Short-chain fatty acids mediate enteric and central nervous system homeostasis in Parkinson’s disease: Innovative therapies and their translation

Abstract

Short-chain fatty acids, metabolites produced by the fermentation of dietary fiber by gut microbiota, have garnered significant attention due to their correlation with neurodegenerative diseases, particularly Parkinson’s disease. In this review, we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease, highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease. Focusing on the nervous system, we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system. We identify key processes, including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids. Importantly, structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormal α-synuclein expression and gastrointestinal dysmotility, which could serve as an initiating event in Parkinson’s disease. Furthermore, we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve, immune circulation, and endocrine signaling. This communication may shed light on their potential role in the transmission of α-synuclein from the gut to the brain. Finally, we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice. In conclusion, this review emphasizes the pivotal role of short-chain fatty acids in regulating gut–brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system. Moreover, it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease. Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.

Introduction

Parkinson’s disease (PD) is primarily characterized by motor dysfunctions such as tremors and postural imbalance, resulting from dopaminergic neuron loss and α-synuclein (α-syn) deposition in the midbrain neurons (Morris et al., 2024; Jiao et al., 2025; Ni, 2025). Approximately 80% of patients with PD experience gastrointestinal symptoms, including excessive salivation, dysphagia, delayed gastric emptying, nausea, constipation, and changes in bowel habits, prior to the onset of classical motor symptoms (Kim and Sung, 2015; Zhang et al., 2023a). Notably, α-syn can accumulate in the enteric nervous system (ENS) before affecting central dopaminergic neurons. This finding suggests that PD involves both central and gastrointestinal pathology (Braak et al., 2006; Del Tredici and Duda, 2011; Gelpi et al., 2014).

The ENS primarily consists of two main nerve plexuses: the myenteric plexus, which regulates gastrointestinal motility, and the submucosal plexus, which controls mucosal electrolyte flow, hormone secretion, and intestinal epithelial cell (IEC) permeability (Sharkey and Mawe, 2023). The gut-brain axis theory proposed by Braak suggests that α-syn aggregation and misfolding in PD may begin in the ENS due to infection and inflammation, later spreading to the central nervous system (CNS) and causing central neuropathy (Braak et al., 2006; Bonaz, 2024). Studies show that α-syn injected into the intestinal muscular layer translocates to the brain via vagus nerve fibers in a time-dependent manner, supporting the hypothesis that PD may originate in the gastrointestinal tract (Holmqvist et al., 2014; Kim et al., 2019). Therefore, disrupting the structural and functional integrity of the ENS may initially trigger PD development.

Short-chain fatty acids (SCFAs) are organic acids produced via dietary fiber fermentation by gut microbiota in the host intestine (Cai et al., 2025). SCFAs primarily include acetate (60%), propionate (25%), and butyrate (15%), which regulate nervous system function and modulate various neurophysiological processes. In particular, SCFAs promote neuroprotection by regulating neuronal proliferation and differentiation (Yang et al., 2020a), oxidative stress (Saikachain et al., 2023), electrophysiological activity (Jessup et al., 2023), and neurotrophic factor secretion (Church et al., 2023), all essential for nervous system survival and functioning. They also promote neuroregeneration by facilitating neuronal repair (Jing et al., 2023). Therefore, SCFAs play a crucial role in ENS and CNS homeostasis, offering insights into PD pathology and potential therapeutic strategies.

Several studies have emphasized that SCFAs influence PD development and progression through their impact on ENS/CNS homeostasis (Paiva et al., 2017; Dalile et al., 2019; Hou et al., 2021b). While their protective effects in PD are well-documented, a comprehensive summary of their actions on neurons and glial cells is still lacking. This review aims to integrate existing literature and explore the role of SCFAs in PD, emphasizing their regulatory effects on ENS and CNS homeostasis within the gut–brain axis. It discusses their neuroprotective effects in PD and the potential to promote neuroregeneration, providing new insights into their clinical applications for PD treatment.

Retrieval Strategy

This review retrieved studies on the impact of SCFAs on the homeostasis of the ENS and CNS in PD. The search was conducted using the Web of Science, Google Scholar, and PubMed databases. Keywords included both Medical Subject Headings and free-text terms. Initial selection of articles for evaluation was based on the following keyword combinations: Parkinson’s disease, short-chain fatty acids, gut–brain axis, enteric nervous system, central nervous system homeostasis, neuron, glial cell, and alpha-synuclein. Most of the selected studies were published between 2019 and 2025. The search results were manually screened to include experimental and clinical studies, as well as relevant review articles that aligned with the research topic. Additionally, reference lists of included studies were reviewed to ensure comprehensiveness and accuracy.

Alteration of Short-Chain Fatty Acids in Patients With Parkinson’s Disease

Composition characteristics of short-chain fatty acids in patients with Parkinson’s disease

SCFAs are the most studied gut microbiota metabolites, primarily comprising acetate, propionate, and butyrate, which account for 95% of total SCFAs. Smaller amounts of valerate, iso-valerate, valproate, caproate, isocaproate, succinate, iso-butyrate, and hexanoate are also present (O’Riordan et al., 2022). SCFAs are key mediators of gut-brain communication, supporting various physiological processes within the body, including intestinal function, immune regulation, and neural development. This review examines the SCFA composition in different samples from patients with PD and its relationship with PD-related symptoms, highlighting the protective role of SCFAs in PD (Table 1).

Table 1.

Composition characteristics of SCFAs in different samples of patients with PD

Sample sources	Participants	Composition changes	Clinical characteristics	References
Fecal samples	14 PD, 14 HC	BA↓	NM	Liu et al., 2024
	77 PD, 113 HC	PA ↓, BA↓	BA (–) colonic transit	Augustin et al., 2023
	37 PD, 35 HC	AA↓, PA↓, BA↓	CA (+) MDS-UPDRS total	Huang et al., 2023
	95 PD, 33 HC	AA↓, PA↓, BA↓, IBA↓	AA, BA, IBA (–) Wexner score /H-Y stage/MDS-UPDRS I/II/total; AA, BA (–) Disease duration; BA, IBA (–) MDS-UPDRS III	Yang et al., 2022
	96 PD, 85 HC	AA↓, PA↓, BA↓	AA, PA, BA (–) UPDRS Part III score; BA (+) MMSE score	Chen et al., 2022
	35 PD, 50 HC	AA↓, PA↓, BA↓, VA↓	NM	De Pablo-Fernandez et al., 2022
	104 PD, 96 HC	BA↓	BA (+) cognitive score; BA (–) postural instability-gait disorder score; BA (–)/constipation severity	Tan et al., 2021
	55 PD, 56 HC	PA ↓, BA↓	BA (+) age NMS onset/age MS onset;	Aho et al., 2021
	17 PD, 17 HC	AA↓, PA↓, BA↓	NM	Huang et al., 2021
	34 PD, 34 HC	AA↓, PA↓, BA↓	BA (–) the use of COMT inhibitor	Unger et al., 2016
Blood samples	44 PD, 42 HC	AA↑, PA↓	NM	Qi et al., 2023a
	50 PD, 50 HC	PA↓, BA↓, CA↓, HA↑	PA (–) UPDRs part III score / MMSE score; PA (+) HAMD score / trihexyphenidyl /tizanidine	Wu et al., 2022a
	95 PD, 33 HC	AA↑, PA↑	AA, PA (+) α1-AT in feces / Wexner score / MDS-UPDRS I/II/total; PA (+) H-Y stage / MDS-UPDRS III; BA (–) MMSE score	Yang et al., 2022
	96 PD, 85 HC	PA↑, BA↑, VA↑	PA (–) UPDRS Part III score; BA (–) MMSE score	Chen et al., 2022
	46 PD, 46 HC	PA↑	NM	He et al., 2021
	38 PD, 33 HC	AA↑	AA (+) age; PA (–) UPDRS part III score / the use of COMT inhibitor; BA (+) use of monoamine oxidase inhibitors / anticholinergic drugs	Shin et al., 2020
	19 PD, 21 HC	AA↑	NM	Toczylowska et al., 2020
Saliva samples	76 PD, 37 HC	AA↑, PA↑	NM	Kumari et al., 2020a
Urine samples	100 PD, 50 HC	BA↑	NM	Kumari et al., 2020b

This table summarizes the changes in SCFAs in feces, blood, saliva, and urine from patients with PD compared to healthy individuals. It also highlights the correlations between SCFAs and various clinical features. (+) Positive correlation; (–) negative correlation. α1-AT: α1-Antitrypsin; AA: acetic acid; BA: butyric acid; CA: caproic acid; COMT: catechol-O-methyltransferase; HA: heptanoic acid; HC: healthy controls; H–Y stage: Hoehn–Yahr stage; IBA: isobutyric acid; MDS-UPDRS: Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; MMSE: Mini-Mental State Examination; MS: motor symptoms; NM: not mentioned; NMS: non-motor symptoms; PA: propanoic acid; PD: Parkinson’s disease; SCFAs: short-chain fatty acids; VA: valeric acid.

Unger et al. (2016) first analyzed SCFA concentrations in fecal samples, reporting significantly lower acetic, propionic, and butyric acid levels in the feces of patients with PD than in age-matched controls. These findings are consistent with those of subsequent studies (Huang et al., 2021, 2023; Chen et al., 2022). In another study, Unger et al. (2016) found no significant differences in fecal valeric acid, isovaleric acid, or isobutyric acid levels between patients with PD and controls, whereas De Pablo-Fernandez report significant reductions in isobutyric acid and valeric acid levels in the feces of patients with PD (De Pablo-Fernandez et al., 2022; Yang et al., 2022). Although the conclusions of these studies vary, they collectively indicate significantly reduced SCFA levels in the feces of patients with PD. Further analysis reveals a negative correlation between fecal butyric acid levels and disease duration (Yang et al., 2022), motor performance (Chen et al., 2022), postural instability-gait disorder, and constipation severity (Tan et al., 2021). Conversely, fecal butyric acid levels positively correlate with the age of onset of non-motor and motor symptoms (Aho et al., 2021). These findings highlight the significant role of butyric acid in PD onset and progression.

Notably, SCFA changes in peripheral blood samples do not correspond with those in fecal samples. Current studies consistently show significantly higher plasma SCFA concentrations in patients with PD than in healthy individuals (Shin et al., 2020; Toczylowska et al., 2020; He et al., 2021; Chen et al., 2022; Yang et al., 2022). Most SCFAs produced in the colon are absorbed and utilized by colon cells, with only a small fraction entering the peripheral circulation (Dalile et al., 2019). While fecal SCFA levels in patients with PD continuously decrease, their levels in the blood increase. This may be attributed to increased intestinal permeability, which allows SCFAs to enter systemic circulation, indicating intestinal epithelial barrier (IEB) dysfunction. One study measured SCFA levels in both feces and plasma of patients with PD while evaluating changes in α1-antitrypsin, a marker of intestinal-blood barrier permeability. Patients with PD exhibited higher fecal α1-antitrypsin levels than healthy controls. Moreover, plasma concentrations of acetic and propionic acids positively correlated with fecal α1-antitrypsin levels (Yang et al., 2022), suggesting that the abnormally high blood SCFA levels in these patients may result from SCFA translocation due to IEB damage. Additionally, Wu et al. (2022a) first measured SCFA levels in serum samples, revealing lower propionic, butyric, and caproic acid levels but higher heptanoic acid levels in patients with PD than in controls. These discrepancies may stem from differences in sample treatment methods, warranting further investigation.

