Probiotics as Potential Treatments for Neurodegenerative Diseases: a Review of the Evidence from in vivo to Clinical Trial

Abstract

Neurodegenerative diseases (NDDs), characterized by the progressive deterioration of the structure and function of the nervous system, represent a significant global health challenge. Emerging research suggests that the gut microbiota plays a critical role in regulating neurodegeneration via modulation of the gut-brain axis. Probiotics, defined as live microorganisms that confer health benefits to the host, have garnered significant attention owing to their therapeutic potential in NDDs. This review examines the current research trends related to the microbiome-gut-brain axis across various NDDs, highlighting key findings and their implications. Additionally, the effects of specific probiotic strains, including Lactobacillus plantarum, Bifidobacterium breve, and Lactobacillus rhamnosus, on neurodegenerative processes were assessed, focusing on their potential therapeutic benefits. Overall, this review emphasizes the potential of probiotics as promising therapeutic agents for NDDs, underscoring the importance of further investigation into this emerging field.

INTRODUCTION

Neurodegenerative diseases (NDD) are characterized by the progressive degeneration and death of neurons, resulting in cognitive decline, motor dysfunction, and behavioral changes (Kim and Joh, 2012; Heemels, 2016). Representative NDDs include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Although NDDs share common pathological features, such as protein aggregation, oxidative stress, and neuroinflammation, their exact underlying mechanisms have not been elucidated due to their significant complexity (Gupta et al., 2023; Gadhave et al., 2024). The prevalence of NDDs has increased significantly with the aging of the global population, highlighting the urgent need for a clearer understanding of their underlying mechanisms and the development of effective treatments (Ding et al., 2022; Huang et al., 2023).

Recent studies on the pathogenesis of NDDs have resulted in the development of diverse therapeutic strategies (Kostrzewa and Segura-Aguilar, 2003; Dar et al., 2020). While initial approaches focused on small-molecule drugs and immunotherapy, recent efforts have expanded to include innovative techniques, such as gene therapy (Sapko et al., 2022; Mead et al., 2023; Van de Roovaart et al., 2023; McFarthing et al., 2024). Notably, there is growing interest in systemic factors beyond the central nervous system (CNS), with increasing evidence supporting interactions along the microbiota-gut-brain (MGB) axis in the context of NDDs (Quigley, 2017; Mou et al., 2022). These studies have suggested the existence of a significant link between gut health and neurodegeneration, opening up new therapeutic possibilities, including the potential use of probiotics and other gut-targeting interventions.

Probiotics are defined by the FAO and WHO as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host.” (Latif et al., 2023). These beneficial microbes play a crucial role in promoting health by improving the composition of the gut microbiota, as well as enhancing immune function, leading to a range of positive health effects (Sanders et al., 2019). Recent research has also highlighted the potential advantages of probiotics in the context of neurological health, particularly their influence on the MGB axis (Snigdha et al., 2022). This connection indicates that probiotics may help to manage symptoms and support the treatment of NDDs, such as AD and PD. This report focused on the role of probiotics in the treatment of NDDs through a review of existing clinical and preclinical studies.

THE MICROBIOTA-GUT-BRAIN AXIS IN NEURODEGENERATIVE DISEASES

The gut, which is the largest endocrine organ in the body, produces an array of hormones and peptides that play pivotal roles in systemic health (Drucker, 2002; Hu et al., 2024b). Among the many specialized intestinal epithelial cells, enteroendocrine cells monitor luminal contents and release signaling molecules such as hormones and peptides, which interact with afferent vagal receptors (Gribble and Reimann, 2016). Additionally, the gut microbiota regulates the synthesis and secretion of these hormonal signals, by metabolites such as short-chain fatty acids (SCFAs), which significantly influence the intestinal environment and are linked to neural health (Dalile et al., 2019).

Studies have indicated that gut microbiota dysbiosis can potentially affect disease pathology in patients with NDDs such as AD and PD (Sun and Shen, 2018; Liu et al., 2020; Chidambaram et al., 2022). Dysbiosis can also decrease beneficial bacterial populations and increase harmful strains, leading to gut inflammation, which, in turn, promotes the production of inflammatory factors and increases intestinal permeability (Thevaranjan et al., 2017). Previous studies have shown that the ratio of Firmicutes/Bacteroidetes is disturbed in patients with NDDs compared to healthy controls (Ojha et al., 2023). This cascade is often accompanied by a reduction in neuroprotective metabolites, such as butyrate, and an increase in pathological proteins, such as amyloid-beta (Aβ) and alpha-synuclein (α-syn) (Marizzoni et al., 2020; Mahbub et al., 2024). Although these processes may vary with the specific disease, they generally amplify neuroinflammation in NDDs and are recognized as contributing factors to neuronal death.

The MGB axis employs multiple pathways to facilitate communication between the gut and brain. For example, the vagus nerve functions as a primary conduit, directly linking microbial signals to the central nervous system and connecting microbial activity to neural processes (Fulling et al., 2019). Neuroendocrine pathways, particularly the hypothalamic-pituitary-adrenal (HPA) axis, also play a crucial role in this interaction (Morais et al., 2021; Mlynarska et al., 2022). For example, stress-induced activation of the HPA axis stimulates cortisol release, which increases gut permeability and disrupts the microbial balance, thereby influencing the MGB axis. Furthermore, blood-mediated interactions enable gut microbiota-derived metabolites to enter the bloodstream and influence brain function (Swer et al., 2023). Collectively, these mechanisms demonstrate how the MGB axis dynamically responds to environmental and physiological changes, ultimately influencing neurological health and the progression of neurodegenerative conditions (Fig. 1).

Fig. 1.

Overview image of the microbiota-gut-brain axis in neurodegenerative diseases. HPA axis; Hypothalamic-pituitary-adrenal axis.

Alzheimer’s disease

One of the primary pathological features of AD is the accumulation of abnormal extracellular Aβ plaques, arising from the cleavage of amyloid precursor protein (APP) (Boxer and Sperling, 2023). This pathological process, combined with tau protein hyperphosphorylation and misfolding, results in the formation of neurofibrillary tangles within neurons. In addition to these primary pathologies, oxidative stress, neuroinflammation, and mitochondrial dysfunction can all critically contribute to neuronal damage, and intensify neurodegenerative processes (Scheltens et al., 2021). Collectively, these pathological changes drive substantial neuronal loss, impair synaptic function, and disrupt the neurotransmitter system, particularly the cholinergic system, which plays an essential role in memory and learning (Khan et al., 2020).

The MGB axis is increasingly being recognized as a key factor influencing the onset and progression of AD (Kesika et al., 2021). Recent studies have proposed that Aβ and tau proteins, which play central roles in AD pathology, may originate in the gut as well as the brain (Jin et al., 2023). Although the exact mechanisms remain unclear, these pathological proteins may be transported from the gut to the brain via the vagus nerve or systemic circulation, potentially contributing to AD development.

In patients with AD, dysbiosis of the gut microbiota has been consistently observed. This condition is characterized by an increase in species such as Helicobacter pylori, Klebsiella pneumoniae, Bacteroides fragilis, and Eggerthella lenta, alongside a decrease in Butyrivibrio hungatei, Butyrivibrio proteoclasticus, and Lactobacillales (Roubaud-Baudron et al., 2012; Haran et al., 2019). Moreover, gut dysbiosis has been shown to influence several neuroinflammatory processes that can exacerbate AD pathology. For example, microbial imbalance is associated with increased production of pro-inflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor-α, both of which are linked to neuroinflammation and neurodegeneration (Zhao et al., 2023). This inflammatory state can disrupt intestinal integrity or increase blood-brain barrier (BBB) permeability, thereby facilitating the entry of gut-derived Aβ and tau proteins into the CNS (Mou et al., 2022). This infiltration can thus activate brain-resident immune cells, further accelerating the neurodegenerative changes associated with AD.

