Precision Nutrition and Gut–Brain Axis Modulation in the Prevention of Neurodegenerative Diseases

Probiotics are live microorganisms that, when ingested in sufficient quantities, have a positive effect on the health of the host organism. It has been established that probiotics have a wide range of beneficial physiological effects, including anti-allergic action, improvement of intestinal condition (elimination of dysbiosis, strengthening of the epithelial barrier), enhancement of the immune response, reduction in symptoms of lactose intolerance, prevention of cancer, as well as a positive effect on the psychoemotional state [74].

The effect of probiotics on the pathogenesis of neurodegenerative diseases Is mediate by their interaction in the "gut–brain" system [75]. These microorganisms modulate the release of neurotransmitters by changing the species composition of the intestinal microbiota, which contributes to neuroprotective effects, including increased survival and differentiation of neurons [76]. In addition, probiotics have a regulatory effect on immune processes by controlling the synthesis of proinflammatory cytokines, changing the functional activity of dendritic cells and stimulating the differentiation of T-regulatory lymphocytes (Treg), which together helps to reduce the intensity of systemic inflammation associated with the pathogenesis of neurodegenerative diseases [77].

Particular attention is paid to psychobiotics—a subgroup of probiotics that can produce neuroactive compounds (such as GABA, serotonin, BDNF) and potentially affect cognitive functions and emotional state [78]. The mechanism of action of probiotics and psychobiotics is determined by a set of specific characteristics of these microorganisms. Key properties include their ability to maintain viability under the influence of acids, bile and pancreatic juice, which is a prerequisite for successful colonization and proliferation in the gastrointestinal tract [79].

A practical confirmation of the significance of these properties is provided by the examples of the Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 strains, which demonstrate high survivability in the gastrointestinal tract (81.58% in the gastric phase). Their role as psychobiotics lies in their ability to modulate the host's immuno-inflammatory response and microbial metabolome, which is manifested in a significant increase in the levels of anti-inflammatory cytokines (IL-10, IL-6) and SCFAs, accompanied by a simultaneous reduction in ammonia and the pro-inflammatory factor TNF-α [80].

These immunometabolic effects translate into clinically significant improvements in mental health outcomes. Clinical investigations have demonstrated that these psychobiotic strains significantly reduce symptoms of anxiety and depression, as assessed by the Hospital Anxiety and Depression Scale (HADS) and the Hopkins Symptom Checklist-90 (HSCL-90) [81]. The administration of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 has been associated with reduced stress levels and enhanced cognitive health, thereby substantiating their role in modulating the gut–brain axis and highlighting their therapeutic potential in stress-related disorders.

Some microorganisms can directly affect the vagus nerve by stimulating its motor nucleus. It is known that stress, which is a significant risk factor for the development of neurodegenerative diseases, induces hyperactivation of the HPA axis, which leads to an increase in the level of glucocorticoids, which, penetrating through the BBB, interact with specific receptors, promoting the development of neuroinflammation and oxidative damage [82].

Modern studies indicate that psychobiotics have a positive effect on the body by activating the enteric nervous system or stimulating the immune response. Their effect on psychophysiological markers of depression and anxiety has been established. The mechanisms of this effect can be realized through modulation of the HPA axis stress response, leading to a decrease in systemic inflammation, direct effects on the immune system, regulating its activity, secretion of bioactive molecules, including neurotransmitters, proteins and SFCAs [83].

It has been established that probiotic strains of the genera Bifidobacterium and Lactobacillus help to maintain the immune status and intestinal homeostasis, have a neuroprotective effect by suppressing neuroinflammatory processes and demonstrate a positive effect on cognitive functions [84]. In particular, experimental data indicate that the Bifidobacterium breve A1 strain causes a decrease in the expression of immunoreactive genes and a decrease in the concentration of proinflammatory markers in the hippocampus in mouse models of Alzheimer's disease [85]. Clinical observations suggest the presence of a similar neuroprotective effect in elderly people with cognitive impairment [86].

In addition, these strains demonstrate an effect on neurodegenerative processes induced by the introduction of Aβ. After probiotic therapy using Lactobacillus and Bifidobacterium, animals showed restoration of synaptic plasticity in the hippocampus, as well as normalization of the long-term potentiation mechanism, which contributed to the improvement of neuronal transmission [87]. In addition, a decrease in the expression of microglial activation markers was noted against the background of an increase in the level of BDNF and synapsin. The obtained data indicates a potential role of these strains in the modulation of cognitive functions and spatial learning.

