Exploring the role of gut microbiota in Parkinson’s disease: insights from fecal microbiota transplantation

Dysbiosis of gut microbiota can compromise the intestinal epithelial barrier, leading to increased penetration. This "leaky gut" condition permits neuroactive small molecules, including potentially toxic metabolites derived from bacteria and microbial sources, to translocate into systemic circulation, accelerating pathological processes and elevating PD risk. Mucin, a key structural component of gastrointestinal mucosa, is essential for preserving barrier integrity. In PD patients, Prevotella deficiency is correlated to impaired mucin production, increased gut permeability, and disease progression (Scheperjans et al., 2014). Fang et al. (2024) demonstrated that chronic rotenone administration significantly reduced colonic mucus thickness and downregulated the expression of tight junction proteins (e.g., Zonula Occludens-1, occludin), confirming the essential role of gut microbiota in maintaining intestinal barrier integrity. Notably, FMT effectively alleviated rotenone-induced intestinal barrier impairment. The study further revealed that gut microbiota dysbiosis promotes excessive hydrogen sulfide production by sulfate-reducing bacteria, which subsequently degrades the mucus layer, disrupts the intestinal epithelial barrier, enhances intestinal permeability, and ultimately contribute to gut leakage (Munteanu et al., 2024). Short-chain fatty acids (SCFAs) contribute to intestinal barrier maintenance. According to studies, PD patients have much less bacteria that produce SCFA, resulting in lower fecal SCFA levels (Bisaglia, 2022). Experimental evidence suggests that administering butyrate to PD animal models can delay disease progression by improving motor function, preserving intestinal barrier integrity, reducing intestinal leakage, and secondary translocation of intestinal contents (Zheng et al., 2021).

According to compelling data, chronic intestinal inflammation and neuroinflammation are exacerbated by pro-inflammatory dysbiosis of the gut microbiota, which are thought to potentially contribute to the PD pathophysiology. Lin et al. (2019) reported elevated concentrations of pro-inflammatory cytokines, including Tumor Necrosis Factor-alpha (TNF-α), Interferon-gamma, and Interleukin-13, in the plasma of PD patients. There were positive correlations between the levels of TNF-α and Interferon-gamma and the abundance of Bacteroides and Verrucomicrobia, respectively. Additionally, fecal calprotectin, a hallmark of intestinal inflammation, was considerably increased in PD patients (Weis et al., 2019). Keshavarzian et al. (2015) used high-throughput ribosomal RNA sequencing to reveal that PD patients had lower "anti-inflammatory" bacteria, including Blautia, Coprococcus, and Roseburia, alongside more "pro-inflammatory" bacteria like Faecalibacterium. Preclinical studies demonstrate that dysbiosis exacerbates neuroinflammation through pathways such as Toll-like receptor 4 (TLR4)/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which raises the production of inflammatory markers, such as Glycogen synthase kinase 3 beta, inducible nitric oxide synthase, and Interleukin-1 beta, along with activating microglia and astrocytes in the SN (Varesi et al., 2022).

α-syn aggregation, a characteristic of PD pathophysiology, might be impacted by gut dysbiosis. Altered microbiota promotes α-syn misfolding in the ENS and gastrointestinal epithelial cells, promoting pro-inflammatory immune activation and facilitating its spread to the CNS (Sterling et al., 2022). On the one hand, it has been shown that certain gut bacteria or their secreted metabolites promote the aggregation and dissemination of α-syn. In mice with leucine-rich repeat kinase 2 gene, Liang et al. (2023) demonstrated that giving them Escherichia coli by mouth caused curli-mediated phosphorylation and accumulation of α-syn in the colon, which then spread along the gut-brain axis to the CNS. Additionally, hemolysin A secreted by Proteus mirabilis triggers α-syn oligomerization via activation of Mechanistic Target of Rapamycin-dependent autophagy signaling pathways in intestinal cells, ultimately inducing motor deficits and neurodegeneration (Huh et al., 2023). Notably, Dubosiella has been implicated in α-syn aggregation via the suppression of branched-chain amino acid catabolism, leading to the peripheral accumulation of valine and isoleucine, which disrupts lysosomal function and hinders α-syn clearance (Wu et al., 2025). On the other hand, Wang et al. (2022) discovered that the probiotic Lactobacillus plantarum DP189 could suppress oxidative stress, restore microbial diversity, and decrease α-syn aggregation in the SN of PD mice, thus delaying disease progression. The findings indicate that targeted modulation of gut microbiota could be a possible therapeutic approach to reduce α-syn aggregation in PD pathogenesis.