In addition to fecal and blood analyses, some studies have measured SCFA levels in saliva and urine, finding elevated salivary acetic and propionic acid (Kumari et al., 2020a) and urinary butyric acid (Kumari et al., 2020b) in patients with PD. Since SCFAs cross the blood–brain barrier (BBB) and are present in cerebrospinal fluid (O’Riordan et al., 2022), assessing SCFA levels in the cerebrospinal fluid of patients with PD could provide valuable insights into their direct effects on the CNS.

Short-chain fatty acids-producing bacteria in patients with Parkinson’s disease

Studies show a significant reduction in SCFA-producing bacteria in patients with PD compared to healthy controls, primarily affecting Firmicutes, the dominant SCFA-producing phylum in the human gut (Table 2). A large meta-analysis by Romano et al. (2021) reveals lower abundances of Roseburia, Blautia, Fusicatenibacter, and Faecalibacterium in the gut of patients with PD than in controls. Additionally, bacteria such as Agathobacter, Lachnospira, Lachnospiraceae ND3007_group, Lachnospiraceae UCG-004, Oscillospira, and Butyricicoccus were reduced in patients with PD. Spearman correlation analysis further revealed a significant negative correlation between levodopa dosage and SCFA-producing bacteria levels (Wallen et al., 2020). Hill-Burns et al. (2017) found that PD medications independently affect gut microbiota composition. Compared to controls, the abundance of SCFA-producing bacteria such as Blautia, Faecalibacterium, and Roseburia was significantly reduced in patients with PD. However, after excluding individuals using catechol-O-methyltransferase inhibitors and anticholinergic drugs, the differences in the abundance of Blautia and Faecalibacterium between the control and PD groups were no longer significant (Hill-Burns et al., 2017). Given the gastrointestinal side effects of these drugs (Kaakkola, 2000; Ness et al., 2006), gut microbiota composition may provide valuable insights into their efficacy and side effects.

Table 2.

Composition characteristics of SCFAs-producing bacteria in patients with PD

Participants	Taxonomic level		Abundance of bacteria in PD	Clinical characteristics	References
	SCFA-producing bacteria (Family)	SCFA-producing bacteria (Genus)
14 PD, 14 CON	Lachnospiraceae	Blautia	↓	The abundance of these genera is negatively correlated with UPDRS part II/ III score and H–Y staging.	Liu et al., 2024
199PD,131CON	Lachnospiraceae	Agathobacter	↓	These genera mediate PD-associated underweight.	Shih et al., 2024
	Lachnospiraceae	Fusicatenibacter
	Lachnospiraceae	Roseburia
	Ruminococcaceae	Ruminococcaceae_UCG_013
224 PD, 112 CON	Lachnospiraceae	Fusicatenibacter	↓	The decrease in the abundance of these genera is a sign of the early rapid progression of PD. These genera decrease with the progression of α-syn pathology.	Nishiwaki et al., 2022
	Ruminococcaceae	Faecalibacterium
	Lachnospiraceae	Blautia
199 PD, 131 CON	Lachnospiraceae	Anaerostipes	↓	These genera mediate PD-associated constipation.	Fu et al., 2022
	Lachnospiraceae	Fusicatenibacter
	Lachnospiraceae	Coprococcus
	Lachnospiraceae	Dorea
	Lachnospiraceae	Blautia
	Ruminococcaceae	Faecalibacterium
	Ruminococcaceae	Ruminococcaceae_UCG_013
	Lachnospiraceae	Lachnospiraceae_ND3007_group
	Lachnospiraceae	Lachnospiraceae_UCG_004
680 PD, 523 CON	Lachnospiraceae	Roseburia	↓	NM	Romano et al., 2021
	Lachnospiraceae	Blautia
	Lachnospiraceae	Fusicatenibacter
	Ruminococcaceae	Faecalibacterium
306 PD, 177 Con	Lachnospiraceae	Agathobacter	↓	The abundance of these genera is negatively correlated with Levodopa dose.	Wallen et al., 2020
	Lachnospiraceae	Blautia
	Lachnospiraceae	Roseburia
	Lachnospiraceae	Fusicatenibacter
	Lachnospiraceae	Lachnospira
	Lachnospiraceae	Lachnospiraceae_ND3007_group
	Lachnospiraceae	Lachnospiraceae_UCG-004
	Ruminococcaceae	Faecalibacterium
	Ruminococcaceae	Oscillospira
	Ruminococcaceae	Butyricicoccus
223 PD, 137 CON	Lachnospiraceae	Roseburia	↓	NM	Nishiwaki et al., 2020a
	Ruminococcaceae	Faecalibacterium
	Lachnospiraceae	Lachnospiraceae_ND3007_group
64 PD, 51 CON	Lachnospiraceae	Blautia	↓	NM	Vascellari et al., 2020
	Lachnospiraceae	Lachnospira
64 PD, 64 CON	Lachnospiraceae	Roseburia	↓	NM	Aho et al., 2019
80 PD, 72 CON	Lachnospiraceae	Roseburia	↓	The abundance of Lachnospiraceae is negatively correlated with UPDRS part III score and H–Y staging.	Pietrucci et al., 2019
193 PD, 113 NC	Lactobacillaceae	Unclass. Lachnospiraceae	↓	These genera mediate PD-associated gait disturbances and postural instability.	Barichella et al., 2019
	Lachnospiraceae	Roseburia		NM
	Ruminococcaceae	Oscillospira
	Ruminococcaceae	Oscillospira
24 PD, 14 CON	Lachnospiraceae	Blautia	↓	The abundance of these genera is negatively correlated with PD duration and disease severity.	Li et al., 2017
	Ruminococcaceae	Ruminococcus
	Ruminococcaceae	Faecalibacterium
89 PD, 66 CON	Ruminococcaceae	Faecalibacterium	↓	NM	Petrov et al., 2017
197 PD, 130 CON	Lachnospiraceae	Blautia	↓	NM	Hill-Burns et al., 2017
	Ruminococcaceae	Faecalibacterium
	Lachnospiraceae	Roseburia
38 PD, 34 CON	Lachnospiraceae	Blautia	↓	The abundance of Lachnospiraceae is negatively correlated with PD duration.	Keshavarzian et al., 2015
	Lachnospiraceae	Coprococcus
	Lachnospiraceae	Roseburia

This table shows that the level of SCFAs-producing bacteria in the intestines of patients with PD is significantly reduced. CON: Controls; H–Y stage: Hoehn–Yahr stage; NM: not mentioned; PD: Parkinson’s disease; SCFAs: short-chain fatty acids; α-syn: alpha-synuclein.

Gut microbiota composition is linked to various clinical features of PD. Several SCFA-producing bacteria correlate with disease duration, severity, and α-syn pathology (Keshavarzian et al., 2015; Li et al., 2017; Pietrucci et al., 2019; Nishiwaki et al., 2022). Nishiwaki et al. (2022) used bacterial and clinical data to predict the association between gut dysbiosis and PD progression over 2 years. They applied the area under the receiver operating characteristic curve of the random forest method and assessed model performance through nested cross-validation with recursive feature elimination. The resulting area under the receiver operating characteristic curves (AUROCs) for Hoehn–Yahr (H–Y) stages 1–3 were 0.799, 0.705, and 0.509, indicating the reliability of these microbiota-based models in detecting early PD stages. Furthermore, patients with reduced levels of SCFA-producing genera, specifically Fusicatenibacter, Faecalibacterium, and Blautia, exhibited accelerated disease progression. Notably, Fusicatenibacter emerged as a potential predictive biomarker for early PD progression, achieving an AUROC of 0.861 in the random forest model for predicting H–Y stage progression. A 2-year follow-up of patients with PD indicates that the initially reduced levels of Fusicatenibacter, Faecalibacterium, and Blautia remained unchanged, suggesting that the reduction of these bacteria is not a consequence of PD progression but rather a potential contributing factor to the disease’s advancement (Nishiwaki et al., 2022). Notably, individuals with idiopathic rapid eye movement sleep behavior disorder showed no significant differences in these bacteria levels (Nishiwaki et al., 2020b). Therefore, the decline in SCFA-producing bacteria may serve as both a biomarker for the rapid PD progression and a predictor for the transition from idiopathic rapid eye movement sleep behavior disorder to PD. Additionally, Blautia, Ruminococcus, and Faecalibacterium at the genus level showed a significant negative correlation with disease duration and the Unified Parkinson’s Disease Rating Scale (UPDRS) score. However, Keshavarzian et al. (2015) found no such correlations with disease duration or the UPDRS score at the species level. Only Lachnospiraceae at the family level was negatively correlated with disease duration. Another study indicated that disease duration significantly influenced overall microbiota composition, although no significant changes were observed at the family and genus levels (Pietrucci et al., 2019). Specifically, decreased Lachnospiraceae levels in PD correlated inversely with H–Y staging and the MDS-UPDRS Part III score (Pietrucci et al., 2019).

Short-Chain Fatty Acids-Mediated Enteric Nervous System Homeostasis in Parkinson’s Disease

Intestinal pathological features in Parkinson’s disease

Gastrointestinal dysfunction is a key non-motor symptom of PD and can manifest several years before the onset of motor symptoms. Patient and animal model data indicates that PD affects both neuronal and glial cells within the ENS, implicating it in PD pathogenesis. α-syn pathology in the myenteric and submucosal plexus neurons has been consistently reported in patients with PD (Braak et al., 2006; Beach et al., 2010, 2016; Ohlsson and Englund, 2019; Tanei et al., 2021). Similar α-syn pathology has been observed in the intestines of transgenic mice expressing mutant α-syn (either A53T or A30P), where α-syn aggregation in the ENS precedes CNS involvement (Kuo et al., 2010). Immunohistochemical staining shows significantly fewer dopaminergic neurons in the myenteric plexus of patients with PD than in controls (Singaram et al., 1995). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, dopaminergic marker alterations in the intestines appeared before lesions in the substantia nigra, suggesting that PD pathology may begin in the ENS (Tian et al., 2008). Enteric glial cells (EGCs) support ENS neuron survival and function while regulating gastrointestinal activities such as intestinal motility and epithelial integrity through complex interactions with neurons, immune cells, and IECs (Seguella et al., 2020). In response to injury, EGCs upregulate glial fibrillary acidic protein (GFAP) and S100B expression via toll-like receptors and MHC II on their surface, releasing numerous pro-inflammatory factors (such as interleukin [IL]-1β, IL-6, tumor necrosis factor-α [TNF-α], and inducible nitric oxide synthase). This process activates EGCs, thereby enhancing the pro-inflammatory environment, causing IEB damage, and inducing neurochemical changes (Seguella et al., 2020). Reactive intestinal EGC proliferation and pro-inflammatory cytokine upregulation are key intestinal features of PD in both humans and mice (Devos et al., 2013; Clairembault et al., 2014, 2015a; Perez-Pardo et al., 2019; Pellegrini et al., 2020; Thomasi et al., 2022). EGC-driven neuroinflammation in the intestines triggers early α-syn misfolding, aggregation, and gastrointestinal motility disorders in PD. The deposited α-syn may further exacerbate intestinal neuroinflammation, accelerating PD pathology (Seguella et al., 2020). Consequently, the “pathological loop” between EGCs and α-syn strongly indicates ENS involvement in PD pathogenesis.