A number of clinical studies, despite the variability of results, also recorded positive effects of probiotics, including Lactobacillus and Bifidobacterium strains, in cognitive assessment, a decrease in the levels of proinflammatory cytokines, markers of oxidative damage (malondialdehyde, 8-hydroxy-2′-deoxyguanosine), as well as an improvement in metabolic parameters in patients with Alzheimer's disease [88,89,90].

The presented data indicates a pronounced neuroprotective effect of probiotics and psychobiotics, manifested in a decrease in cognitive impairment and correction of dysbiotic changes. It is assumed that the observed effects may be associated with the modulation of oxidative and inflammatory processes. However, further large-scale clinical studies are needed to confirm the therapeutic potential of probiotics in the treatment of neurodegenerative diseases.

According to the consensus statements of the International Scientific Association for Probiotics and Prebiotics (ISAPP), probiotics are regarded as evidence-based agents that support human health by modulating the gut microbiome, including the prevention of inflammatory and metabolic disorders. Although direct clinical data on the prevention of neurodegenerative diseases remain limited, international experts emphasize the necessity of further research in this field and highlight the promising potential of probiotics for maintaining cognitive health in elderly patients.

Dietary fiber, including prebiotics, plays a key role in modulating the composition and metabolic activity of the gut microbiota, mainly through fermentation to produce SFCAs, especially butyrate, which has systemic anti-inflammatory and immunomodulatory effects (Figure 2). Consumptions of these bioactive components promotes the abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus, and indirectly influences the balance of neurotransmitters (GABA and serotonin) and the integrity of the intestinal barrier by reducing permeability. Current evidence indicates an association between prebiotic and dietary fiber intake and improved cognitive function, as well as reduced anxiety and depression, highlighting their potential as a dietary component for maintaining mental health [91,92].

Dietary fiber refers to heterogenous group of non-digestible carbohydrates that can modulate the gut–brain axis through both microbiome-dependent and microbiome-independent mechanisms [93]. The most studied and significant mechanism of action is the microbiome-dependent pathway, in which fermentable dietary fibers such as inulin, fructo-oligosaccharides (FOS), and galactooligosaccharides (GOS) stimulate the growth of probiotic strains and increase the synthesis of SFCAs—acetate, propionate, and butyrate [94].

In animal experiments, GOS were found to increase the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, which is important for neurogenesis in adults [95]. Increased BDNF levels are associated with improved cognitive function and reduced severity of depressive symptoms, which has been confirmed in both experimental and clinical studies. In addition, it has been established that taking the prebiotic 2′-fucosyllactose (an oligosaccharide from breast milk) for five weeks in rats leads to accelerated acquisition of operant learning skills compared to the control group, indicating a potential improvement in neurocognitive processes [96].

Clinical studies indicate that the use of GOS is associated with a decrease in cortisol levels upon awakening and a modification of patterns of unconscious processing of emotional stimuli [97]. At the same time, in individuals with high personal anxiety, a statistically significant decrease in subjectively assessed anxiety is noted, while in healthy individuals without clinically pronounced symptoms, the effects are less pronounced. In individuals with functional disorders, such as irritable bowel syndrome, taking GOS is accompanied by an increase in the number of Bifidobacteria and a decrease in anxiety, while in patients with clinical depression, convincing data on the effect of prebiotics on depressive symptoms has not been obtained [98].

Despite the growing body of evidence indicating the beneficial effects of GOS on psychophysiological health in clinical populations, their impact on healthy individuals remains insufficiently studied and somewhat inconsistent. Results from a double-blind, placebo-controlled trial demonstrated that a 28-day intake of GOS did not lead to a statistically significant reduction in trait anxiety among healthy women. However, it was associated with a transient increase in Bifidobacterium abundance within the gut microbiota, as well as modulation of neurochemical markers (GABA) in specific brain regions [99]. These findings suggest a limited yet discernible influence of GOS on the gut–brain axis, particularly reflected in trends toward neurochemical and behavioral changes in subpopulations characterized by elevated baseline anxiety.