Parkinson’s disease

PD, along with AD, is one of the most actively-researched NDDs associated with the MGB axis. The presence of abnormal intracellular aggregates of α-syn, known as Lewy bodies, within neurons is a defining pathological hallmark of PD (Wakabayashi et al., 2013; Taylor et al., 2020). This aggregation of misfolded α-syn, often combined with mitochondrial dysfunction and oxidative stress, disrupts neuronal homeostasis and leads to the progressive degeneration of dopaminergic neurons in the substantia nigra, a brain region critical for motor control (Antony et al., 2013; Kalia and Lang, 2015). Consequently, α-syn has been recognized as both a signature pathology and a primary pathogenic agent in PD progression.

Research linking the MGB axis to PD originated with Braak’s hypothesis in 2003, which proposed that an unknown pathogen, such as a virus or bacterium, could initiate sporadic PD in the gut (Braak et al., 2003). This hypothesis was further supported by the observation that many patients with PD experience gastrointestinal disturbances, including constipation and nausea, often years prior to the onset of motor symptoms (Rietdijk et al., 2017). These early symptoms have also drawn attention to the gut as a potential starting point in the cascade of PD pathology, encouraging a more extensive exploration of gut-brain connections in the disease.

A study on patients with PD revealed significant alterations in the composition of gut microbiota. Specifically, there were increased abundances of genera such as Verrucomicrobia, Mucispirillum, Porphyromonas, Lactobacillus, and Parabacteroides, alongside decreased levels of Prevotella and Prevotellaceae when compared to healthy controls (Scheperjans et al., 2015; Lin et al., 2019). Following Braak’s hypothesis, subsequent studies have identified specific bacterial strains in the gut microbiota, including Proteus mirabilis and Citrobacter rodentium, as potential contributors to PD (Choi et al., 2018; He et al., 2024). These strains have further been suggested to induce misfolding and aggregation of α-syn within the ENS (Huh et al., 2023). Once misfolded in the gut, α-syn can travel along the vagus nerve to the brain in a prion-like fashion, potentially seeding Lewy pathologies in key brain regions associated with PD. Experimental models have further supported this mechanism, demonstrating that misfolded α-syn can spread from the gut to the brain, triggering neurodegenerative changes similar to those observed in patients with PD (Kim et al., 2019).

In addition to bacterial contributions, severe Lewy pathology has been identified in the enteric nervous system (ENS) of patients with PD, correlating with gastrointestinal symptoms, such as chronic constipation, and reflecting early dysfunction within the MGB axis (Hirayama et al., 2023). This gut-origin hypothesis is further supported by the finding that intestinal inflammation and gut permeability increase in PD, allowing bacterial toxins and inflammatory cytokines to influence both α-syn aggregation and neuroinflammatory processes (Sampson et al., 2016; Mou et al., 2022). These disruptions may compromise the BBB, and facilitate the translocation of misfolded proteins and inflammatory mediators to the CNS. Consequently, this cascade of events can amplify neuroinflammation, further contributing to dopaminergic neuronal loss and accelerating the progression of PD (Tansey et al., 2022).

Multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disorder that affects the CNS and presents in both relapsing-remitting and progressive forms (Correale et al., 2017). This condition involves the development of numerous demyelinating lesions, accompanied by lymphocyte infiltration and antibody deposition, resulting in various neurological impairments. The pathogenesis of MS is believed to stem from an autoimmune response primarily involving T cells that react to myelin autoantigens, such as myelin basic protein (Garg and Smith, 2015). Genetic studies have previously established associations between MS susceptibility and genes involved in the activation and proliferation of CD4+ T cells, while evidence has highlighted the critical roles of Th1 and Th17 cells in disease progression (Moser et al., 2020). Moreover, emerging research has indicated that B cells play a significant role in CNS inflammation through mechanisms beyond antibody production, including antigen presentation and cytokine secretion, thereby adding to the complexity of MS immunopathogenesis (van Langelaar et al., 2020).

Recent studies have also indicated that the MGB axis significantly influences MS (Dunalska et al., 2023). Research utilizing spontaneous experimental autoimmune encephalomyelitis (EAE) mouse models has demonstrated that gut microbiota dysbiosis induces CNS autoimmunity through alterations in the gut and peripheral immunity (Johanson et al., 2020; Moles et al., 2021). Correspondingly, patients with MS exhibit an altered gut microbiota, which is linked to increased disease activity. Notably, stool transplantation from patients with MS into germ-free mice exacerbates EAE severity, suggesting that dysbiosis may facilitate immune dysregulation and trigger CNS autoimmunity (Wang et al., 2021). Accordingly, patients with MS exhibit gut dysbiosis characterized by reduced levels of Faecalibacterium, Roseburia, Haemophilus, and Bilophila, alongside an increased abundance of Clostridia, which has been linked to heightened disease activity (Ventura et al., 2019; Ling et al., 2020; Saresella et al., 2020). Specific microbial strains, such as Pseudomonas, Mycoplasma, and Faecalibacterium, are more prevalent in patients with MS, and are correlated with changes in dendritic cell maturation and inflammatory signaling pathways (iMSMS consortium, 2022; Thirion et al., 2023). Moreover, mice transplanted with feces from patients with MS showed reduced levels of IL-10, a cytokine crucial for regulating CNS autoimmunity, leading to increased disease severity. The interplay between the gut microbiota and MS is complex and involves microbial metabolites such as SCFAs, which possess anti-inflammatory properties and may enhance blood-brain barrier integrity. Disruption of this barrier allows inflammatory cells to infiltrate the CNS, thereby exacerbating neuroinflammation and MS 38022314 (Sharifa et al., 2023). Consequently, changes in microbial diversity may contribute to disease onset and progression by modulating immune responses and promoting inflammatory processes.

Amyotrophic lateral sclerosis

Despite extensive research similar to that conducted for other NDDs, the pathophysiology of motor neuron loss in ALS remains unclear (Hardiman et al., 2017). Studies have commonly focused on mutations in genes such as superoxide dismutase 1, transactive response DNA binding protein 43 kDa (TDP-43), fused in sarcoma/translated in liposarcoma, and C9ORF72 repeats, along with additional low-frequency genes linked to ALS risk (Van Es, 2024). While many studies have emphasized the role of motor neurons, the detrimental effects of these mutations on astrocytes indicate their contribution to motor neuron loss.

Recent studies have highlighted the significant impact of gut health on the pathophysiology of ALS, particularly via the MGB axis (Zheng et al., 2023; Noor Eddin et al., 2024). For example, phosphorylated TDP-43 has been detected in the gut prior to the onset of neurological symptoms, indicating that gut alterations play a critical role in ALS development. Several factors, such as intestinal inflammation and increased barrier permeability, can profoundly affect brain function and overall well-being. Moreover, gastrointestinal symptoms, including pain, dysphagia, reflux, and constipation, have been commonly reported in patients with ALS, thus reinforcing the notion of a gut-brain connection (Adamske et al., 2021; Lee et al., 2021b).

Dysbiosis, or an imbalance in the composition of the gut microbiome, has also been observed in both patients with ALS and experimental animal models (Kim et al., 2022; Lee et al., 2024). The patients with ALS exhibit a higher abundance of the Bacteroidetes and a lower abundance of Prevotella spp., Eubacterium rectale and Roseburia intestinalis when compared to healthy controls (Zeng et al., 2020; Nicholson et al., 2021; Hertzberg et al., 2022). In addition, although progress has been made in understanding the relationship between the gut microbiome and NDDs, this field is still in its infancy. Further exploration of the complex interactions within the MGB axis and their contributions to the pathogenesis of ALS may provide novel insights into the mechanisms underlying this disease. Ultimately, this study highlights the potential of direct gut modulation as a therapeutic strategy for managing ALS, paving the way for innovative treatment approaches.

