Review
Affiliation:
1Semillero de Neurociencias y Envejecimiento, Pontificia Universidad Javeriana, Bogotá 110231, Colombia
ORCID: https://orcid.org/0009-0005-9488-8868
,
Affiliation:
1Semillero de Neurociencias y Envejecimiento, Pontificia Universidad Javeriana, Bogotá 110231, Colombia
ORCID: https://orcid.org/0009-0002-0425-4991
,
Affiliation:
2Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac Campus Norte, Anáhuac 52786, México
ORCID: https://orcid.org/0000-0003-1884-5389
,
Affiliation:
3Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland
ORCID: https://orcid.org/0000-0002-6644-1971
,
Affiliation:
4Department of Neurology, Clínica Universidad de Navarra, 31008 Pamplona, Spain
ORCID: https://orcid.org/0000-0001-5962-772X
,
Affiliation:
4Department of Neurology, Clínica Universidad de Navarra, 31008 Pamplona, Spain
5Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, 4068 Stavanger, Norway
Email: mmborda@gmail.com
ORCID: https://orcid.org/0000-0001-5832-0603
Explor Neuroprot Ther. 2025;5:1004129 DOI: https://doi.org/10.37349/ent.2025.1004129
Received: August 18, 2025 Accepted: November 28, 2025 Published: December 15, 2025
Academic Editor: Ming Xiao, Nanjing Medical University, China
The article belongs to the special issue Role of Microbiota in Neurological Diseases
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, in which gut microbiota alterations have emerged as a potential pathogenic factor, causing disruption of the brain-gut-microbiota (BGM) axis. Recent evidence supports the role of BGM axis disruption in enhancing neuroinflammation, alpha-synuclein (α-syn) aggregation, and dopaminergic neurodegeneration. Emerging therapeutic strategies targeting dysbiosis, such as probiotics and fecal microbiota transplantation (FMT), have become a new focus of investigation for PD treatment. Proposed mechanisms include modulation of immune responses, enhancement of intestinal barrier integrity, production of neuroactive metabolites such as short-chain fatty acids, and reduction of oxidative stress. This narrative review summarizes current evidence on probiotics as a therapeutic strategy in PD. By analyzing data from randomized controlled trials and preclinical studies, we highlight the beneficial effects of probiotics in improving motor and non-motor symptoms of PD, including constipation, depression, and anxiety. Strains such as Lactobacillus plantarum PS128 and Bifidobacterium animalis Probio-M8 show particular promise. Although probiotics have demonstrated a favorable safety profile and potential as an adjunctive therapy for PD, future research should focus on standardized protocols, biomarker identification, and exploration of combined microbiota-targeted strategies.
Parkinson’s disease (PD) is a complex and progressive neurodegenerative disorder recognized as the second most prevalent worldwide, with an estimated prevalence of approximately 1.5 cases per 1,000 individuals [1, 2]. Its classic pathology centers in the loss of dopaminergic neurons in the substantia nigra of the midbrain, leading to dopamine deficiency in the striatum and the manifestation of cardinal motor symptoms such as bradykinesia, rigidity, resting tremor, and postural instability. At the molecular level, the disease is characterized by the abnormal misfolding and aggregation of the alpha-synuclein (α-syn) protein into intracellular inclusions known as Lewy bodies and Lewy neurites [3, 4]. The cause of most PD cases remains uncertain, considered to be the result of a complex interaction between genetic susceptibility and environmental factors [5]. Current therapies, primarily based on dopamine replacement, offer symptomatic relief for motor disorders but do not halt disease progression, and they often fail to address the broad spectrum of non-motor symptoms, such as autonomic dysfunction, sleep disorders, cognitive impairment, and neuropsychiatric symptoms, which impose a significant burden on patients’ quality of life [6].
Interestingly, PD patients experience gastrointestinal (GI) symptoms years before their motor signs appear [7]. Chronic constipation, dysphagia, and other gut disturbances are frequently reported in early prodromal stages of PD [6, 7]. These observations align with Braak’s “gut-origin” hypothesis, where misfolded α-syn may first arise in the enteric nervous system and then subsequently reach the brain via the vagus nerve [8]. In this context, the brain-gut-microbiota (BGM) axis has emerged as a key pathogenic mechanism. Gut microbes synthesize a wide array of bioactive molecules such as short-chain fatty acids (SCFAs), neurotransmitters [e.g., serotonin, gamma-aminobutyric acid (GABA)], and other metabolites that can either enter the circulation or signal through the vagus nerve to influence the central nervous system (CNS) [9]. The gut microbiota also shapes immune status. Experimental work has shown that microbiota-derived SCFAs regulate microglial maturation and function, while microbiota perturbations can alter the blood-brain barrier integrity, mechanisms that are highly relevant to neuroinflammation in PD [10], highlighting the bidirectional communication between the gut and the brain. To support this, recent studies have found that the gut microbiota of PD patients differ markedly from healthy controls, and may contribute to disease progression by facilitating α-syn aggregation, disruption of SCFA metabolism, and enhancing microglial activation [6].
Given these connections, multiple strategies that modulate the gut microbiome are under active investigation as potential therapeutic options in PD. Current approaches include dietary modulation, administration of prebiotics and certain probiotic strains, fecal microbiota transplantation (FMT), and targeted microbial-based therapies [11, 12], all seeking to restore microbial balance and attenuate gut-brain axis-driven neurodegeneration. Regarding probiotic supplementation, several human and in vivo studies have shown it to improve motor function and non-motor symptoms (e.g., constipation, depression, anxiety, sleep disturbances) in PD patients [13–15]. Fecal microbiota transplants have also been reported to have beneficial effects [7]. In general, dietary approaches, probiotics, and FMT are able to transform the gut microbiota and have been observed to attenuate neuroinflammation and improve neurological function in neurodegenerative models [10]. In vitro studies show that probiotics can enhance neuroprotection and gut health in PD models by activating neurotrophic pathways, including the upregulation of brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) [16]; reducing oxidative stress, particularly by decreasing reactive oxygen species (ROS) [17]; strengthening intestinal barrier integrity and modulating inflammatory responses [18–20].
Although probiotics have been recognized as a potential therapeutic strategy in PD patients by showing a beneficial effect in both PD motor and non-motor symptoms, the precise mechanisms underlying these effects, the strain-specific actions of probiotics, optimal dosing strategies, and the long-term clinical efficacy of microbiome-targeted interventions remain largely undefined. Moreover, few studies have comprehensively integrated molecular insights with clinical outcomes across both motor and non-motor domains [16, 21].
Therefore, in this narrative review, we synthesize mechanistic and translational evidence from animal and human studies to explore the potential therapeutic impact of probiotics and other microbiome-modulating strategies in PD, highlighting current advances, knowledge gaps, and future research directions.
A comprehensive literature search was conducted using PubMed, EMBASE, Scopus, Web of Science, and Google Scholar databases. The search strategy employed a combination of Medical Subject Headings (MeSH), Emtree terms, and free-text keywords, including “Parkinson’s Disease,” “Microbiota,” “Gut-Brain Axis,” “Brain-Gut-Microbiota Axis,” “Probiotics,” “Prebiotics,” “Synbiotics,” “Psychobiotics,” “Postbiotics,” “Fecal Microbiota Transplantation,” “Diet, Microbiota-Directed,” “Dietary Supplements,” “Dysbiosis,” “Antibiotics,” “Short-Chain Fatty Acids,” “Lipopolysaccharides,” “Neuroinflammation,” “Enteric Nervous System,” “Intestinal Permeability”.