In addition to elevating neurobehavioral effects, another study investigated the potential ability of GOS to modulate eating behavior and macronutrient intake, an aspect of prebiotic influence on the gut–brain axis that remains less extensively studied. The results demonstrated that GOS consumption was associated with significant alterations in macronutrient intake, specifically a reduction in carbohydrate and sugar consumption accompanied by an increase in fat intake [100]. A correlational relationship was established between the GOS-induced increase in Bifidobacterium abundance and the observed shifts in dietary preferences, suggesting an indirect influence of the prebiotic on diet through modulation of gut microbiota consumption.

Given the pivotal role of dosage in determining the efficacy of prebiotic interventions, an important subsequent task is to establish the minimal effective dose of GOS capable of inducing significant modulation of the gut microbiome. Findings from a double-blind interventional study demonstrated that a three-week intake of low doses of GOS (1.3 and 2.0 g per day) led to a significant increase in the relative abundance of Bifidobacterium in the gut microbiota of healthy women [101]. Moreover, supplementation with 2.0 g/day was associated with statistically significant alterations in the overall microbial composition, with the intervention's efficacy correlating with participants' baseline microbial profiles.

In addition to microbiome-dependent mechanisms of gut–brain axis modulation, the effect of dietary fiber on brain function mediated by reduction in systemic inflammation, modulation of immune activity, and changes in metabolic processes, including regulation of glucose and lipid levels, is of considerable interest [93]. Thus, dietary fiber and prebiotics represent a promising tool for use in precision nutrition aimed ate modulating the gut–brain axis and maintaining cognitive health, but further randomized controlled trials are needed taking into account the type of fiber, dosage, duration of intervention, and initial status of the gut microbiota.

In its scientific opinions prepared within the framework of evaluating health claims of food ingredients, the European Food Safety Authority (EFSA) consistently emphasizes the importance of prebiotics and dietary fibers in maintaining normal intestinal function, as well as in regulating lipid and carbohydrate metabolism. Although EFSA traditionally refrains from making direct claims regarding the relationship of these effects with cognitive functions, experts note that the beneficial influence on gut microbiota composition and immune status can be considered an integral component of a comprehensive strategy for the prevention of various diseases, including cognitive disorders.

Polyphenols, with their pronounced antioxidant and anti-inflammatory properties, play an important role on modulating the gut–brain axis, which opens up new prospects for the prevention and treatment of neurodegenerative diseases. Consumption of these bioactive compounds is associated with an increase in microbial diversity, an increase in populations of beneficial bacteria (e.g., Bifidobacterium, Akkermansia, Lactobacillus) and a decrease in the number of pathogenic microorganisms, which helps restore the potential barrier, reduce permeability and reduce the level of systemic inflammation [102].

Dietary polyphenols, when ingested, undergo bacterial transformation with the formation of bioavailable metabolites that can affect neuroinflammation, oxidative stress and neuroplasticity. In particular, therapeutically significant polyphenols, including enterolactone and enterodiol, are secondary metabolites of lignans—non-flavonoid polyphenolic compounds abundant in plant-derived foods—produced through the metabolism of the intestinal microbiota [103]. These metabolites demonstrate acetylcholinesterase-inhibitory activity, positioning them as promising candidates for the treatment of Alzheimer's disease and other neurological disorders [104].

Furthermore, dietary polyphenols including resveratrol and quercetin have been shown to modulate gut–brain axis activity by reducing corticotropin-releasing factor (CRF) levels, inflammation, and microbiota imbalance, which is accompanied by improvements in behavioral and cognitive performance in experimental models [105].

Microbial enzymes such as β-glucosidases produced by representatives of the genera Bifidobacterium spp. and Lactobacillus spp. Play a key role in the bacterial transformation of polyphenols and antioxidants [106]. These enzymes effectively catalyze the hydrolysis of flavonoid glycosides, promoting their activation.

As a result of enzymatic transformations, the intestinal microbiota is able to metabolize flavonoids and other antioxidants into a wide range of compounds, including glycosides, glucuronides, sulfates, amides, esters and lactones, characterized by increased bioavailability [107]. These bioactive components exhibit pronounced antihyperglycemic, anti-inflammatory and neuroprotective properties [108]. The process of polyphenol metabolism is carried out with the participation of various microbial populations and is largely determined by the composition of the intestinal microbiota, which affects the final profile of metabolites and related compounds [109].