Beyond ENS involvement, PD is also marked by functional and morphological changes in the IEB. Numerous reports indicate decreased expression and localization of tight junction proteins, such as zonula occludens-1 (ZO-1) and occludin, in colonic mucosal samples from patients with PD (Clairembault et al., 2015b; Perez-Pardo et al., 2019). This decrease correlates with increased intestinal permeability (Forsyth et al., 2011; Hasegawa et al., 2015) and chronic intestinal inflammation (Schwiertz et al., 2018; Dumitrescu et al., 2021), both of which appear early and persist as PD progresses. Similar changes in tight junction proteins and IEB function occur in neurotoxin-induced PD models, such as 6-hydroxydopamine (6-OHDA) (Pellegrini et al., 2020), rotenone (Ma et al., 2021; Fang et al., 2024), MPTP, and in mice overexpressing human α-syn (Gorecki et al., 2019). IEB dysfunction and increased intestinal permeability expose the ENS to the gut microbiome and its metabolites. Toxins from the intestinal lumen can enter the ENS through IEC breakdown, triggering neuroinflammation in EGCs and promoting neurotoxic α-syn aggregation in neurons. Thus, ENS and IEB involvement is closely linked to PD onset and progression, highlighting the potential role of the gastrointestinal tract in its pathogenesis.

Effects of short-chain fatty acids on enteric nervous system

Constipation, a common non-motor symptom in PD, significantly impacts patient quality of life and therapeutic outcomes. Studies involving patients with PD and animal models link constipation to ENS dysfunction and delayed intestinal transit (Wang et al., 2008; Hallett et al., 2012; Barbut et al., 2019; Rota et al., 2019; Camilleri, 2021). Environmental factors, especially luminal components such as glucose, ions, microorganisms, and their metabolites, influence ENS phenotype and function by regulating enteric neurons. Notably, SCFA levels negatively correlate with constipation severity in patients with PD (Yang et al., 2022). Fu et al. (2022) report a significant decrease in nine SCFA-producing bacteria genera, including Fusicatenibacter, Dorea, Blautia, and Faecalibacterium, in patients with PD. These bacterial changes accounted for 76.56% of the impact of constipation on PD (Fu et al., 2022). Therefore, understanding the relationship between SCFAs and the ENS will help elucidate the pathogenesis of constipation in patients with PD.

Distribution of short-chain fatty acid receptors and transporters in the gut

SCFAs are primarily produced in the lower gut by microbial fermentation of dietary fibers. Once generated in the intestinal lumen, SCFAs are rapidly transported into IECs via monocarboxylate transporters (MCTs) and sodium-coupled MCTs (SMCTs). They inhibit the activity of histone deacetylase (HDAC) (van der Hee and Wells, 2021), inducing histone hyperacetylation in gene promoter regions, which ultimately increases gene expression (Ediriweera, 2023). Additionally, SCFAs act as signaling molecules by binding to G protein-coupled receptors (GPCRs) such as GPR41 (also known as free fatty acid receptor 3 [FFAR3]), GPR43 (FFAR2), and GPR109A (Mann et al., 2024). This binding promotes IEC structure and function (Figure 1). FFAR2 and FFAR3 bind to acetate, propionate, and butyrate, while GPR109A primarily binds to butyrate for signal transduction (Ikeda et al., 2022). Goblet cells, essential to IECs, produce mucus as a first-line defense against microbial invasion. Research indicates that when butyrate is the sole energy source, it modulates mucin (MUC) gene expression in goblet cells, potentially through FFAR3, thereby influencing mucus production (Gaudier et al., 2004). Propionate activates GPR43 and STAT3, inhibits HDAC, and consequently increases IEC migration speed and persistence, promoting epithelial renewal and repair while preventing ulcers (Bilotta et al., 2021). In MPTP-induced PD mice, butyrate activates GPR109A, inhibits NF-κB signaling, and upregulates tight junction proteins such as occludin and claudin-1 in IECs, thereby restoring IEB integrity (Xu et al., 2022b).

Figure 1.

Expression of SCFA receptors and their transporters in the gut.

SCFAs can enter the cells through transporters such as MCT/SMCT, and can also bind FFAR2/FFAR3/GPR109A on IECs to regulate the intestinal barrier. In the lamina propria, a variety of immune cells express transporters or receptors for SCFAs, including FFAR2/FFAR3/GPR109A and MCT/SMCT in monocytes, macrophages and dendritic spines. FFAR2 is primarily expressed in neutrophils and Treg cells. In the enteric nervous system, nitrergic and cholinergic neurons express FFAR3. Created with Figdraw.com (copyright code: WUOPWf3f66). MCT: Monocarboxylate transporter; SCFA: short-chain fatty acid; SMCT: sodium conjugated monocarboxylate transporter; Treg cell: regulatory T cell.

Immune cells beneath IECs express MCTs and SMCTs, facilitating SCFA transport (Parada Venegas et al., 2019; Mann et al., 2024). SCFAs regulate intestinal immune balance via GPCR signaling. FFAR2 and FFAR3 are expressed in monocytes, macrophages, and dendritic cells (Priyadarshini et al., 2018). In neutrophils, acetate signaling through FFAR2 accelerates their recruitment to inflammation sites, enhancing inflammasome activation and IL-1β secretion, making them a first line of defense against toxins (Fachi et al., 2020; Yan et al., 2023). Additionally, FFAR2 is highly expressed in regulatory T (Treg) cells and group 3 innate lymphoid cells (ILC3s) (Smith et al., 2013; Chun et al., 2019). Docampo et al. (2022) first reported GPR109A expression in activated T cells, where it stabilizes T cell metabolism and reduces apoptosis. Butyrate binds to GPR109A on monocytes, macrophages, and dendritic cells, facilitating signal transduction that regulates NF-κB signaling and NLRP3 activation, thereby promoting the anti-inflammatory properties of immune cells (Singh et al., 2014; Wu et al., 2022b; Qi et al., 2023b; Mamedova et al., 2024).

SCFA transporters and receptors are also present in the ENS. Immunohistochemical analyses show that 62% of HuC/D-positive neurons (pan-neural markers) and 38% of choline acetyltransferase (ChAT)-positive neurons (cholinergic neural markers) co-localize with MCT2 in primary cultures of the ENS. After 24-hour butyrate (500 μmol/L) treatment, MCT2 expression in neurons significantly increases (Soret et al., 2010). In the ENS, intestinal neurons possess SCFA-responsive receptors. In FFAR3-mRFP reporter mice, FFAR3-mRFP was identified in the somas of PGP9.5-immunoreactive ganglia cells, a general marker for enteric neurons, particularly in the intestinal submucosa and muscle layers (Nohr et al., 2013). Subsequently, Hertati et al. (2020) identified FFAR3 expression in nerve-like fibrous structures within the intestinal lamina propria and muscular layer, indicating its presence in nerve fibers and cell bodies of intestinal neurons, especially intermuscular neurons. FFAR3 receptors co-localize with nitric oxide synthase (nNOS)-immunoreactive inhibitory motor neurons and ChAT-immunoreactive excitatory motor neurons in the ENS (Kaji et al., 2016, 2018; Caetano et al., 2023). In the myenteric plexus, FFAR3 is expressed in both cholinergic and nitrergic nerves, whereas in the mucosa and submucosal plexus, FFAR3 is predominantly expressed in cholinergic nerves (Kaji et al., 2016). While GFAP-positive EGCs do not co-localize with FFAR3, EGCs may possess other SCFA receptors, potentially interacting with SCFAs via MCTs (Caetano et al., 2023). Thus, the presence of multiple SCFA receptors in the ENS indicates the importance of SCFAs in regulating ENS homeostasis.

Direct interactions between short-chain fatty acids and enteric nervous system

In the ENS, SCFAs influence enteric neuron survival and stimulate neurogenesis. Vicentini et al. (2021) report that supplementation with a SCFA mixture (67.5 mM acetate, 25.9 mM propionate, and 40 mM butyrate) restored antibiotic-induced neuronal loss and improved neuronal survival rates. Wang et al. (2023) evaluated the effects of butyrate (0, 0.1, 0.5, 1, and 2.5 mM) on intestinal neuronal cell proliferation in vitro, identifying 0.5 mM butyrate as the optimal concentration. Notably, both deficient and excessive butyrate concentrations inhibited neuronal proliferation through distinct mechanisms. Butyrate deficiency caused cell cycle dysregulation and subsequent apoptosis, while excess butyrate induced cellular damage and cell cycle arrest by upregulating neuronal oxidative phosphorylation pathways (Wang et al., 2023). These findings suggest that intestinal neuron growth depends on maintaining SCFA concentrations within an optimal range.

SCFAs regulate intestinal motility. A decreased abundance of butyrate-producing Fusobacterium is linked to functional constipation (Wang et al., 2023). Butyrate enhances colonic motility by inhibiting HDAC activity through the upregulation of the Src kinase signaling pathway, increasing H3K9 acetylation in enteric neurons. This process results in a higher proportion of excitatory ChAT-immunoreactive neurons within the myenteric plexus (Soret et al., 2010). In contrast, propionate reduces colonic motility (Hurst et al., 2014) but increases the number of vasoactive intestinal peptide (VIP) neurons in the submucosal plexus, promoting intestinal gluconeogenesis and regulating glucose and energy metabolism (De Vadder et al., 2015). These distinct effects of various SCFAs on intestinal motility warrant further investigation.

SCFAs protect against PD by directly acting on the ENS. In a 6-OHDA-induced PD mouse model, propionate and an FFAR3 agonist (the receptor for propionate in the ENS) alleviated motor deficits and dopaminergic neuronal loss. Furthermore, the neuroprotective effects of propionate in PD mice diminished when PGP9.5-positive enteric neurons were depleted via neurotoxicity (Hou et al., 2021b). These findings suggest that propionate helps prevent PD by targeting FFAR3 in enteric neurons. Additionally, SCFAs may help treat PD by regulating EGC function. Transcriptomic analysis revealed that butyrate significantly altered gene expression in the neurotrophic signaling pathway of rat EGCs. By inhibiting HDAC, butyrate enhances EGC secretion of nerve growth factor (Hou et al., 2021b). In PD, pramipexole combined with nerve growth factor improves cognitive function, enhances clinical efficacy, suppresses inflammation, and regulates brain neurotransmitters (Wang and Cheng, 2022).

Indirect interactions between short-chain fatty acids and the enteric nervous system

Crosstalk between short-chain fatty acids, intestinal endocrine and enteric nervous system

Enteroendocrine cells (EECs), primarily consisting of enterochromaffin (EC) and L cells, line the intestinal epithelium, directly facing the gut lumen. They respond to various chemical and mechanical stimuli from the lumen by releasing signaling molecules. Specifically, FFAR2 and FFAR3 receptors on EEC detect SCFAs, triggering the release of 5-hydroxytryptamine (5-HT), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY) (Nøhr et al., 2013; Lu et al., 2018; Engevik et al., 2021; Tao et al., 2022; Masse and Lu, 2023). In addition to FFARs, colonic EECs express olfactory receptors such as Olfr78 (human ortholog: OR51E2) and Olfr558 (human ortholog: OR51E1), which also act as SCFA receptors (Bellono et al., 2017; Dinsart et al., 2024). These receptors facilitate EEC differentiation into ECs and regulate 5-HT secretion (Dinsart et al., 2024). Moreover, Olfr78 enhances protein kinase A signaling, increases cyclic adenosine monophosphate (cAMP) levels in EECs, and directly promotes PYY secretion (Nishida et al., 2021). EECs are anatomically and functionally linked to the ENS. EECs regulate neural development, gastrointestinal secretion, and motility through hormone and neurotransmitter release. This highlights the significant signaling interactions among SCFAs, EECs, and the ENS.

