Gut Microbiome's Influence on Protein Function in Parkinson's Disease

This narrative review included experimental designs, clinical studies, and intervention‐based studies. The selected information was organized according to specific research items. Following organization, data were analyzed and synthesized to draw conclusions and highlight the key findings. This analysis summarizes the current preclinical and clinical evidence about the relationship between the GM and the α‐syn function in PD, along with potential microbiota‐targeted interventions to alleviate the symptoms of PD.

This review was written according to the recommended methodology for the preparation of narrative reviews and applied the Scale for the Assessment of Narrative Review Articles (SANRA) to critically appraise the article produced (Baethge et al. 2019). The article selection process was conducted using Evidence for Policy and Practice Reviewer version 6 (EPPI v6). Although this software is primarily used for systematic reviews and meta‐analysis, it also enhances reliability and reproducibility in narrative review management. Article selection, analysis, and data organization were conducted by a single researcher, and the final manuscript was reviewed and approved by all co‐authors.

The article selection process is illustrated in Figure 2. A literature search was conducted in the EPPI Reviewer web using the PubMed database with search terms: ("gut microbiota") AND ("alpha synuclein") AND ("Parkinson"). Duplicate records were removed, resulting in 254 unique articles. The inclusion criteria were as follows: (1) Only research articles published between 2019 and 2024, (2) Articles only written in English, (3) Full‐text articles available (open access), and (4) Articles aligned with the specific aims of this review.

The exclusion criteria include: (1) review articles, protocols, or meta‐analysis; (2) Articles published before 2019 (unless deemed theoretically relevant); and (3) Articles without full‐text access.

The following data were extracted from preclinical studies: author, year, experimental model, assessment methodology, intervention, endpoints, outcome measures (Parkinsonism symptoms, description of GM, and relationships), and key findings. For clinical studies, the extracted data included the following: author, year, demographics (age and sex), sample size, intervention, follow‐up duration, assessment methodology (Parkinsonism symptoms, description of GM, and relationships), outcome measures, and key findings.

Each selected manuscript was critically analyzed, and the extracted information was synthesized and presented in alignment with the aims of this narrative review, aiming to provide a coherent and comprehensive understanding of how GM may influence α‐syn function in PD and the potential implications for treatment or prevention.

Recent evidence supports the involvement of GM in PD pathophysiology. Here, we explore key studies demonstrating the essential role of GM in motor and gastrointestinal dysfunction. Findings from preclinical research in mice and Drosophila melanogaster have shown that gut microbiota is necessary to trigger progression (Liu et al. 2022a; Sampson et al. 2016). Antibiotic treatment has been reported to restore intestinal homeostasis and ameliorate disease progression, whereas untreated animals exhibit typical PD hallmarks, including a shortened life span, loss of dopaminergic neurons, progressive motor impairments, and increased reactive oxygen species activity (Sampson et al. 2016; Liu et al. 2022b).

Metagenomic analyzes have identified several taxa associated with motor and gastrointestinal dysfunctions observed in PD. At the phylum level, alterations in the GM have been linked to PD‐related dysfunctions. An increased abundance of Bacillota (formerly Firmicutes) has been positively correlated with motor dysfunction, while Actinobacteria levels show a negative correlation with colonic mucosa thickness. At the family level, pathogenic taxa such as Ruminococcaceae, Desulfovibrionaceae, and Faecalibacterium have demonstrated positive associations with motor impairments (Fang et al. 2024b). The presence of Desulfovibrio, Sutterella, and E. coli has been positively correlated with both motor and colonic dysfunctions (Liang et al. 2023; Yang et al. 2018). Conversely, certain beneficial genera exert protective effects. Lactobacillus has shown an inverse correlation with motor impairments, while both Clostridium and Adlercreutzia are negatively associated with colonic dysfunction (Yang et al. 2018).

In PD patients, positive correlations have also been found between motor symptom severity and the abundance of bacterial genera such as Anaerotruncus, Clostridium, and members of the Lachnospiraceae family (Heintz‐Buschart et al. 2018). In a transgenic model of overexpressing α‐syn, specific pathogen‐free (SPF‐ASO) mice exhibit severe motor dysfunctions compared to germ‐free α ‐syn overexpressing (GF‐ASO) mice (Sampson et al. 2016). In addition to motor symptoms, gastrointestinal alterations have also been observed. SPF‐ASO mice displayed decreased colonic motility, along with a reduced number and water content of stool pellets when compared to GF‐ASO counterparts (Sampson et al. 2016; Yang et al. 2018). Furthermore, studies employing rotenone‐induced models of PD have identified associations between a broad spectrum of gut pathogens and both motor and gastrointestinal impairments.