According to modern concepts, polyphenols and antioxidants of microbial origin in combination with nanotechnological approaches that provide targeted delivery across the BBB have significant therapeutic potential in the treatment of various neurological diseases, including traumatic brain injury, Alzheimer's disease and Parkinson's disease.

Current data highlight the critical role of omega-3 polyunsaturated fatty acids (PUFA), in particular eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), in the regulation of physiological processes, including their participation in the functioning of the gut–brain axis [110]. As key structural components of phospholipids in cell membranes, these acids help optimize their fluidity and stability. This property is essential for neuronal signaling, since it determines the efficiency of neurotransmitter biding, the speed of impulse conduction, and the integrity of intracellular signaling [111,112].

Omega-3 fatty acids demonstrate a pronounced ability to modulate the quantitative and qualitative composition of the intestinal microbiome, while the microbiota itself if actively involved in the processes of absorption and metabolic transformation of these compounds. Studies in this area have revealed a number of consistent changes in the composition of the intestinal microbiota under the influence of omega-3 fatty acids. In particular, a significant decrease in the number of representatives of the genus Faecalibacterium was recorded, which in some cases was combined with an increase in the proportion of bacteria of the Bacteroidetes type, as well as butyrate-producing microorganisms belonging to the Lachnospiraceae family [113].

Experimental data on animal models demonstrate that the interaction between the intestinal microbiota, omega-3 fatty acids and the immune system can play a key role in maintaining the integrity of the intestinal barrier and modulating the activity of immunocompetent cells [114]. In addition, both preclinical and clinical studies have confirmed the ability of these bioactive compounds to modulate the gut–brain axis by inducing changes in the composition of the intestinal microbiota [115,116,117].

Intestinal microbiota is able to modulate the absorption, bioavailability and biotransformation of omega-3 fatty acids both directly and indirectly [118,119]. Certain bacterial species, such as Bacillus proteus and Lactobacillus plantarum, catalyze the conversion of α-linolenic and linoleic acids into conjugated forms, linoleic (CLA) and α-linolenic (CALA) acids, which are subsequently hydrogenated to form stearic acid. This process contributes to changes in the PUFA profile in brain and myocardial tissues [120].

Despite significant progress in studying the effects of omega-3 fatty acids on the microbiota and the gut–brain axis, the mechanisms of their mutual regulation, including the effects of specific bacterial strains on PUFA metabolism, remain incompletely understood. A promising direction if the study of individual differences in the response of the microbiota to omega-3 fatty acids, which may form the basis for precision nutritional strategies. Furthermore, the long-term effects of microbiota modulation by polyunsaturated fatty acids in the context of neurodegenerative diseases require further study.

Table 2 presents summarized data from clinical studies on the effects of key bioactive component groups on regulatory mechanisms of the gut–brain axis.

In recent decades, convincing evidence has accumulated on the key role of the intestinal microbiota in regulating the function of the CNS via the gut–brain axis. It has been established that dysbiotic changes in the microbial composition are associated with the development of neuroinflammation, oxidative stress and pathological accumulation of protein aggregates, which contributes to the progression of neurodegenerative diseases, including dementia and Alzheimer's disease (AD) [134,135]. Microbiota disturbances can lead to increased permeability of the intestinal barrier, systemic inflammation and impaired signaling along the vagus nerve, which ultimately affects neuroplasticity and cognitive functions.

Table 3 presents intestinal microbiota disturbances in Alzheimer's disease and their relationship with the pathogenesis of neurodegeneration.

Of particular interest are data on the environment of bacterial factors in the pathogenetic cascade of neurodegenerative diseases characterized by impaired aggregation of endogenous proteins that spread via a prion-like mechanism [136,137].

In particular, the role of the enterobacteria within the concept of the "gut–brain" axis has attracted considerable attention. Experimental data demonstrate that bacterial endotoxin contributes to the aggravation of brain pathology in Alzheimer's disease, including through the stimulation and aggregation of β-amyloid (Aβ) [138,139].

Research in this area indicates a constant expansion of the list of known amyloid systems. These structures have been identified in representatives of both Gram-positive and Gram-negative bacteria, including the genera Bacillus, Pseudomonas, Staphylococcus, Streptomyces and others, indicating a wide distribution of functional amyloids among the microbiota and their recognition through the TLR2 receptor [140,141].