(1) 5-Hydroxytryptamine

Most 5-HT (serotonin) is produced in ECs via tryptophan hydroxylase 1 (TPH1), which converts tryptophan. Butyrate enhances TPH1 expression via the zinc finger transcription factor ZBP-89, thereby promoting 5-HT production and release (Nishida et al., 2021). Additionally, a smaller proportion of 5-HT is synthesized by tryptophan hydroxylase 2 (TPH2) in myenteric plexus neurons (Gershon, 2022; Zhu et al., 2022). Endogenous 5-HT is involved in regulating neurogenic gastrointestinal motility. Acetate, propionate, butyrate, and 5-HT can induce calcium (Ca²⁺) signaling in intestinal neurons to varying extents (Fung et al., 2021). 5-HT binds to its receptors on myenteric and submucosal cholinergic neurons in the gut, transmitting signals to enteric neurons. This signaling extends nerve fibers toward EECs, establishing direct contact and further stimulating calcium activity in cholinergic neurons. Consequently, acetylcholine secretion increases, thereby improving intestinal motility and secretion (Figure 2; Keating and Spencer, 2019; Ye et al., 2021; Martin et al., 2022; Zhai et al., 2023).

Figure 2.

Close link between SCFAs, intestinal endocrine system and ENS.

There are two primary subtypes of EECs in the gut: ECs, which secrete the majority of 5-HT (or serotonin), with a small portion produced by enteric neurons; and L cells, which specifically secrete GLP-1 and PYY. SCFAs-related receptors are present on the surface of both ECs and L-cells. SCFAs promote the expression of TPH1 via the zinc finger transcription factor ZBP-89. In ECs, tryptophan is converted to 5-HTP through the action of TPH1, while in enteric neurons, tryptophan is converted to 5-HTP by TPH2. Additionally, 5-HTP is converted to 5-HT by ADCC. Both ECs and neurons express SERT, which is responsible for the reuptake and recycling of 5-HT. SCFAs trigger PLC activity in L cells, increase IP3 levels, activate Ca²⁺ channels in the endoplasmic reticulum, and induce GLP-1 release. 5-HT and GLP-1 regulate the release of Ach in enteric neurons by binding to the 5-HT and GLP-1 receptors on the surface of these neurons, thus playing an important role in gastrointestinal motility. At the same time, they also contribute to the development and maturation of neurons. Created with figdraw.com (copyright code: WSPTAae3b6). 5-HT: 5-Hydroxytryptamine; 5-HTP: 5-hydroxytryptophan; 5-HTR: 5-HT receptor; Ach: acetylcholine; ADCC: aromatic L-amino acid decarboxylase; EC: enterochromaffin cell; EECs: enteroendocrine cells; ENS: enteric nervous system; ER: endoplasmic reticulum; GLP-1: glucagon-like peptide-1; IP3: inositol triphosphate; PLC: phospholipase C; PYY: peptide YY; SCFAs: short chain fatty acids; SERT: serotonin transporter; SERT: serotonin transporter; TPH: tryptophan hydroxylase; TPH2: tryptophan hydroxylase 2; Trp: tryptophan.

The role of 5-HT and its receptors in PD remains unclear. Intestinal biopsies from patients with PD show reduced 5-HT4 receptor expression (Barrenschee et al., 2017). Similarly, decreased 5-HT4 receptors in the colonic muscular layer of 6-OHDA rats is a key mechanism underlying colonic motility disorders and constipation (Zhang et al., 2015). In Thy1-α-syn PD mice, electroacupuncture-induced 5-HT release upregulates 5-HT4 receptor expression in the colon, activating the downstream cAMP/PKA signaling pathway. This activation promotes neurotransmitter secretion, including substance P and calcitonin gene-related peptide (CGRP), facilitating coordinated gastrointestinal smooth muscle contraction and relaxation. Consequently, this process accelerates intestinal transit and improves fecal excretion in the mice (Shen et al., 2022). Serotonergic neurons are among the first to develop in the ENS, influencing neurogenesis and driving the development and survival of later-born enteric neurons. Adding 5-HT to isolated enteric crest-derived cell cultures increases dopaminergic neuron number and survival rate and enhances neurite extension (Schertzer and Lam, 2021). Furthermore, TPH2 deficiency reduces dopaminergic neurons in the gut. Terminal immunoreactivity of the serotonin transporter surrounds dopaminergic neurons, suggesting serotonergic innervation (Li et al., 2011).

(2) Glucagon-like peptide-1

GLP-1, an incretin secreted by L cells, regulates glucose metabolism (Guo et al., 2024). SCFAs from gut microbiota stimulate GLP-1 secretion by activating FFAR2 and FFAR3 on L cells. This activation triggers phospholipase C activity, increases inositol triphosphate levels, and promotes calcium release from the endoplasmic reticulum, thereby inducing calcium responses in L cells (Figure 2; Ducastel et al., 2020; Peng et al., 2022). In the human L cell line NCI-H716, the olfactory receptor OR51E1 signaling upregulates intracellular cAMP and phosphorylated ERK, which enhances GLP-1 secretion (Han et al., 2018). These findings indicate the role of these receptors in mediating SCFA-regulated L-cell function within EECs.

In the ENS, GLP-1 receptors (GLP-1R) are expressed in ChAT- and nNOS)-positive nerve fibers within the myenteric plexus, extending from the gastric corpus to the distal colon, with the highest expression in the mid- and hindgut (Grunddal et al., 2022). This suggests a close relationship between GLP-1 and the ENS. While the exact mechanisms remain unclear, GLP-1 appears to activate neurons. Buckley et al. (2020) demonstrated that L cells detect bacterial signals in the intestinal lumen and act on colonic neurons expressing GLP-1R by secreting GLP-1. This secretion increases phosphoinositide 3-kinase expression and enhances calcium signaling, thereby boosting intestinal neuronal activity. GLP-1 significantly and dose-dependently enhances the survival of myenteric neurons in the rat small intestine. Notably, the neuroprotective effect of GLP-1 is reversed by the GLP-1R antagonist exendin (9-39) amide (Voss et al., 2012). In the gut, vagal sensory neurons expressing mechanosensory and chemosensory GLP-1R have been identified (Brierley and de Lartigue, 2022). GLP-1-positive cells, which express secretory cell markers such as SNAP25 and NEFM, communicate with vagal neurons in the lower intestinal plexus through a paracrine mechanism rather than direct synaptic contact (Cao et al., 2024). Notably, GLP-1 also regulates gastrointestinal motility. In response to the intestinal microbial environment, colonic L cells release GLP-1, which stimulates CGRP-positive neurons, accelerating gastrointestinal motility and promoting fecal excretion (Nakamori et al., 2024).

GLP-1 is closely associated with PD pathogenesis, and its analogs or receptor agonists are potential therapeutic strategies for this condition (Javed et al., 2024; Qi et al., 2025). These analogs reduce colonic inflammation, enhance intestinal permeability, and increase the levels of brain-derived neurotrophic factor, which supports neuronal survival, development, and differentiation. Notably, they effectively inhibit dopaminergic neuron loss and α-syn oligomer accumulation in the colon (Su et al., 2022). Studies show that probiotic Clostridium butyricum increases gut GLP-1 secretion and upregulates GLP-1R expression in brain tissue, significantly reversing motor deficits in PD mice (Sun et al., 2018, 2021). Additionally, sodium butyrate restores reduced colonic GLP-1 levels in PD mice, improving defecation rate and stool water content (Zhang et al., 2023b). Therefore, SCFA-mediated GLP-1 secretion is crucial for ENS homeostasis and plays a significant role in PD pathogenesis and treatment.

In addition to 5-HT and GLP-1, SCFAs directly stimulate EECs to produce neuropeptides such as PYY, neuropeptide Y, cholecystokinin, gastric inhibitory polypeptide, and substance P. These neuropeptides influence gastrointestinal functions and ENS development (Wang et al., 2010; Larraufie et al., 2018; Nishida et al., 2021; Geng et al., 2022). Therefore, SCFAs indirectly impact ENS homeostasis via the intestinal endocrine system.

Crosstalk between short-chain fatty acids, intestinal immune, and enteric nervous system

In mammals, the gastrointestinal tract is the largest immune system in the body. The immune system and ENS closely interact to regulate the gut neural network development, maturation, structure, and function. Gut microbiota activates resident immune cells, prompting them to release immune mediators that transmit signals to enteric neurons, thereby influencing ENS growth and function. Conversely, the ENS supports and enhances immune cell function by releasing neurotransmitters. As mentioned earlier, various gut immune cells express SCFA receptors, indicating that SCFAs may potentially maintain ENS integrity by regulating the gut immune system.

(1) Macrophages

Macrophages exhibit remarkable plasticity and adopt two main activation states depending on their environment: M1 or pro-inflammatory (classically activated) and M2 or anti-inflammatory (alternatively activated) macrophages. M1 macrophages release pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which trigger immune responses. In contrast, M2 macrophages release anti-inflammatory factors, including IL-10, IL-13, and TGF-β, promoting tissue repair and suppressing inflammation. In the gut, macrophages are primarily located in the lamina propria, with some in the muscle layer. Lamina propria macrophages typically exhibit the M1 phenotype and they are recruited from the bloodstream in response to microbial stimulation, contributing to immune defense against pathogens. Conversely, macrophages in the muscle layer exhibit the M2 phenotype and are involved in gut motility and inflammation repair (Figure 3A; Gabanyi et al., 2016). Macrophages and the ENS are closely located throughout the gut, and the macrophage state plays a crucial role in regulating ENS function. In vitro, Yao et al. (2021) observed that M1 macrophages secrete pro-inflammatory cytokines (including IL-1β, IL-6, and TNF-α), which activate the STAT3 and NF-κB pathways in enteric neurons and inhibit oxytocin signaling. This endogenous neuropeptide regulates secretion, motility, and immunity in the gastrointestinal tract. Conversely, M2 macrophages secrete TGF-β, activating Smad2/3 in enteric neurons and inhibiting Peg3, thereby promoting oxytocin signaling.

Figure 3.

Close link between SCFAs, intestinal immune system, and ENS.