In addition to the classical examples AD, PD, MS, and ALS, NDDs encompass a variety of other disorders, including Huntington’s disease. The MGB axis has emerged as a significant area of research, particularly in relation to AD, PD, MS, and ALS, owing to its potential impact on disease pathophysiology and progression. Although investigations into the role of the MGB axis in other neurodegenerative conditions are beginning, these studies are still in the nascent stages and require further exploration to fully elucidate the mechanisms involved.

PROBIOTICS FOR NDDS TREATMENT

Lactobacillus plantarum (Lactiplantibacillus plantarum)

Lactobacillus plantarum (L. plantarum) is a non-gas-producing lactic acid bacterium found in dairy products, vegetables, meat, wine, the gastrointestinal tract, and the genitourinary system, which is generally recognized as safe (Seddik et al., 2017). Numerous studies have reported the therapeutic effects of this species on NDDs. For example, in AD in vivo models, L. plantarum has been shown to reduce neuroinflammation and the accumulation of Aβ in the brain (Hu et al., 2024a). It further enhances synaptic plasticity, improving cognitive function. Additionally, several studies have shown that L. plantarum contributes to a healthier gut environment by restoring the microbial balance and reducing gut inflammation (Wang et al., 2022b; Di Salvo et al., 2024). For example, Song et al. reported that the anti-AD effects of L. plantarum are mediated by the regulation of the phosphoinositide-3-kinase/ protein kinase B (Akt)/ glycogen synthase kinase-3β (GSK-3β) pathway (Song et al., 2022).

L. plantarum demonstrated similarly promising effects in PD models. In animal models of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and 6-hydroxydopamine (6-OHDA), L. plantarum consistently improved motor deficits and protected dopaminergic neurons in the brain (Chu et al., 2023; Ma et al., 2023b; Qi et al., 2024). Qi et al. further reported that L. plantarum exerts these therapeutic effects on PD by modulating the glucagon-like peptide 1 (GLP-1)/peroxisome proliferator-activated receptor gamma coactivator-1α pathway, while Ma et al. demonstrated that L. plantarum reduces the exaggerated cortical beta oscillations associated with PD symptoms (Ma et al., 2023b; Qi et al., 2024). Furthermore, Lu et al. discovered that after 12 weeks of L. plantarum administration, patients with PD showed significant improvements in unified PD rating scale (UPDRS) motor and PD questionnaire-39 scores, indicating its potential therapeutic impact in human PD cases, as well as in animal models (Lu et al., 2021).

Moreover, in an MS model induced by cuprizone, L. plantarum improved motor function, promoted the myelination of nerve fibers in the brain, and regulated blood levels of leptin and serotonin, indicating its broader therapeutic potential across NDDs (Sajedi et al., 2021, 2023) (Table 1).

Table 1.

Overview of the therapeutic effects of L. plantarum on NDDs

Disease	Research types	Strain	Model	Dose	Key effects	Ref
AD	in vivo	L. plantarum ATCC8014	APP/PS1 mice	1×108 CFU/kg for 6 weeks	- Alleviation of neuroinflammation and neurodegeneration - Reduction in brain Aβ accumulation and tau protein phosphorylation - Enhancement of synaptic plasticity in the brain - Restoration of gut microbiota and intestinal barrier integrity	Hu et al., 2024a
	in vivo	L. plantarum HEAL9	SAMP8 mice	1×109 CFU/mouse for 2 months	- Alleviation of cognitive impairment and gut motility disorders - Reduction in neuroinflammation and Aβ accumulation in the brain	Di Salvo et al., 2024
	in vivo	L. plantarum MWFLp-182	D-galactose injected mice	1×109 CFU/mL (0.2 mL/mouse) for 8 weeks	- Increase in anti-inflammatory cytokines and expression of tight junction proteins in the gut - Enhancement of postsynaptic plasticity in the brain - Increase in BDNF and Nrf2 levels in the brain	Nie et al., 2024
	in vivo	L. plantarum MA2	D-galactose/ AlCl3-injected rats	1×108 or 109 CFU/kg for 12 weeks	- Improvement in cognitive impairment and anxiety-related behaviors - Protection of neurons and reduction of Aβ accumulation in the brain - Reduction of neuroinflammation - Alleviation of intestinal mucosal damage and restoration of gut microbiota composition	Wang et al., 2022b
	in vivo	L. plantarum DP189	D-galactose/ AlCl3-injected mice	1×109 CFU/mL for 10 weeks	- Improvement in cognitive impairment - Increase in serotonin, dopamine, and GABA levels - Protection of neurons and reduction of Aβ accumulation in the brain - Inhibition of tau hyperphosphorylation via modulation of the PI3K/Akt/GSK-3β pathway in the brain	Song et al., 2022
	in vivo	L. plantarum MTCC 1325	D-galactose-injected albino rats	12×108 CFU/mL (10 mL/kg) for 60 days	- Improvement in cognitive impairment - Increase in acetylcholine levels in the brain - Inhibition of Aβ accumulation	Nimgampalle and Kuna, 2017
	in vivo	L. plantarum C29	D-galactose injected mice	1×1010 CFU/mouse for 5 weeks	- Improvement in cognitive impairment - Regulation of BDNF and CREB activation - Reduction in expression of inflammatory factors	Woo et al., 2014
PD	in vivo	L. plantarum SG5	MPTP-injected mice	1×109 CFU for 35 days	- Improvement in motor dysfunction - Protection of neurons and inhibition of α-synuclein aggregation - Reduction in neuroinflammation and mitigation of BBB damage - Restoration of gut microbiota composition and regulation of GLP-1 secretion	Qi et al., 2024
	in vivo	L. plantarum CCFM405	Rotenone-injected mice	1×109 CFU/mL (0.2 mL/mouse) for 9 weeks	- Improvement in motor dysfunction and constipation - Protection of neurons and alleviation of neuroinflammation - Increase in dopamine and serotonin levels in the brain - Reduction of gut inflammation and restoration of gut microbiota composition - Enhanced biosynthesis of branched-chain amino acids in the gut	Chu et al., 2023
	in vivo	L. plantarum PS128	6-OHDA-injected rats	1.5×1010 CFU for 6 weeks	- Normalization of power spectral density of beta oscillations in the cortex - Improvement in motor dysfunction	Ma et al., 2023b
	in vivo	L. plantarum DP189	MPTP-injected mice	1×109 CFU/mL (0.2 mL/mouse) for 14 days	- Reduction of inflammation and oxidative stress-related factors in the brain - Decrease in α-synuclein accumulation in the brain - Restoration of gut microbiota composition	Wang et al., 2022a
	Case reports	L. plantarum PS128	Patients with PD	2 capsules (3×109 CFU/capsule) for 12 weeks	- Improvement in UPDRS motor scores - Improvement in PDQ-39	Lu et al., 2021
MS	in vivo	L. plantarum PTCC1058	Cuprizone-induced mice	1×108 CFU/kg for 2 months	- Improvement of motor impairment - Improvement of myelination of the nerve fibers in the brain	Sajedi et al., 2023
	in vivo	L. plantarum PTCC1058	Cuprizone-induced mice	1×108 CFU/kg for 2 months	- Decrease in blood leptin - Increase in blood serotonin	Sajedi et al., 2021

AD, Alzheimer’s disease; L. plantarum, Lactobacillus plantarum; APP/PS1, amyloid precursor protein and mutant human presenilin 1; CFU, colony forming unit; Aβ, Amyloid β; SAMP8, Senescent accelerated prone 8; BDNF, brain-derived neurotrophic factor; NRF-2, Nuclear factor erythroid-2-related factor 2; GABA, γ-aminobutyric acid; CREB, c-AMP response element binding protein; PD, Parkinson’s disease; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; BBB, Blood-Brain Barrier; GLP-1, Glucagon-Like Peptide 1; UPDRS, Unified Parkinson's disease rating scale; PDQ-39, Parkinson's Disease Questionnaire-39; MS, Multiple sclerosis.