In another experimental study using a transgenic mouse model of AD, age-dependent alterations in the gut microbiota composition were observed, accompanied by a decrease in the concentration of SCFAs [142]. These disturbances were correlated with the accumulation of amyloid deposits and ultrastructural damage in intestinal tissue.

As a result of the identified changes in microbial metabolism, emerging evidence indicates that the gut microbiota plays as active role in the regulation of cognitive functions, and that its imbalance is associated with the development of Alzheimer's disease. A longitudinal study in APP/PS1 transgenic mice demonstrated that disruptions in gut microbiota composition-particularly the increased abundance of pro-inflammatory taxa such as Escherichia-Shigella and Desulfovibrio represent an early event in AD pathogenesis, preceding amyloid plaque accumulation and microglial activation [143].

Clinical studies further support the existence of substantial alterations in the composition of the gut microbiota in patients with Alzheimer's disease. A recent study found a significant decrease in α-diversity of the microbiota, a decrease in the relative abundance of Firmicutes and Bifidobacterium, and an increase in the proportion of Bacteroides compared to control groups [144]. The identified dysbiotic changes were found to correlate significantly with key pathological markers of AD in cerebrospinal fluid (CSF), including a decrease in the Aβ42/Aβ40 ratio and an increase in phosphorylated tau (p-tau).

Another study found significant association between intestinal dysbiosis and AD pathology, demonstrating a decrease in the abundance of SCFA-producing bacteria (Lachnospiraceae, Roseburia hominis) and an increase in [Clostridium] leptum in patients with abnormal amyloid and p-tau levels in CSF, which also confirms the role of microbiota in the pathogenesis of neurodegenerative diseases through the modulation of neuroinflammation [145].

In another study, patients with Alzheimer's disease showed a significant increase in the relative abundance of taxa such as Acidobacteriota, Verrucomicrobiota, Planctomycetota, and Synergistota, as well as a decrease in the content of representatives of the genera Bifidobacterium, Roseburia, Monoglobus, Lactobacillaceae, and others [146]. Differential analysis revealed an increase in the representation of the genera Christensenellaceae R-7 group, Prevotella, Akkermansia, and Eubacterium. In addition, statistically significant correlations were found between certain bacterial taxa and blood biochemical parameters, including adiponectin, bilirubin, and C-reactive protein levels.

Significant microbial disturbances are also observed in the oral microbiome of patients with Alzheimer's disease. And increase in overall bacterial diversity, an increase in the relative abundance of Firmicutes, and a simultaneous decrease in the abundance of Bacteroidota have been reported [154]. Additionally, significant decreases in the abundance of species such as Haemophilus parainfluenzae, Prevotella melaninogenica, Prevotella histiola, and Actinomyces oris have been revealed. These observations indicate a possible pathogenetic role of the microbial imbalances in the oral cavity in the development and progression of the disease.

Thus, intestinal and oral microbiota dysbiosis can be considered a significant risk factor for the development and progression of dementia and Alzheimer's disease, which opens up new prospects for the development of preventive and therapeutic strategies aimed at modulating the microbial composition.

Unlike the Alzheimer's disease, where the role of the microbiota has been actively studied only in recent years, the link between intestinal dysbiosis and Parkinson's disease (PD) was identified much earlier, due to pronounced gastrointestinal symptoms preceding motor disorders in patients. Microbiota disturbances in PD are characterized by a decrease in anti-inflammatory bacteria producing SCFAs and an increase in microorganisms associated with neuroinflammation and oxidative stress [155,156]. The main dysbiotic changes in the microbiota in Parkinson's disease are presented in Table 4.

Parkinson's disease is a neurodegenerative disorder characterized by α-synucleinopathy affecting all levels of the gut–brain axis, including the central, autonomic, and enteric nervous systems [165]. α-synuclein plays a central role in the pathogenesis of PD, as evidenced by its presence in Lewy bodies and neurites, characteristic morphological markers of the disease [166]. Dysbiotic changes in the microbiota typical of PD contribute to increased inflammatory responses and impaired homeostasis in the intestine. These changes are accompanied by increased permeability of the intestinal barrier and translocation of bacterial components, including lipopolysaccharides, into the systemic circulation, which can induce the expression, post-translational modifications, and aggregation of α-synuclein in neurons [167].

