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.

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].

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.

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.