The initial database searches allowed for a preliminary selection of relevant articles, which served as the foundation for further identification of studies through the snowball method. This technique involved reviewing the reference lists of the selected articles and tracking citations of key sources to identify additional literature relevant to the topic.
This review included all types of scientific articles, as determined by the authors’ criteria, addressing the relationship between PD, gut microbiota, and/or probiotics, including randomized controlled trials (RCTs), observational studies, systematic reviews, meta-analyses, experimental animal studies, narrative reviews, and book chapters. There was no language restriction. Although no publication year restrictions were applied, studies published from 2020 onward were prioritized to ensure the inclusion of recent evidence.
Studies that did not assess the effect of probiotics on the specific PD symptoms considered in this review, as well as those for which full-text access was unavailable or that were available only in abstract form, were excluded.
Articles were screened based on title, abstract, and full text. Those deemed relevant to the pathophysiological mechanisms linking microbiota to PD or addressing the therapeutic implications of probiotics were selected for qualitative synthesis. A total of 105 articles were ultimately included in this review.
To understand the therapeutic potential of probiotics in PD, it is first essential to explore the BGM axis and its pathogenic role in the disease. The BGM axis is a complex, bidirectional communication network between the GI tract (GIT) and the nervous system [22], tightly regulated by the local microbial community, collectively known as the gut microbiota [11]. These microorganisms (mainly composed of Lactobacillus spp., Bifidobacterium spp., Faecalibacterium prausnitzii, and Prevotella spp., among others [11, 16]) influence multiple physiological processes, including neurotransmission and neural development [23]. The main components of the BGM axis include: (1) the GIT, from the epithelial barrier to the associated immune system; (2) the gut microbiota, encompassing bacteria, fungi, viruses, and other resident microorganisms; and (3) the nervous system, particularly the enteric, autonomic, and central branches [23, 24], as well as the blood-brain barrier [25, 26]. Communication within this axis occurs through various mechanisms, including direct neural pathways (e.g., the vagus nerve) [22], immune signaling, and microbial metabolites such as SCFAs (particularly acetate, propionate and butyrate) [27, 28], neurotransmitters (such as dopamine, serotonin, GABA and acetylcholine) [29, 30], lipopolysaccharides (LPS) [31], and bile acids [32].
The gut microbiota plays a central role in shaping immune responses [33, 34]. Alterations in its composition, commonly referred to as dysbiosis, can disrupt gut barrier integrity (mainly by the decrease of SCFAs production, which are essential for maintaining tight junction protein expression and epithelial barrier function), leading to increased intestinal permeability, or so-called “leaky gut” [35]. These alterations facilitate the translocation of bacterial products and inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and interferon-gamma (IFN-γ), from the gut lumen into the systemic circulation, leading to the activation of Toll-like receptors (TLR), consequently triggering the release of systemic proinflammatory cytokines, endotoxins, and oxidative stress markers [36–38]. Systemic inflammation is linked to the pathogenesis of PD, as circulating inflammatory mediators can cross the blood-brain barrier, promoting neuroinflammation (by activating microglia and astrocytes), α-syn aggregation, and degeneration of dopaminergic neurons [34, 39].
Beyond immune modulation, the microbiota also contributes to neural development and brain function [23]. Animal studies have shown that germ-free models lacking a microbiota exhibit abnormal brain morphology and altered behavior [40, 41]. External factors such as chronic stress and diet, known to impact microbiota composition, may also indirectly influence the BGM axis and are associated with neuropsychiatric symptoms like anxiety and depression [30, 42].
Disruption of the BGM axis in PD is strongly associated with dysbiosis. Multiple studies have reported a reduction in bacterial diversity, particularly a decreased abundance of taxa such as Prevotellaceae, Faecalibacterium, Lachnospiraceae, and Roseburia, organisms generally considered beneficial due to their anti-inflammatory properties (as they have the ability to produce SCFAs) and role in maintaining gut barrier integrity [22, 43, 44]. Conversely, increased levels of certain pro-inflammatory taxa associated with LPS production have been reported in PD patients. These include Akkermansia muciniphila (implicated in mucosal barrier degradation and pro-inflammatory responses), Lactobacillus, Bifidobacteriaceae (though some studies have also linked its reduction with disease progression), Ruminococcaceae, Christensenellaceae, Enterobacteriaceae, and Megasphaera, among others [22, 43, 44].
This microbial imbalance may contribute to PD pathophysiology through multiple, interconnected mechanisms that lead to the creation of a pro-inflammatory microenvironment [22, 45]. A central process involves the modulation of α-syn aggregation and propagation, considered key pathological features of PD [24]. Bacterial components such as functional amyloids and LPS have been shown to promote α-syn misfolding by inducing its production and neuroinflammation by activating the microglia [46]. According to Braak’s hypothesis, α-syn has been detected in enteric neurons and GI tissues long before the onset of motor symptoms, contributing to GI symptoms [8, 22]. This model proposes a prion-like propagation of misfolded α-syn from the gut to the CNS, potentially via the vagus nerve [22, 47]. Other theories suggest bidirectional transmission between the gut and the brain, possibly involving systemic circulation or alternative neural routes [22, 47].
Together, these findings highlight the central role of the BGM axis and its dysregulation in PD pathogenesis, positioning the gut microbiota as both a potential biomarker and a promising therapeutic target. This provides strong support for exploring probiotics as a potential disease-modifying approach.
The World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO) define probiotics as live microorganisms that, when administered in adequate amounts, confer health benefits to the host by supporting the intestinal microbiota and, consequently, the gut-brain axis [48]. They are commonly classified as dietary supplements and are available in various formulations, including tablets, powders, and capsules [34, 39].
Recent evidence suggests that probiotics may exert neuroprotective effects in PD by modulating inflammation and restoring gut-brain homeostasis [13]. By reshaping gut microbiota, increasing SCFA production, and strengthening the intestinal barrier, probiotics reduce inflammation and oxidative stress that favor α-syn misfolding [21, 27]. Preclinical studies also show that probiotic supplementation can attenuate microglial activation and limit α-syn propagation via the vagus nerve, highlighting a bidirectional interaction between gut dysbiosis and α-syn pathology [49]. Below are several representative examples of probiotic strains that have shown promise in both preclinical and clinical studies of PD.
Firstly, Lactobacillus plantarum PS128 has demonstrated a reduction in nigral dopaminergic neuronal death and improvement in motor deficits in mouse models with PD. This probiotic strain was shown to reduce inflammation (by decreasing the abundance of proinflammatory bacteria such as Enterobacteriaceae and reducing LPS levels) and to increase the expression of brain neurotrophic factors (BDNF and GDNF) [50, 51]. In a study conducted by Lee et al. (2023) [51], PS128 in male mice was administered for 6 weeks and compared to a control group, resulting in improved coordination and balance. Another study conducted by Liao et al. (2020) [52] evaluated the neuroprotective properties of PS128 in a PD mice model, reporting that the intervention improved walking time according to the narrow-beam scale test (p = 0.001) and increased dopaminergic neuronal survival [restoring striatal tyrosine hydroxylase (TH) expression from ~30 to ~75% of control levels; p < 0.001], compared to the control group. Finally, Lu et al. (2021) [53] evaluated a 12-week intervention with PS128 in PD patients, showing an improvement in Unified Parkinson’s Disease Rating Scale (UPDRS) scores (p = 0.004), demonstrating its potential effects on motor symptoms in patients with PD.
