei et al., 2014)
	↑TET2	C57BL/6 J mice	Cerebral cortex	↑5hmC, ↑5fC	↑DNA demethylation	Prevents diabetic cognitive dysfunction	(Chen et al., 2024)
Propionate	↓HDAC2, ↓HDAC8	SD rats	DRG	↑H3ac	↑Catalase	Increases resistance to oxidative stress	(Grüter et al., 2023)
	–	Murine C2C12 myoblasts	–	↑H3K23pr	↑Myod gene	Regulates muscle differentiation and aging	(Lagerwaard et al., 2021)

Abbreviations: 5fC, 5-formylcytosine; 5hmC, 5-hydroxymethylcytosine; Aβ, amyloid-β; Aβ1–40, amyloid β-protein (1–40); Aβ1–42, amyloid β-protein (1–42); ACSS2, acetyl-CoA synthetase 2; ADAM10, a disintegrin and metalloproteinase domain-containing protein 10; AMPARs, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; APP, amyloid precursor protein; BACE1, β-site APP-cleaving enzyme 1; Bax, BCL2-associated X protein; Bcl-2, B-cell lymphoma 2; BDNF, brain-derived neurotrophic factor; CaMK22ac, Ca²⁺/calmodulin-dependent protein kinase 2 lysine 22 acetylation; CaMK95ac, Ca²⁺/calmodulin-dependent protein kinase 2 lysine 95 acetylation; CaMK116ac, Ca²⁺/calmodulin-dependent protein kinase 2 lysine 116 acetylation; Caspase 3, cysteinyl aspartate-specific proteinase-3; DCD, diabetic cognitive dysfunction; DRG, dorsal root ganglia; FAD, familial Alzheimer’s disease; FRL, Flinders resistant line; FSL, Flinders sensitive line; GF, germ-free; GPR43, G protein-coupled receptor 43; H3ac, histone H3 acetylation; H3K9ac, histone H3 lysine 9 acetylation; H3K14ac, histone H3 lysine 14 acetylation; H3K23pr, histone H3 lysine 23 propionylation; H4K8ac, histone H4 lysine 8 acetylation; H4K12ac, histone H4 lysine 12 acetylation; H4K16ac, histone H4 lysine 16 acetylation; HAT, histone acetyltransferase; HDAC, histone deacetylase; HI, hypoxia-ischemia; IL-1α, interleukin-1 alpha; IL-1β, interleukin-1 beta; INF-γ, interferon-gamma; MCP-1, monocyte chemoattractant protein-1; mtDNA, mitochondrial DNA; NEP, neprilysin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NMDARs, N-methyl-D-aspartate receptors; PFC, prefrontal cortex; PKM2, pyruvate kinase M2; PKM2K135ac, PKM2 lysine 135 acetylation; PKM2K206ac, PKM2 lysine 206 acetylation; PS1, presenilin-1; PSEN1, presenilin 1; p-CREB, phosphorylated cAMP response element-binding protein; SCFAs, short-chain fatty acids; SD, Sprague-Dawley; SIRT, sirtuin; STAT1, signal transducer and activator of transcription 1; TET, ten-eleven translocation methylcytosine dioxygenase; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase.

Among these pathways, HDAC inhibition is the most well-characterized. Butyrate, in particular, acts as a potent HDAC inhibitor, increasing histone acetylation levels and promoting the expression of neuroprotective genes. SCFAs also fine-tune DNA methylation patterns by modulating enzymes such as DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, which in turn adjust the expression of both pathogenic and protective genes. Moreover, emerging evidence suggests that SCFAs help regulate histone lactylation, a metabolic-state-sensitive modification, potentially counteracting abnormal lactylation linked to microglial dysfunction. Collectively, these actions establish SCFAs as important epigenetic modulators in NDs, with HDAC inhibition representing a foundational mechanism (Munteanu et al., 2024, Alpino et al., 2024).

Histone deacetylation inhibition

Histone acetylation is a key reversible modification that regulates gene expression by altering chromatin structure. Nucleosomes, the basic units of chromatin, are composed of histone proteins (H2A, H2B, H3, H4) around which DNA is wrapped. Among various chemical modifications of histones, such as acetylation, methylation, and lactylation, acetylation plays a central role in controlling gene activity. This process involves the addition of acetyl groups to specific lysine residues on histone tails, which reduces their positive charge and weakens their interaction with negatively charged DNA. As a result, chromatin becomes more relaxed, allowing transcription factors to access DNA and activate gene expression. Conversely, deacetylation, catalyzed by HDACs, restores tight DNA-histone binding, leading to chromatin condensation and gene silencing (Liu et al., 2023).

The balance of histone acetylation is regulated by two enzyme groups: histone acetyltransferases (HATs), which add acetyl groups, and HDACs, which remove them. HATs are categorized into structural families such as GNAT, MYST, and p300/CBP (Damiano et al., 2024). HDACs are divided into four classes: class I, II, and IV HDACs depend on zinc for activity, whereas class III HDACs, known as sirtuins, require NAD⁺ and are involved in metabolic and aging-related pathways (Milazzo et al., 2020, Flick and Lüscher, 2012). This regulatory framework underpins the epigenetic influence of SCFAs. Altered histone acetylation patterns are strongly associated with NDs. Reduced acetylation, in particular, is a prominent epigenetic abnormality in this context. For example, elevated levels of p300/CBP proteins have been observed in the cerebrospinal fluid of AD patients, suggesting a link to disease mechanisms (Chen et al., 2020). HDAC2, which is abundant in the CNS, suppresses memory and synaptic plasticity. In AD, HDAC2 expression declines in the nucleus basalis of Meynert (NBM), correlating with neuronal loss, neurofibrillary tangle formation, and cognitive impairment (Mahady et al., 2019). Postmortem studies further support this, showing increased histone acetylation in AD brain tissues, reinforcing the connection between histone modifications and disease progression.

SCFAs, particularly butyrate, propionate, and acetate, regulate histone acetylation through two complementary mechanisms. First, they directly inhibit HDAC activity. Butyrate exhibits the strongest effect, with high affinity for Class I HDACs (HDAC1–3) and moderate inhibition of Class II enzymes. It also influences Class III HDACs (sirtuins) (Zhang et al., 2025, Yi et al., 2025). Propionate similarly targets Class I HDACs, though less potently than butyrate, while acetate shows weak HDAC inhibition, mainly at elevated concentrations (Nshanian et al., 2025). Interestingly, acetate has also been shown to enhance HAT activity in neuroinflammatory models, reducing IL-1β expression. Mechanistically, SCFAs act as carboxylic acids that chelate zinc ions in the catalytic site of HDACs, impairing deacetylase function. This results in increased histone acetylation, chromatin relaxation, and activation of gene transcription. The second mechanism involves SCFAs serving as metabolic precursors for acetyl-CoA, the essential cofactor for HAT-mediated acetylation (Li et al., 2024). Acetate is directly converted to acetyl-CoA via acetyl-CoA synthetase 2 (ACSS2). In contrast, propionate and butyrate enter TCA cycle, ultimately generating acetyl-CoA. For instance, in AD model mice, acetate elevates acetylation of H3K9 and H4K12 in hippocampal and prefrontal cortex neurons via ACSS2, enhancing expression of NMDA and AMPA receptors and supporting synaptic plasticity (Lin et al., 2023). Similarly, butyrate induces ACSS2 in lead-exposed mice, promoting BDNF expression through the ACSS2/H3K9ac/BDNF pathway (Li et al., 2024). Beyond acetylation, propionate and butyrate also directly modify histones via propionylation and butyrylation, two novel epigenetic marks that further extend their regulatory roles (Nshanian et al., 2025, Lagerwaard et al., 2021).