(A) SCFAs promote the polarization of intestinal macrophages toward the M2 phenotype, which secretes IL-10 and IL-13, while inhibiting the polarization of M1 macrophages that secrete IL-6 and IL-1β. M1 macrophages can induce the death of intestinal neurons, whereas M2 macrophages help maintain neuronal survival. (B) CSF-1, secreted by enteric neurons, is essential for the development of MM. These MMs produce BMP2, which activates enteric neurons and influences muscular contractions. (C) Pathogen infection activates sympathetic neurons to release NE. When MM receives NE signals, it releases polyamines that protect intestinal neurons from death and prevent gastrointestinal motility disorders. (D) MM directly interacts with neurons containing p-α-syn in the myenteric plexus and can phagocytose p-α-syn, thus limiting the early spread of pathological alpha-synuclein in the gut. (E) SCFAs promote the differentiation of naïve intestinal T cells into Tregs cells while inhibiting their differentiation into Th17 cells. (F) IL-6 secreted by enteric neurons inhibits the differentiation of Tregs. (G) CD8⁺ T cells secrete perforin, which induces the death of intestinal neurons or EGCs through Fas signaling. (H) Intestinal CD4⁺ T cells can also induce the death of intestinal dopaminergic neurons, although the exact mechanism remains unclear. (I) SCFAs upregulate AKT/STAT3 or ERK/STAT3 signaling pathways through FFAR2, promoting the secretion of IL-22 by ILC3s to counteract intestinal inflammation. (J) IL-6 secreted by enteric neurons enhances the proliferation and secretion of IL-5, IL-9, and IL-13 by ILC2s. (K) VIP secreted by enteric neurons inhibits IL-22 release by ILC3s, which is detrimental to maintaining IEB integrity. (L) ILC3s increase IL-22 secretion in response to GFL secreted by EGCs through the RET receptor. Created with Figdraw.com (copyright code: TPOWU2eeb2). BMP2: Bone morphogenetic protein 2; CSF-1: colony-stimulating factor 1; EGCs: enteric glial cells; ENS: enteric nervous system; IEB: intestinal epithelial barrier; IL: interleukin; ILC3: group 3 innate lymphoid cells; MM: muscularis macrophages; NE: norepinephrine; NMU: neuropeptide neuromedin; p-α-syn: phosphorylated alpha-synuclein; SCFAs: short-chain fatty acids; VIP: vasoactive intestinal peptide.

Muscularis macrophages (MMs), located between the circular and longitudinal muscles, MMs play a crucial role in helping maintain immune homeostasis and regulate gut motility and secretion by interacting with the ENS under gut microbiota influence (Pendse et al., 2023). Recently, their close communication has garnered significant attention. MMs secrete bone morphogenetic protein 2, activating enteric neurons with corresponding receptors, thereby altering smooth muscle contraction patterns. MM depletion disrupts muscle coordination, prolonging colon transit time. Conversely, enteric neurons secrete colony-stimulating factor 1, a growth factor essential for macrophage development (Figure 3B; Muller et al., 2014). During early development, MMs shape the ENS by pruning synapses and phagocytosing enteric neurons. Depleting MMs before weaning disrupts ENS development, leading to structural abnormalities and impaired gut transit. After weaning, ENS-derived transforming growth factor-β enables MMs to adopt a neurosupportive phenotype. A specific MM subtype, associated with neuronal cell bodies and fibers, is vital for adult neuron survival. This subtype upregulates the transcription factor Nrf2, which protects enteric neurons from oxidative stress. Its dedifferentiation or depletion leads to enteric neuron loss and delays gut transit time (Viola et al., 2023). MMs also protect neurons via noradrenaline signaling. During microbial infection, the NLRP6 inflammasome activates the caspase-11 cell death pathway, reducing excitatory VGLUT2⁺ neurons and impairing gastrointestinal motility. In response, MMs upregulate neuroprotective programs. Specifically, MMs express β2-adrenergic receptors, allowing them to receive noradrenaline signals from gut-projecting sympathetic neurons. This interaction upregulates Arg1, promoting polyamine release, thereby enhancing enteric neuron survival and mitigating infection-induced gastrointestinal motility disorders (Figure 3C; Gabanyi et al., 2016; Matheis et al., 2020). MMs also phagocytose dying neurons and actively clear neuronal debris (Kulkarni et al., 2017). Their depletion in adulthood causes enteric neurodegeneration and functional impairment (Becker et al., 2018). With aging, MMs shift from an anti-inflammatory “M2” phenotype to a pro-inflammatory “M1” phenotype, partly due to reduced expression of the longevity-associated transcription factor FOXO3. This shift reduces enteric neuron density, depletes gut neural stem cells, and delays gut transit (Becker et al., 2018).

Macrophages and the ENS communicate bidirectional, with the ENS influencing macrophage-related inflammation. Stakenborg et al. (2019) further investigated the interaction between MMs and enteric neurons. MMs are situated near cholinergic neuronal fibers, which inhibit their activation in response to ATP. Cholinergic neurons trigger MMs to express the α7 nicotinic acetylcholine receptor, thereby exerting anti-inflammatory effects through cholinergic signaling (Stakenborg et al., 2019). Cholinergic neuron activation in the ENS reduces pro-inflammatory cytokine secretion in lipopolysaccharide (LPS)-stimulated MMs, thus alleviating intestinal inflammation (Rahman et al., 2024). In addition, EGCs play a crucial role in communicating with intestinal macrophages. They detect inflammation within the muscularis layer and, in their early stages, recruit monocytes via CCL2 to promote tissue repair. These monocytes differentiate into pro-resolving CD206⁺ and Timp2⁺ MMs through colony-stimulating factor 1. This differentiation promotes gut motility restoration after tissue damage. In turn, these MMs stimulate EGC proliferation, thereby serving a neurotrophic role (Stakenborg et al., 2022).

The interaction between macrophages and the ENS plays a complex role in intestinal α-syn pathology. MMs directly engage with myenteric neurons that produce pathological α-syn. Utilizing a complement C1q-dependent mechanism, MMs upregulate synaptic pruning-related genes, enabling them to phagocytose α-syn within neurons and limiting its early spread in the gut (Figure 3D; Mackie et al., 2023). However, prolonged pathological α-syn phagocytosis induces endolysosomal stress in MMs, depleting their synaptic clearance capacity and facilitating its spread within the ENS (Mackie et al., 2023). This study underscores the dynamic nature of macrophage responses to α-syn in the ENS, emphasizing their role in clearing toxic protein aggregates. A recent morphological study identified α-syn aggregates within macrophages, with phosphorylated S129-α-syn co-localizing with the pan-macrophage marker F4/80 during trinitrobenzenesulfonic acid-induced colitis. Furthermore, α-syn expression increased in cholinergic and VIP neurons, while tyrosine hydroxylase (TH) expression decreased (Casini et al., 2024). These findings further illustrate the intricate relationship between macrophages, the ENS, and α-syn.

SCFAs promote macrophage polarization toward the M2 phenotype. Recent studies show that SCFA-producing strains promote M2 macrophage polarization in the gut by inactivating the JAK/STAT3/FOXO3 axis, which alleviates inflammation (Zhao et al., 2024). Butyrate, a prominent SCFA, reprograms intestinal macrophage metabolism to achieve M2 polarization by upregulating genes associated with oxidative phosphorylation and lipid metabolism (Scott et al., 2018). As an HDAC inhibitor, butyrate increases H3K9 acetylation and reduces the production of pro-inflammatory mediators such as nitric oxide, IL-6, and IL-12 in intestinal macrophages (Chang et al., 2014). This enhances macrophage antibacterial activity and limits bacterial translocation (Schulthess et al., 2019). Additionally, butyrate enhances macrophage anti-inflammatory properties via GPCR signaling, enabling them to induce Treg and IL-10-producing T cell differentiation (Singh et al., 2014). In a colitis mouse model, the SCFA receptor GPR41 was expressed alongside increased CGRP-positive nerve fibers—neurotransmitters of intestinal cholinergic neurons—in the colonic lamina propria, with a large number of F4/80⁺ macrophages surrounding these nerve fibers (Hertati et al., 2020). This suggests that SCFA-sensitive gut neurons and macrophages interact during the pathological development of intestinal inflammation, highlighting the link between SCFAs, macrophages, and the ENS. Therefore, SCFAs may regulate ENS homeostasis through macrophages, warranting further study.

(2) T cells

The ability of SCFAs to regulate gastrointestinal T-cell homeostasis is widely documented. SCFAs influence the size and function of the colonic Treg cell pool and promote Foxp3⁺ IL-10⁺ Tregs production in an FFAR2-dependent manner to prevent colitis in mice (Smith et al., 2013). Additionally, SCFAs suppress IL-17 production by intestinal T cells through a histone deacetylase-dependent mechanism to counteract the development of intestinal inflammation (Figure 3E; Dupraz et al., 2021; Wang et al., 2021). These findings highlight the significance of gut microbiota-mediated interactions between the ENS and T cells in maintaining gut health.

T cells are categorized by surface markers into CD4⁺ T cells (helper T cells) and CD8⁺ T cells (cytotoxic T cells). CD4⁺ T cells further differentiate into various subsets, primarily including Th1, Th2, Th17, and Treg cells, which directly interact with the ENS to maintain neuroimmune stability under physiological conditions. Anatomically, Treg cells are found near CGRP⁺ and NOS1⁺ nerve fibers in the colonic lamina propria, mainly associated with nitrergic inhibitory motor neurons originating from the myenteric plexus. Functionally, enteric neurons release IL-6 to inhibit microbiota-induced Treg cell differentiation, thereby regulating immune cells (Figure 3F; Yan et al., 2021). Microbiota-mediated IL-17A signaling in Th17 cells and neurons in the gut promotes myenteric neurogenesis, evidenced by increased nestin expression. This process contributes to gut motility normalization (Marques de Souza et al., 2025).

Under pathological conditions, T cells disrupt the ENS integrity and cause functional dysregulation. Activated T lymphocytes increasingly adhere to enteric neurons or EGCs through the intercellular adhesion molecule-1/lymphocyte function-associated antigen-1 pathway, which promotes plexitis development (Pabois et al., 2020, 2024). In Crohn’s disease, an inflammatory bowel disease linked to increased risk of PD, early pathology includes EGC network destruction. This destruction involves cytotoxic autoimmune responses from CD8⁺ T cells that target EGCs. This immune response induces submucosal edema and vascular inflammation, ultimately causing severe intestinal inflammation and hemorrhagic necrosis (Cornet et al., 2001). CD8⁺ T cells mediate enteric neuron damage and impair colonic motility via perforin, TNF-α, and Fas signaling (Figure 3G; Brun et al., 2021; Sanchez-Ruiz et al., 2021; Janova et al., 2024). A recent study identified CD4⁺ T cells as key drivers of dopaminergic neuron damage in the gut (Garretti et al., 2023), although the molecular mechanisms underlying this process remain unclear (Figure 3H). These findings highlight the role of T cells in regulating ENS homeostasis and their participation in early PD-related gut pathology.

(3) Innate lymphoid cells

Innate lymphoid cells (ILCs) help maintain intestinal immune homeostasis by defending against infections, regulating IEB function, and interacting with the gut microbiota. Despite their lymphoid morphology, ILCs lack T cell receptors, classifying them as “innate” immune cells. Similar to T cells, they produce cytokines and play key roles in immune responses. Based on cytokine secretion and function, ILCs are classified into three major subsets: ILC1s, which produce IFN-γ; ILC2s, which mainly secrete IL-5, IL-13, and IL-9; and ILC3s, which include LTi ILC3s that secrete IL-17 and NCR⁺ ILC3s that secrete IL-22. ILCs are closely associated with the ENS.

SCFAs regulate ILC differentiation and function. In the gut, ILC3s predominantly express FFAR2 and FFAR3, with FFAR2 being the most abundant. Sepahi et al. (2021) report that soluble dietary fiber increases the number of ILC3s in both the small and large intestines. Acetate and propionate enhance ILC3 abundance and promote IL-22 secretion via FFAR2, utilizing the AKT/STAT3 or ERK/STAT3 signaling pathway (Figure 3I). FFAR2deletion in ILC3s reduces proliferation and IL-22 secretion, which impairs intestinal epithelial function. This impairment reduces mucin-associated proteins and antimicrobial peptides, increasing susceptibility to bacterial infections (Chun et al., 2019). Additionally, butyric acid shifts the ILC3 subset balance from Lti ILC3s to NCR⁺ ILC3s, enhancing IL-22 production, which regulates IEB function and limits intestinal inflammation (Chen et al., 2023). Therefore, SCFAs may indirectly regulate ENS development and function by modulating ILC composition and cytokine secretion.