Secondly, Bifidobacterium infantis and Bifidobacterium breve. A systematic review conducted by Reiriz et al. (2025) [54] demonstrated that the use of these probiotic strains in PD animal models, alone or in combination, enhanced neuroprotective effects and delayed the progression of the disease by preventing the decrease in spinal column density and by improving motor deficits (p < 0.0001). Additionally, a study conducted by Georgescu et al. (2016) [55] demonstrated that a 3-month intervention with this probiotic strain improved abdominal pain and the severity of Non-Motor Symptoms Scale-Movement Disorder Society (NMS-MDS) score compared to the control group (p = 0.0001).
Another promising strain is Clostridium butyricum, demonstrated to improve motor function and decrease neuroinflammation in vivo models. A study conducted by Sun et al. (2021) [56] evaluated a 4-week intervention of this probiotic strain in mice with PD, showing an improvement in dopaminergic neuron preservation, a reduction in microglial activation, and an enhancement in motor function. Similarly, Liao et al. (2025) [57] showed a reduction in oxidative stress after an intervention with Clostridium butyricum in PD mice, protecting dopaminergic neurons, decreasing neuroinflammation, and improving motor deficits. Finally, Wang et al. (2023) [58] conducted an experimental in vivo study with mice with PD showing that this intervention significantly improved motor function, as evidenced by better performance in the pole and hanging wire tests, and increased mobility and exploratory behavior in the open field test.
A combination of Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum strains has also been shown to improve cognitive function, reduce neuronal damage, and exhibit neuroprotective and immunomodulatory functions through GABA elevation in vivo models [59]. Nosrani et al. (2021) [59] demonstrated that a 14-day intervention with these probiotic strains in Wistar rats with PD improved cognitive function (spatial learning and memory), as the performance in the Morris maze improved (p < 0.0001), and also showed a reduction in the number of injured neurons. Moreover, Dong et al. (2025) [60] demonstrated that Lactobacillus reuteri-derived GABA improved motor performance and reduced nigrostriatal neuron loss in MPTP-induced PD mice (p < 0.05), accompanied by lower markers of oxidative damage and iron overload (p < 0.01).
SLAB51, another probiotic strain, has been demonstrated to improve motor impairment and cognitive performance in animal models with PD [61]. Castelli et al. (2020) [18] performed a controlled in vitro and in vivo laboratory experimental study demonstrating that SLAB51 exerted neuroprotective effects in rats with induced PD, enhancing BDNF/TrkB signaling, reducing oxidative stress and neuroinflammation, preserving dopaminergic markers, and improving motor performance.
Finally, Visñuk et al. (2020) [62] conducted an in vivo study that demonstrated that a 6-week intervention with a combination of Lactobacillus plantarum CRL 2130, Streptococcus thermophilus CRL 807, and Streptococcus thermophilus CRL 808 improved motor function by reducing α-syn accumulation and decreasing inflammatory cytokines using the polo test.
In addition to the probiotic strains described above, several other microorganisms have demonstrated potential benefits in PD through mechanisms such as modulation of neuroinflammation and preservation of dopaminergic neurons, therefore improving both motor and non-motor symptoms. Furthermore, other microbiome-targeted strategies, including specific dietary interventions, prebiotics, FMT, and targeted microbial-based therapies, are at various stages of translational and clinical development and have also shown therapeutic promise. The mechanisms underlying their therapeutic effects are summarized in Table 1 [27, 42, 63–72].
Mechanistic pathways and therapeutic effects of microbiome-targeted interventions in PD.
| Microbiota-targeted strategy | Mechanistic pathways | Examples | References |
|---|---|---|---|
| Dietary interventions |
| High-fiber diet and Mediterranean diet. | [27, 42, 63, 64] |
| Prebiotics |
| Resistant fermentable fiber blend (starch and inulin). | [64–67] |
| Fecal microbiota transplantation (FMT) |
| Randomized placebo-controlled trial of FMT improves autonomic symptoms in PD. | [68, 69] |
| Specific microbial therapies |
| Targeted or engineered strains (e.g., next-generation probiotics, bacteriophages, SCFA-producing bacteria). | [64, 70, 71] |
| Probiotics |
| Lactobacillus + Bifidobacterium regimens. | [27, 72] |
α-syn: alpha-synuclein; SCFAs: short-chain fatty acids; PD: Parkinson’s disease.
GI dysfunction, especially constipation, is a prevalent non-motor symptom in PD, affecting up to 90% of patients and often appearing years before motor symptoms [73–75]. Consequently, this domain has been widely explored as a target for probiotic interventions in PD.
The body of evidence includes numerous double-blind, RCTs with intervention periods typically ranging from 4 to 12 weeks. Meta-analyses of these trials, which have collectively enrolled hundreds of patients, show remarkably consistent and positive results [14, 72, 76]. Probiotic supplementation leads to a clinically meaningful increase in bowel movement frequency, with pooled data indicating an average increase of approximately one additional spontaneous bowel movement (SBM) per week [14, 72, 76].
Beyond frequency, probiotics have also been shown to improve stool consistency, as measured by the Bristol Stool Scale (BSS), leading to softer, more normalized stools. These physiological improvements are accompanied by significant enhancements in patient-reported outcomes such as stool frequency and stool consistency [14]. Studies consistently show that probiotics improve constipation-related quality of life, measured by the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire, and reduce the need for rescue laxative use [13, 14].
In the current body of literature, probiotic interventions in humans have predominantly been evaluated over treatment periods of 4, 8, or 12 weeks, with the following outcomes.
A study by Barichella et al. (2016) [77] provided fermented milk containing multiple strains and reported a significant increase in the number of complete bowel movements compared to placebo. A landmark class I evidence trial by Tan et al. (2021) [78] used a capsule with eight strains (Lactobacillus and Bifidobacterium species) and found it increased SBMs by 1.3 per week and significantly improved stool consistency and quality of life compared to placebo (p < 0.01 for all).
A trial by Ibrahim et al. (2020) [79] using an 8-week course of a multi-strain probiotic sachet with prebiotics found significant improvements in both bowel movement frequency and overall gut transit time. More recently, Ghalandari et al. (2023) [80] conducted an 8-week trial using a high-dose, multi-strain probiotic containing eight strains of Lactobacillus, Bifidobacterium, and Streptococcus thermophilus. This intervention doubled the median bowel movement frequency from two to four per week compared to placebo and significantly improved stool consistency.
A study by Du et al. (2022) [81] reported that a multi-strain supplement containing Bacillus, Lactobacillus, Bifidobacterium, and Enterococcus species led to an increase of 1.09 complete bowel movements per week and improved scores on constipation symptom and quality of life scales. In another 12-week study, Sun et al. (2022) [82] focused on a single-strain intervention with Bifidobacterium animalis subsp. lactis Probio-M8, demonstrating significant improvements in stool consistency and constipation-related quality of life (p < 0.001).