Bifidobacterium breve

Bifidobacterium breve (B. breve) is one of the first bacteria isolated from the feces of healthy infants, and has been recognized as an early colonizer of the infant gut with antimicrobial activity (Sushma et al., 2023). This strain is primarily found in the breast milk and feces of healthy infants (Laursen et al., 2021).

B. breve has shown promising effects on cognitive improvement in animal models of AD, as well as in patients with cognitive impairment (Kobayashi et al., 2019a; Xiao et al., 2020; Ohno et al., 2022; Zhu et al., 2023). In multiple AD animal models, B. breve consistently reduced neuroinflammation and inhibited Aβ accumulation, both of which key factors in AD pathology. Abdelhamid et al. further demonstrated that B. breve exerts its effects through different pathways, including regulation of the Akt/GSK-3β pathway in wild-type mice and activation of the extracellular signal-regulated kinase (ERK)/ hypoxia inducible factor-1α (HIF-1α) pathway in APP knock-in mice (Abdelhamid et al., 2022a, 2022b). Moreover, findings from four randomized controlled trials (RCTs) indicated that B. breve improves cognitive scores (AD assessment scale-cognitive component-Japanese version, Mini-Mental State Examination [MMSE] and repeatable battery for neuropsychological status [RBANS]) in elderly patients with mild cognitive impairment (MCI) (Kobayashi et al., 2019b; Xiao et al., 2020; Asaoka et al., 2022). Notably, the RBANS scores correlated with hemoglobin A1c levels, suggesting a link between cognitive function and metabolic health (Bernier et al., 2021).

B. breve has further demonstrated therapeutic benefits in both animal models of PD and MS. In PD models, B. breve significantly improved MPTP-induced cognitive and behavioral deficits, and helped to restore the gut balance (Valvaikar et al., 2024). Ishii et al. also reported that B. breve promotes fear extinction by normalizing abnormal neuropsin expression in the hippocampus in MPTP-treated mice (Ishii et al., 2021). Furthermore, Hasaniani et al. found that B. breve outperformed another probiotic, Lactobacillus casei in a cuprizone-induced MS rat model, by more effectively enhancing cognitive function, reducing oxidative stress, and alleviating demyelination, underscoring B. breve’s potential as a therapeutic agent across multiple NDDs (Hasaniani et al., 2024) (Table 2).

Table 2.

Overview of the therapeutic effects of B. breve on NDDs

Disease	Research types	Strain	Model	Dose	Key effects	Ref
AD	in vivo	B. breve MCC1274	AppNL-G-F mice	1×109 CFU/mouse for 4 weeks	- Improvement in cognitive function - Reduction in Aβ accumulation and neuroinflammation in the brain - Increase in synaptic protein expression in the brain	Abdelhamid et al., 2024
	in vivo	B. breve HNXY26M4	APP/PS1 Mice	1×109 CFU/mouse for 12 weeks	- Improvement in cognitive function - Alleviation of neuroinflammation and synaptic dysfunction - Restoration of gut microbiota balance	Zhu et al., 2023
	in vivo	B. breve MCC1274	APP Knock-In mice	1×109 CFU/mouse for 4 months	- Increase in antioxidant-active metabolites in plasma - Increase in glutathione-related metabolites in plasma	Ohno et al., 2022
	in vivo	B. breve MCC1274	Wild type mice	1×109 CFU/mouse for 4 months	- Reduction in Aβ42 levels and tau phosphorylation in the brain - Activation of the AKT/GSK-3β pathway in the brain - Inhibition of neuroinflammation	Abdelhamid et al., 2022a
	in vivo	B. breve MCC1274	APP Knock-In mice	1×109 CFU/mouse for 4 months	- Improvement in memory impairment - Inhibition of Aβ accumulation - Activation of the ERK/HIF-1α signaling pathway - Inhibition of neuroinflammation	Abdelhamid et al., 2022b
	in vivo	B. breve MCC1274	Aβ-Injected mice	1×109 organisms/mouse for 11 days	- Improvement in cognitive function - Inhibition of gene expression related to inflammation and immune responsiveness in the brain	Kobayashi et al., 2017
	RCT	B. breve MCC1274	Older patients with MCI	2×1010 CFU for 24 weeks	- Improvement in the "orientation" subscale of ADAS-Jcog - Improvement in the "orientation in time" and "writing" subscales of MMSE	Asaoka et al., 2022
	RCT	B. breve MCC1274	Older patients with MCI	2×1010 CFU for 16 weeks	- Total RBANS scores are correlated with hemoglobin A1c levels.	Bernier et al., 2021
	RCT	B. breve MCC1274	Older patients with MCI	2×1010 CFU for 16 weeks	- Increase in total RBANS scores - Increase in scores of immediate memory, visuospatial/constructional, and delayed memory in both intention-to-treat analysis and per-protocol analysis	Xiao et al., 2020
	RCT	B. breve MCC1274	Older adults with memory comlaints	2 capsules (1×1010 CFU/capsule) for 12 weeks	- Increase in the 'immediate memory' subscale of RBANS and MMSE	Kobayashi et al., 2019b
	Clinical trials	B. breve MCC1274	Older patients with MCI	2 capsules (2×1010 CFU/capsule) for 24 weeks	- Increase in MMSE scores - Increase in POMS2 and GSRS scores	Kobayashi et al., 2019a
PD	in vivo	B. breve Bif11	MPTP-injected rats	1 or 2×1010 CFU/mouse for 21 days	- Improvement in cognitive and motor functions - Protection of neurons and inhibition of neuroinflammation - Restoration of SCFAs in the gut and reduction of intestinal permeability	Valvaikar et al., 2024
	in vivo	B. breve CCFM1067	MPTP-injected mice	1.0×109 CFU/mL (0.2 mL/mouse) for 33 days	- Protection of neurons and inhibition of neuroinflammation - Alleviation of oxidative stress and mitigation of BBB damage - Restoration of gut microbiota balance	Li et al., 2022
	in vivo	B. breve MCC1274	MPTP-injected mice	1×109 organisms/mouse for 4 days	- Recovery of facilitation of contextual fear extinction - Enhancement of synaptic plasticity in the brain - Reduction of neuropsin levels in the brain	Ishii et al., 2021
MS	in vivo	B. breve PTCC1367	Cuprizone-induced rats	2×109 CFU/mouse for 28 days	- Improvement in cognitive function - Alleviation of oxidative stress and demyelination	Hasaniani et al., 2024

AD, Alzheimer’s disease; B. breve, Bifidobacterium breve; APP/PS1, amyloid precursor protein and mutant human presenilin 1; CFU, colony forming unit; Aβ, Amyloid β; APP, Amyloid precursor protein; AKT, Protein kinase B; GSK-3β, glycogen synthase kinase-3β; ERK, Extracellular signal-regulated kinase; HIF-1α, Hypoxia Inducible Factor 1α; RCT, Randomized controlled trial; MCI, Mild cognitive impairment; ADAS-Jcog, Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale; MMSE, Mini-Mental State Examination; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; POMS2, Profile of Mood States 2nd Edition; GSRS, Gastrointestinal Symptom Rating Scale; PD, Parkinson’s disease; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; SCFAs, Short-chain fatty acids; BBB, Blood-Brain Barrier; MS, Multiple sclerosis.