SCFAs confer neuroprotection via HDAC inhibition through coordinated effects on neuroinflammation, synaptic function, and neuronal viability. In the brain, activated microglia release pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, exacerbating neuronal injury. Butyrate counteracts this process by elevating histone acetylation at promoters of anti-inflammatory genes like IL-10 and TGF-β, thereby enhancing their transcription and curbing cytokine release. It also stabilizes the NF-κB inhibitor IκBα through acetylation, preventing NF-κB nuclear translocation and downstream inflammation (Fock and Parnova, 2023, Hu et al., 2024). Notably, in atopic dermatitis models, sodium butyrate suppresses HDAC3 and increases acetylated STAT1, which sequesters NF-κB and limits its transcriptional activity (Hu et al., 2024). This anti-inflammatory axis is particularly relevant in Alzheimer’s pathology, where Aβ accumulation activates NF-κB in glial cells, amplifying neuroinflammation and degeneration (Lei et al., 2025). Butyrate further amplifies the IL-10/STAT3 signaling cascade, reinforcing immune homeostasis. Concurrently, SCFAs enhance synaptic plasticity, essential for learning and memory, by elevating expression of key plasticity-related genes such as BDNF and postsynaptic density protein 95 (PSD-95) through histone hyperacetylation (Zhang et al., 2023a). BDNF supports neuronal survival and synapse formation, while PSD-95 stabilizes synaptic architecture. SCFAs also mitigate oxidative and excitotoxic damage by increasing histone acetylation at promoters of antioxidant enzymes (e.g., superoxide dismutase and catalase) and anti-apoptotic factors like Bcl-2. Together, these mechanisms sustain neuronal integrity and cognitive function, highlighting the therapeutic potential of SCFAs in counteracting neurodegenerative processes.

Emerging preclinical evidence indicates that SCFAs contribute to neuroprotection in AD through immunomodulation, antioxidant activity, and suppression of neuroinflammation (Patricio-Martínez et al., 2025). These benefits are largely mediated via epigenetic mechanisms, particularly HDAC inhibition (Mafe and Büsselberg, 2025). In AD brains, reduced histone acetylation and elevated HDAC levels are linked to disease progression. Butyrate, for example, enhances histone acetylation at the amyloid precursor protein (APP) promoter, reducing APP expression and Aβ production. It also upregulates neprilysin (NEP), an Aβ-degrading enzyme, by blocking HDAC1-mediated repression of NEP transcription (Song et al., 2022). In tau pathology, butyrate inhibits HDAC1 and increases inhibitory phosphorylation of GSK3β, thereby reducing tau hyperphosphorylation (Zhang et al., 2023b). HDAC3 overexpression correlates with memory deficits in AD mice, and butyrate-mediated HDAC3 inhibition reduces Aβ accumulation and improves cognition (McClarty et al., 2024). Similarly, HDAC9 inhibition enhances calmodulin acetylation and activates CaMKIIα, supporting hippocampal memory (Zhang et al., 2024a), while HDAC6 knockdown reduces APP and secretase levels via JNK pathways, further limiting Aβ generation (Zhang et al., 2024b). Acetate also exerts anti-inflammatory effects by upregulating microglial GPR41 and suppressing ERK/JNK/NF-κB signaling (Liu et al., 2020). SCFAs further promote a protective microglial phenotype, aiding Aβ clearance (Senarath et al., 2024). Nevertheless, some studies suggest that gut dysbiosis and altered SCFA production may under certain conditions exacerbate neuroinflammation and tau pathology, indicating context-dependent effects (Sun et al., 2020b).

In PD, characterized by dopaminergic neuron loss and α-synuclein aggregation, epigenetic alterations, especially in histone acetylation, have been widely observed (Toker et al., 2021). Butyrate increases histone acetylation at the tyrosine hydroxylase (TH) promoter, enhancing dopamine synthesis (Qiao et al., 2019), and upregulates chaperones such as HSP70, reducing α-synuclein aggregation (Du et al., 2021). Butyrate also inhibits HDAC4, alleviating mitochondrial dysfunction and supporting neuronal survival (Wu et al., 2024). Interestingly, SIRT1 activation in glia exerts anti-inflammatory effects via deacetylation of HSPA4 (Yang et al., 2022). Despite these benefits, SCFAs may under certain conditions worsen PD pathology by activating the NLRP3 inflammasome through GPR43, highlighting a dual role in disease progression (Qu et al., 2025). Reductions in SCFA-producing bacteria have been reported in both PD and inflammatory bowel disease, suggesting a common microbial deficit (Krueger et al., 2025). In Huntington’s disease (HD), SCFAs also show therapeutic potential. Butyrate increases BDNF expression via histone hyperacetylation at its promoter, supporting neuronal survival and reducing inflammation (Alpino et al., 2024). HDAC4 inhibition further promotes neural stem cell differentiation and hippocampal plasticity (Xu et al., 2023).

Overall, SCFAs modulate histone acetylation through direct HDAC inhibition and metabolic provision of acetyl-CoA, influencing pathways critical to neuronal health and inflammatory response. Their ability to target multiple HDAC isoforms supports their potential as broad-spectrum epigenetic therapeutics for NDs. Future studies should focus on clarifying disease-specific mechanisms and optimizing SCFA-based interventions.

DNA methylation reprogramming

DNA methylation is a dynamic epigenetic process that critically regulates gene expression and cellular function. This modification involves the addition of a methyl group to cytosine bases, primarily within CpG dinucleotides, often concentrated in promoter regions known as CpG islands. Methylation of these regions typically suppresses gene expression by inhibiting transcription factor binding. The process is regulated by two enzyme families with opposing functions: DNMTs, which add methyl groups, and TET enzymes, which initiate their removal (Del Castillo Falconi et al., 2022). DNMT1 maintains methylation patterns during cell division, while DNMT3a and DNMT3b establish new methylation marks. Conversely, TET enzymes (TET1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine(5hmC), initiating the demethylation process (Zhang et al., 2023c). The balance between these enzymes fine-tunes gene expression in health and disease.