In the gastrointestinal tract, ILC2s (IL-5, IL-9, and IL-13) co-localize with cholinergic neurons expressing neuromedin U, which rapidly activates their proliferation and secretion (Figure 3J), accelerating worm expulsion (Klose et al., 2017). Conversely, CGRP secreted by cholinergic neurons suppresses ILC2 expansion while increasing IL-5 expression (Xu et al., 2019). In the lamina propria, ILC3s selectively expressing the vasoactive intestinal peptide receptor 2 (also called VPAC2) are located near VIP-expressing neuronal projections. VPAC2 activation inhibits IL-22 production in ILC3s, potentially contributing to IEB collapse during infection (Figure 3K; Talbot et al., 2020). ILC3s are also found near EGCs expressing neurotrophic factors. Through the neuroregulatory receptor RET, ILC3s detect glial-derived neurotrophic factor ligands, activating STAT3 to release downstream IL-22 (Figure 3L). RET ablation in ILC3s reduces IL-22 production, impairs epithelial responses, disrupts microbiota balance, and increases susceptibility to intestinal inflammation and infection (Ibiza et al., 2016).

Short-Chain Fatty Acids–Mediated Central Nervous System Homeostasis in Parkinson’s Disease

Short-chain fatty acids and blood–brain barrier

The BBB is a tight junction formed between brain microvascular endothelial cells, astrocytes, pericytes, and the basal membrane, facilitated by tight junction proteins such as claudin, occludin, and ZO-1. This highly selective barrier prevents harmful and inflammatory substances from entering the brain. SCFAs can cross the BBB, as demonstrated through the uptake of ¹⁴C-labeled organic acids (Oldendorf, 1973). This process is associated with MCT1 or FFAR3 expression in cerebrovascular endothelial cells (Mac and Nalecz, 2003; Uhernik et al., 2011; Hoyles et al., 2018). SCFAs also regulate BBB integrity. In germ-free mice, increased BBB permeability was reversed by SCFA-producing bacteria and sodium butyrate, which upregulate tight junction proteins (Braniste et al., 2014). Additionally, SCFAs regulate GPR41-mediated levels of ZO-1, which is essential for the epithelial barrier in bovine rumen epithelial cells (Zhan et al., 2019). By binding and activating GPRs, SCFAs increase tight junction protein expression, maintaining BBB integrity. Furthermore, epigenetic factors such as increased HDAC expression and histone hypoacetylation contribute to BBB injury (Stamatovic et al., 2019). As known HDAC inhibitors, SCFAs reduce HDAC expression and increase histone acetylation, thereby restoring BBB function through epigenetic pathway regulation (Wang et al., 2011; Yu et al., 2013). SCFAs also inhibit systemic inflammation, reducing inflammatory cytokine and chemokine infiltration in circulation (Eslick et al., 2022b). They also diminish the excessive activation of glial cells (Caetano-Silva et al., 2023), indirectly protecting the BBB integrity.

Immunohistochemistry, cerebrospinal fluid analysis, and positron emission tomography reveal increased BBB permeability in patients with PD during disease progression (Kortekaas et al., 2005; Pisani et al., 2012; Gray and Woulfe, 2015; Al-Bachari et al., 2020). However, the role of SCFAs in BBB regulation remains unclear. In the MPTP model, sodium butyrate upregulates occludin and ZO-1, thereby restoring BBB integrity (Liu et al., 2017). Dong et al. (2020) found that polymanuronic acid inhibits peripheral inflammation in the gut, brain, and systemic circulation, improves BBB integrity, and restores dopaminergic neuron density in the substantia nigra through gut microbiota-derived SCFAs. Conversely, while SCFAs have protective effects in PD, Wang et al. (2024) recently observed that MPTP mice had significantly higher fecal SCFA levels than controls. Furthermore, chitosan administration alleviated motor symptoms and PD pathology by reducing acetate levels and restoring intestinal and brain barrier integrity rather than merely inhibiting MPTP-induced SCFA levels. Therefore, future studies must validate whether SCFA supplementation protects the BBB and clarify the underlying mechanisms in various PD models.

Mechanisms of short-chain fatty acids affecting the central nervous system

Effects of short-chain fatty acids on dopaminergic neurons

The degeneration and loss of dopaminergic neurons in the substantia nigra are key neuropathological features of PD. Reducing α-syn deposition and restoring dopaminergic neuron function are critical goals in PD treatment. Recent studies show that SCFAs promote dopaminergic neuron survival. Physiological doses of acetate, propionate, and butyrate promote the growth of human neural progenitor cells, suggesting that SCFAs regulate early neuronal development (Yang et al., 2020a). Histopathological analyses reveal that histone deacetylase 6 is enriched in neural Lewy bodies within the brains of patients with PD and colocalizes with α-syn (Miki et al., 2011; Mazzetti et al., 2020). Francelle et al. (2020) found that HDAC6 inhibitors protect dopaminergic neurons from α-syn toxicity. Sodium butyrate, an HDAC inhibitor (HDACi), mitigates α-syn-induced DNA damage in dopaminergic neurons by upregulating DNA repair genes and increasing acetylated histone 3 levels (Paiva et al., 2017). Furthermore, sodium butyrate inhibits apoptosis in dopaminergic neurons by enhancing histone acetylation (Kidd and Schneider, 2010). Thus, SCFAs act as HDAC inhibitors, promoting histone acetylation in dopaminergic neurons and protecting against α-syn neurotoxicity. SCFAs also regulate the TH gene expression (Dalile et al., 2019; Maisterrena et al., 2022), influencing dopaminergic neuron function. For instance, propionic acid increases the number of TH-positive dopaminergic neurons and promotes neuronal overgrowth in rotenone-treated rat midbrain neurons (Ostendorf et al., 2020). Additionally, valproic acid, though present at lower levels in the intestine, also promotes dopaminergic neuron growth. It restores the mammalian target of rapamycin (mTOR) signaling and autophagy pathways (Jayaraj et al., 2020), reduces intracellular reactive oxygen species (Hsu et al., 2020), and inhibits apoptosis in dopaminergic neurons. In summary, SCFAs and valproic acid show therapeutic potential for protecting and promoting dopaminergic neuron survival in PD.

Effects of short-chain fatty acids on glial cells

Under physiological conditions, microglia and astrocytes secrete neurotrophic factors and anti-inflammatory cytokines, supporting neuronal growth, synaptic pruning, metabolite clearance, and inflammation balance. However, prolonged exposure to danger signals triggers uncontrolled activation, leading to excessive pro-inflammatory substance secretion, neuronal damage, and chronic neuroinflammation (Wang et al., 2022). Clinical and molecular evidence strongly links glial-induced neuroinflammation to PD pathogenesis and progression. Neuroimaging studies on microglia-specific radiotracers show increased microglial activation in the early stages of PD. This activation negatively correlates with dopaminergic terminal density and positively correlates with motor symptoms (Ouchi et al., 2005). SCFAs derived from gut microbiota regulate microglia maturation and homeostasis. A decade ago, researchers discovered that germ-free (GF) mice exhibited abnormal microglia morphology and function, including altered cell proportions and an immature phenotype, impairing their innate immune response. Similar microglial immaturity was observed in FFAR2^–/– mice (Erny et al., 2015). Adding SCFAs to the drinking water of GF mice reversed their defective microglial phenotype. However, studies on the relationship between SCFAs and microglia yield conflicting findings. For instance, Sampson et al. (2016) reported that α-syn overexpressing mice raised in a GF environment exhibited reduced microglia activation in the substantia nigra, along with significantly fewer α-syn aggregates and improved motor function compared to those under pathogen-free conditions. However, when SCFA administration increased microglial activation in GF-α-syn overexpressing mice, characterized by larger cell bodies, reduced branching, and more severe motor impairments compared to GF wild-type mice.

Studies on PD models suggest that SCFAs shift microglia from a pro-inflammatory to an anti-inflammatory state, enhance their phagocytic and clearance capabilities, and protect against α-syn-induced neurotoxicity. For instance, sodium butyrate activates GPRs, inhibits the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, and decreases the number of microglia and pro-inflammatory cytokine expression, thereby preventing neuroinflammation and neurodegeneration (Hou et al., 2021a; Xu et al., 2022b; Guo et al., 2023). In BV2 cells treated with 1-methyl-4-phenylpyridinium, sodium butyrate facilitated KATP channel opening by increasing Kir6.1 and Kir6.2 expression. This reduced nitric oxide and pro-inflammatory cytokine production, effectively inhibiting the pro-inflammatory phenotype activation of microglia (Xu et al., 2024). Beyond their effects on microglia, SCFAs also influence astrocyte function. For example, VA decreased the number of activated astrocytes in response to rotenone (Jayaraj et al., 2020). Sodium butyrate and valproic acid have shown potential as neuroprotective agents, reversing manganese-induced reductions in glutamate aspartate transporter and glutamate transporter 1 mRNA and protein levels in astrocytes, thereby protecting the dopaminergic system (Johnson et al., 2018a, b). Although the precise mechanisms by which SCFAs affect glial function in the CNS remain unclear, their anti-neuroinflammatory potential in PD remains promising.

How Do Short-Chain Fatty Acids Connect the Enteric and Central Nervous System?

Vagus nerve pathway

Braak proposed that α-syn aggregates spread retrogradely from the intestine to the brain (Braak et al., 2006). Since then, the vagus nerve has been identified as a crucial conduit for transmitting information between the ENS and CNS. Holmqvist et al. (2014) demonstrated time-dependent transport of visualized α-syn from the intestinal myenteric plexus to the brain via the vagus nerve. Patients who underwent full truncal vagotomy exhibited a significantly lower risk of PD, particularly with follow-up beyond 20 years, supporting α-syn transmission through the vagus nerve (Svensson et al., 2015). Thus, the vagus nerve is the fastest and most direct communication pathway between the ENS and CNS. SCFAs can directly influence vagus nerve function. FFAR3 expression has been identified in vagal sensory neurons innervating the entire intestine (Cook et al., 2021). In anesthetized male rats, intraluminal sodium butyrate administration induced vagal afferent fiber discharge, an effect that was abolished after subphrenic vagotomy. Notably, this persisted even after pretreatment with L-type calcium channel antagonists, suggesting that SCFAs directly activate vagal afferent fibers independent of smooth muscle involvement (Lal et al., 2001). These findings suggest that SCFAs may directly induce vagus nerve signal transduction through FFAR3 and activate different CNS neuronal populations (Figure 4, middle panel).

Figure 4.

SCFAs connect pathological events in the gut and brain through the vagus nerve, blood circulation, and endocrine pathways in PD.