Lacticaseibacillus rhamnosus (Lactobacillus rhamnosus)

Many bacterial strains that were once classified as Lactobacillus casei have now been reclassified, including the species Lactobacillus rhamnosus (Lacticaseibacillus rhamnosus; L. rhamnosus) and Lactobacillus paracasei (Huang et al., 2018). L. rhamnosus has been isolated from various environments, including the human gut and vagina, and has been shown to exert therapeutic effects in numerous animal models of NDDs (Chung et al., 2023).

In various animal models of AD, L. rhamnosus consistently improved cognitive and memory functions, and further inhibited neuroinflammation and reduced blood levels of Aβ (Li et al., 2023). Akhgarjand et al. previously conducted an RCT involving patients with AD, finding that a 12-week supplementation of L. rhamnosus significantly improved MMSE, CFT, and GAD-7 scores (Akhgarjand et al., 2022). Thus, L. rhamnosus exhibited significant therapeutic effects in both animal models and human patients with AD.

Furthermore, in models of PD, L. rhamnosus has been shown to improve motor deficits and protect neurons (Xie and Prasad, 2020; Aktas et al., 2024). It also helps restore the gut microbial balance. Notably, Xie et al. discovered that supplementation with L. rhamnosus alleviated hippocampus-dependent cognitive deficits in 6-OHDA-injected rats (Xie and Prasad, 2020). Additionally, in models of HD and ALS, specifically mutant TDP-43^A315T and mutant FUS5^7Δ Caenorhabditis elegans, L. rhamnosus exerted neuroprotective effects via the regulation of fatty acid metabolism (Labarre et al., 2022) (Table 3).

Table 3.

Overview of the therapeutic effects of L. rhamnosus on NDDs

Disease	Research types	Strain	Model	Dose	Key effects	Ref
AD	in vivo	L. rhamnosus	D-galactose injected rats	12×108 CFU/mL (10 mL/kg) for 5 weeks	- Improvement in cognitive function - Reduction of inflammatory cytokines in the brain	Heydari et al., 2025
	in vivo	L. rhamnosus	AlCl3-injected rats	1×106 CFU/mouse for 5 weeks	- Inhibition of p-tau and Aβ accumulation in the brain - Improvement in cognitive function - Regulation of liver inflammation and fibrosis-related markers	Abu-Elfotuh et al., 2023
	in vivo	L. rhamnosus GG	Noise-induced rats	1×108 CFU/mouse for 56 days	- Alleviation of memory impairment - Restoration of gut microbiota balance - Improvement in serum Aβ and inflammation levels	Li et al., 2023
	in vivo	L. rhamnosus UBLR-58	Scopolamine-injected mice	1×106 CFU/mouse for 10 days	- Improvement in cognitive function - Protection of neurons in the brain	Patel et al., 2020
	RCT	L. rhamnosus HA-114	Patients with AD	1×1015 CFU twice daily for 12 weeks	- Improvement in total MMSE scores - Increase in CFT scores - Improvement in GAD-7 scores	Akhgarjand et al., 2022
PD	in vivo	L. rhamnosus E9	MPTP-injected mice	1×108 CFU/mL (0.1 mL/mouse) for 10 days	- Alleviation of motor dysfunction - Protection of neurons and increase in dopamine levels in the brain - Reduction of intestinal barrier damage and restoration of gut microbiota balance	Aktas et al., 2024
	in vivo	L. rhamnosus HA-114	6-OHDA-injected rats	1×108 and 109 CFU/mouse for 6 weeks	- Recovery of hippocampal-dependent cognitive deficits	Xie and Prasad, 2020
HD/ ALS	in vivo	L. rhamnosus HA-114	Mutant TDP-43A315T, mutant FUSS57Δ C. elegans	-	- Neuroprotective effects through the regulation of fatty acid metabolism genes	Labarre et al., 2022

AD, Alzheimer’s disease; L. rhamnosus, Lactobacillus rhamnosus; CFU, colony forming unit; Aβ, Amyloid β; RCT, Randomized controlled trial; MMSE, Mini-Mental State Examination; CFT, Categorical verbal fluency test; GAD-7, Generalized Anxiety Disorder-7; PD, Parkinson’s disease; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA, 6-Hydroxydopamine; HD, Huntington’s disease; ALS, Amyotrophic lateral sclerosis; TDP-43, TAR DNA-binding protein-43; FUS, Fused in Sarcoma; C. elegans, Caenorhabditis elegans.

Clostridium butyricum

Clostridium butyricum (C. butyricum), an anaerobic bacterium known for its ability to produce butyrate and form spores, has been safely used as a probiotic for decades (Cassir et al., 2016). This bacterium is found in various environments including soil, fermented dairy products, and vegetables. C. butyricum is recognized for its efficacy against various diseases, particularly its therapeutic effects against NDDs.

In animal models of AD, C. butyricum improves cognitive function while inhibiting neuroinflammation and the accumulation of Aβ (Sun et al., 2020). Su et al. proposed a mechanism of action for C. butyricum, demonstrating that it reduces the expression of Toll-like receptor 4 and nuclear factor kappa B in both the brain and gut (Su et al., 2023). In PD models, C. butyricum improved motor function and protected neurons in MPTP-induced mice (Wang et al., 2023). It also helps regulate imbalances in the gut microbiota. Sun et al. provided evidence that C. butyricum restores the levels of GLP-1 receptors that had been damaged by MPTP in both the brain and gut, supporting its therapeutic mechanisms (Sun et al., 2021a). Finally, C. butyricum has been shown to increase microbial diversity in the gut and regulate p38 and c-Jun N-terminal kinases in the spinal cord of mice with EAE, which is a model for MS (Chen et al., 2019). Thus, C. butyricum has demonstrated significant therapeutic effects and elucidated mechanisms in various NDDs (Table 4).

Table 4.

Overview of the therapeutic effects of C. butyricum on NDDs

Disease	Research types	Strain	Model	Dose	Key effects	Ref
AD	in vivo	C. butyricum	ICV-STZ-injected mice	2×108 CFU/mouse for 21 days	- Improvement in cognitive impairment - Protection of neurons and reduction of p-tau levels in the brain - Decreased expression of TLR4, MYD88, and NF-κB p65 in the brain and gut - Alleviation of intestinal barrier damage	Su et al., 2023
	in vivo	C. butyricum	APP/PS1 mice	1×109 CFU/mL (0.2 mL/mouse) for 4 weeks	- Improvement in cognitive function - Inhibition of Aβ accumulation and neuroinflammation	Sun et al., 2020
PD	in vivo	C. butyricum NCU-02	MPTP-injected mice	1×109 CFU/mL for 7 days	- Alleviation of motor dysfunction - Protection of neurons and reduction of α-synuclein levels - Improvement in gut microbiota imbalance	Wang et al., 2023
	in vivo	C. butyricum WZMC1016	MPTP-injected mice	5×108 CFU/mouse for 4 weeks	- Improvement in motor dysfunction - Protection of neurons and enhancement of synaptic function - Inhibition of neuroinflammation - Restoration of gut microbiota balance - Recovery of GLP-1 receptor levels in the gut and brain	Sun et al., 2021a
MS	in vivo	C. butyricum	EAE-injected mice	5×105 or 106 or 107 CFU/mL (0.2 mL/mouse) for 3 weeks	- Increase in the diversity of gut microbiota composition - Decrease in Th17 response and increase in Treg response - Reduction in p38 and JNK activation in the spinal cord	Chen et al., 2019

AD, Alzheimer’s disease; C. butyricum, Clostridium butyricum; ICV-STZ, Intracerebroventricularly-streptozotocin; CFU, colony forming unit; TLR-4, Toll-like receptor 4; MYD88, Myeloid differentiation primary response 88; NF-κB, Nuclear factor kappa B; Aβ, Amyloid β; PD, Parkinson’s disease; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; GLP-1, Glucagon-Like Peptide 1; MS, Multiple sclerosis; EAE, Experimental autoimmune encephalomyelitis; JNK, c-Jun N-terminal kinases.