SCFAs significantly influence this epigenetic balance, particularly in the context of NDs. SCFAs modulate DNA methylation by regulating the activity of DNMT and TET enzymes while supporting one-carbon metabolism, which provides the essential methyl donor S-adenosylmethionine (SAM). SCFAs suppress DNMT expression while enhancing TET levels, shifting the balance toward demethylation (Wang et al., 2024c). Furthermore, SCFAs enter the TCA cycle, increasing production of α-ketoglutarate, an essential cofactor for TET enzymes. This enhanced TET activity promotes active DNA demethylation, as demonstrated in models where SCFAs stabilize TET2 and support neuroregeneration (Chen et al., 2024b). Additionally, SCFAs contribute to maintaining SAM pools by supporting the metabolic cycle that regenerates this universal methyl donor, thereby ensuring proper methylation of critical genes.

Aberrant DNA methylation patterns represent a key feature of neurodegenerative pathologies. In AD and PD, pathogenic genes frequently show reduced methylation, leading to their overexpression and disease progression (Cao et al., 2025a, Zainuddin et al., 2025). SCFAs may counteract this dysregulation through multiple mechanisms. Butyrate has been shown to alleviate neurodegeneration by upregulating DNA repair genes, while SCFAs collectively may promote methylation of disease-relevant gene promoters. Conversely, SCFAs can reverse hypermethylation of neuroprotective genes such as BDNF through TET1 activation, restoring their expression (Alpino et al., 2024, Wei et al., 2014). The brain-enriched demethylation product 5hmC, which declines in AD, may be restored by SCFAs through enhanced TET activity. Given that TET enzymes support neuronal function and protect against Aβ toxicity, SCFAs’ ability to boost TET activity represents a significant neuroprotective mechanism.

Taken together, SCFAs modulate DNA methylation in NDs through coordinated regulation of DNMT and TET enzymes, coupled with metabolic support for SAM and α-ketoglutarate production. By correcting aberrant methylation patterns of both pathogenic and protective genes, SCFAs emerge as important epigenetic regulators with substantial therapeutic potential. Future research should examine cell-type and region-specific methylation dynamics to further elucidate how SCFAs influence neurodegenerative processes.

Histone delactylation

Histone lactylation is a recently discovered reversible post-translational modification where lactyl groups attach to histone lysine residues, altering chromatin structure and gene expression (Wang et al., 2024d). This modification is dynamically regulated by enzyme complexes: p300/CBP catalyzes lactylation, while HDAC1–3 and SIRT1–3 remove lactyl marks, and reader proteins such as DFF2 recognize them to recruit transcriptional machinery (Yang et al., 2024a, Moreno-Yruela et al., 2022, Zhai et al., 2024). Although implicated in cancer and cardiovascular diseases, histone lactylation has recently gained attention in neurodegenerative research.

In AD, microglia undergo metabolic reprogramming from oxidative phosphorylation to glycolysis, increasing ATP generation but impairing phagocytosis and promoting inflammation. This glycolytic shift elevates intracellular lactate, which in turn drives histone lactylation, particularly at H4K12, in brain regions affected by Aβ plaques (Yang et al., 2024b). Lactylation of H4K12 enhances the expression of glycolytic genes, creating a pathogenic cycle that sustains metabolic dysfunction (Yang et al., 2025b, Wang et al., 2025). The glycolytic enzyme PKM2 further amplifies this process. Normally a tetramer, PKM2 shifts to a dimeric form in AD, entering the nucleus to activate transcription of glycolytic and inflammatory genes (Zhu et al., 2024). This reinforces lactate production, microglial hyperactivation, and defective Aβ clearance, accelerating disease progression (Chen et al., 2025).

SCFAs may interrupt this harmful cycle in colorectal cancer models, such as butyrate suppresses PKM2 expression and favors its tetrameric form, curbing proliferation. Although not yet confirmed in neural contexts, these findings suggest SCFAs could similarly modulate microglial PKM2 to restore metabolic balance. Butyrate also inhibits glycolysis in liver cancer via hexokinase-2, raising the possibility that SCFAs limit lactate generation and lactylation in the brain. Furthermore, as HDAC inhibitors, SCFAs may influence delactylation. HDAC3 and H4K12la regulate each other in macrophages, and SCFA-mediated HDAC inhibition could shift this balance (Zou et al., 2025). SCFAs also support mitochondrial metabolism, potentially boosting sirtuin activity and promoting lactyl group removal.

In PD, analogous lactylation mechanisms may contribute to dopaminergic neuron loss. By stabilizing PKM2 in its tetrameric form, butyrate could improve glycolytic efficiency and neuronal energy supply. SCFAs also exert anti-inflammatory effects by suppressing NF-κB, countering PKM2-driven neuroinflammation (Sun et al., 2025). Notably, SIRT1, modulated by SCFAs, can deacetylate PKM2 and restore lactate homeostasis in PD models (Lian et al., 2024). Through combined effects on lactylation, acetylation, and DNA methylation, SCFAs may help reestablish a neuroprotective epigenetic state.

Collectively, histone lactylation sustains a toxic feedback loop in neurodegeneration by linking glycolytic metabolism to pro-inflammatory gene activation. SCFAs offer a multi-level intervention strategy by targeting PKM2, modulating metabolic enzymes, and influencing delactylation, presenting a promising epigenetic approach to treating NDs.

LncRNAs regulation

LncRNAs, which exceed 200 nucleotides in length, belong to the non-coding transcriptome and play vital regulatory roles in the CNS. They are expressed in a cell- and region-specific manner, localizing to the nucleus, cytoplasm, and mitochondria, where they influence key neural processes such as Aβ aggregation, neurogenesis, synaptic plasticity, and neurotrophic signaling through epigenetic, transcriptional, and post-translational mechanisms (Tripathi et al., 2021, Tan et al., 2022).

One of the best-characterized lncRNAs in AD is BACE1-AS, a 2.1-kb transcript originating from the antisense strand of the BACE1 gene. BACE1-AS forms a stable RNA duplex with BACE1 mRNA, preventing its degradation by microRNAs such as miR-485-5p. This stabilization enhances BACE1 expression, promotes β-secretase activity, and accelerates Aβ peptide production. Clinically, BACE1-AS is elevated in the cerebrospinal fluid and plasma of AD patients and correlates with poorer cognitive scores (Su et al., 2024). Moreover, systemic inflammation, often linked to gut dysbiosis, can further induce BACE1-AS via NF-κB signaling, creating a feed-forward loop that exacerbates AD pathology (Chen et al., 2012).

Another significant lncRNA, NEAT1, is upregulated in both AD and PD. In AD, NEAT1 promotes Aβ deposition by sponging miR-27a-3p, and its knockdown improves cognitive performance in AD SD rat models (He et al., 2022, Dong et al., 2021). In PD, elevated NEAT1 in peripheral blood contributes to dopaminergic neuron loss by increasing pro-apoptotic signaling and impairing mitophagy through PINK1 stabilization (Yan et al., 2018). These findings underscore the role of lncRNAs in bridging neuropathological mechanisms across different neurodegenerative conditions.