It is also important to highlight that intestinal motility depends, in part, on bacterial‐derived serotonin. Spore‐forming bacteria are crucial contributors to serotonin synthesis in the gut, and their abundance is significantly reduced in PD. This suggests that PD‐associated constipation may result not only from neuronal degeneration but also from depleted levels of tryptophan and serotonin, both of which are influenced by the composition of the GM (Wallen et al. 2022). These findings support the hypothesis of gene‐microbiome interactions influencing PD progression, through the production of bacterial metabolites and the modulation of host immune responses, which in turn can promote α‐syn expression or aggregation, leading to behavioral and functional impairments.

The enteric nervous system (ENS), often referred to as the "second brain," plays a vital role in regulating gastrointestinal motility, secretion, and barrier integrity. It is intricately connected with GM and the immune system through bidirectional communication pathways. Microbial metabolites can influence ENS activity by modulating neurotransmitter synthesis and enteric neuron function. In parallel, GD alters intestinal immune signaling, promoting local inflammation that impairs ENS integrity and contributes to neurodegeneration. The composition of gut microbiota in models and PD patients plays a crucial role in shaping immune responses and influencing neurodegenerative processes. In this section, we address the characteristic imbalance between increased proinflammatory bacteria abundance and the reduction of those capable of producing short‐chain fatty acids (SCFAs), key metabolites involved in gut and brain homeostasis.

The Enterobacteriaceae family, often enriched under dysbiotic conditions, has been reported to release endotoxins such as lipopolysaccharides (LPS), which activate the innate immune system and promote both intestinal and neuroinflammation (Fang et al. 2024b; Ortiz de Ora et al. 2024). This proinflammatory environment facilitates the aggregation and propagation of α‐syn from the gut to the brain (Sampson et al. 2016; Yang et al. 2018; Hegelmaier et al. 2020). At the class level, an increased abundance of Gammaproteobacteria has been positively associated with systemic inflammation and compromised intestinal barrier function, primarily through LPS production (Gorecki et al. 2019). Specific LPS‐producing species, such as E. coli, Klebsiella, and Porphyromonas asaccharolytica, have been identified in the GM of PD patients (Wallen et al. 2022). Moreover, E. coli has been shown to elicit a heightened pro‐inflammatory response in individuals with genetic susceptibility to PD (Liang et al. 2023).

Periodontal diseases have recently been associated with intestinal dysbiosis and neurodegenerative diseases due to their inflammatory mechanisms, including PD. In this regard, Proteus mirabilis can create a urease‐enriched environment that exacerbates inflammation by inducing cytokines such as TNF‐α and IL‐1β. This proinflammatory environment has been linked to alterations in α‐syn aggregate morphology (Grahl et al. 2023). Additional genera associated with increased proinflammatory responses in models of PD include Rikenellaceae, Allobaculum (Perez‐Pardo et al. 2018), Subdoligranulum, Erysipelatoclostridium, Ruminococcus, Alloprevotella, and Flavonifractor (Yang et al. 2024b). At the preclinical level, Porphyromonas gingivalis induced a pronounced proinflammatory response, upregulating IL‐17A, IL‐1β, and TNF‐α, which in turn led to microglial activation and dopaminergic neuron death in the SNpc (Feng et al. 2020). Although the mechanisms by which systemic inflammation promotes α‐syn aggregation remain unclear, GD has been strongly associated with the activity of mutant Leucine‐rich repeat kinase 2 (LRRK2), a kinase involved in immune signaling. Pathogenic variants like R1441G increase LRRK2 activity, leading to neuroinflammation and α‐syn aggregation. As LRRK2 is expressed in immune and intestinal epithelial cells, it may serve as a molecular link between dysbiosis, inflammation, and neurodegeneration in Parkinson's disease (Feng et al. 2020).