Dysbiosis can worsen oxidative stress by changing microbial metabolism and decreasing antioxidant metabolite production. This promotes neuronal damage and α-syn misfolding in the ENS, which subsequently spreads to the CNS (Bullich et al., 2019; Shandilya et al., 2022). Studies have shown that Akkermansia increases intestinal permeability, exposing neurons to oxidative conditions that favor α-syn aggregation (Nishiwaki et al., 2020b). Yu et al. (2023) found that gut dysbiosis aggravated oxidative stress responses and neurobehavioral impairments by downregulating Nicotinamide mononucleotide adenylyltransferase 2, a gene involved in NAD⁺ synthesis, in PD rat models. Emerging evidence indicates that the modulation of gut microbiota can reduce oxidative stress responses. Zhu et al. (2025) demonstrated that sleep deprivation promotes the synthesis of microbiota-derived adenosine, which elevates the production of reactive oxygen species by upregulating the pro-oxidant enzyme NADPH oxidase 4 and inhibiting the antioxidant factor Nuclear factor erythroid 2-related factor 2, consequently exacerbating oxidative damage to dopaminergic neurons. Probiotic supplements significantly mitigated these effects. Nurrahma et al. (2022) revealed that a high dose of the mangosteen pericarp, abundant in antioxidants, restores gut microbiota balance by diminishing pro-inflammatory bacterial genera (e.g., Sutterella, Rothia, Aggregatibacter), which exhibited a negative correlation with antioxidant gene expression. This improves antioxidant levels and alleviates PD motor deficits. Additionally, Gao et al. (2024) demonstrated that in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, administration of ginkgolide C could restore gut microbiota homeostasis, exert antioxidant effects by activating the Protein Kinase B/Nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 pathway in SN4741 neuronal cells, and alleviate pathological damage in mice.

It has been shown that the gut microbiota synthesize numerous neurotransmitters that are present in the human brain, such as DA, serotonin, γ-aminobutyric acid, and noradrenaline. Gut microbiota dysbiosis may disrupt neurotransmitters synthesis, perturbing the CNS homeostasis through gut-brain axis signaling pathways, which may contribute to the pathological progression of PD neurological dysfunction (Strandwitz, 2018; Wang et al., 2021). Research by Gao et al. (2018) revealed that when gut microbiota in experimental animals was changed through antibiotic infusion, there were significant reductions in the concentrations of serotonin, DA, and aromatic amino acids in their blood and hypothalamus compared to a control group infused with normal saline. This discovery emphasizes how vital the gut bacteria is to preserving neurotransmitter and precursor levels. Similarly, van Kessel et al. (2019) investigated the impact of microbial tyrosine decarboxylase in the proximal small intestine—a primary area for Levodopa absorption—in PD patients. They observed an increase in tyrosine decarboxylase activity, which led to premature transformation of L-dopa, significantly reducing its plasma levels and bioavailability. This, in turn, increased therapeutic dose requirements and reduced drug efficacy. According to these findings, gut dysbiosis may directly or indirectly influence the pharmacokinetics, bioavailability, and side effects of medications used to treat PD.

Overall, the findings presented underscore the role that gut microbiota plays in regulating neurotransmitter production and its profound implications for PD pathophysiology as well as the optimization of therapy approaches.

SCFAs, including acetate, propionate, and butyrate, are microbial metabolites derived from anaerobic fermentation of dietary fibers. Emerging evidence establishes a link between SCFA homeostasis disruption and neurodegenerative pathogenesis. In PD, reduced fecal SCFA levels compromise the structural integrity of the intestinal barrier and the blood–brain barrier (BBB), promote α-syn pathological aggregation, and exacerbate intestinal inflammation and neuroinflammation (Chen et al., 2022; Duan et al., 2023). Preclinical studies demonstrate that SCFA supplementation attenuates dopaminergic neurodegeneration and alleviates motor impairments in PD mice by inhibiting NF-κB/mitogen-activated protein kinase pathway inhibition in the SN and reducing α-syn aggregation (Hou Y. F. et al., 2021; Hou Y. et al., 2021). The neuroprotective effects of SCFAs extend to AD pathophysiology by modulating synaptic plasticity, amyloid-β (Aβ) and tau pathology, and neuroinflammation (Tang et al., 2022). Clinically, mild cognitive impairment patients exhibit a significant reduction of fecal SCFAs that inversely correlates with Aβ burden in cognition-associated brain regions (Gao et al., 2023). Notably, in models of amyotrophic lateral sclerosis, the abundance of butyrate-producing bacteria decreases in SOD1^G93A mice, whereas butyrate supplementation enhances gut barrier integrity, reduces SOD1^G93A aggregates, decelerates motor neuron degeneration, and prolongs survival of these mice (Loh et al., 2024).