Additional lncRNAs also contribute to PD pathogenesis. X-inactive specific transcript (XIST), for example, acts as a competitive endogenous RNA for miR-199a-3p, leading to SP1-mediated upregulation of LRRK2 and enhanced α-synuclein phosphorylation (Zhou et al., 2021b). Similarly, HOX transcript antisense intergenic RNA (HOTAIR) facilitates PD progression through multiple routes: it recruits PRC2 to modify histones at the LRRK2 promoter, activates NLRP3 inflammasome signaling via miR-326, and disrupts autophagy through miR-874-5p/ATG10 interference (Zhang et al., 2021c). Interestingly, HOTAIR can also exert neuroprotective effects in certain contexts, highlighting the contextual complexity of lncRNA functions.

Although direct evidence linking microbial SCFAs to lncRNA regulation remains sparse, early studies suggest plausible indirect pathways. Butyrate, for instance, upregulates lncLy6C, which promotes anti-inflammatory macrophage differentiation (Gao et al., 2020). SCFAs may also influence lncRNA networks through histone acetylation, DNA methylation modulation, and metabolic support of TET enzyme activity. For example, BACE1-AS expression could be epigenetically tuned via promoter methylation (Marques et al., 2012, Paniri et al., 2024). Altogether, the interface between gut microbiota-derived metabolites and lncRNA regulation represents a promising area for future research in ND mechanisms.

A novel paradigm of epigenetic regulation in the GBA

The GBA represents a sophisticated bidirectional communication network that integrates neural, immune, endocrine, and metabolic signals to coordinate gastrointestinal and CNS functions. While gut-derived SCFAs are established GBA mediators, emerging evidence reveals the critical role of epigenetic mechanisms in modulating GBA homeostasis. This evolving paradigm extends beyond conventional signaling-based models, showing a dynamically regulated system where SCFAs serve as “metabolic epigenetic cues” that bridge gut microbial activity with sustained functional adaptations in intestinal and neural tissues. In the following sections, we examine how SCFAs shape the epigenetic landscape across gut and brain compartments to influence GBA communication, drawing on mechanistic and translational evidence.

SCFAs strengthen gut barrier function through epigenetic mechanisms

The intestinal epithelium forms a critical barrier that separates the gut lumen from systemic circulation, playing a fundamental role in maintaining GBA integrity. Disruption of epithelial barrier function enables translocation of microbial metabolites and pathogens into the bloodstream, provoking systemic inflammation that perturbs CNS function. SCFAs, particularly butyrate, strengthen this barrier through targeted epigenetic modifications that enhance epithelial resilience.

As a primary metabolic substrate for colonocytes, butyrate functions as a potent inhibitor of class I HDACs, promoting chromatin relaxation at genes essential for barrier maintenance. In human colonic epithelial cells, butyrate elevates histone H3 and H4 acetylation at the promoters of the tight-junction proteins occludin and ZO-1, boosting their expression and reducing intestinal permeability (Huang et al., 2021). Mechanistically, this is achieved through the inhibition of HDAC1 and HDAC3, which otherwise repress occludin transcription (Fujino et al., 2001). Beyond tight junction regulation, butyrate also enhances histone acetylation at the MUC2 promoter, increasing production of mucin-2, a key component of the protective mucus layer (Fu et al., 2024). Complementary mechanisms involve propionate, which attenuates DNMT1-mediated hypermethylation of the GPR43 promoter to enhance receptor expression and downstream PI3K/Akt signaling (Hou et al., 2021), and acetate, which upregulates ACSS2 to boost acetyl-CoA levels and HAT activity, thereby increasing H3K9ac at the IL-10 promoter and suppressing epithelial inflammation (Soliman et al., 2012). Evidence from animal models supports the physiological relevance of these mechanisms. Germ-free (GF) mice, which lack SCFA-producing microbiota, exhibit diminished histone acetylation in the colon, reduced expression of tight junction proteins, and impaired barrier function. Colonization with butyrate-producing F. prausnitzii restores H3ac levels at occludin and ZO-1 promoters and normalizes intestinal barrier integrity (Wang et al., 2024a). Conversely, antibiotic-induced depletion of SCFA-producing bacteria lowers colonic butyrate, elevates HDAC activity, and downregulates MUC2, and these effects can be reversed by butyrate supplementation (Duan et al., 2022). Together, these findings indicate that SCFAs coordinate a multi-layered epigenetic program that strengthens the intestinal barrier. By enhancing junctional integrity, promoting mucus production, and reducing inflammation, SCFAs help prevent the systemic spread of gut-derived inflammatory mediators, thereby protecting GBA function.

SCFAs modulate gut immune function via epigenetic reprogramming

The gut-associated lymphoid tissue (GALT), the largest immune organ in the body, regulates local and systemic inflammation by balancing pro-inflammatory and anti-inflammatory immune cell populations. SCFAs modulate GALT function through epigenetic mechanisms, shaping immune responses that indirectly influence CNS health. For instance, by reducing systemic inflammation, SCFAs help mitigate neuroinflammation in AD and PD.

Butyrate promotes the differentiation of Tregs through HDAC inhibition. In human CD4⁺ T cells, butyrate increases H3K27ac at the promoter of Foxp3 by inhibiting HDAC2 and HDAC6 (Park et al., 2015). This epigenetic activation increases Foxp3 expression by 3–4 fold, driving Treg differentiation and enhancing their suppressive activity against pro-inflammatory Th1/Th17 cells. In a mouse model of colitis, butyrate supplementation increases colonic Treg numbers and reduces pro-inflammatory cytokines (TNF-α, IL-6), effects abrogated by Tregs depletion (Park et al., 2015). Propionate, meanwhile, drives anti-inflammatory macrophage polarization via DNA demethylation. It activates the TET2 enzyme, which reduces DNA methylation at the promoter of the anti-inflammatory cytokine IL-10 (Chen et al., 2024b). This epigenetic shift promotes IL-10 expression and encourages macrophages to adopt an anti-inflammatory phenotype. Notably, patients with IBD, who often exhibit low SCFA levels, show hypermethylation of the IL-10 promoter in gut macrophages, a defect reversible with propionate treatment (He et al., 2023b). Acetate modulates innate immunity through a more recently discovered mechanism: histone lactylation. By enhancing glycolysis and increasing intracellular lactate, acetate promotes histone lactylation at the NLRP3 inflammasome gene promoter (Yang et al., 2024a). This modification recruits transcriptional repressors that suppress NLRP3 expression, thereby curbing excessive innate immune activation and helping maintain gut immune homeostasis (Zhai et al., 2024).

These immunomodulatory effects extend to the GBA. By tempering systemic inflammation through epigenetic regulation of gut immune cells, SCFAs reduce the levels of circulating inflammatory factors that can cross BBB and activate microglia. For example, in an AD mouse model, butyrate-induced expansion of gut Tregs lowered peripheral TNF-α levels and significantly reduced microglial activation in the hippocampus (Sun et al., 2020a). Thus, SCFAs act as a “peripheral brake” on neuroinflammation, linking gut immune-epithelial crosstalk to brain health through targeted epigenetic mechanisms.