The beneficial effects observed in human trials are strongly supported by preclinical research in animal models of PD, which allows for a deeper investigation into the foundational processes. These studies show that probiotics can directly counteract the GI pathology associated with the disease.
For instance, Chu et al. (2023) [83] demonstrated the protective effects of Lactobacillus plantarum CCFM405. The administration of this probiotic led to an increase in colon length, restored the integrity of the gut microbiota by upregulating the expression of tight junction proteins like occludin and ZO-1, and increased the number of fecal pellets in PD mice.
A study by Dong et al. (2024) [84] in a mouse model of PD evaluated the effects of Bifidobacterium animalis subsp. lactis NJ241. This probiotic not only mitigated weight loss but also significantly improved GI motility, as measured by an increased travel distance of Evans blue dye in the small intestine compared to untreated PD mice (p = 0.024). Critically, the study linked this gut-level improvement to neuroprotection, as NJ241 treatment protected dopaminergic neurons, inhibited the activation of inflammatory glial cells in the substantia nigra, and increased the levels of beneficial SCFAs. The researchers also found that these effects were connected to an increase in the gut hormone glucagon-like peptide-1 (GLP-1) and the activation of the protective GLP-1 receptor (GLP-1R)/PGC-1α signaling pathway in the brain.
Taken together, these high-quality trials indicate that multi-strain probiotic supplementation confers measurable benefits in alleviating PD-related constipation and enhancing quality of life, as outlined in Table 2 [77–84].
Experimental studies showing gastrointestinal symptoms improvement induced by probiotic interventions in PD.
| Study (year) | Probiotic(s) | Duration | Dose/Presentation | Outcome |
|---|---|---|---|---|
| Human studies | ||||
| Barichella et al. (2016) [77] | Fermented milk with strains of (Streptococcus, Enterococcus, Lactobacillus, Bifidobacterium) and prebiotic fiber | 4 weeks | 125 g of fermented milk containing 250 × 109 CFU, once daily | Superior to placebo in improving the number of complete bowel movements (p = 0.002). |
| Ibrahim et al. (2020) [79] | Multi-strain probiotic (Hexbio) (Lactobacillus spp., Bifidobacterium spp.) with fructo-oligosaccharides (FOS) | 8 weeks | Hexbio sachet with 30 × 109 CFU, 2% FOS, and lactose, twice daily | Improved bowel movement frequency (p < 0.001) and total gut transit time (p = 0.028). |
| Tan et al. (2021) [78] | Multistrain (Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus gasseri, Lactobacillus rhamnosus, Bifidobacterium bifidum, Bifidobacterium longum, Enterococcus faecalis, Enterococcus faecium) | 4 weeks | 10 × 109 CFU capsule, once daily | Increased spontaneous bowel movements by 1.3/week (p < 0.001); improved stool consistency (p = 0.009) and quality of life (p = 0.001). |
| Sun et al. (2022) [82] | Probio-M8 (Bifidobacterium animalis subsp. lactis) | 3 months | 2 g of Probio-M8 powder (3 × 1010 CFU/day; maltodextrin as excipient) daily | Significant improvement in gastrointestinal symptoms, including Bristol scores (p < 0.001) and Patient Assessment of Constipation Quality of Life Questionnaire (p < 0.001). |
| Du et al. (2022) [81] | Bacillus licheniformis, Lactobacillus acidophilus, Bifidobacterium longum; Enterococcus faecalis | 12 weeks | 2.5 × 109 CFU two capsules, three times daily | Increased complete bowel movements by 1.09/week (p < 0.001); improved Bristol Stool Scale, Patient Assessment of Constipation Symptoms Questionnaire, and Patient Assessment of Constipation Quality of Life Questionnaire scores (p < 0.05 for all). |
| Ghalandari et al. (2023) [80] | Comflor® (Lactobacillus plantarum, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve, and Streptococcus thermophilus) | 8 weeks | 4.5 × 1011 CFU capsule, once daily | Doubled bowel movement frequency (p = 0.02) and improved stool consistency (p = 0.04). |
| In vivo studies of animals | ||||
| Chu et al. (2023) [83] | Lactobacillus plantarum CCFM405 | 8 weeks | 1 × 109 CFU/0–2 mL in saline by oral gavage, once daily | Alleviated motor deficits (p < 0.05) and constipation symptoms (p < 0.05). Reduced dopaminergic neuron loss (p < 0.05), intestinal inflammation, and neuroinflammation (p < 0.05). Increased number of fecal pellets in PD mice (p < 0.05) and fecal/serum branched-chain amino acids. |
| Dong et al. (2024) [84] | Bifidobacterium animalis subsp. lactis NJ241 | 28 days | 1 × 109 CFU/0.2 mL in saline by oral gavage, once daily | Mitigated gastrointestinal dysfunction (p = 0.024) and motor deficits (p < 0.05). Protected dopaminergic neurons (p < 0.05). Reduced neuroinflammation (p < 0.05). Increased SCFAs and colonic GLP-1 (p < 0.05). |
PD: Parkinson’s disease; SCFAs: short-chain fatty acids; GLP-1: glucagon-like peptide-1.
Neuropsychiatric symptoms are highly prevalent in PD [85]. Depression and anxiety are the most common neuropsychiatric manifestations of PD, affecting up to 40% and over 50% of patients, respectively, and are considered intrinsic to its pathophysiology [86, 87]. The gut-brain axis has emerged as a key pathophysiological link in several neuropsychiatric disorders, and growing evidence supports the role of probiotics as potential modulators of this bidirectional communication. Based on current evidence, ongoing research is exploring probiotics as potential interventions for neuropsychiatric symptoms in PD. Recent studies indicate that the use of certain probiotic strains has a positive impact on anxiety and depression in PD patients [13, 88, 89].
Anxiety is a common non-motor symptom in PD, with prevalence ranging from 25–40% in different cohorts and clinical stages [90]. Recent evidence suggests that probiotic supplementation may have a clinically relevant effect on these symptoms. Disease-specific evidence comes from a key RCT by Sun et al. (2022) [82], which evaluated a Bifidobacterium, Lactobacillus, and Enterococcus probiotic combination in PD patients over 12 weeks. The probiotic intervention significantly reduced anxiety scores on the Hamilton Anxiety Rating Scale (HAMA). Similarly, Kim et al. (2019) [91] demonstrated that the use of Bifidobacterium bifidum probiotic strain reduced stress levels and enhanced cognitive flexibility, supporting its mental health, and Yang et al. (2023) [92] demonstrated a reduction in HAMA score following an intervention with Lacticaseibacillus paracasei. Finally, Zeng et al. (2024) [93] showed a decrease in the Self-Rating Anxiety Scale (SAS) compared to the placebo group, using a 12-week course of Bacteroides fragilis BF839 combined with earthworm protein, showing an improvement of anxiety symptoms.
Corroborating these findings, two meta-analyses by Park et al. (2023) [89] and Nisa et al. (2024) [88] reported a significant reduction in anxiety associated with probiotic use, aligning with other comprehensive reviews, which consistently note that effects are modest in the general population but become more pronounced in PD patients [94].
There was only one in vivo study that evaluated this outcome. It was conducted by Xie et al. (2020) [95], showing no effects in anxiety-like behavior after 6 weeks of treatment with Lacticaseibacillus rhamnosus HA-114 probiotic strain, in mouse models with PD (measured by the elevated plus maze test, p = 0.973).