Considering the established link between microbial lipopolysaccharides and α-synuclein aggregation, experimental data demonstrate that chronic rotenone administration induces degeneration of tyrosine hydroxylase (TH)-positive neurons regardless of microbial status. However, the development motor deficits and increased intestinal barrier permeability were observed exclusively in conventional mice with an intact microbiota [168].

Parallel investigations in other models have revealed variability in the contribution of the microbiota to the pathogenesis of Parkinson's disease. For instance, in SNCA A53T transgenic mice, early motor impairments, gastrointestinal dysfunction, and reduced α-diversity of the gut microbiota were observed [169]. At the same time, microbiota alterations induced by antibiotic treatment or co-housing with wild-type mice exerted only minimal modulatory effects on symptom severity.

Clinical studies have also identified significant structural alterations in the gut microbiota of patients with Parkinson's disease. In particular, there is a decrease in the number of butyrate-producing and cellulose-degrading bacteria (Blautia, Faecalibacterium, Ruminococcus) against the background of an increase in the proportion of opportunistic genera, including Escherichia-Shigella, Proteus, Enterococcus, Streptococcus [170]. These changes are associated with disease progression, increase in inflammatory processes and a potential decrease in the production of short-chained fatty acids, which play a neuroprotective role.

The results of another study indicate that patients with PD have a significantly increased number of taxa such as Verrucomicrobia, Mucispirullum, Porphyromonas, Lactobacillus and Parabacteroides, while in the control group, bacteria of the genus Prevotella predominated [171]. In addition, a comparative analysis of PD subtypes revealed that patients with the non-tremor form of the disease had a more pronounced increase in the number of Bacteroides compared to individuals with the tremor subtype. It should be noted that the observed alterations in the microbiota were associated with increased plasma concentrations of pro-inflammatory cytokines in the patients, specifically interferon-γ (IFNγ) and TNFα. Correlation analysis revealed a positive relationship between the relative abundance of Bacteroides and TNFα levels, as well as between the abundance of Verrucomicrobia and IFNγ. These findings suggest a potential role of the gut microbiota in the pathogenesis of neuroinflammation in Parkinson's disease.

Another study also confirmed a decrease in the number of bacterial taxa with anti-inflammatory and neuroprotective properties in patients with Parkinson's disease. In particular, a decrease in the number of representatives of the Lachnospiraceae family, including SCFA-producing genera Butyrivibrio, Pseudobutyrivibrio, Coprococcus and Blautia, was found, which was accompanied by significant changes in the fecal metabolomic profile, characterized by a decrease in the concentrations of neuroprotective compounds: lipids, vitamins, amino acids and other organic metabolites [172]. The data obtained indicated a violation of metabolic homeostasis mediated by intestinal dysbiosis and emphasizes the potential of microbial and metabolic biomarkers for the diagnosis and therapy of Parkinson's disease.

These changes are accompanied by a decrease in the phylogenetic diversity of the microbiota and significant shifts in beta-diversity, which reflects a stable restructuring of microbial communities. A recent study found a statistically significant association between the phenomenon of dopaminergic therapy wear-off and an increase in Lactobacillus with a decrease in Blautia, while in dyskinesias no significant differences in the microbiota composition were observed after taking into account confounding factors [173]. In addition, age, disease duration, the presence of motor complications, as well as lifestyle parameters (body mass index, physical activity level, diet, weight fluctuations) affect the microbiota structure and can act as confounding factors or independent modifiers.

The results of another study in this area indicate a positive correlation between the degree of the considered microbial disturbances and the severity of motor symptoms assessed by the MDS-UPDRS III scale, as well as disease progression according to the Hoehn & Yahr scale [174]. Functional metagenomic analysis revealed activation of metabolic pathways involved in lipopolysaccharide biosynthesis, as well as decreased activity of pathways for the synthesis of amino acids—precursors of neurotransmitters (including phenylamine, tyrosine and tryptophan), indicating the potential involvement of dysbiosis in disruption of neurotransmitter metabolism and the formation of a pro-inflammatory environment in the intestine.

Thus, current data confirm the key role of intestinal dysbiosis in the pathogenesis of Parkinson's disease, mediated by disruption of the gut–brain axis through mechanisms of neuroinflammation, oxidative stress and dysregulation of α-synuclein metabolism. Further research in this direction may open new opportunities for the development of precision dietary and therapeutic strategies aimed at modulating the microbiota in order to correct neurodegenerative processes.