SCFAs influence enteric nervous system function via epigenetic pathways

The enteric nervous system (ENS), often termed the “second brain”, regulates gastrointestinal motility, secretion, and sensory signaling, and communicates bidirectionally with CNS via the vagus nerve and spinal pathways (Schneider et al., 2019, Dicks, 2023). Emerging evidence indicates that SCFAs modulate ENS development and function through specific epigenetic mechanisms, thereby contributing to GBA homeostasis. Butyrate promotes the differentiation of enteric neural progenitor cells through HDACs inhibition. In human cellular models, butyrate enhances H3K9 acetylation at BDNF promoter, leading to a significant upregulation of BDNF expression (Yang et al., 2020). This facilitates neuronal and glial differentiation via TrkB signaling. Consistent with these findings, GF mice exhibit reduced BDNF levels and decreased enteric neuronal density, and these defects are reversed by butyrate treatment (Yang et al., 2020). Furthermore, butyrate enhances synaptic plasticity in the ENS by increasing histone acetylation at synaptic gene promoters such as postsynaptic density protein 95 (PSD95), improving gastrointestinal motility in animal models of ileus (Zhang et al., 2023a).

Propionate modulates neuronal excitability via DNA methylation mechanisms. In rat enteric neurons, propionate downregulates DNMT3a, leading to reduced methylation of the potassium channel gene KCNQ1 and a corresponding increase in its expression (Grüter et al., 2023). This change hyperpolarizes neurons and normalizes gut motility in irritable bowel syndrome (IBS) models. Clinically, IBS patients with low fecal propionate show increased KCNQ1 promoter methylation and heightened neuronal excitability, underscoring the translational relevance of this pathway (El-Salhy et al., 2021). Acetate, in turn, supports glial–neuronal communication by enhancing histone acetylation. In mouse enteric glia, acetate upregulates histone acetyltransferase activity and increases H4K12ac at the connexin 43 (CX43) promoter, a key gap junction protein (Sasaki et al., 2022). This enhances potassium buffering and maintains ENS stability. GF mice deficient in acetate display impaired glial CX43 expression, which is restored upon acetate administration (Sasaki et al., 2022).

Dysregulation of these SCFA-mediated epigenetic pathways is implicated in gut–brain disorders. For instance, PD patients frequently present with early gastrointestinal dysfunction, correlated with reduced SCFA levels and diminished BDNF in the ENS (Nishiwaki et al., 2020). In mouse models of PD, butyrate supplementation restores BDNF expression through HDAC inhibition, ameliorating gut motility and reducing pathological α-synuclein accumulation in the ENS (Sun et al., 2021b). These findings highlight the ENS as a promising target for epigenetically informed interventions aimed at restoring GBA function.

SCFAs epigenetically regulate hypothalamic control of metabolism and stress

The hypothalamus serves as a CNS hub for GBA, integrating peripheral signals, including SCFAs, to regulate metabolism, stress responses, and feeding behavior. SCFAs cross the BBB and act on hypothalamic neurons through epigenetic mechanisms, thereby linking gut microbial activity to central homeostatic control. Butyrate, for example, regulates hypothalamic feeding circuits by inhibiting HDACs and activating anorexigenic genes. In the arcuate nucleus (ARC) of mice, butyrate increases histone H3 acetylation at the promoter of pro-opiomelanocortin (POMC), enhancing its expression and reducing food intake and body weight in obese models (Bastings et al., 2023). Conversely, HDAC3 overexpression in the ARC abolishes these effects, confirming the role of HDAC inhibition (Bastings et al., 2023). Butyrate also suppresses the orexigenic neuropeptide Y (NPY) by increasing H3K27ac at the FOXO1 promoter, a transcriptional repressor of NPY (Portincasa et al., 2022). Propionate modulates hypothalamic stress responses via TET-mediated DNA demethylation. In the paraventricular nucleus (PVN) of rats, propionate activates TET1, leading to increased 5hmC at the corticotropin-releasing hormone (CRH) promoter. This reduces CRH promoter methylation and downregulates CRH expression, attenuating hypothalamic–pituitary–adrenal (HPA) axis hyperactivity under chronic stress (Wei et al., 2014). Clinically, reduced fecal propionate and CRH hypermethylation have been observed in individuals with chronic stress and anxiety-like behaviors (Wei et al., 2014). Acetate contributes to hypothalamic metabolic regulation through histone lactylation. In the ventromedial nucleus (VMN) of mice, acetate enhances mitochondrial β-oxidation, increasing intracellular lactate and promoting H3K18la lactylation at the AMPKα promoter (Wada et al., 2025). This activates AMPKα transcription, improves fatty acid oxidation, and enhances insulin sensitivity. Disruption of this pathway, such as in mice depleted of acetate-producing microbiota, leads to impaired AMPK activation and insulin resistance (Wada et al., 2025). Dysregulation of these hypothalamic epigenetic pathways is implicated in NDs. AD patients often exhibit insulin resistance and HPA axis dysfunction, associated with reduced SCFA levels and hypermethylation of POMC and CRH (Mafe and Büsselberg, 2025). In AD mouse models, oral SCFA supplementation restores hypothalamic POMC and CRH expression via epigenetic mechanisms, improving metabolic and cognitive outcomes (Mafe and Büsselberg, 2025).

Thus, SCFAs function as “metabolic epigenetic messengers”, translating gut microbial signals into stable, adaptive changes in GBA function. By modulating histone acetylation, lactylation, and DNA methylation, SCFAs help maintain systemic homeostasis and offer promising therapeutic targets for GBA-related disorders. Future research should focus on identifying cell-type-specific epigenetic mechanisms and developing personalized interventions based on individual microbiome-epigenome profiles.

Therapeutic potential of SCFAs in NDs

As the understanding of the role of gut-derived SCFAs in NDs deepens, it becomes increasingly clear that these compounds can be therapeutically modulated to enhance their effects. By modulating key processes including epigenetic regulation, neuroinflammation and neuronal integrity, SCFAs exert distinct yet overlapping roles in AD and PD, making them promising therapeutic intervention targets. This section outlines practical strategies to enhance SCFA levels and function, including dietary modifications, probiotics, prebiotics, postbiotics, FMT, and novel epigenetic-based intervention strategies. Each of these avenues aims to improve SCFA bioavailability and strengthen their neuroprotective potential, as summarized in Fig. 3.

Fig. 3.

SCFA-modulating strategies for neurodegenerative disease therapy.