Depression is another prevalent non-motor symptom in PD, affecting approximately 30–50% of patients and frequently preceding the onset of motor manifestations [90]. Sun et al. (2022) [82] and Yang et al. (2023) [92] demonstrated significant improvements in Hamilton Depression Rating Scale 17 (HAMD-17) scores in the probiotic-treated group (Bifidobacterium, Lactobacillus, and Enterococcus probiotic combination and Lacticaseibacillus paracasei, respectively) compared to placebo [82, 92]. In contrast, Lu et al. (2021) [53] evaluated this outcome with the Beck Depression Inventory-II (BDI-II), showing no significant results with probiotic intervention. On the other hand, Zeng et al. (2024) [93] conducted a clinical trial using an intervention with Bacteroides fragilis BF839 combined with earthworm protein for 12 weeks in PD patients, showing a decrease in the scores of an extended version of the HAMD-24, compared to the placebo group. Meta-analyses such as Park et al. (2023) [89], Chu et al. (2023) [83], and Nisa et al. (2024) [88] reported a significant reduction in depressive symptoms following probiotic supplementation. There is limited direct animal research evaluating the effect of probiotics on depression in PD models.
Evidence regarding the effect of probiotics on neuropsychiatric symptoms in PD is scarce, with only a small number of human studies and a single in vivo study evaluating this outcome. Although most of these studies have shown beneficial effects and the pooled effect from meta-analyses was positive, further research should focus on this area. Table 3 summarizes the studies reporting a beneficial effect on anxiety and depression symptoms [82, 92, 93].
Experimental studies showing depression and anxiety symptoms improvement induced by probiotic interventions in PD.
| Study (year) | Probiotic(s) | Duration | Dose/Presentation | Outcome |
|---|---|---|---|---|
| Human studies | ||||
| Sun et al. (2022) [82] | Probio-M8 (Bifidobacterium animalis subsp. lactis) | 3 months | 2 g of Probio-M8 powder (3 × 1010 CFU/day; maltodextrin as excipient) daily | Depression (HAMD-17): significant improvement vs. control (p < 0.001). Anxiety (HAMA): significant improvement vs. control (p < 0.001). |
| Yang et al. (2023) [92] | Lacticaseibacillus paracasei strain Shirota (LcS) | 12 weeks | Fermented milk drink containing 1 × 1011 CFU of LcS, once daily | Depression (HAMD-17): significant improvement vs. control (p = 0.010). Anxiety (HAMA): significant improvement vs. control (p = 0.005). |
| Zeng et al. (2024) [93] | Bacteroides fragilis BF839 + earthworm protein | 12 weeks | 10 g supplement dissolved in 200 mL water, twice daily (each 10 g containing 106 BF839 and 0.3 g earthworm protein) | Depression: significant reduction in HAMD-24 score (−3.91 ± 3.99 vs. +1.15 ± 3.42, p < 0.001). Anxiety: significant reduction in SAS score (−7.04 ± 5.71 vs. −1.23 ± 2.34, p < 0.001). Both improvements sustained through 12 weeks compared to placebo. |
PD: Parkinson’s disease; HAMD-17: Hamilton Depression Rating Scale 17; HAMA: Hamilton Anxiety Rating Scale; SAS: Self-Rating Anxiety Scale.
Sleep disturbances, including insomnia and rapid eye movement (REM) sleep behavior disorder (RBD), affect up to 80% of PD patients [96]. Recent studies highlight the potential of probiotics to alleviate these issues, such as an RCT by Sun et al. (2022) [82], which found that Bifidobacterium animalis Probio-M8 significantly improved sleep quality on the Parkinson’s Disease Sleep Scale (PDSS). Additionally, a 2025 pilot RCT by Du et al. (2025) [97] found that 8-week probiotic therapy improved scores on the Pittsburgh Sleep Quality Index (PSQI) in PD patients with probable RBD. Probiotics showing benefits of PD-related sleep disorders are shown in Table 4 [82, 97].
Experimental studies showing sleep parameters improvement induced by probiotic interventions in PD.
| Study (year) | Probiotic(s) | Duration | Dose/Presentation | Sleep outcome |
|---|---|---|---|---|
| Human studies | ||||
| Sun et al. (2022) [82] | Probio-M8 (Bifidobacterium animalis subsp. lactis) | 3 months | 2 g of Probio-M8 powder (3 × 1010 CFU/day; maltodextrin as excipient) daily | Improved sleep quality on the Parkinson’s Disease Sleep Scale (PDSS) (p = 0.05). |
| Du et al. (2025) [97] | Bacillus licheniformis, Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis | 12 weeks | Bacillus licheniformis (2.5 × 109 CFU/capsule once daily); Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis (each 1.0 × 107 CFU/capsule once daily) | UPDRS scores decreased significantly in the probiotic group, p = 0.048. |
PD: Parkinson’s disease; UPDRS: Unified Parkinson’s Disease Rating Scale.
In contrast to the positive findings for mood and sleep, the evidence supporting the benefit of probiotics for cognitive impairment in PD patients is currently understudied or inconclusive [30, 88, 98, 99]. Numerous studies in rodent models of PD show that probiotics can improve cognitive performance and offer neuroprotection (Table 4) [59, 95, 100]. Two RCTs conducted in patients with PD evaluated the effects of specific probiotic strains on cognitive function. Sun et al. (2022) [82] was the only study to report a significant improvement in Mini-Mental State Examination (MMSE) scores in the intervention group, whereas Yang et al. (2023) [92] found no difference in MMSE scores between the intervention and control groups after 12 weeks of treatment. Meta-analyses assessing cognition have either focused on other conditions like Alzheimer’s disease or have not reported specific cognitive outcomes for their PD cohorts [30, 88, 98, 99]. Although in vivo studies have demonstrated a beneficial effect of probiotics on cognitive function, robust clinical evidence in human populations is still lacking and should be a focus for future research [76]. The duration of the interventions that measured this outcome varied from 2 to 12 weeks. Future research should focus on longer treatment durations, as cognitive effects may require extended periods to manifest and be sustained. Studies showing a beneficial effect of probiotic treatment on the cognitive function of PD patients are described in Table 5 [59, 82, 95, 100].
Experimental studies showing cognitive symptoms improvement induced by probiotic interventions in PD.
| Study (year) | Probiotic(s) | Duration | Dose/Presentation | Cognitive outcome |
|---|---|---|---|---|
| Human studies | ||||
| Sun et al. (2022) [82] | Bifidobacterium animalis subsp. lactis Probio-M8 (Probio-M8), Benserazide | 3 months | 3 × 1010 CFU/daily | MMSE scores were greater in the Probio-M8 group than in the placebo group at baseline (p < 0.001), 1 month (p < 0.001), and 3 months (p = 0.042). |
| In vivo studies of animals | ||||
| Valvaikar et al. (2024) [100] | Bifidobacterium breve Bif11 | 21 days | 1 × 1010 CFU daily | It was reported that PD rats had lower cognitive performance in the maze test, and when treated with Bif11, their working memory improved significantly (p = 0.001). |
| Nosrani et al. (2021) [59] | Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, Lactobacillus fermentum | 14 days | 2 × 109 CFU of each strain/day, oral administration | In 6-OHDA PD rats, decreased escape latency in the Morris water maze (p < 0.0001) and increased time in the target quadrant during probe trial (p < 0.0001), indicating improved spatial learning and memory. |
| Xie et al. (2020) [95] | Lacticaseibacillus rhamnosus HA-114 | 6 weeks | Rehydrated with distilled water; initial concentration 1 × 109 CFU/mL, reduced to 1 × 108 CFU/mL from day 5; provided in drinking water, changed every 2 days | Novel Object Recognition (hippocampal-independent, 5 min retention): all groups showed good memory retention (sham + probiotics: p = 0.001; PD + placebo: p = 0.031; PD + probiotics: p < 0.001). Novel Place Recognition (hippocampal-dependent, 5 min retention): PD + placebo group impaired: p = 0.62; PD + probiotics group restored memory retention: p = 0.032. |
PD: Parkinson’s disease; MMSE: Mini-Mental State Examination; 6-OHDA: 6-hydroxydopamine.