In contrast to the neurodegenerative diseases discussed above, such as Alzheimer's disease and Parkinson's disease, the pathogenesis of multiple sclerosis (MS) is determined primarily by autoimmune mechanisms directed against components of the CNS, primarily myelin [175,176]. According to modern studies, myelin-reactive CD4+ T-helpers (TH-cells) play a leading role in the development of MS. Among the various subpopulations of TH-cells, TH1 and TH17 attract the greatest attention of researchers, which is due to their ability to produce proinflammatory cytokines—IFN-γ and interleukin-17 (IL-17), respectively [177]. The discovery of TH17 cells as ana independent subpopulation of CD4+ T-lymphocytes has radically changed the traditional paradigm of the TH1/TH2 dichotomy in the immunopathogenesis of autoimmune diseases. This subpopulation is characterized by a unique proinflammatory profile due to the secretion of IL-17, IL-21, IL-22 and IL-23, which contributes to the development of chronic inflammation [178]. TH17-mediated pathogenesis of multiple sclerosis includes a complex of interconnected processes: production of inflammatory cytokines (IL-17, GM-CSF), disruption of the integrity of BBB, activation of microglia and chronic recruitment of inflammatory cells of the CNS, forming a self-sustaining inflammatory cascade, which defines TH17 cells and their mediators as promising targets for targeted therapy [179].

In recent years, increasing evidence indicates that the intestinal microbiota may play a critical role in modulating the immune response and triggering the autoimmune cascade underlying multiple sclerosis [180]. According to recent data, patients with relapsing-remitting multiple sclerosis (RRMS) exhibit characteristic dysbiosis, manifested by a reduced abundance of bacteria associated with the production of SCFAs and the induction of regulatory T-cells, along with an increased prevalence of opportunistic and pro-inflammatory microorganisms [181,182]. These changes in the composition of the microbiota contribute to the activation of TH1/TH17-mediated immune responses, increased synthesis of proinflammatory cytokines (such as IL-6, TNF-α and IL-17), decreased immunoregulatory activity and increased permeability of the intestinal epithelium [183].

In an experimental study using an autoimmune encephalomyelitis model that mimics multiple sclerosis, it was established that the baseline composition of the gut microbiota determines whether the disease develops into a chronic-progressive or a relapsing -remitting form [184]. Metagenomic analysis demonstrated that immunization was accompanied by both general and phenotype-specific alterations in the microbial community, highlighting the pivotal role of the microbiota in modulating either a pro-inflammatory or a tolerogenic environment. Building on these findings regarding the role of the microbial community, the study of exogenous factors capable of inducing dysbiosis becomes increasingly important. In another experimental investigation, diet-induced obesity was shown to exacerbate the course of autoimmune encephalomyelitis in HLA-DR3 transgenic mice, leading to gut dysbiosis characterized by an increased abundance of Proteobacteria and Desulfovibrionaceae, as well as heightened intestinal permeability and systemic inflammation [185]. These results underscore the critical role of the microbiota and its associated metabolic pathways in the pathogenesis of the disease, thereby opening new perspectives for the development of targeted therapies for patients with MS and comorbid obesity.

In addition to its indirect effects through modulation of barrier function, the gut microbiota directly regulates the immune response by influencing the expression of key chemokine receptors on lymphocytes. Clinical studies have demonstrated that the gut microbiota also modulates the expression of the CCR9 receptor and the frequency of CCR9+ CD4+ T-cells, which play a crucial role in shaping both local and systemic immune responses [186]. Disruption of these mechanisms is associated with decreased immune tolerance and increased proinflammatory processes, while correction of microbial imbalance can contribute to clinical remission, which confirms the important role of microbiota in the pathogenesis of the disease.

Numerous clinical and experimental data confirm the importance of intestinal microbiota in the pathogenesis of multiple sclerosis, demonstrating stable changes in both the composition and functional activity of microbial communities in patients with this disease. Patients show a significant increase if the number of genera Akkermansia municiphila, Methanobrevbacter smithii, Clostridium perfringens, Pseudomonas, Streptococcus, Dorea, Blautia, which if accompanied by increased permeability of the mucous barrier, activation of innate and adaptive immunity and increased production of proinflammatory mediators [187,188,189]. At the same time, a deficiency of bacteria with immunosuppressive and barrier-protective properties is recorded, including Faecalibacterium prausnitzii, Anaerostipes, Prevotella, Bacteroides, Parabacteroides, Adlercreutzia, Lactobacillus, which leads to a decrease in the level of SCFAs (butyrate and propionate), impaired differentiation of regulatory T cells and an imbalance of TH17/Treg [187,190,191].

