Probiotics as a Complementary Medicine in Neurologic Disorders

Probiotics have emerged as promising adjunctive therapies for neurological disorders, primarily due to their modulatory effects on the GBA [13]. The GBA is a bidirectional communication network that links the enteric and central nervous systems through neural, immune, endocrine, and metabolic pathways [14]. Probiotics exert their influence via four principal mechanisms: modulation of the immune system, neurochemical signaling, maintenance of intestinal barrier integrity, and facilitation of gut–brain communication [15, 16, 17]. Probiotics influence the GBA by signaling through the vagus nerve, modulating the hypothalamic–pituitary–adrenal (HPA) axis, and generating microbial metabolites. Strains such as Lactobacillus plantarum and Streptococcus thermophilus, found in formulations like Bactolac, have been shown to activate vagal afferents and affect hippocampal receptors involved in mood regulation [18]. The vagus nerve detects microbial signals through gut chemoreceptors, while enteroendocrine cells establish direct connections with vagal fibers to facilitate gut‐to‐brain communication [19]. Probiotic administration can help restore GBA functionality that is often disrupted by dysbiosis or chronic stress [20] (Figure 1).

Probiotics contribute to immune homeostasis by enhancing regulatory T‐cell activity and reducing pro‐inflammatory cytokines such as IL‐6 and TNF‐α. They also promote the production of short‐chain fatty acids (SCFAs), notably butyrate, which mitigate inflammation by inhibiting histone deacetylases [21]. Moreover, probiotics help reinforce both the intestinal epithelial barrier and the BBB, thereby limiting peripheral immune activation that can impact the brain [22]. Through modulation of the kynurenine pathway, probiotics may promote the synthesis of neuroprotective kynurenic acid (KYNA) over neurotoxic quinolinic acid (QUIN) [15]. Clinical studies support these immunomodulatory effects; for instance, a multi‐strain probiotic formulation significantly reduced circulating IL‐6 and TNF‐α levels in patients with Parkinson's disease [23], suggesting a decrease in neuroinflammation relevant to conditions such as depression, Alzheimer's disease, Parkinson's disease, MS, and ASD [24].

Several probiotic strains are capable of producing or modulating key neurotransmitters, including GABA, dopamine, and glutamate [25]. Bifidobacterium dentium has been shown to synthesize GABA and increase tyrosine concentrations in both the colon and brain of mono‐associated mice [26]. Probiotic formulations like Bactolac have demonstrated the capacity to enhance the expression of serotonergic and dopaminergic receptors in the hippocampus [18]. In zebrafish, administration of Lactobacillus rhamnosus altered the expression of genes related to serotonin signaling and increased the relative abundance of Firmicutes, underscoring the microbiota's influence on neurochemical pathways [27].

Probiotics also play a critical role in maintaining intestinal barrier integrity by strengthening tight junctions and preventing the translocation of endotoxins, a process closely linked to neuroinflammation [28]. They help sustain mucosal integrity and reduce the permeability that allows pro‐inflammatory molecules to enter circulation [29]. Lacticaseibacillus rhamnosus GG has been shown to reinforce mucosal defenses and lower systemic cytokine levels associated with neurodegenerative diseases [21]. Bactolac has demonstrated protective effects on intestinal architecture under stress conditions, further emphasizing its potential therapeutic value [15, 16, 17, 18]. These mechanisms are interconnected: a robust intestinal barrier influences immune function, which in turn affects neurotransmission and overall brain health. However, continued clinical research is essential to elucidate strain‐specific effects and validate the therapeutic relevance of probiotics in neurological contexts.

Clinical evidence suggests that the efficacy of probiotics is primarily dependent on the "exact strain" and the "target disease"; therefore, pooling heterogeneous results and interpreting them at the class level can be misleading [30]. In the Alzheimer's triple‐arm trial, intervention with two distinct strains, Lactobacillus rhamnosus HA‐114 and Bifidobacterium longum R0175, produced distinct patterns in plasma free amino acids and pathways involved, highlighting the "strain‐specificity" of the effect even in a single disorder [31].

However, "class/genus‐level" evidence has also been reported: in healthy elderly subjects, a multi‐strain formulation of common Lactobacillus/Bifidobacterium genera showed significant improvements in cognition and emotional symptoms (BDI/STAI); a result that is interpreted at the formulation/genus level, not a single strain [32]. Also, in major depression, increased abundance of the genus Lactobacillus in the probiotic group was associated with reduced HAM‐D/BDI scores, although data were reported at the "genus" level [33]. Overall, distinguishing "strain‐specific" from "class/genus" outcomes is essential to standardize strain selection, dosage, and formulation and avoid arbitrary pooling; it is recommended that clinical inferences be based primarily on the specific strain, and that class‐level evidence be used only contextually and with caution [30, 31, 32, 33] (Figure 2).