SCFAs, produced by the intestinal microbiota during the breakdown of dietary fiber, pass through IECs via MCT, SMCT, and FFARs. SCFAs can inhibit the transition of EGCs to a pro-inflammatory state, decrease abnormal alpha-synuclein (α-syn) expression in intestinal neurons, and consequently reduce the spread of α-syn from the ENS to the CNS (middle panel). Additionally, SCFAs are vital for maintaining the integrity of the IEB, which helps prevent the activation of intestinal immune cells and the release of pro-inflammatory cytokines triggered by microbial and toxin attacks. This, in turn, limits the polarization of immune cells toward a pro-inflammatory state in the bloodstream, indirectly protecting dopaminergic neurons and glial cells from inflammation (left panel). SCFAs also influence the function of EECs and stimulate the secretion of neuroprotective factors such as 5-HT, GLP-1, and PYY. These factors enter the brain via systemic circulation and play a crucial role in protecting against neuroinflammation and degeneration of dopaminergic neurons. Furthermore, SCFAs impact the expression of α-syn in EECs, thereby reducing the spread of α-syn from EECs to intestinal and brain neurons (right panel). Created with Figdraw.com (copyright code: TTTAY4b464). 5-HT: 5-Hydroxytryptamine; CNS: central nervous system; EECs: enteroendocrine cells; EGC: enteric glial cell; ENS: enteric nervous system; FFAR: free fatty acid receptor; GLP-1: glucagon like peptide-1; IEB: intestinal epithelial barrier; IECs: intestinal epithelial cells; MCT: monocarboxylate transporters; PD: Parkinson’s disease; PYY: peptide YY; SCFAs: short chain fatty acids; SMCT: sodium-coupled monocarboxylate transporters; α-syn: α-synuclein.

Blood circulation pathway

When IEB integrity is compromised, microorganisms, toxins, inflammatory cytokines, and α-syn enter the bloodstream, triggering systemic inflammation. Various blood immune cells become abnormally activated in response to these toxins and inflammatory factors, which subsequently activate pro-inflammatory signaling pathways and secrete additional inflammatory mediators. Prolonged systemic inflammation weakens the BBB, allowing inflammatory factors to penetrate the brain parenchyma, resulting in neuroinflammation and neurodegeneration. Upregulated pro-inflammatory factors and α-syn in the CNS can also enter the intestine via the bloodstream, further affecting the ENS. Consequently, blood circulation establishes a bidirectional connection between the intestine and brain, playing a key role in PD onset and progression (Chaudhry et al., 2023). In 2014, Grozdanov et al. discovered that circulating peripheral blood monocytes in patients with PD were altered in function and composition, displaying pathological hyperactivity in response to LPS, which correlated with disease severity. Conversely, Nissen et al. (2019) reported reduced monocyte viability and lower sensitivity to LPS and fibrillar α-syn, potentially affecting disease progression. Despite these differences, peripheral blood mononuclear cells clearly mediate central and peripheral inflammation in PD. Thus, maintaining immune cell balance in peripheral blood may help prevent or treat PD.

SCFAs are highly expressed in various immune cells and they play key roles in innate immunity. Butyrate alters the metabolic profile of human peripheral blood monocyte-derived macrophages, enhancing LC3-related antibacterial activity via mTOR by inhibiting HDAC3 (Schulthess et al., 2019). A mixture of SCFAs significantly reduces the release of cytotoxic molecules such as IL-1β, MCP-1, TNF-α, and reactive oxygen species in LPS-stimulated human THP-1 monocytic cells and differentiated human HL-60 myelomonocytic cells (Wenzel et al., 2020). SCFAs also regulate neutrophil migration to inflammatory sites in response to immune reactions by activating intracellular protein kinase P38 and coupling G proteins through the GPR43 receptor (Le Poul et al., 2003). Natural killer cells link innate and adaptive immunity by secreting pro-inflammatory cytokines that activate and polarize other immune cells. However, butyrate strongly inhibits NK cell activation by downregulating mTORC1 activity, c-Myc mRNA expression, and metabolic pathways (Zaiatz-Bittencourt et al., 2023). In adaptive immunity, butyrate inhibits HDAC activity, leading to epigenetic regulation of T cells by suppressing Th17-related RORγt and IL-17 expression while increasing Treg cell-related FoxP3 expression (McBride et al., 2023). In B cells, SCFAs elevate acetyl-CoA levels and enhance cellular metabolism, thereby supporting B cell activation, differentiation, and antibody production (Kim et al., 2016). These studies support the regulatory roles of SCFAs in innate and adaptive immunity within the circulatory system (Figure 4, left panel). Additionally, SCFAs inhibit pro-inflammatory cytokine expression in the serum of MPTP PA models, thereby reducing systemic inflammation and endotoxemia (Guo et al., 2023).

Endocrine pathway

EECs detect microbial structural components, such as LPS, through surface toll-like receptors and respond by releasing hormones and neurotransmitters into the bloodstream or CNS. GLP-1 and PYY, secreted by EECs, influence CNS activity by binding to functional receptors in different brain regions (Morimoto et al., 2008; Holzer et al., 2012; Katsurada and Yada, 2016). Enhancing GLP-1 signaling alleviates neuroinflammation, dopaminergic neuron damage, and motor disorders in patients with PD and animal models (Li et al., 2009; Athauda et al., 2017; Brauer et al., 2020; Sun et al., 2021).

SCFAs significantly influence endogenous GLP-1 secretion into the systemic circulation by binding to FFAR on EECs (Tolhurst et al., 2012; Psichas et al., 2015). In an MPTP-induced PD mouse model, oral sodium butyrate improved neurobehavioral disorders by enhancing EEC activity, specifically increasing GLP-1 levels in the colon and upregulating GLP-1 receptors in the brain (Liu et al., 2017). This finding was recently confirmed in a rotenone-induced PD mouse model (Zhang et al., 2023b).

Morphologically, EECs possess neurofilament-containing axon-like processes (neuropods) that transmit signals to intestinal neurons, EGCs, and vagal neurons (Bohorquez et al., 2014, 2015; Kaelberer et al., 2018). In human intestinal tissue, α-syn co-localizes with EECs (Chandra et al., 2017; Casini et al., 2021) and is situated near α-syn-immunoreactive enteric neurons (Chandra et al., 2017). This suggests that danger signals in the intestinal lumen may induce α-syn misfolding in EECs, facilitating its transmission to intestinal neurons. This process may contribute to ENS degeneration and promote a bottom-up spread of PD pathology, ultimately leading to CNS degeneration (Figure 4, right panel). Notably, sodium butyrate concentrations exceeding 10 mM inhibited the proliferation and survival of murine neuroendocrine STC-1 cells while increasing α-syn mRNA expression without affecting protein expression. Additionally, conditioned media from sodium butyrate-stimulated STC-1 cells induced pro-inflammatory cytokine release in SH-SY5Y cells (Qiao et al., 2020a).

Synergistic interactions between short chain fatty acids and other gut microbiota and microbial metabolites in Parkinson’s disease

We previously reviewed the effects of microbiota-derived SCFAs on the ENS and CNS. Beyond their independent functions, SCFAs interact with other gut microbiota components or metabolites to form a complex synergistic network in PD pathogenesis. SCFAs, particularly butyrate, help maintain intestinal homeostasis by connecting the ENS and CNS. Sodium butyrate is commonly used to evaluate the effects on gut microbiota in the MPTP mouse model. Results show that sodium butyrate restores gut microbiota diversity and composition balance by reducing the abundance of Proteobacteria, Bacteroides, and Akkermansia. Notably, Proteobacteria is a key biomarker of intestinal microbiota dysbiosis (Guo et al., 2023). Mishra et al. (2024) found that butyric acid levels decrease in aged mice due to reduced butyrate-producing bacteria within the gut microbiota. Furthermore, butyrate supplementation mitigates aging-related gut permeability and inflammation. These findings indicate that butyrate and butyrate-producing bacteria influence mucin formation and intestinal permeability, thereby affecting brain function.

Bile acids, key microbial metabolites, significantly impact gut microbiome structure and function. Generally, they regulate gut microbiota abundance, diversity, and metabolism. Li et al. (2021) found significant microbiota differences in the appendix tissues of patients with PD linked to bile acid disturbances. This suggests that the interaction between SCFAs and bile acids may play a crucial role in the complex relationship between gut microbiota and PD (Hasuike et al., 2020). Unlike SCFAs, which result from bacterial fermentation of dietary fiber, amino acids primarily stem from protein metabolism. Mi et al. (2023) report that dietary branched-chain amino acids increased serum levels of propionic, butyric, isobutyric, and acetic acids in a PD mouse model, potentially enhancing their pharmacological efficacy.

Short Chain Fatty Acids for Guiding Parkinson’s Disease Therapeutic Strategies

Targeting gut microbiota

Numerous studies suggest that SCFAs and their associated microorganisms may help identify novel therapeutic targets for PD. The Mediterranean diet (NCT06705517), probiotics, prebiotics, and fecal microbiota transplantation (FMT) have been widely researched in animal and cellular models (Zhang et al., 2023a). Clinical trials have begun to assess their safety, feasibility, and effectiveness (Cheng et al., 2023). In the Netherlands, researchers are conducting safety and feasibility studies on FMT for patients with PD, although these studies have not been completed (Vendrik et al., 2023). In China, institutions such as Huashan Hospital and the Third Military Medical University have investigated the effectiveness of microbial therapy for patients with PD (ChiCTR1900027055, ChiCTR1900021405). The ChiCTR1900021405 project reports that freeze-dried fecal microbiota capsules significantly improved autonomic and gastrointestinal symptoms in patients with PD while increasing gut microbiota diversity, thereby confirming the feasibility of oral FMT (Cheng et al., 2023). In addition to FMT, probiotics such as Lactobacillus casei and Bifidobacterium lactis M8 have been studied in patients with PD (ChiCTR1800016795, ChiCTR1800016977). A team from Ruijin Hospital found that Lactobacillus casei significantly reduced non-motor symptoms, such as constipation, in patients with PD (Yang et al., 2023). Furthermore, combining Bifidobacterium lactis M8 with PD medications enhanced their clinical efficacy, potentially by regulating lipid, SCFA, and neurotransmitter metabolism (Sun et al., 2022).

Short-chain fatty acids–related pharmacological action

SCFAs regulate homeostasis by activating GPCR signaling through various pathways (Ikeda et al., 2022). GPCRs, the most diverse transmembrane protein family, were first identified as SCFA receptors in 2003 (Brown et al., 2003). Functionally, they belong to the FFAR family, with SCFAs acting as natural ligands for activating GPCRs. Five major GPCRs—GPR43, GPR41, GPR109A, Olfr78, and Olfr558—have been identified (Ikeda et al., 2022). Yang et al. (2020b) demonstrated that GPR41 activation and HDAC inhibition are critical pathways for SCFAs, particularly butyrate. This activation promotes IL-22 production in ILCs and CD4⁺ T cells. Tetrastigma hemsleyanum polysaccharide restores butyrate levels and upregulates GPR41 and GPR43 expression in vivo and in vitro, thus protecting against intestinal inflammation and IEB impairment (Lin et al., 2023). These studies suggest that the SCFA family represents a novel target for maintaining intestinal homeostasis. Therefore, given the similar intestinal pathological alterations in PD, further research should explore whether SCFAs exert neuroprotective effects against PD through the GPCR pathway. Chinese researchers confirmed that butyrate and monomethyl fumarate (a GPR109A agonist) improve motor symptoms and pathological alterations in PD mouse models by activating GPR109A (Xu et al., 2022b). Additionally, Olfr78 and Olfr558, olfactory receptors expressed in the olfactory epithelium, colonic endocrine cells, autonomic ganglia, and vascular smooth muscle, are also considered SCFA receptors. Olfr78 regulates blood pressure and food intake (Nishida et al., 2021; Xu et al., 2022a); however, it is rarely studied in neurological diseases. Recent research indicates that Olfr78 overexpression inhibits calcium overload and reduces neuronal apoptosis in a rat model of middle cerebral artery occlusion/reperfusion by activating the cAMP/PKA-MAPK pathway (Kang et al., 2024). This provides new insights into potential therapeutic targets for other neurological diseases.