This figure summarizes therapeutic strategies to elevate SCFA levels for treating Alzheimer’s disease (AD) and Parkinson’s disease (PD), along with their mechanisms in countering disease pathology. A high-fiber diet stimulates SCFA production by beneficial gut bacteria such as Faecalibacterium prausnitzii and Roseburia species. Probiotics like Clostridium butyricum and Lactobacillus plantarum PS128 enhance SCFA synthesis, promote histone acetylation, inhibit histone deacetylases (HDACs), and activate neuroprotective gene expression. Fecal microbiota transplantation (FMT) restores a balanced gut microbiome, thereby increasing SCFA production. Postbiotics—which contain SCFAs, extracellular polysaccharides, functional proteins, and microbial components—act on SCFA receptors (GPR41, GPR43, GPR109A), while nanocarriers improve the brain-targeting efficiency of SCFA-based therapeutics. Novel epigenetic-based intervention strategies include: combining SCFAs with epigenetic drugs, engineering SCFA-producing microbes, and deploying brain-penetrant nanocarriers. These multi-faceted approaches target key pathological features of AD (amyloid-β plaques, neurofibrillary tangles, neuronal and synaptic loss) and PD (degeneration of dopaminergic neurons in the substantia nigra, Lewy body formation), ultimately alleviating clinical symptoms such as cognitive decline and bradykinesia.

Dietary interventions

Dietary interventions influence host health by modulating gut microbiota composition and promoting the production of SCFAs. Current dietary strategies for AD and PD often include the Mediterranean, Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), and high-fiber diets. These diets share an emphasis on high fiber intake, which has been shown to alleviate oxidative stress and neuroinflammation, slow disease progression, and ameliorate clinical symptoms in NDs (Briglia et al., 2024, Iyer et al., 2024, Liuzzi et al., 2023). High-fiber diets rich in fruits, vegetables, and whole grains selectively enrich beneficial bacteria such as Faecalibacterium prausnitzii and Roseburia species. These microbes ferment dietary fiber into butyrate, a SCFA that exerts neuroprotective effects partly through inhibition of HDACs (Alpino et al., 2024). In AD models, butyrate enhances acetylation of histones H3 and H4 in hippocampal and cortical regions, increasing expression of synaptic plasticity-related genes such as BDNF and improving cognitive performance. Similarly, in PD, butyrate elevates H3K27ac in the substantia nigra, activating antioxidant enzymes like superoxide dismutase and catalase, which protect dopaminergic neurons from oxidative damage (Silva et al., 2012).

The MIND diet, which combines elements of Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, has been linked in observational studies to reduced AD risk and better cognitive outcomes (Agarwal et al., 2023). Low-carbohydrate, high-fat ketogenic diets also modulate gut microbial communities and boost SCFA levels, potentially countering neuroinflammation and cognitive decline (Nagpal et al., 2019, Morris et al., 2020). Moving forward, personalized nutrition based on individual microbiome profiles offers a promising avenue to optimize SCFA production and enhance clinical efficacy (Mafe and Büsselberg, 2025, Shukla et al., 2024).

As a natural and accessible approach, dietary modification represents a powerful tool for managing neurological diseases via GBA regulation. To fully realize this potential, future studies should clarify the mechanistic basis of diet-microbiota interactions, account for interindividual variability, and establish practical dietary guidelines. Overcoming socioeconomic and practical barriers to implementation will be essential to maximize the reach and impact of dietary strategies in preventing and treating NDs.

Probiotics and prebiotics

Probiotics and prebiotics play a pivotal role in modulating the gut microbiota and enhancing the production of SCFAs. Specific probiotic strains, including Clostridium butyricum and Lactobacillus plantarum PS128, have been shown to elevate SCFA levels and exert neuroprotective effects in animal models of PD (Sun et al., 2021b, Lee et al., 2023). In PD, butyrate enhances the activity of JHDM enzymes, reducing repressive histone methylation (H3K9me3) at TH promoter, thereby promoting TH expression and supporting dopaminergic neuron function (Zhang et al., 2023d). Engineered microbial therapeutics, such as GLP-1-expressing Escherichia coli Nissle 1917 (ECN-GLP-1), further restore microbial balance and increase SCFAs that modulate histone methylation associated with TH expression (Wu et al., 2023). In AD models, probiotics that boost propionate production influence DNMT activity, leading to reduced methylation of the neprilysin promoter. This enhances neprilysin-mediated clearance of Aβ. High-fiber diets, as prebiotic interventions, promote the growth of butyrate-producing bacteria such as C. butyricum, indirectly elevating SCFA levels and attenuating neuroinflammation in both AD and PD (Chen et al., 2024c). In AD, butyrate induces histone acetylation at the miR-124 promoter, increasing its expression and suppressing toll-like receptor 4 (TLR4) signaling in microglia. In PD, SCFAs promote histone acetylation that upregulates miR-let-7, which in turn targets α-synuclein mRNA and reduces its accumulation (de Paiva et al., 2023). Thus, probiotics, prebiotics, and engineered microbes act synergistically to elevate SCFAs and support brain health through multiple epigenetic mechanisms.

Despite their promise, translating these interventions into clinical practice requires further validation. Key challenges include identifying optimal microbial strains, establishing effective dosing protocols, and ensuring product consistency and safety across diverse populations. The development of standardized manufacturing and regulatory guidelines will be essential to maximize the therapeutic potential of probiotic and prebiotic strategies in NDs.

Fecal microbiota transplantation (FMT)

FMT involves transferring gut microbial communities from healthy donors to patients to restore a balanced intestinal flora and achieve therapeutic outcomes. This approach has shown promise not only in gastrointestinal conditions such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), but also in NDs. For example, a clinical case reported that one month of FMT in AD patients modified fecal microbiota composition, elevated SCFAs levels, and improved cognitive performance (Park et al., 2021). Similarly, studies in PD models indicate that FMT can mitigate motor deficits and cognitive decline by reestablishing a healthy gut microbiome (Cheng et al., 2023, Wang et al., 2021). However, standardized procedures and long-term safety profiles are still needed before broader clinical implementation.

A key mechanism underlying the benefits of FMT may involve increased production of SCFAs. For instance, FMT elevated total SCFAs in IBS patients, with butyrate showing the most marked increase (El-Salhy et al., 2021). In models of ischemic stroke, FMT-induced neuroprotection was associated with raised levels of butyrate, isobutyrate, and isovalerate, suggesting SCFA-mediated recovery (Chen et al., 2019). In the context of NDs, butyrate may play a central role as a HDAC inhibitor. It promotes expression of neuroprotective factors like BDNF, suppresses pro-inflammatory signaling molecules such as NF-κB, IL-1β, and IFN-γ, and in AD models, reduces the expression of amyloid-related proteins including APP, BACE1, and PSEN1.

Despite these promising findings, several challenges remain. Current evidence comes largely from preclinical models and small human studies, with a lack of large randomized trials and long-term data. There is also a need for uniform protocols for donor screening, patient preparation, treatment frequency, and outcome assessment. Rigorous standardization and comprehensive safety evaluations are essential before FMT can be widely used in neurological practice.