Probiotics, prebiotics, and fecal microbiota transplantation (FMT) are among the approaches that have been proposed to modulate the gut microbiota and affect mental and neurological health. Probiotics are live microorganisms that help improve brain and nervous system function by producing beneficial metabolites such as SCFA and regulating immune responses [34]. Despite these positive effects, probiotics face practical limitations in drug delivery, particularly due to problems with persistence in the gut and limited ability to achieve specific therapeutic targets. For this reason, methods to improve their stability and more precise targeting have been proposed [35].

Prebiotics, which are non‐digestible substances, stimulate the growth of beneficial bacteria in the gut. These substances can also have positive effects on gut and overall health, similar to probiotics, but their effects may vary depending on the host's microbiota composition and may not be effective in individuals with specific microbial disorders [34, 35, 36, 37]. FMT, which involves the transfer of healthy microbiota from a donor to a recipient, has been proposed as a promising approach to treat neurological diseases such as Alzheimer's and Parkinson's. However, this approach faces challenges such as heterogeneity in microbial uptake, limited scalability, a lack of standardized protocols, and the need for careful screening of donors to prevent the transfer of pathogens and resistance genes [34, 35].

Overall, the available evidence suggests that all three of these approaches can improve mental and cognitive health through their metabolic and immune effects. Probiotics and prebiotics are more targeted tools with subtler effects, while FMT is capable of completely reorganizing the gut microbiota. In general, probiotics can be said to provide a more defined modulation and are safer, although their effects are usually less intense and dependent on specific strains. More research is needed to better understand the exact mechanisms of these effects (Table 1).

Depression and anxiety are among the most prevalent mental health disorders, characterized by persistent low mood, anhedonia, excessive worry, and various somatic symptoms with‐out clear physiological causes [39]. Globally, depression affects more than 350 million people, contributing to substantial disability and socioeconomic burden and underscoring the urgent need for innovative and accessible therapeutic strategies [40]. While conventional treatments, including pharmacotherapy and psychotherapy, remain the cornerstone of management, growing interest in the GBA has prompted exploration of microbiota‐targeted interventions. Probiotics have emerged as a promising adjunctive approach due to their ability to modulate gut microbiota composition, reduce systemic inflammation, and influence neurotransmitter synthesis involved in mood regulation [41].

However, probiotics offer distinct advantages including a favorable safety profile with minimal adverse effects and may be particularly valuable for patients who are reluctant to use or unable to tolerate conventional medications [42, 43]. Most importantly, randomized controlled trials suggest that probiotics may serve as effective adjunctive therapies, enhancing the efficacy of antidepressants in reducing treatment‐resistant symptoms and improving quality of life. Therefore, rather than positioning probiotics as substitutes for established psychiatric medications, the evidence supports their role as low‐risk complementary strategies that may optimize treatment outcomes when integrated with standard care, particularly in patients seeking multimodal therapeutic approaches or experiencing suboptimal responses to conventional treatments alone [44, 45].

Alterations in gut microbiota, particularly reductions in Firmicutes and increases in Bacteroidetes and Proteobacteria, have been associated with depressive symptoms. Probiotic supplementation, particularly with strains of Lactobacillus and Bifidobacterium, has shown beneficial effects in some clinical trials. However, findings regarding anxiety are more variable, likely due to differences in study design, probiotic strains, and sample sizes [39]. Although still in its early stages, research into psychobiotics offers a novel and biologically plausible approach to managing mood disorders. Continued clinical investigation is needed to clarify strain‐specific effects and optimize therapeutic regimens.

Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline and neurodegeneration. Emerging evidence suggests a strong link between gut microbiota and AD pathogenesis, particularly through neuroinflammation, oxidative stress, and disruption of the gut–brain axis [46]. Animal studies have shown that probiotic supplementation can reduce amyloid‐beta (Aβ) accumulation and improve cognitive function by modulating inflammatory responses and enhancing antioxidant activity. For example, in transgenic AD mouse models, probiotics such as Lactobacillus plantarum and Bifidobacterium breve have improved memory performance and reduced hippocampal inflammation [47].

Human studies, although still limited, support these findings. A double‐blind randomized controlled trial (RCT) by Akbari et al. in a small sample (n = 60) showed that 12 weeks of multistrain probiotic milk supplementation resulted in significant improvements in Mini‐Mental State Examination (MMSE) scores in Alzheimer's patients compared to a milk control group; since microbiota assessment (fecal markers) was not performed and only a cognitive test was used, the sustainability of the effects in more diverse cognitive tests or over longer periods remains uncertain [48]. Improvements were accompanied by reductions in serum malondialdehyde and high‐sensitivity C‐reactive protein, suggesting decreased oxidative stress and systemic inflammation.

While promising, most clinical studies are small and short‐term. Thus, further large‐scale RCTs are necessary to confirm the long‐term efficacy and identify optimal probiotic strains and dosages for AD prevention or treatment [49].