As previously mentioned, gut dysbiosis has been increasingly recognized as a contributor to the pro-inflammatory state that may worsen the clinical course of PD. Rebalancing the gut microbiota through probiotic supplementation has emerged as a potential strategy to reduce neuroinflammation and microglial activation, which in turn could help protect dopaminergic neurons and improve motor symptoms [101]. Since tremor, rigidity, bradykinesia, and gait disturbances are key features of PD and significantly affect patients’ quality of life, therapeutic approaches aimed at alleviating these symptoms are of particular clinical interest.
Several RCTs have assessed the impact of probiotic interventions on motor outcomes in patients with PD. Motor function has been primarily evaluated using validated tools such as the UPDRS and its MDS revision, with parts III (motor examination) and IV (motor complications) being the most relevant for motor assessment [102].
Probiotic interventions have typically been administered over 8-week to 12-week periods, with MDS-UPDRS (particularly parts III and IV) frequently used to assess motor outcomes.
Ibrahim et al. (2020) [79] conducted an 8-week trial using a multi-strain probiotic with Lactobacillus and Bifidobacterium species (30 × 109 CFU) plus fructo-oligosaccharides, showing no significant differences in MDS-UPDRS scores compared to placebo. Similarly, Ghalandari et al. (2023) [80] administered Comflor® capsules for 8 weeks (total 4.5 × 1011 CFU of Lactobacillus plantarum, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve, and Streptococcus thermophilus), reporting no significant differences in motor outcomes.
Yang et al. (2023) [92] evaluated a 12-week intervention using Lacticaseibacillus paracasei fermented milk (1 × 1010 CFU) and found no significant changes in MDS-UPDRS motor scores, though there was a notable reduction in non-motor symptoms (MDS-UPDRS I: mean difference −0.99; 95% CI: −1.62 to −0.37; p = 0.002). Zeng et al. (2024) [93] combined Bacteroides fragilis 839 with an earthworm protein supplement for 12 weeks, reporting reductions in all UPDRS sub-scores. Andreozzi et al. (2024) [103] tested Enterolactis Duo (Lacticaseibacillus paracasei DG + inulin) for 12 weeks but found no significant improvements in UPDRS-III scores. Zali et al. (2024) [104] administered a probiotic and vitamin D supplement (BioZen D, containing 2 × 109 CFU of Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus paracasei, Bifidobacterium longum, and Bacillus coagulans, plus 400 IU of vitamin D), showing significant improvements in all UPDRS domains except part II (activities of daily living).
Sun et al. (2022) [82] assessed the effects of Probio-M8 (Bifidobacterium animalis subsp. lactis) over a 3-month period, observing a significant reduction in UPDRS-III scores at both 1 and 3 months (p = 0.037 and p = 0.016, respectively).
Notably, Lu et al. (2021) [53] used Lactobacillus plantarum PS128 over 12 weeks and incorporated symptom diaries to better capture ON/OFF fluctuations. Their findings showed significant improvements in UPDRS motor scores in both OFF and ON states (p = 0.004 and p = 0.007, respectively), along with a reduction in fluctuation duration.
Several in vivo studies support the neuroprotective and motor benefits of probiotics in PD models. Hsieh et al. (2020) [105] reported that 16 weeks of a six-strain probiotic mix improved balance, coordination, and gait, while preserving dopaminergic neurons in transgenic mice (p < 0.05). Similarly, Sun et al. (2021) [56] showed that a 4-week course of Clostridium butyricum enhanced motor performance (p < 0.01), reduced microglial activation, and preserved nigral neurons.
Parra et al. (2023) [106] found that Microbiot® (Lactobacillus rhamnosus GG and Bifidobacterium animalis ssp. lactis Bb12) partially improved motor performance and reduced neuroinflammation in LPS-induced PD rats. Likewise, Castelli et al. (2020) [18] demonstrated that SLAB51 supplementation improved motor tests and preserved dopaminergic neurons while reducing microgliosis and oxidative stress. Finally, Wang et al. (2023) [58] showed that an engineered Clostridium butyricum-GLP-1 strain enhanced motor outcomes, preserved dopaminergic neurons [↑ TH and dopamine transporter (DAT) expression, ↓ α-syn accumulation], promoted mitophagy, attenuated oxidative stress, restored gut microbiota balance, and improved intestinal barrier integrity.
Taken together, these preclinical studies complement human findings by demonstrating that probiotics not only modulate neuroinflammatory and neuroprotective pathways but also translate into measurable motor benefits in animal models of PD. Future human research should aim to replicate the probiotic strains and treatment durations that demonstrated efficacy in animal models, in order to confirm their translational potential in motor symptoms of PD.
Although the exact mechanisms linking gut dysbiosis to motor symptom progression in PD remain not fully understood, current findings support the hypothesis that microbial modulation, especially through targeted probiotic interventions, may have beneficial effects on motor outcomes and serve as a potential complementary intervention for PD patients (shown in Table 6). Despite a few studies showing inconsistent results, pooled data suggest a general trend toward improved motor function despite the duration of the interventions (that varied from 8 to 12 weeks), particularly reflected in reduced UPDRS-III scores following probiotic supplementation [14, 89, 107, 108]. Two meta-analyses, by Xie et al. (2023) [14] and Park et al. (2023) [89], aligned with the results of human-based RCTs available in current literature, demonstrated significant associations between probiotic use and reductions in UPDRS-III scores [weighted mean difference (WMD) = −6.58; 95% CI: −12.02 to −1.14 and standardized MD (SMD) = −0.65; 95% CI: −1.11 to −0.19, respectively]. These effects are thought to result from reduced neuroinflammation, increased production of SCFAs, and improved gut-brain axis signaling.