Postbiotics

Postbiotics comprise inactivated probiotic cells and their metabolic byproducts, such as extracellular polysaccharides, SCFAs, bacteriocins, and organic acids, produced during microbial fermentation. These compounds can be administered directly and exert bioactivity through interaction with SCFA receptors, including GPR41, GPR43, and GPR109A. Targeting these receptors represents a promising strategy for treating NDs, given their central role in modulating immune and neuronal functions. Agonists or antagonists of SCFA receptors have shown potential in enhancing neuroprotective effects (Taing et al., 2023). For instance, in PD models, butyrate activates GPR109A, suppressing the NF-κB pathway, restoring intestinal barrier integrity, and ameliorating motor deficits (Xu et al., 2022). Similarly, propionate supplementation preserves dopaminergic neurons likely via GPR41 activation (Hou et al., 2021). Synthetic agonists such as GLPG0974 also replicate SCFA-mediated anti-inflammatory effects by inhibiting microglial NF-κB signaling (Ikeda et al., 2022). In AD, propionate administration reduces hippocampal expression of pro-inflammatory cytokines and upregulates synaptic proteins such as synaptophysin and postsynaptic density protein 95 (PSD95), indicating improved synaptic function (Lang et al., 2022). These findings underscore the broad therapeutic relevance of SCFA receptor modulation across NDs.

Compared with FMT, direct SCFA supplementation allows better control over composition and dosing while avoiding issues related to donor variability and safety. However, clinical translation is hampered by the short half-life and widespread tissue distribution of SCFAs. Advanced delivery systems, such as controlled-release formulations, nanocarriers, or ligand-gated liposomes, are being developed to enhance brain targeting and stability, thereby improving therapeutic efficacy.

Novel epigenetic-based intervention strategies

The complex pathogenesis of NDs involves significant epigenetic dysregulation and GBA impairment. Targeting SCFA-mediated epigenetic mechanisms has therefore emerged as a promising therapeutic strategy. Recent advances now combine precision epigenetic modulation, microbial engineering, and targeted delivery to enhance treatment efficacy while minimizing adverse effects (Table 3).

Table 3.

Registered clinical trials of SCFAs targeted interventions for Alzheimer’s disease and Parkinson’s disease (from ClinicalTrials.gov).

NCT number	Research title	Disease	Intervention	Primary outcome measures	Phase	Status	Sponsor	Link
NCT03472664	Brain Energy for Amyloid Transformation in Alzheimer’s Disease Study (BEAT-AD)	AD	Low carbohydrate /high fat diet Low fat/high carbohydrate diet	CSF Aβ42	Not Applicable	Recruiting	Wake Forest University Health Sciences	https://clinicaltrials.gov/study/NCT03472664
NCT06681948	The Ketogenic Diet in the Treatment of Alzheimer’s Disease (JT821)	AD	Ketogenic diet Placebo	Changes in cognitive function	Not Applicable	Recruiting	Capital Medical University	https://clinicaltrials.gov/study/NCT06681948
NCT06181513	Probiotics in Mild Alzheimer’s Disease	AD	Probiotic blend capsule	Level of inflammatory markers	Early Phase 1	Recruiting	University of Nicosia	https://clinicaltrials.gov/study/NCT06181513
NCT06019117	Effectiveness of Probiotic K10 in Managing Health Outcomes in Parkinson and Alzheimer Disease	AD PD	Probiotic K10 Placebo	Changes in cognitive function	Not Applicable	Completed	Deivis de Oliveira guimaraes	https://clinicaltrials.gov/study/NCT06019117
NCT06948929	Synbiotic Formula (SCV09) in Alzheimer’s Disease Patients	AD	SCV09	Changes in cognitive function	Not Applicable	Recruiting	Chinese University of Hong Kong	https://clinicaltrials.gov/study/NCT06948929
NCT05145881	Effect of Probiotics in Alzheimer’s Disease	AD	Low dose probiotics Normal dose probiotics	Changes in cognitive function	Not Applicable	Completed	Hsieh-Hsun Ho	https://clinicaltrials.gov/study/NCT05145881
NCT06920212	Clinical Safety and Efficacy of Fecal Microbiota Transplantation in the Treatment of Alzheimer’s Disease	AD	FMT capsule	Changes in cognitive function	Not Applicable	Active, not recruiting	Shanghai 10th People’s Hospital	https://clinicaltrials.gov/study/NCT06920212
NCT03998423	Oral Fecal Microbiota Transplant Feasibility Study in Alzheimer’s Disease (AMBITION)	AD	FMT	Change in gut composition	Phase 1	Terminated	University of Wisconsin, Madison	https://clinicaltrials.gov/study/NCT03998423

Abbreviations: Aβ42: Amyloid-beta 42; AD: Alzheimer’s disease; CSF: Cerebrospinal fluid; FMT: Fecal microbiota transplantation; PD: Parkinson’s Disease; SCFAs: Short-chain fatty acids.

SCFAs act synergistically with epigenetic drugs to correct aberrant histone and DNA modifications. In AD models, butyrate potentiates the HDAC3 inhibitor RGFP966, elevating H3K27ac marks at BDNF and NEP promoters, reducing amyloid and tau pathology without the gastrointestinal side effects of high-dose HDAC inhibition (Zhang et al., 2024a). Similarly, in PD models, propionate enhances TET2-mediated demethylation of the tyrosine hydroxylase promoter when combined with TEPP-46, restoring dopaminergic function and motor performance (Cao et al., 2025a). Histone lactylation represents another emerging target; butyrate co-administered with a PKM2 lactylation inhibitor suppresses H4K12la-induced microglial M1 polarization and improves amyloid clearance (Pan et al., 2022).

Microbial engineering approaches optimize SCFA production for targeted epigenetic effects. Engineered probiotics, such as ECN-GLP-1, restore gut microbiota balance in PD models, elevating butyrate levels that modulate histone methylation at neuronal gene promoters (Wu et al., 2023). Bacteroides strains engineered for enhanced butyrate synthesis similarly strengthen HDAC inhibition and neuroprotective gene expression in AD models (Chen et al., 2024c). These synthetic biology strategies enable precise spatiotemporal control over SCFA delivery to match central epigenetic requirements.

Advanced delivery systems overcome the limited brain bioavailability of SCFAs and epigenetic drugs. BBB-targeted lipid nanoparticles co-encapsulating sodium butyrate and vorinostat synergistically enhance hippocampal H3K9ac and BDNF expression without systemic toxicity (Yao et al., 2018). Exosome-based carriers derived from mesenchymal stem cells successfully deliver both propionate and TET2 mRNA, promoting DNA demethylation of neuroprotective genes with high targeting efficiency (Chen et al., 2024b). These nanoplatforms address key pharmacokinetic challenges while enabling multi-target epigenetic regulation.

Collectively, these integrated approaches—combining SCFAs with epigenetic drugs, engineering SCFA-producing microbes, and deploying brain-penetrant nanocarriers—represent a next-generation paradigm for treating NDs. They harness endogenous SCFA signaling while overcoming conventional delivery limitations, offering more precise and sustainable epigenetic interventions.