Multi-strain probiotics

Probiotics are generally applied as combinations of various bacterial strains, rather than individually. Although not all multi-probiotic formulations consistently demonstrate enhanced effects, prior in vitro studies have indicated that some multi-strain probiotics may offer greater benefits than single-strain probiotics (Kwoji et al., 2021). Consequently, extensive research has been conducted on multiple prebiotic combinations. Among these, L. plantarum and Lactobacillus acidophilus (L. acidophilus) have frequently been used to treat NDDs.

As previously mentioned, L. plantarum is abundant in many food sources, including dairy products and milk, and can also be found in the gastrointestinal tract. In contrast, although L. acidophilus is less common in dairy products, it is widely distributed in the gastrointestinal tract and exhibits excellent resistance to acid and bile salts (Gao et al., 2022).

Sahu et al. demonstrated that a complex probiotic formulation containing L. plantarum, L. acidophilus, Lactobacillus delbrueckii subsp. Bulgaricus, Lactobacillus paracasei, B. breve, Bifidobacterium longum, Bifidobacterium infantis, and Streptococcus salivarius subsp (Sahu et al., 2023). Thermophilus effectively inhibited neuroinflammation and Aβ accumulation in App^NL-G-F mice induced by colitis-associated AD. Additionally, Ghalandari et al. conducted an RCT involving patients with PD, finding that a combination of L. plantarum, L. acidophilus, Lactobacillus casei, Lactobacillus bulgaricus, Bifidobacterium infantis, Bifidobacterium longum, B. breve, and Streptococcus thermophilus positively affected the frequency of bowel movements in patients with PD, although they did not significantly influence motor function (Ghalandari et al., 2023).

Moreover, Zhang et al. found that probiotics containing L. plantarum and L. acidophilus maintained the gut barrier integrity and neuromuscular function, while clearing protein aggregates in an ALS mouse model (Zhang et al., 2024b). Farber et al. further demonstrated in an RCT involving patients with MS that probiotics, including L. plantarum and L. acidophilus, improved overall symptoms and enhanced gut regulation (Straus Farber et al., 2024).

As such, combinations of various probiotics show promise for the treatment of NDDs, particularly combinations of L. plantarum and L. acidophilus, which are frequently present in probiotic formulations.

Other Species

In addition to the aforementioned strains, various probiotics have demonstrated notable therapeutic potential in the treatment of NDDs. Among these, Lactobacillus acidophilus (L. acidophilus), commonly found in multi-strain probiotic formulations, is frequently included in combined preparations, although its effects as a single strain have not been extensively studied. Nevertheless, this bacterium has shown promise in the treatment of conditions such as AD, PD, and ALS, with some effects validated in clinical studies (Yang et al., 2020; Sancandi et al., 2022; Xiao-Hang et al., 2024; Zhang et al., 2024b).

Studies of AD involving various strains, such as Bifidobacterium longum, Lactobacillus paracasei, and Bifidobacterium lactis, have shown significant effects in both in vivo and clinical studies (Cao et al., 2021; Li et al., 2022; Parra et al., 2023). However, Lactococcus lactis (L. lactis) is a unique strain commonly engineered for therapeutic applications in PD (Fang et al., 2020; Pan et al., 2022; Yue et al., 2022). In prior studies, L. lactis has been engineered to modulate in MPTP-induced mouse models as a strain engineered to modulate GLP-1. This engineered probiotic effectively regulates GLP-1, a key factor in the gut-brain axis, resulting in improvements not only in motor function but also in non-motor symptoms of PD, such as cognitive function.

Lactobacillus casei (L. casei) has been shown to be effective at reducing demyelination and inflammation in MS, particularly in cuprizone-induced mouse models, by modulating inflammasome activity (Digehsara et al., 2021; Gharehkhani Digehsara et al., 2021). Other strains, such as Lactobacillus reuteri and Streptococcus thermophilus, have also demonstrated benefits against MS by reducing demyelination, underscoring ongoing research on effective probiotics for this condition (Dargahi et al., 2020; He et al., 2019; Montgomery et al., 2022).

While several prior studies have focused on ALS and HD, Labarre et al. showed that probiotics in C. elegans models of these diseases could improve lipid homeostasis and protect neurons via β-oxidation regulation (Labarre et al., 2022). This study highlights the emerging therapeutic role of probiotics in NDDs, and supports the further investigation of strain-specific effects for targeted treatments. Thus, current research on probiotics is most actively focused on AD and PD among the NDDs, whereas studies on other NDDs are still in their early stages (Table 5).

Table 5.