Experimental studies showing motor symptom improvement induced by probiotic interventions in PD.
| Study (year) | Probiotic(s) | Duration | Dose/Presentation | Motor outcome |
|---|---|---|---|---|
| Human studies | ||||
| Lu et al. (2021) [53] | Lactobacillus plantarum PS128 | 12 weeks | Two capsules containing PS128 (30 billion colony-forming units per capsule) daily, oral | Improvement in UPDRS motor scores in both ON and OFF states (p = 0.004 and 0.007, respectively). Decreased akinesia subscores in the OFF state (p = 0.012). Reduced duration of OFF periods (p = 0.04) and increased ON periods (p = 0.031). |
| Sun et al. (2022) [82] | Probio-M8 (Bifidobacterium animalis subsp. lactis) | 3 months | 2 g of Probio-M8 powder (3 × 1010 CFU/day; maltodextrin as excipient) daily | Significant reduction in UPDRS part III at 1 and 3 months (p = 0.037, 0.016, respectively). |
| Zali et al. (2024) [104] | BioZen D® containing: Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus paracasei, Bifidobacterium longum, Bacillus coagulans + vitamin D | 12 weeks | 2 × 109 CFU + 400 IU vitamin D per capsule, 1 oral capsule a day | Significant improvement in all MDS-UPDRS domains (parts I, III, and IV), except for part II (p ≤ 0.001). |
| Zeng et al. (2024) [93] | Bacteroides fragilis 839 + earthworm protein supplement | 12 weeks | 10 g of BF839 + earthworm protein supplement solution (contains 106 BF839 and 0.3 g earthworm protein) dissolved in 200 mL of water, twice daily | Reduction in all UPDRS subscale scores, including part III (p varying from 0.001 to 0.026 in UPDRS parts I to IV). |
| In vivo studies of animals | ||||
| Hsieh et al. (2020) [105] | Bifidobacterium bifidum, Bifidobacterium longum, Lactobacillus rhamnosis, Lactobacillus rhamnosus GG, Lactobacillus plantarum LP28, Lactococcus lactis subsp. Lactis | 16 weeks | 1010 CFU/mouse/day, oral | Improved balance and coordination (beam walking test and reduced traversal time, p < 0.05 to p < 0.001), and gait (measured by walking speed, step length, stride length, step width, stance and swing phase times, p < 0.05); preserved TH + dopaminergic neurons in substantia nigra pars compacta (p < 0.05). |
| Sun et al. (2021) [56] | Clostridium butyricum | 4 weeks | 5 × 108 CFU/mouse/day, intragastric | Shorter pole descent times, reduced beam latency and foot slips, decreased immobility, and increased open field crossings (all with a p < 0.01). |
| Parra et al. (2023) [106] | Microbiot®: Lactobacillus rhamnosus GG + Bifidobacterium animalis ssp. lactis Bb12) | 15 days | 1 × 109 CFU/strain/day, oral | Partial motor benefits: reduced type 3 step errors (day 7, p < 0.05) and improved stand phase (day 13, p < 0.01). |
| Castelli et al. (2020) [18] | SLAB51 (Bifidobacterium and Lactobacillus strains) | 5 weeks (2 pre + 3 post-lesion) | Oral gavage, daily (dose not specified in summary) | Restored contralateral forelimb use (p < 0.005), reduced biased swings (p < 0.005), and decreased apomorphine-induced rotations (p < 0.005). |
| Wang et al. (2023) [58] | Clostridium butyricum-pMTL007-GLP-1 (engineered strain expressing GLP-1) | 7 days | 1 × 108 CFU/mL, oral gavage, resuspended in saline with 0.01% gelatin | Significant motor improvement in MPTP-induced PD mice: reduced pole test descent time (p < 0.01), improved hanging wire test score, increased total distance traveled, and central area exploration in the open field test (both p < 0.01). |
PD: Parkinson’s disease; MDS-UPDRS: Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; TH: tyrosine hydroxylase; MPTP: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Other strategies, such as FMT, have also been explored. FMT involves transplanting processed stool from a thoroughly screened healthy donor into a recipient’s GIT to restore microbial diversity, improve SCFA production, reduce pro-inflammatory taxa, and enhance intestinal barrier integrity and motility [109, 110]. Bruggeman et al. (2024) [111] reported a significant improvement in MDS-UPDRS motor scores 12 months post-FMT in an OFF-medication state (−5.8 points; 95% CI: −11.4 to −0.2; p = 0.0235). DuPont et al. (2023) [68] used an orally administered, lyophilized FMT product twice weekly for 12 weeks in PD patients with constipation, showing improvements in motor scores at 1, 4, and 9 months, though full comparison with placebo across all time points was not reported. In contrast, Scheperjans et al. (2024) [112] used a single-dose FMT via colonoscopy without antibiotic pre-treatment and observed no significant differences in motor scores compared to placebo at 6- and 12-month follow-up. Regarding safety, FMT is generally well tolerated, with most adverse events being mild and transient GI symptoms such as diarrhea, abdominal discomfort, or bloating [113]. Serious adverse events are rare, and direct safety comparisons with probiotic interventions have not yet been conducted [7].
The findings summarized in this review suggest that targeting the BGM axis may offer a promising therapeutic pathway in PD. Across RCT and systematic reviews, probiotics have shown consistent benefits for motor and non-motor symptoms. Preclinical studies further strengthen this concept, showing that various probiotic strains and related microbiome-based approaches such as prebiotics, dietary modulation, FMT, and engineered microbial therapies can reduce neuroinflammation, protect dopaminergic neurons, and restore gut-brain homeostasis, supporting the biological rationale for these clinical outcomes.
Despite the growing number and diversity of studies exploring the therapeutic role of probiotics in PD, several key challenges remain. Many clinical trials are limited by small sample sizes, short intervention periods, and inconsistent outcome measures, particularly the lack of comprehensive tools to assess non-motor symptoms [14, 15]. In addition, there is significant heterogeneity across studies in terms of probiotic strains, dosages, treatment durations, and administration methods [14, 15]. This variability makes direct comparison between trials difficult and limits reproducibility, as differences in bacterial composition, CFU concentration, and delivery formats may lead to divergent outcomes even when assessing similar endpoints. In addition, most clinical trials have been limited to short durations (4–12 weeks), leaving the long-term efficacy and sustainability of probiotic benefits in PD largely unknown. These factors not only complicate comparisons between studies but also increase the risk of bias and limit the generalizability of the findings.
Moreover, most of the data supporting the therapeutic effects of probiotics and other microbiome-targeted interventions in PD come from preclinical studies. Although these models have been valuable for advancing our understanding of gut-brain interactions and clarifying mechanisms of neuroprotection, they only reproduce selected aspects of PD, such as dopaminergic neuronal loss or α-syn aggregation, and fail to capture its complex, progressive, and multifactorial nature [13, 21, 27]. Furthermore, interspecies differences in microbiota composition, immune responses, and environmental factors limit the direct translation of these findings to humans [114–116]. Even so, preclinical research remains essential for identifying mechanistic pathways and prioritizing promising probiotic and microbiome-based strategies for future clinical evaluation.
Another potential limitation is that mechanistic insights are still limited, as few studies have explored how probiotics affect the body at a molecular level, including changes in microbiota, gene expression, or inflammation. Although recent trials have increasingly included microbiota sequencing [82, 92, 93, 103], metabolomic profiling [82, 92, 93, 103], and inflammatory marker analyses [53, 98, 104], mechanistic evidence remains indirect and incomplete, especially in human studies [117]. Some reports have shown associations between probiotic use and changes in gut microbial composition [118, 119], SCFA production [120], and circulating cytokines [82, 104]. However, most authors also acknowledge that these analyses were limited in depth and scope. Overall, while current findings suggest possible BGM interactions involving SCFA metabolism and neuroinflammation, the causal relationships and long-term biological relevance of these effects remain unclear. Many studies did not include metabolomic or transcriptomic validation [53, 77–80], failed to confirm probiotic colonization [79, 81, 103], or combined multiple interventions (e.g., vitamin D or prebiotics) [93, 104], which makes it difficult to isolate specific mechanisms. Therefore, our current understanding of how probiotics exert their effects in PD is still preliminary and requires more focused mechanistic research in human populations.