Limitations

While this review synthesizes a substantial body of evidence linking gut microbiota-derived SCFAs to epigenetic mechanisms and NDs, several limitations should be acknowledged. A primary constraint is the heavy reliance on preclinical animal models, which, despite their utility, cannot fully recapitulate the complex pathophysiology, genetic diversity, and chronic progression of human neurodegenerative conditions such as AD and PD. Furthermore, while strong correlative and mechanistic associations are presented, establishing direct causal relationships between specific SCFAs, discrete epigenetic modifications, and clinical disease outcomes in humans remains challenging and is often inferred from indirect evidence or multi-step pathways. The considerable heterogeneity in gut microbiota composition across individuals, influenced by genetics, diet, geography, and lifestyle, also poses a significant challenge for generalizing findings and developing universally effective therapeutic strategies. Additionally, the dynamic and context-dependent nature of epigenetic regulation adds a layer of complexity, making it difficult to predict the long-term stability and specificity of SCFA-induced epigenetic changes in different neuronal and glial cell types. Finally, although therapeutic interventions such as probiotics, prebiotics, and FMT show promise, their efficacy, optimal dosing, safety profiles, and long-term impacts in human populations require rigorous validation through large-scale, randomized controlled trials with standardized protocols and extended follow-up periods. Addressing these limitations will be crucial for translating this promising mechanistic knowledge into reliable clinical applications.

Conclusion and perspectives

This comprehensive review consolidates the compelling evidence that positions gut microbiota-derived SCFAs as pivotal epigenetic mediators at the intersection of environmental factors, host metabolism, and brain health in NDs. The scientific significance of this synthesis lies in its systematic delineation of a mechanistic pathway, from dietary fiber intake and microbial fermentation to epigenetic reprogramming in the brain, that had been previously fragmented across disparate fields. By establishing SCFAs as key modulators of histone acetylation, DNA methylation, and the novel modification histone lactylation, this review moves beyond mere correlation to propose a causal, biologically plausible framework for how the gut microbiome can directly influence CNS gene expression and neuronal fate. This paradigm elevates GBA from a conceptual model to a tractable, multi-layered signaling pathway with specific molecular players, thereby providing a unified explanatory model for how lifestyle and microbial factors can contribute to the risk and progression of complex neurological disorders.

In contrast to earlier reviews that often presented a more generalized view of GBA, this work offers a significant advancement by focusing specifically on the epigenetic machinery as the core mechanism of action. Previous research predominantly highlighted systemic effects, such as immune modulation or vagus nerve signaling, whereas this review places epigenetic regulation at the forefront, detailing how SCFAs, particularly butyrate, function as endogenous HDAC inhibitors and metabolic substrates to reshape the neuronal and glial epigenome. The inclusion of emerging mechanisms like histone lactylation and its intersection with microglial metabolic dysfunction in AD represents a novel and forward-looking perspective, distinguishing this work from its predecessors. This focus on fine-grained, molecular-level regulation provides a more profound and actionable understanding, suggesting that the gut microbiome's influence is not merely systemic but is etched directly into the chromatin landscape of brain cells.

The clinical and application significance of these findings is substantial, as they illuminate a suite of readily translatable therapeutic strategies. The detailed exploration of dietary interventions, probiotics, postbiotics, and FMT provides a rational basis for developing microbiota-targeted therapies. The proposed combination of SCFAs with pharmacological epigenetic modulators, such as HDAC inhibitors or TEPP-46, opens a promising avenue for synergistic treatment regimens that could enhance efficacy while minimizing side effects. For clinical practice, this review underscores the potential of personalized nutrition and microbiome profiling to identify individuals who would benefit most from SCFA-boosting interventions, such as those with a Prevotella-dominant microbiota or low endogenous butyrate production. This moves the field closer to a precision medicine approach for NDs, where interventions are tailored based on an individual's gut microbial and metabolic phenotype.

The universality and scientific value of this review's conclusions are underscored by their relevance across two major neurodegenerative conditions, AD and PD. While pathological protein profiles and vulnerable neuronal populations differ between disorders, SCFA-mediated core neuroprotective mechanisms, including neuroinflammation repression, synaptic plasticity augmentation, mitochondrial function preservation, and BBB integrity maintenance, are evolutionarily conserved across neurodegenerative conditions. This suggests a universal principle whereby microbial metabolites serve to maintain CNS homeostasis and resilience against diverse insults. The proposed biomarkers, such as plasma butyrate levels and histone acetylation marks, offer the potential for developing objective measures to monitor therapeutic response, bridging a critical gap between basic science and clinical application.

Looking forward, the perspectives outlined chart a clear and ambitious course for future research. The integration of single-cell multi-omics technologies will be crucial to deconvolute the cell-type-specific epigenetic effects of SCFAs in the brain, revealing how neurons, microglia, and astrocytes each respond to these microbial signals. The development of “smart” microbial therapeutics and brain-targeted nanocarriers represents the next frontier in translating these insights into effective treatments, ensuring precise delivery and action. Ultimately, the construction of digital twin models, integrating multi-omics data from gut and brain, could revolutionize our approach to NDs, shifting the paradigm from managing symptoms to predicting, preventing, and modifying disease progression through targeted modulation of the gut-brain-epigenetic axis. This review, therefore, not only synthesizes our current understanding but also lays the foundational roadmap for a new era of microbiome-based neurotherapeutics.

Funding

This work was supported by the National S&T Major Project of China under Grant No. 2023YFC2308400 (to ZXL), the Fundamental Research Funds for the Central Universities under Grant No. 2025ZFJH03 (to ZXL), the Jiangsu Provincial Research Hospital under Grant No. YJXYY202204-YSB31 (to YTG), the Zhejiang Provincial Natural Science Foundation of China under Grant No. LQ24H090005 (to YWC), Shandong Provincial Laboratory Project under Grant No. SYS202202 (to ZXL), the Taishan Scholar Foundation of Shandong Province under Grant No. tsqn202103119 (to ZXL), and the Foundation of China’s State Key Laboratory for Diagnosis and Treatment of Infectious Diseases under Grant No. ZZ202316 (to ZXL) and ZZ202319 (to YWC).

Ethics and consent to participate declarations

Not applicable.

Data availability statement

Not applicable.

CRediT authorship contribution statement

Xiaocui Xu: Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review & editing. Yiwen Cheng: Methodology, Formal analysis, Writing – original draft, Writing – review & editing, Funding acquisition. Xia Liu: Methodology, Formal analysis, Writing – original draft, Writing – review & editing. Wenwen Ding: Methodology, Formal analysis, Writing – review & editing. Zhangcheng Zhu: Methodology, Formal analysis, Writing – review & editing. Lingbin Wu: Methodology, Formal analysis, Writing – review & editing. Zongxin Ling: Conceptualization, Methodology, Validation, Writing – original draft, Writing – review & editing, Supervision, Funding acquisition. Yongtao Gao: Conceptualization, Methodology, Validation, Writing – original draft, Writing – review & editing, Supervision, Funding acquisition. Jing Yue: Conceptualization, Methodology, Validation, Writing – original draft, Writing – review & editing, Supervision.

Declaration of competing interest

The authors declare no conflicts of interest. Figures are drawn using Figdraw (https://www.figdraw.com).