Intestinal microbiota mediate the biotransformation of primary to secondary bile acids. In PD patients, increased levels of deoxycholic acid and lithocholic acid in the cecum are closely related to increased abundance of bile acid-synthesizing microbiota. These secondary bile acids induce pathologic α-syn aggregation and propagation through exerting pro-inflammatory and cytotoxic effects while simultaneously impairing mitochondrial function and autophagy regulation, contributing to neurodegenerative disease pathology (Castro-Caldas et al., 2012; Kiriyama and Nochi, 2023). Notably, taurodeoxycholic acid, a neuroprotective bile acid, demonstrates therapeutic potential across neurodegenerative models. In PD mice, taurodeoxycholic acid administration significantly delays dopaminergic neurodegeneration by inhibiting the c-Jun N-terminal kinase apoptosis pathway, reducing mitochondrial reactive oxygen species, and activating the Protein Kinase B survival pathway (Li et al., 2021). AD rodent models further reveal the capacity of taurodeoxycholic acid to reduce Aβ deposition in the hippocampus and prefrontal cortex and rescue cognitive deficits in spatial, recognition, and contextual memory domains (Lo et al., 2013).

The gut microbiota mediates enzymatic conversion of dietary choline and carnitine to trimethylamine, which undergoes hepatic oxidation to generate TMAO, a compound implicated in neurodegeneration through various mechanisms (Caradonna et al., 2025). Clinical metabolomic profiling reveals elevated circulating TMAO concentrations in PD patients, though independent of disease progression (Voigt et al., 2022). Mechanistically, TMAO promotes abnormal α-syn conformational changes and pathological aggregation and activates pro-inflammatory signaling pathways, such as NF-κB. Additionally, TMAO penetrates the BBB, exacerbating neuroinflammation and neuronal damage (Caradonna et al., 2024). Lee et al. (2022) demonstrated that TMAO-treated midbrain organoids showed impaired brain-derived neurotrophic factor signaling, loss of dopaminergic neurons, astrocyte activation, and neuromelanin accumulation. Furthermore, TMAO induced the pathological phosphorylation of α-syn and tau proteins, facilitating their aggregation. Vogt et al. (2018) identified a correlation between elevated TMAO levels and AD pathology and markers of neuronal degeneration in the cerebrospinal fluid. Individuals with mild cognitive impairment and AD dementia exhibited higher TMAO levels in the cerebrospinal fluid compared to cognitively normal individuals.

LPS, an endotoxin produced by Gram-negative bacteria, plays a multifaceted role in neurodegenerative pathology. Gorecki et al. (2019) found that PD patients had a significantly higher abundance of LPS-producing Gammaproteobacteria in the gut compared to healthy controls, and LPS reduces the expression and disrupts the distribution of intestinal epithelial tight junction markers (e.g., Zonula Occludens-1, e-Cadherin). A clinical study indicated that plasma LPS rose with cognitive decline, and in non-dementia participants, high plasma LPS was independently linked to mild cognitive impairment (Saji et al., 2022). LPS activates TLR4 receptors, triggering downstream Myeloid differentiation primary response protein 88 and TIR-domain-containing adapter-inducing interferon-β pathways. It also induces the release of pro-inflammatory cytokines (e.g., TNF-α, Interleukin-1 beta) from microglia and astrocytes, causes oxidative stress and mitochondrial dysfunction, promotes Aβ deposition, Tau hyperphosphorylation, and α-syn aggregation, and results in neuronal and synaptic damage, thus driving neurodegeneration (Batista et al., 2019; Kesika et al., 2021; Brown et al., 2023).

In summary, the metabolites of gut microbiota regulate organismal homeostasis through complex mechanisms, and their dysregulation may raise the risk of neurodegenerative diseases. Thus, targeting the generation or signaling pathways of these metabolites may provide potential therapeutic strategies for PD and other neurodegenerative conditions.