Parkinson's disease (PD) is increasingly associated with gut dysbiosis, with gastrointestinal (GI) disturbances—particularly constipation—often preceding motor symptoms by several years. Alterations in the gut microbiota in PD include reduced populations of butyrate‐producing bacteria (e.g., Roseburia spp.) and increased abundance of pro‐inflammatory taxa (e.g., Enterobacteriaceae), contributing to intestinal permeability ("leaky gut"), systemic inflammation, and neurodegenerative processes [50]. These changes may facilitate α‐synuclein aggregation, a hallmark of PD pathology, through gut–brain axis disruption. Probiotics have shown promise as adjunctive therapies in managing PD‐related symptoms. Strains such as Lactobacillus casei, Bifidobacterium longum, and Clostridium butyricum have demonstrated beneficial effects by improving gut motility, reinforcing gut barrier integrity, reducing endotoxin translocation, and lowering circulating pro‐inflammatory cytokines like TNF‐α and IL‐6 [50].

In preclinical studies, C. butyricum enhanced intestinal function and increased the production of neuroprotective SCFAs such as butyrate. Clinical trials using multi‐strain formulations (Lactobacillus/Bifidobacterium blends) have also reported improvements in constipation and modest alleviation of motor symptoms in PD patients [51]. Currently available evidence supports symptom relief, particularly for gastrointestinal complaints such as constipation, with secondary improvements in quality of life; in contrast, evidence for direct effects on motor symptoms or disease progression is scarce and limited by small, short‐term studies or heterogeneous trial designs. Further research is needed to identify specific probiotic formulations for Parkinson's and validate their long‐term efficacy through well‐designed randomized controlled trials [23, 50, 51].

Alterations in gut microbiota composition have been consistently observed in individuals with ASD and are associated with both GI symptoms and neuroinflammatory processes. Dysbiosis involving genera such as Bifidobacterium, Lactobacillus, and Clostridium may disrupt neurotransmitter synthesis and immune regulation, potentially contributing to ASD pathophysiology [52]. Probiotic interventions targeting the gut–brain axis have emerged as promising adjunctive strategies. Mechanistic studies suggest that probiotics may ameliorate ASD‐related symptoms by modulating inflammatory cytokine levels, reducing neuroinflammation, and promoting the synthesis of neurotransmitters such as GABA and dopamine [53].

Rojo‐Martísella et al. demonstrated that supplementation with Lactiplantibacillus plantarum and Levylactobacillus brevis improved impulsivity and quality of life in children with ASD [52]. Similarly, a randomized controlled trial by Khanna et al. reported that a 3‐month probiotic intervention significantly improved behavioral symptoms, including social withdrawal and hyperactivity, as well as GI complaints in children with ASD [54]. This trial suggests a significant correlation between the severity of behavioral and GI symptoms in children with ASD, such that the available evidence suggests that subgroups of children with prominent GI symptoms may be more responsive to probiotics; However, the certainty is not yet high. Consequently, response to treatment may differ in subgroups of children with ASD [54, 55, 56].

Despite these encouraging findings, results across studies remain heterogeneous. Meta‐analyses emphasize the need for more rigorous and large‐scale trials to confirm efficacy and identify responsive subpopulations [57]. Nevertheless, current evidence supports the use of probiotics as a complementary therapeutic approach, particularly in ASD patients with prominent GI dysfunction.

Neuroinflammation plays a pivotal role in the progression of neurodegenerative and neuropsychiatric disorders, including MS. MS is a chronic autoimmune condition characterized by demyelination and CNS inflammation. Growing evidence suggests that gut dysbiosis contributes to the immunopathogenesis of MS through dysregulation of the gut–immune–brain axis. Probiotic administration has shown potential in modulating this axis. Strains such as Lactobacillus plantarum, Bifidobacterium lactis, and Streptococcus thermophilus have been found to shift immune responses by downregulating Th1/Th17 activity, enhancing regulatory T‐cell differentiation, and reducing the secretion of pro‐inflammatory cytokines including IL‐17 and IFN‐γ [58].

Both clinical and preclinical studies, including experimental autoimmune encephalomyelitis (EAE) models, have reported symptom alleviation and reduced disease severity following probiotic supplementation, with genera like Prevotella implicated in beneficial outcomes [59]. Additionally, probiotics may counteract age‐related gut dysbiosis and increased intestinal permeability, thereby mitigating systemic and CNS inflammation [60]. A murine study by Pei et al. showed that extracellular vesicles derived from probiotic‐modified gut microbiota could cross the blood–brain barrier and suppress hippocampal inflammation, resulting in measurable behavioral improvements [61]. These findings support the therapeutic potential of probiotics in restoring immune homeostasis and reducing chronic neuroinflammation in MS and other neuroinflammatory conditions.

Since the findings in MS come from animal models of EAE, which provide mechanistic insights, they may not fully reflect the complexity of human disease due to differences in immune regulation, microbiota composition, and disease heterogeneity between rodents and humans [58, 61]. Although further clinical validation and larger human trials are needed, probiotics are a promising adjunct to conventional therapies in such disorders (Figure 2).