Histone deacetylase inhibitor–related pharmacological action

Histone acetylation becomes imbalanced with aging and in age-related neurodegenerative conditions, including PD. A recent study on HDACi show their benefits in both in vivo and in vitro PD models (Zhang et al., 2024). Butyrate, a widely studied HDACi and SCFA discovered over a decade ago, improves motor impairment and survival in a rotenone-induced Drosophila PD model. Specifically, a loss-of-function mutation in Sin3A, which reduces HDAC activity, conferred resistance to rotenone-induced locomotor impairment and early mortality in flies. Furthermore, butyrate supplementation in these mutant flies improves locomotor function (St Laurent et al., 2013). In a 6-OHDA rat model with lesions, butyrate administration increases striatal dopamine levels, brain-derived neurotrophic factor, and histone acetylation, demonstrating its neuroprotective effects against PD (Sharma et al., 2015). The pharmacological HDACi valproic acid, a well-known anti-epileptic drug, protects against PD-like behavior and neuropathological alterations in various PD models (Zhang et al., 2024). Newly synthesized pan-HDACi, such as cinnamyl sulphonamide hydroxamate derivatives (NMJ-2 and NMJ-3), attenuates MPTP-induced abnormal behavioral changes in motor and non-motor functions by preventing inflammation and restoring dopamine levels (Meka et al., 2023). While these new compounds have been extensively designed, they are not discussed here (Toledano-Pinedo et al., 2024). Overall, SCFAs as natural HDACi, combined with synthetic compounds, show promise for treating PD, supported by pharmacological evidence. Their potential mechanisms include activating neuronal survival genes, such as brain-derived and glial cell-derived neurotrophic factors, and restorating histone acetylation homeostasis (Sharma and Taliyan, 2015; Zhang et al., 2024). Although HDACi has primarily been studied for cancer, clinical trials for other conditions, including PD, are expected.

Limitations

Translating SCFA-based therapies into clinical practice faces several significant challenges: 1) Limited bioavailability and metabolism: SCFAs are predominantly produced in the gut through microbial fermentation, absorbed by the intestine, and rapidly metabolized in the liver. As a result, the bioavailability of exogenously administered SCFAs is often limited, particularly with oral supplementation. A substantial proportion of orally administered SCFAs undergo first-pass metabolism in the liver, which reduces their systemic concentration and effectiveness. The rapid metabolism of SCFAs in vivo complicates efforts to achieve efficient absorption and maintain therapeutic levels. 2) Unclear optimal dosage and duration: The optimal dose and duration of SCFA supplementation remain undefined, presenting challenges for long-term safety and efficacy. Low doses may yield minimal therapeutic effects, while high concentrations could lead to adverse reactions such as gut irritation, acid-base imbalances, or disruption of the microbiota. The variability in individual responses, coupled with the absence of standardized treatment protocols, makes it difficult to establish clear therapeutic guidelines. 3) Challenges in targeted delivery: Developing targeted delivery systems or strategies to ensure that SCFAs reach the brain and exert beneficial effects is a significant hurdle. The therapeutic potential of SCFAs often relies on their local effects in the gut and their ability to modulate the gut–brain axis indirectly. Given that the blood-brain barrier restricts the passage of many compounds, including SCFAs, systemic effects may be insufficient for effectively treating neurological disorders without targeted delivery mechanisms. 4) Variable clinical responses: Variability in clinical responses presents another challenge. Patients with different genetic backgrounds, stages of disease progression, or comorbidities may respond differently to SCFA-based treatments. This heterogeneity complicates the prediction of SCFA efficacy across a broad patient population. Understanding the factors influencing patient response variability and developing personalized SCFA therapies will be essential for successful clinical translation.

Discussion

Numerous studies have reported significant differences in the total SCFA concentrations in blood or fecal samples from patients with PD compared to healthy controls. This highlights the close association between SCFAs and the pathogenesis and progression of PD. However, current research faces several limitations, leaving many questions unanswered. Since SCFAs are primarily produced in the colon and can enter the bloodstream through the IEB, most human studies have focused on fecal or blood samples as convenient detection targets. These samples better reflect the peripheral origin and effects of SCFAs. Nevertheless, the majority of existing studies have either analyzed SCFA concentrations from a single source (e.g., feces or blood) or assessed only the abundance of SCFA-producing bacteria. Relying on a single research metric provides limited insights into the role and prognostic value of SCFAs in the pathogenesis of PD. It is also worth noting that changes in SCFA levels or SCFA-producing bacteria are not unique to PD; similar reductions in fecal SCFAs have been observed in cardiovascular diseases, inflammatory bowel diseases, chronic kidney diseases, and obesity (Lau et al., 2021; Eslick et al., 2022a; Moleón et al., 2023; Ozturk et al., 2024). This suggests that alterations in SCFAs may broadly reflect host homeostatic imbalances rather than serving as specific markers of a particular disease. Therefore, when evaluating the potential of SCFAs as early diagnostic biomarkers for PD, it may be insufficient to monitor only SCFA concentrations or the abundance of SCFA-producing bacteria. A more comprehensive approach would involve combining SCFA measurements with the detection of PD-related pathological markers (such as α-syn) or other biomarkers (including inflammatory cytokines and barrier proteins) in intestinal tissues or blood, along with imaging techniques to assess CNS pathological changes. This multidimensional analytical strategy could provide critical insights into the role of SCFAs in PD pathogenesis and facilitate the development of early diagnostic and therapeutic strategies for the disease.

Most existing studies adopt a cross-sectional design, which is insufficient for establishing causal relationships between SCFAs and the progression of PD. Therefore, longitudinal follow-up studies are urgently needed. It can be hypothesized that in the early stages of PD, when gastrointestinal symptoms emerge, alterations in the gut microbiota have already occurred, characterized by a reduction in the abundance of SCFA-producing bacteria, leading to decreased SCFA levels in the gut. These changes may trigger an imbalance in inflammatory responses within the body, transmitting inflammatory signals to the CNS via the gut-brain axis and initiating neuropathological changes associated with PD. As the disease progresses, inflammatory signals originating in the CNS may propagate back to the gut, further disrupting intestinal homeostasis and creating a vicious cycle. This cycle could exacerbate the ecological imbalance of SCFA-producing bacteria, ultimately impairing SCFA synthesis. To determine whether changes in the composition of SCFA-producing bacteria are a cause or consequence of PD, future studies should prioritize large-scale prospective cohort studies and long-term follow-up investigations.

It is important to emphasize the dual role of SCFAs in neuroinflammation. While most studies suggest that SCFAs primarily exert neuroprotective effects, some findings present contradictory evidence. For instance, Qiao et al. (2020b) reported that sodium butyrate exacerbated MPTP-induced reductions in the neurotransmitters dopamine and 5-HT, promoted neuronal loss in the striatum, and induced intestinal inflammation. In contrast, Liu et al. (2017) demonstrated that sodium butyrate treatment improved cognitive behavior and motor coordination in MPTP-treated mice, prevented dopaminergic neuron degeneration, and reduced tyrosine hydroxylase expression in the striatum. A possible explanation for these inconsistencies could be differences in experimental models, dosing regimens, and treatment durations. In the former study, sodium butyrate was administered at a dose of 165 mg/kg for 1 week, while MPTP was given at 30 mg/kg for 5 consecutive days. In the latter study, sodium butyrate was administered at 200 mg/kg for 3 weeks, with MPTP given at the same dose for 7 consecutive days. These differences in recovery conditions following MPTP administration may alter the therapeutic effects of sodium butyrate. Future studies could employ dose-gradient experiments (e.g., low, medium, and high doses) to determine the effective threshold of SCFAs in different PD models. The dose-dependent neuroprotective effects of butyrate have been well demonstrated in vitro. For instance, in enteric neurons, optimal concentrations of butyrate support cell vitality, while either a deficiency or excessive concentrations inhibit neuronal proliferation (Wang et al., 2023). Similarly, high concentrations of sodium butyrate can suppress the proliferation and survival of neuroendocrine cells (Qiao et al., 2020a), potentially due to cell cycle arrest caused by upregulated oxidative phosphorylation pathways at excessive concentrations (Wang et al., 2023). Moreover, in germ-free conditions, SCFAs have been shown to activate microglia in α-syn overexpression mouse models, exacerbating motor impairments (Sampson et al., 2016). These findings suggest that the effects of SCFAs in the nervous system are regulated by multiple factors, including their type, concentration, treatment duration, experimental conditions, and the host environment. When treating neurodegenerative diseases such as PD, it is crucial to precisely control the dosage and duration of SCFAs according to the disease stage and individual patient variability.

Conclusions

In recent years, research has consistently unveiled the substantial impact of gut microbiota and their metabolites on human health. Since the gut–brain axis theory was proposed, a growing number of studies have focused on the effects of the intestinal microenvironment on CNS disorders. This review provides an overview of the composition of SCFAs and SCFA-producing bacteria in patients with PD. From a nervous system perspective, we summarize the potential molecular mechanisms by which SCFAs modulate ENS and CNS homeostasis in the development of PD. We propose that SCFAs may facilitate communication between the ENS and the CNS through the vagus nerve, blood circulation, and endocrine pathways, thereby enabling bidirectional communication between the gut and the brain (Figure 5). By focusing on the nervous system, our review highlights the pivotal role of SCFAs in mediating neural function regulation and regenerative capacity, offering significant protective effects in PD. Furthermore, we emphasize that SCFAs-mediated homeostasis of the ENS may serve as a potential early-targeting mechanism for the occurrence and intervention of PD.

Figure 5.

SCFAs are a crucial bridge in the gut-brain communication.

SCFAs play a crucial role in maintaining gut health by regulating microbial composition, preserving intestinal barrier integrity, and modulating the structure and function of the ENS. SCFAs also help protect the integrity of the blood-brain barrier and promote the development and maturation of the CNS. A decrease in the abundance of SCFA-producing bacteria in the gut can lead to microbial imbalance, allowing harmful bacteria and their metabolic byproducts to disrupt the intestinal epithelial barrier. Furthermore, environmental toxins and inflammatory factors can induce the abnormal expression and aggregation of α-synuclein in the enteric nervous plexus, triggering the initial signals of PD pathology. The ENS communicates directly with the CNS via the vagus nerve, transmitting the abnormal α-synuclein retrogradely to the CNS. This process leads to glial cell activation, central nervous inflammation, and the degeneration of dopaminergic neurons, ultimately resulting in PD-related motor dysfunction. Additionally, environmental toxins and inflammatory factors can circulate through the bloodstream, breaching the blood-brain barrier to attack the CNS. Therefore, maintaining gut homeostasis may be a prerequisite for the onset of PD and represents a critical therapeutic target for the disease. By preserving gut microbial balance and regulating the synthesis and action of SCFAs, new avenues for early intervention, prevention, and even treatment of PD may be explored. Created with figdraw.com (copyright code: ISURU7ba87). CNS: Central nervous system; ENS: enteric nervous system; PD: Parkinson’s disease; SCFAs: short chain fatty acids.

Funding Statement

Funding: This work was supported by the National Key R&D Program of China, No. 2021YFC2501200 (to PC).

Data availability statement:

Not applicable.