In contrast, SCFAs as butyrate, propionate, and acetate—produced by the fermentation of dietary fiber by commensal gut bacteria—exert neuroprotective and anti‐inflammatory effects (Hegelmaier et al. 2020; Vascellari et al. 2020). A reduction in SCFAs‐producing bacteria, including Faecalibacterium, Bifidobacterium, Lachnospiraceae, Holdemanella, Howardella, and Anaerofustis, was also observed in the GM of PD patients and animal models (Perez‐Pardo et al. 2018; Yang et al. 2024b; Vascellari et al. 2020). The depletion of these bacteria is associated with gut permeability, chronic inflammation, and enhanced α‐syn aggregation, all of which may contribute to PD pathogenesis and progression (Hegelmaier et al. 2020). Specifically, Roseburia, Eubacterium, Ruminococcus, and Faecalibacterium prausnitzii have been reported as significantly reduced in PD patients (Wallen et al. 2022). These bacterial species may represent a dysbiotic signature associated with PD. The reported mechanisms by which SCFAs promote neuroprotection include microglial maturation and a reduction in proinflammatory cytokines (Hegelmaier et al. 2020). However, most studies describe only associations between SCFA levels and motor or cognitive impairments (Vascellari et al. 2020), as the underlying mechanisms remain an emerging area of research.

In addition to compositional changes in GM, growing evidence highlights the metabolic consequences of dysbiosis in PD. GM generates a variety of metabolites that can cross physiological barriers and modulate host metabolism, immune responses, and neuronal integrity. Understanding how specific microbial products interact with host systems is key to understanding the GM's role in α‐syn aggregation and neurodegeneration in PD. This section explores recent findings related to metabolomic disruptions and microbiota‐derived neuroactive compounds implicated in disease progression.

Metabolic analyzes have demonstrated that intestinal dysbiosis disrupts the metabolism of key molecules involved in energetic metabolism―triglycerides, diglycerides―antioxidants like taurine, and structural components of the cell like phosphatidylcholines, in both the gastrointestinal tract and brain. In addition, several bacterial‐synthesized metabolites signaling of inflammatory and neurotoxic processes have been identified, including amine oxides, bile acids, and indole derivatives such as indoxyl sulfate, a byproduct of bacterial tryptophan metabolism. These metabolites have been identified as signaling molecules involved in inflammatory and neurotoxic processes. Notably, the branched‐chain amino acid valine and trimethylamine N‐oxide—both of bacterial origin—have been found to increase in the gut, plasma, and brain of PD animal models and patients, suggesting a systematic microbial signature associated with the disease (Morais et al. 2024).

Certain gut bacteria produce metabolites that can exert deleterious effects on neural function. For example, Desulfovibrio, a sulfate‐reducing bacterium, produces hydrogen sulfide (H₂S). This neurotoxic metabolite can disrupt iron homeostasis, promote oxidative stress, and induce α‐syn aggregation, contributing to intestinal constipation and neurodegeneration associated with PD (Murros et al. 2021). Other bacterial species, such as E. coli, Klebsiella, and P. gingivalis, are known to produce amyloid proteins, such as curli fibrils, which can promote α‐syn aggregation. This enhances the prion‐like spread of α‐syn from the gut to the brain, exacerbating PD pathology (Liang et al. 2023; Wallen et al. 2022; Feng et al. 2020; Bhoite et al. 2022; Wang et al. 2021). Mechanistic studies have shown that E. coli‐related α‐syn aggregation is the result of anaerobic nitrate respiration, which leads to a cascade of oxidation reactions. These include dopamine oxidation, α‐syn misfolding, and its subsequent aggregation in intestinal epithelial cells (Ortiz de Ora et al. 2024).

Additional bacterial families, such as Rikenellaceae and Ruminococcaceae, have been associated with α‐syn accumulation in the colonic plexuses (Perez‐Pardo et al. 2018), a process that may serve as a potential biomarker for early PD diagnosis or risk assessment. However, the underlying molecular mechanism remains unclear. Other species associated with host proteostasis by protein aggregation include Ralstonia sp., A. xylosoxidans, Pseudomonas sp., and Klebsiella pneumoniae. This disruption in host proteostasis mechanisms caused by protein aggregation is related to cellular stress and neurodegeneration (Walker et al. 2024).

Several therapeutic strategies aimed at modulating the GM—such as dietary interventions, fecal microbiota transplantation, and targeted bacterial therapies—are examined to alleviate or prevent PD symptoms. Understanding the mechanisms through which gut microbes influence neurodegeneration, including inflammation, immune modulation, and microbial metabolite production, offers promising avenues for the development of novel microbiome‐targeted therapies.