Preclinical evidence reveals several key mechanisms through which FMT improves gastrointestinal function, alleviates motor symptoms, and delays neurodegeneration in PD (Figure 2):Reduction of Inflammatory Effects and Oxidative Stress: FMT relieves the neurotoxic effects of microglia and astrocytes, lowers LPS in the colon and SN, and reduces the secretion of pro-inflammatory cytokines while elevating anti-inflammatory factors. Moreover, FMT modulates inflammatory signaling pathways, including TLR4/TANK-binding kinase 1/NF-κB/TNF-α (Sun et al., 2018), TLR4/Phosphatidylinositol 3-kinase/Protein Kinase B/NF-κB (Zhong et al., 2021), and TLR4/Myeloid differentiation primary response protein 88/NF-κB (Zhao et al., 2021). In addition, Xie et al. (2023) confirmed that FMT activates the AMP-activated protein kinase/Superoxide dismutase 2 pathway, mitigating mitochondrial damage and enhancing mitochondrial antioxidative capacity. Studies have indicated that FMT reduced oxidative stress induced by 6-Hydroxydopamine in PD rat models, a known contributor to PD progression (Yu et al., 2023).Reduction of α-syn Aggregation: Transplantation of fecal microbiota from PD patients into mice has been shown to promote microglial activation and α-syn aggregation by modulating metabolites such as SCFAs, which exacerbates motor dysfunction (Sampson et al., 2016). In PD mouse models, FMT has been reported to restore gut microbiota diversity, elevate SCFA levels (especially butyrate), and reduce pathological α-syn aggregation in both the ENS and SN, ultimately ameliorating motor dysfunction (Sun et al., 2018; Liang et al., 2023). Ni et al. (2025) demonstrated that FMT may regulate SCFA levels by upregulating SCFA receptors Free Fatty Acid Receptor 2 and Free Fatty Acid Receptor 3, thereby mitigating pathological features. Fang et al. (2024) found that rotenone-induced gut dysbiosis promotes α-syn transcription via activation of the CCAAT/Enhancer-Binding Protein Beta/Asparagine Endopeptidase pathway, while FMT alleviates this pathological damage.Restoration of BBB Integrity: FMT has been demonstrated to enhance BBB integrity and mitigate dopaminergic neuronal damage, thereby exerting neuroprotective effects. Studies have revealed that compared to normal controls, germ-free mice and antibiotic-treated mice with gut microbiota depletion exhibit significantly increased BBB permeability. FMT can upregulate the expression of tight junction proteins in the CNS, including Zonula Occludens-1, Zonula Occludens-2, occludin, and claudin-5, thereby restoring BBB integrity and reducing its permeability (Braniste et al., 2014; Sun N. et al., 2021). In PD mouse models, Zhao et al. (2021) found that FMT treatment ameliorated the tight junction structure defects in the SN, alleviated endothelial cell damage, and significantly upregulated the Messenger RNA levels of tight junction proteins.

Clinical trials involving FMT in PD patients further support these preclinical findings. Fecal samples collected before and after FMT have undergone microbiota sequencing, revealing significant restoration of gut microbiota composition. Symptom assessments using scales such as the Unified Parkinson's Disease Rating Scale, Non-Motor Symptoms Scale, and Parkinson's Disease Questionnaire-39 indicate improvements in motor symptoms, constipation, anxiety, depression, sleep, and cognitive function, all of which improve overall quality of life. Furthermore, adverse events are less common and generally self-limiting (Xue et al., 2019; Kuai et al., 2021; Segal et al., 2021; Cheng et al., 2023; DuPont et al., 2023; Liu et al., 2023).

However, FMT's therapeutic effects appear time-dependent. Research indicates that microbiota composition and related motor and non-motor symptoms, except constipation, may partially revert after a certain period post-transplantation (Huang et al., 2019; Xue et al., 2019). Further investigation is needed to determine long-term efficacy and stability. Additionally, transplantation methods may impact therapeutic outcomes. For instance, Xue et al. (2020) compared colonoscope-administered FMT with nasojejunal tube administration and found that the former yielded superior clinical benefits.

Recent studies highlight the promising potential of single-strain microbiota transplantation in PD treatment through modulation of the MGBA. Lactobacillus plantarum PS128, a probiotic strain, has been shown to alleviate motor deficits in PD mice through multi-target mechanisms. Specifically, PS128 restores gut microbiota homeostasis, diminishes neuroinflammation via the microRNA-155-5p/Suppressor of Cytokine Signaling 1 pathway, inhibits the neurotoxic activation of microglia and astrocytes, alleviates oxidative stress damage, protects dopaminergic neurons, and ultimately mitigates neurodegeneration (Liao et al., 2020; Lee et al., 2023). Clinical trials further support its therapeutic efficacy, with PS128 supplementation demonstrating significant improvements in motor symptoms and quality of life in PD patients (Lu et al., 2021).

Additionally, other microbial strains have shown promise in the treatment of PD. For example, Bifidobacterium breve (CCFM1067, Bif11) and Lacticaseibacillus rhamnosus E9 demonstrate neuroprotective effects in PD mouse models by enhancing intestinal barrier integrity and alleviating pathological progression (Li T. et al., 2022; Aktas et al., 2024; Valvaikar et al., 2024). Oral administration of Clostridium butyricum has been shown to restore colonic Glucagon-Like Peptide-1 (GLP-1) and G Protein-Coupled Receptor 41/43 levels, along with cerebral GLP-1 Receptor expression in PD mice, thereby mediating neuroprotection via the GLP-1/GLP-1 Receptor pathway (Sun J. et al., 2021).

These findings collectively emphasize the therapeutic potential of single-strain microbiota transplantation in mitigating PD progression. Future studies should aim to elucidate the molecular mechanisms underlying single-strain interventions and validate the long-term safety and therapeutic efficacy through rigorous clinical trials.