Overview of the key probiotics with therapeutic potential in NDDs

Disease	Strain	Ref					Clinical trials (U.S FDA)
		in vivo study			Clinical study
		Used as a single strain	Used as part of a multi-strain mixture		Used as a single strain	Used as part of a multi-strain mixture
AD	A. muciniphila	Ou et al., 2020; He et al., 2022; Qu et al., 2023; Maftoon et al., 2024	n.a.		n.a.	n.a.	n.a.
	B. animalis	n.a.	Sun et al., 2021b; Hamid and Zahid, 2023; Lee et al., 2023; Webberley et al., 2023		n.a.	Fei et al., 2023	n.a.
	B. breve	Kobayashi et al., 2017; Abdelhamid et al., 2022a, 2022b; Ohno et al., 2022; Bernier et al., 2023; Zhu et al., 2023; Abdelhamid et al., 2024	Bonfili et al., 2018; Kaur et al., 2020; Deng et al., 2022; Sahu et al., 2023		Kobayashi et al., 2019a, 2019b; Xiao et al., 2020; Bernier et al., 2021; Asaoka et al., 2022	Hsu et al., 2023	Early Phase 1 (NCT06181513)
	B. lactis	Balaguer et al., 2023; Choi et al., 2024	Athari Nik Azm et al., 2018; Bonfili et al., 2020; Yang et al., 2020; Bonfili et al., 2021; Cao et al., 2021; Yang et al., 2023b; Kim et al., 2024; Xiao-Hang et al., 2024		n.a.	Fei et al., 2023; Hsu et al., 2023	n.a.
	B. longum	Lee et al., 2019	Athari Nik Azm et al., 2018; Bonfili et al., 2018; Mohammadi et al., 2019; Rezaei Asl et al., 2019; Rezaeiasl et al., 2019; Kaur et al., 2020; Kim et al., 2021b; Lee et al., 2021a; Sun et al., 2021b; Deng et al., 2022; Ma et al., 2023a; Sahu et al., 2023		Akhgarjand et al., 2022; Shi et al., 2022	Tamtaji et al., 2019a; Kim et al., 2021a; Akhgarjand et al., 2024	n.a.
	L. acidophilus	Beltagy et al., 2021	Athari Nik Azm et al., 2018; Bonfili et al., 2018; Rezaei Asl et al., 2019; Rezaeiasl et al., 2019; Bonfili et al., 2020; Kaur et al., 2020; Yang et al., 2020; Bonfili et al., 2021; Deng et al., 2022; Sahu et al., 2023; Webberley et al., 2023; Yang et al., 2023b; Xiao-Hang et al., 2024		n.a.	Akbari et al., 2016; Agahi et al., 2018; Tamtaji et al., 2019a; Fei et al., 2023	n.a.
	L. brevis	n.a.	Bonfili et al., 2018, 2020, 2021; Lee et al., 2023; Kim et al., 2024		n.a.	n.a.	n.a.
	L. paracasei	Smith et al., 2022; Kumaree et al., 2023	Bonfili et al., 2018, 2020; Kaur et al., 2020; Bonfili et al., 2021; Sahu et al., 2023; Lana et al., 2024; Traini et al., 2024		n.a.	Fei et al., 2023	Early Phase 1 (NCT06181513)
	L. plantarum	Woo et al., 2014; Nimgampalle and Kuna, 2017; Cheon et al., 2021; Song et al., 2022; Wang et al., 2022b; Di Salvo et al., 2024; Hu et al., 2024a; Nie et al., 2024	Bonfili et al., 2018, 2020; Kaur et al., 2020; Tan et al., 2020; Lee et al., 2021a; Shamsipour et al., 2021; Sun et al., 2021b; Sahu et al., 2023; Webberley et al., 2023; Wu et al., 2023b; Medeiros et al., 2024; Zaki et al., 2024		n.a.	Bartos et al., 2023; Fei et al., 2023; Hsu et al., 2023	Early Phase 1 (NCT06181513)
	L. rhamnosus	Patel et al., 2020; Abu-Elfotuh et al., 2023; Heydari et al., 2025	Mehrabadi and Sadr, 2020; Hamid and Zahid, 2023; Foster et al., 2024; Lana et al., 2024; Traini et al., 2024; Xiao-Hang et al., 2024		Sanborn et al., 2018; Akhgarjand et al., 2022	Fei et al., 2023; Akhgarjand et al., 2024	Early Phase 1 (NCT06181513)
	S. thermophilus	Zhang et al., 2024a	Bonfili et al., 2018, 2020, 2021			Bartos et al., 2023
PD	B. bifidum	n.a.	Hsieh et al., 2020; Alipour Nosrani et al., 2021; Ilie et al., 2022		n.a.	Borzabadi et al., 2018; Neiworth-Petshow and Baldwin-Sayre, 2018; Tamtaji et al., 2019b; Tan et al., 2021	Phase 2 (NCT03968133)
	B. breve	Valvaikar et al., 2024	Ishii et al., 2021; Li et al., 2022; Zhou et al., 2023		n.a.	Barichella et al., 2016; Magistrelli et al., 2019; Ghalandari et al., 2023	n.a.
	B. lactis	n.a.	Srivastav et al., 2019; Castelli et al., 2020; Cuevas-Carbonell et al., 2022; Ilie et al., 2022; Parra et al., 2023		n.a.	Barichella et al., 2016; Neiworth-Petshow and Baldwin-Sayre, 2018; Magistrelli et al., 2019; Sun et al., 2022	Phase 2 (NCT03968133)
	C. butyricum	Sun et al., 2021a; Fan et al., 2023; Wang et al., 2023; Wu et al., 2023a	n.a.		n.a.	n.a.	n.a.
	L. acidophilus	n.a.	Srivastav et al., 2019; Castelli et al., 2020; Alipour Nosrani et al., 2021; Ilie et al., 2022; Sancandi et al., 2022; Zhou et al., 2023		n.a.	Barichella et al., 2016; Borzabadi et al., 2018; Neiworth-Petshow and Baldwin-Sayre, 2018; Magistrelli et al., 2019; Tamtaji et al., 2019b; Ibrahim et al., 2020; Ghyselinck et al., 2021; Tan et al., 2021; Du et al., 2022; Ghalandari et al., 2023; Zali et al., 2024	Phase 4 (NCT04871464) & Phase 2 (NCT03968133)
	L. fermentum	Marsova et al., 2020	Alipour Nosrani et al., 2021; Napoles-Medina et al., 2023		n.a.	Borzabadi et al., 2018; Tamtaji et al., 2019b
	L. lactis	Fang et al., 2020; Pan et al., 2022; Yue et al., 2022	Hsieh et al., 2020; Hawrysh et al., 2023		n.a.	Ibrahim et al., 2020	Phase 2 (NCT03968133)
	L. paracasei	n.a.	Castelli et al., 2020; Ilie et al., 2022; Zhou et al., 2023		n.a.	Yang et al., 2023a; Zali et al., 2024	n.a.
	L. plantarum	Cheon et al., 2021; Wang et al., 2022a; Chu et al., 2023; Ma et al., 2023b; Qi et al., 2024	Castelli et al., 2020; Hsieh et al., 2020; Perez Visnuk et al., 2020; Ilie et al., 2022; Sancandi et al., 2022; Napoles-Medina et al., 2023; Zhou et al., 2023; Perez Visnuk et al., 2024		34277679 (Lu et al., 2021)	Barichella et al., 2016; Neiworth-Petshow and Baldwin-Sayre, 2018; Magistrelli et al., 2019; Ghyselinck et al., 2021; Ghalandari et al., 2023	n.a.
	L. rhamnosus	Xie and Prasad, 2020; Aktas et al., 2024	Srivastav et al., 2019; Hsieh et al., 2020; Cuevas-Carbonell et al., 2022; Sancandi et al., 2022; Parra et al., 2023		n.a.	Barichella et al., 2016; Neiworth-Petshow and Baldwin-Sayre, 2018; Magistrelli et al., 2019; Ghyselinck et al., 2021; Tan et al., 2021; Zali et al., 2024	n.a.
	S. thermophilus		Castelli et al., 2020; Perez Visnuk et al., 2020; Zhou et al., 2023; Perez Visnuk et al., 2024		n.a.	Barichella et al., 2016; Neiworth-Petshow and Baldwin-Sayre, 2018; Ghalandari et al., 2023	n.a.
MS	B. breve	Hasaniani et al., 2024	n.a.		n.a.	Tankou et al., 2018; Rahimlou et al., 2022a, 2022b; Moravejolahkami et al., 2023; Straus Farber et al., 2024	n.a.
	B. infantis	n.a.	n.a.		n.a.	Tankou et al., 2018; Rahimlou et al., 2022a, 2022b; Moravejolahkami et al., 2023; Straus Farber et al., 2024	n.a.
	B. longum	n.a.	n.a.		n.a.	Tankou et al., 2018; Rahimlou et al., 2022a, 2022b; Moravejolahkami et al., 2023; Straus Farber et al., 2024	n.a.
	L. acidophilus	Ren et al., 2021	n.a.		n.a.	Kouchaki et al., 2017; Tankou et al., 2018; Rahimlou et al., 2022a; Rahimlou et al., 2022b; Moravejolahkami et al., 2023; Straus Farber et al., 2024	n.a.
	L. bulgaricus	n.a.	n.a.		n.a.	Tankou et al., 2018; Rahimlou et al., 2022a, 2022b; Moravejolahkami et al., 2023; Straus Farber et al., 2024	n.a.
	L. casei	Digehsara et al., 2021; Gharehkhani Digehsara et al., 2021	Samani et al., 2022		n.a.	Kouchaki et al., 2017; Rahimlou et al., 2022a, 2022b; Moravejolahkami et al., 2023	n.a.
	L. paracasei	n.a.	Lavasani et al., 2010		n.a.	Tankou et al., 2018; Chakamian et al., 2023; Straus Farber et al., 2024	n.a.
	L. plantarum	Sajedi et al., 2021, 2023	Lavasani et al., 2010; Salehipour et al., 2017; Samani et al., 2022		n.a.	Tankou et al., 2018; Rahimlou et al., 2022a, 2022b; Chakamian et al., 2023; Moravejolahkami et al., 2023; Straus Farber et al., 2024	n.a.
	L. reuteri	He et al., 2019; Montgomery et al., 2022	n.a.		n.a.	n.a.	n.a.
	L. rhamnosus	n.a.	Samani et al., 2022		n.a.	Rahimlou et al., 2022a, 2022b	n.a.
	S. thermophilus	Dargahi et al., 2020	n.a.		n.a.	Tankou et al., 2018; Rahimlou et al., 2022a, 2022b; Moravejolahkami et al., 2023; Straus Farber et al., 2024	n.a.
ALS	B. breve	n.a.	Zhang et al., 2024b		n.a.	n.a.	n.a.
	B. infantis	n.a.	Zhang et al., 2024b		n.a.	n.a.	n.a.
	B. longum	n.a.	Xin et al., 2024; Zhang et al., 2024b		n.a.	n.a.	n.a.
	E. faecium	n.a.	Xin et al., 2024		n.a.	n.a.	n.a.
	L. acidophilus	n.a.	Xin et al., 2024; Zhang et al., 2024b		n.a.	n.a.	n.a.
	L. helveticus	n.a.	Zhang et al., 2024b		n.a.	n.a.	n.a.
	L. paracasei	n.a.	Zhang et al., 2024b		n.a.	n.a.	n.a.
	L. plantarum	n.a.	Zhang et al., 2024b		n.a.	n.a.	n.a.
	L. rhamnosus	Labarre et al., 2022	n.a.		n.a.	n.a.	n.a.
	S. thermophilus	n.a.	Zhang et al., 2024b		n.a.	n.a.	n.a.
HD	L. rhamnosus	Labarre et al., 2022	n.a.		n.a.	n.a.	n.a.