When analyzing RCTs that assessed motor outcomes, it is essential to consider potential confounders that may affect observed improvements, such as the concurrent use of dopaminergic medications, which can influence motor symptom improvements. Most trials investigating the effects of probiotics on motor outcomes reported participants’ baseline pharmacological treatments, with the majority already receiving levodopa and a smaller yet considerable proportion using dopamine agonists or other dopaminergic medications. Although these studies acknowledged medication use at baseline, they generally did not specify its influence on outcomes or report any dosage adjustments or new initiations of dopaminergic therapy during or shortly before the intervention. In the study by Lu et al. (2021) [53], motor assessments were conducted both in OFF and ON states after standardized medication withdrawal, demonstrating significant improvements in UPDRS-III scores and ON-OFF duration after PS128 supplementation, suggesting effects beyond acute dopaminergic influence. Similarly, Zeng et al. (2024) [93] observed greater UPDRS improvement in patients not receiving levodopa, underscoring the need to control for dopaminergic therapy when evaluating probiotic efficacy. To better control for this potential confounder, future studies should explicitly exclude patients who have recently initiated dopaminergic treatment or who require dosage modifications during the trial, as exemplified by Zeng et al. (2024) [93], and should standardize OFF/ON assessments as in Lu et al. (2021) [53] to better isolate the direct effects of probiotic interventions.
In terms of population variability, most trials to date have been conducted in Italy [77], Iran [80, 104], China [53, 82, 92, 93, 97], and Malaysia [78]. Across regions, there is a substantial difference in diet patterns, genetics, and baseline microbiota composition [121, 122]. Therefore, additional studies in other regions are needed to validate these findings and account for population-specific variability that may influence probiotic efficacy.
Although several studies characterize disease severity using the Hoehn and Yahr scale [53, 77, 79–81, 92, 93], none of the trials conducted to date have analyzed outcomes according to early versus advanced PD stages. This gap prevents determining whether probiotic efficacy varies across disease progression. Future trials should include prespecified subgroup analyses by Hoehn and Yahr stage to clarify potential stage-dependent responses to probiotic therapy.
Additionally, identifying reliable biomarkers and understanding each patient’s unique microbial profile could help adjust treatments to those most likely to benefit. Current evidence suggests that probiotics can reduce peripheral systemic inflammation, reflected by decreased CRP, IL-1, IL-8, and TNF-α levels, while showing no effect on intestinal inflammation measured by fecal calprotectin [16, 107]. Oxidative stress markers also appear modulated, with increased glutathione (GSH) and decreased malondialdehyde (MDA) levels, indicating improved antioxidant status [13, 123]. SCFAs quantified in plasma and feces are used to assess microbial metabolic activity, although changes are not always significant [107]. However, further studies are needed to validate these biomarkers and determine their reliability in monitoring probiotic effects in PD.
Publication bias may influence the current evidence, as studies with positive probiotic results are more likely to be published. Among systematic reviews, two evaluated the potential risk of bias. First, Xie et al. (2023) [14], focusing on constipation, found symmetrical funnel plots suggesting a low risk of publication bias, whereas Park et al. (2023) [89] identified significant bias for several outcomes (e.g., GI motility and inflammatory markers) using Egger’s test. Overall, these findings suggest a low to moderate risk of publication bias, highlighting the need for further analyses of bias within RCTs. Upcoming reviews should continue to assess and report publication bias to provide more balanced estimates of probiotic efficacy in PD.
Future research should prioritize larger, multicenter randomized trials with extended follow-up to better establish the long-term efficacy and safety of probiotic interventions in PD. To enhance consistency and comparability across studies, standardized protocols are needed, particularly regarding the assessment of non-motor symptoms and the analytical methods used to characterize the gut microbiota. Promising preclinical findings should be translated into rigorously designed human studies to determine their true clinical relevance. Finally, integrating probiotics with complementary strategies, such as dietary interventions or conventional pharmacologic treatments, may optimize therapeutic outcomes and support more targeted, personalized, and less invasive approaches for patients with PD.
PD is more than just dopaminergic neurodegeneration; it is a complex, multisystem disorder. Increasing evidence suggests that the BGM axis may play a key role, with direct implications for neuroinflammation, glial activation, and disruption of blood-brain barrier integrity. Probiotic therapy has emerged as a promising approach with the potential to influence the progression of central neurodegeneration. Several studies have reported clinical improvements in PD patients treated with various probiotic strains, underscoring both their efficacy and safety. These findings point to new therapeutic avenues that extend beyond the traditional dopaminergic framework. However, further multicenter, controlled studies with longer follow-up and standardized protocols are needed to more conclusively evaluate their therapeutic potential, clarify strain-specific effects, and validate reliable biomarkers that could serve to monitor treatment response and guide personalized interventions in PD.
BDNF: brain-derived neurotrophic factor
BGM: brain-gut-microbiota
CNS: central nervous system
FMT: fecal microbiota transplantation
GABA: gamma-aminobutyric acid
GDNF: glial cell-derived neurotrophic factor
GI: gastrointestinal
GIT: gastrointestinal tract
GLP-1: glucagon-like peptide-1
HAMA: Hamilton Anxiety Rating Scale
HAMD-17: Hamilton Depression Rating Scale 17
IL-1β: interleukin-1 beta
LPS: lipopolysaccharides
MMSE: Mini-Mental State Examination
NMS-MDS: Non-Motor Symptoms Scale-Movement Disorder Society
PD: Parkinson’s disease
PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha
RBD: rapid eye movement sleep behavior disorder
RCTs: randomized controlled trials
SBM: spontaneous bowel movement
SCFAs: short-chain fatty acids
TH: tyrosine hydroxylase
TNF-α: tumor necrosis factor-alpha
UPDRS: Unified Parkinson’s Disease Rating Scale
α-syn: alpha-synuclein
SPG: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing—original draft, Writing—review & editing. DHT: Conceptualization, Formal analysis, Investigation, Resources, Writing—original draft. FES: Conceptualization, Formal analysis, Investigation, Resources, Writing—original draft. GEB: Conceptualization, Project administration, Supervision, Writing—review & editing. MCRO: Conceptualization, Project administration, Supervision, Writing—review & editing. MGB: Conceptualization, Project administration, Supervision, Writing—review & editing, Funding acquisition. All authors read and approved the submitted version.
All authors meet the authorship criteria as defined by the International Committee of Medical Journal Editors (ICMJE), declare that they have no conflicts of interest, and confirm that no related papers from the same study, nor any similar manuscripts, have been published elsewhere.
Not applicable.
Not applicable.
Not applicable.
Not applicable.
Miguel Germán Borda was supported by the Norwegian Health Association. In addition, this paper represents independent research supported by the Norwegian government, through hospital owner Helse Vest (Western Norway Regional Health Authority). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© The Author(s) 2025.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
Copyright: © The Author(s) 2025. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
View: 103
Download: 12
Times Cited: 0
Adnan Akhtar Shaikh ... Niveditha Nair