In this review, we analyze the key role of GM in the pathogenesis of PD in preclinical and clinal research, specifically in how microbiota may influence the α‐syn function. PD is a multisystemic, progressive, and neurodegenerative disorder with a wide range of symptoms, including intestinal dysfunction, microbiota dysbiosis, systemic inflammation, α‐syn misfolding and aggregation in the gut and brain, and neuronal death. As we saw, the increasing body of evidence demonstrates an imbalance of GM in models and PD patients, which is strongly associated with motor and non‐motor symptoms. This fact is supported by preclinical research where chronic treatment with antibiotics depletes motor and non‐motor dysfunction in rotenone‐treated mice (Sampson et al. 2016). However, these observations should be carefully considered in human interventions due to the heterogeneity of protocols, including dosage, type of administration, and animal model.

The vagus nerve has been identified as the main gate by which α‐syn spreads out to the brain, contributing to PD progression. However, this is not consistent with the report by Shan et al (Shan et al. 2022)., since mice subjected to subdiaphragmatic vagotomy before the administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) did not reduce the aggregation of α‐syn in the colon and did not reverse the reduction of tyrosine hydroxylase and the dopaminergic transporter in the striatum. This suggests that the subdiaphragmatic vagus nerve does not play a role in the MPTP‐induced neurotoxicity in the brain and colon. A standardized protocol is needed for surgical interventions to reduce the discrepancy regarding the role of the vagus nerve in the prevention/progression of PD.

Studies often use 16S rRNA gene sequencing to assess GM composition. However, this method provides only relative data, showing bacterial proportions within a community rather than absolute abundances. For example, if a study reports a Bacillota/Bacteroidetes ratio of 60% and 40%, respectively, this reflects their relative proportions but does not indicate their absolute quantities. If the absolute abundance of Bacillota decreases but that of Bacteroidetes decreases, the relative ratio may remain unchanged, potentially masking important shifts in total microbial biomass or specific ecosystem configurations associated with disease. To address this limitation, 16S rRNA sequencing can be complemented with qPCR targeting specific bacterial groups, as demonstrated by Murros et al (Murros et al. 2021)., who found that a higher absolute abundance of Desulfovibrio was associated with greater PD severity.

Additionally, single‐cell RNA sequencing (sc‐RNA‐seq) offers a broader framework to characterize bacterial phenotypic heterogeneity in PD. Within isogenic bacterial populations, single cells can exhibit variation in transcriptional states due to gene regulation, chromosomal replication, and microenvironmental factors—including interspecies competition, physicochemical gradients, host interaction, or stress responses—enabling functional and phenotypic specialization. In this sense, sc‐RNA‐seq provides the ability to determine which species express specific genes and how these functions are distributed among individual bacterial cells (Pountain and Yanai 2025). In the context of PD, this emerging concept suggests that microbial involvement in disease pathogenesis cannot be understood solely through community composition or bulk abundance. Instead, subpopulations of bacteria may differentially produce neuroactive or inflammatory metabolites, interact with the intestinal epithelium, or influence α‐syn misfolding through localized molecular signaling. Thus, integrating single‐cell approaches could redefine how we conceptualize microbial dysbiosis in PD.

Although α‐syn pathology has been repeatedly linked to gut‐derived factors, the exact trigger of its misfolding in the gastrointestinal tract remains unclear. Most of the mechanistic evidence comes from transgenic mouse models, which may not fully recapitulate the complexity of human PD. Furthermore, inconsistencies in the taxa reported across different human studies—influenced by geographic, dietary, and methodological variability—highlight the need for harmonized study protocols. Moreover, it is essential to consider alternative perspectives regarding bacterial‐amyloid protein interactions. For instance, Walker et al (Walker et al. 2024). demonstrate that the folding of neurodegeneration‐associated amyloid proteins does not occur through a direct mechanism. Instead, it happens indirectly by disrupting the host's proteostasis.

On the other hand, therapeutic strategies that aim to restore microbial balance or reduce microbial‐derived toxicity show great promise. The heterogeneity of PD symptomatology and individual microbiota profiles suggest that personalized approaches may be necessary to achieve consistent therapeutic outcomes. Interventions such as fiber‐rich diets, sodium butyrate supplementation, probiotics, phenolic compounds, and botanicals like ginger, curcumin, and ginseng have demonstrated protective effects in animal models by modulating gut bacteria, reducing inflammation, and preventing dopaminergic neuron loss (Goya et al. 2020; Huh et al. 2023; Cui et al. 2022). At present, most of these interventions have only been assessed in rodent models, with limited translation to clinical trials. Moreover, the dose, timing, and combinatory effects of these interventions remain insufficiently explored.