FDA, Food and Drug Administration; AD, Alzheimer’s disease; A. muciniphila, Akkermansia muciniphila; B. animalis, Bifidobacterium animalis; B. breve, Bifidobacterium breve; B. lactis, Bifidobacterium animalis subsp. lactis; B. longum, Bifidobacterium longum; L. acidophilus, Lactobacillus acidophilus; L. brevis, Levilactobacillus brevis; L. paracasei, Lacticaseibacillus paracasei; L. plantarum, Lactiplantibacillus plantarum; L. rhamnosus, Lacticaseibacillus rhamnosus; S. thermophilus, Streptococcus thermophilus; PD, Parkinson’s disease; B. infantis, Bifidobacterium infantis; C. butyricum, Clostridium butyricum; L. fermentum, Lactobacillus fermentum; L. lactis, Lactococcus lactis; MS, Multiple sclerosis; L. bulgaricus, Lactobacillus bulgaricus; L. casei, Lacticaseibacillus casei; L. reuteri, Lactobacillus reuteri; ALS, Amyotrophic lateral sclerosis; E. faecium, Enterococcus faecium; L. helveticus, Lactobacillus helveticus; HD, Huntington’s disease.

PROBIOTICS CURRENTLY UNDERGOING CLINICAL TRIALS FOR THE TREATMENT OF NDDS

The clinical trial progression for NDDs treatments based on U.S. FDA guidelines is briefly summarized in Table 6. Currently, probiotic formulations in the NDD category are being developed as therapeutic agents for AD and PD. For AD, excluding those marked as not applicable, the highest reported trial phase was Phase 1, which involved a combination of Lactobacillus paracasei, L. plantarum, L. rhamnosus, Lactobacillus helveticus, and B. breve.

Table 6.

Probiotics currently undergoing clinical trials for the treatment of NDDs (https://clinicaltrials.gov/)

Disease	Phase	Strain	Indication	Dose	Country	ID
AD	Early Phase 1	Mixture of L. paracasei, L. plantarum, L. rhamnosus, L. helveticus, B. breve	Cognitive function and neuroinflammation in patients with mild AD	2.0×107 CFU/day for 16 weeks	Cyprus	NCT06181513
PD	Phase 4	Mixture of B. longum, L. acidophilus, E. faecalis	On motor symptoms and constipation and sleep in mild to moderate PD	≥1.0×107 CFU/capsule 2 capsules twice daily; Day 15-24 weeks, 4 capsules twice daily	China	NCT04871464
	Phase 3	Mixture of Lactobacillus spp., Bifidobacterium spp., fructo-oligosaccaride	On constipation and whole gut transit time in patients with PD	30×109 CFU/day twice daily for 8 weeks	Malaysia	NCT04451096
	Phase 2	Mixture of B. bifidum W23, B. lactis W51, B. lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, L. lactis W19, L. lactis W58	Anxiety in patients with PD	5.0×109 CFU/day for 12 weeks	Canada	NCT03968133
	Phase 2	Mixture of B. bifidum W23, B. lactis W51, B. lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, L. lactis W19, L. lactis W58	Depression in patients with PD	5.0×109 CFU/day for 12 weeks	Canada	NCT05568498

AD, Alzheimer’s disease; L. paracasei, Lacticaseibacillus paracasei; L. plantarum, Lactiplantibacillus plantarum; L. rhamnosus, Lacticaseibacillus rhamnosus; L. helveticus, Lactobacillus helveticus; B. breve, Bifidobacterium breve; CFU, colony forming unit; B. longum, Bifidobacterium longum; L. acidophilus, Lactobacillus acidophilus; E. faecalis, Enterococcus faecalis; B. bifidum, Bifidobacterium bifidum; B. lactis, Bifidobacterium animalis subsp. lactis; L. acidophilus, Lactobacillus acidophilus; L. brevis, Levilactobacillus brevis; L. casei, Lacticaseibacillus casei; L. salivarius, Lactobacillus salivarius; L. lactis, Lactococcus lactis.

In the case of PD, a broader range of probiotic formulations are undergoing clinical trials, with one in Phase 4, one in Phase 3, two in Phase 2, and the remainder at “Not applicable.” The Phase 4 trial focused on Bifidobacterium triple viable capsules containing Bifidobacterium longum, L. acidophilus, and Enterococcus faecalis, which are anticipated to improve motor symptoms and alleviate constipation in patients with mild-to-severe PD. The Phase 3 formulation consisted of a probiotic-prebiotic blend that included Lactobacillus spp., Bifidobacterium spp., and fructo-oligosaccharides. These findings reflect a proactive effort to develop NDD treatments using probiotics, with PD receiving a particularly high level of interest following advancements in probiotic formulations, with many treatments currently moving through various trial phases.

CONCLUSIONS AND FUTURE PERSPECTIVES

Overall, in recent years, the MGB axis has emerged as a critical component of the pathophysiology and treatment of NDDs. Increasing evidence suggests that alterations in the gut microbiota can influence neuroinflammation, protein aggregation, and overall neural function, all of which are key factors in the progression of NDD. Probiotics, as modulators of the gut microbiota, offer a unique therapeutic approach, particularly diseases such as AD and PD, for which preclinical and clinical data have shown encouraging results.

More extensive research on the role of the MGB axis in NDDs is crucial, particularly to explore how gut dysbiosis can influence disease onset and progression through mechanisms such as neuroinflammation and immune activation. Additionally, understanding the specific effects of different probiotic strains on the MGB axis will be key to optimizing strain selection and dosage for targeted therapeutic outcomes. Investigations should further focus on the impact of probiotics on gut-derived inflammatory mediators, gut permeability, and their interplay with key pathological markers such as Aβ, tau, α-syn, and TDP-43 across different NDDs.

In conclusion, although significant progress has been made in our understanding of the potential of probiotics to modulate the gut-brain axis, translating these findings into effective NDD therapies will require robust clinical trials and mechanistic insights. With careful optimization of multi-strain formulations and deeper exploration of the MGB axis, probiotics have the potential to redefine therapeutic strategies for NDDs by targeting the microbiome as a core component of neuroprotection.