Therapeutic approaches aimed at correcting the composition of the microbiota in patients with multiple sclerosis include direct effects (the use if strain-specific probiotics), indirect effects through dietary interventions and the use of prebiotics, as well as a promising strategy of fecal transplantation [192]. Thus, intestinal microbiota is considered not only as a significant pathogenetic factor in the development of multiple sclerosis, but also as a promising target for therapy and prevention of the disease, and its modulation as a means of increasing the effectiveness of therapy and improving the quality of life of patients.

Precision nutrition aims to develop comprehensive and dynamic dietary recommendations that take into account the changing and interrelated parameters of the internal and external environment of an individual throughout the life cycle [193]. However, the implementation of this approach faces a number of challenges, including the high cost of technology, insufficient standardization of methods for analyzing individual biomarkers, as well as ethical and legal issues associated with the use of genetic and personal data. Figure 3 presents an integrative model of precision nutrition, outlining the main input parameters, analytical methods, and expected clinical outcomes.

The European Society for Clinical Nutrition and Metabolism (ESPEN), in its guidelines, emphasizes the importance of diets rich in antioxidants, omega-3 fatty acids, and dietary fiber for reducing the risk of cognitive impairment in older adults. The guidelines also underscore the necessity of implementing early dietary interventions as a key component of a preventive strategy.

Unlike traditional diets, precision nutrition is based on the principles of nutrigenomics and nutrigenetics, which study the interactions between food components and the molecular mechanisms of the body [194]. In nutrigenomics research, high-throughput omics technologies—including transcriptomics, proteomics, and metabolomics—are employed to analyze the impact of dietary interventions on biological systems and to investigate interactions between nutrition and genes [195]. Transcriptomics assesses changes in gene expression at the genome level and is widely used in nutrigenomics, proteomics studies the full set of proteins modulated by nutrition, and metabolomics focuses on the analysis of low-molecular-weight metabolites reflecting cellular activity [196,197,198]. Additionally, microarray technologies are used to globally analyze gene expression profiles and study transcriptional regulation under the influence of nutrients and bioactive components [199]. The integration and interpretation of data obtained using omics technologies is achieved through the development of bioinformatics, which is necessary for studying gene-nutrient interactions and developing personalized dietary strategies. The combined use of these methods allows us to identify the effects of dietary components on gene regulation, protein expression, and metabolic processes, which forms the basis of nutrigenomics and personalized nutrition. The key barrier in this area remains the interpretation of the obtained data: biological variability, the influence of external factors (e.g., stress and ecology) and the lack of universal algorithms for predicting individual responses to diet limit the transition from scientific research to clinical practice.

In this regard, within the framework of this approach, in addition to genetic characteristics, such as factors like dietary habits, eating behavior, physical activity level, microbiota composition and metabolomic profile are currently actively considered [200,201]. This comprehensive analysis is especially important in the context of the prevention of neurodegenerative diseases, since dysfunction of the gut–brain axis and chronic inflammation, modulated by dietary factors, significantly contribute to the pathogenesis of Alzheimer's disease and Parkinson's disease.

Modern studies demonstrate that the effectiveness of dietary interventions varies significantly among individuals, which is due to gene polymorphisms, microbiome features and metabolic status [202]. Dietary interventions have been shown to induce individual-specific changes in the gut microbiota that correlate with its baseline composition [203,204]. In this regard, the integration of gut microbiota data with other personal biological parameters represents a promising direction for predicting metabolic responses to dietary therapy.

Diet is a key exogenous factor determining the composition and functional activity of the gut microbiota, which determines its importance as a therapeutic tool for microbiome modulation [205]. Numerous intervention studies involving humans confirm that modification of macronutrient composition and inclusion of dietary supplements induce rapid and reproducible changes in the microbial profile; however, the severity and direction of these shifts demonstrate interindividual variability due to the initial α-diversity of the microbiota and phenotypic characteristics of the host [206]. In particular, high-fat and low-fiber diets are associated with reduced diversity and enrichment of pro-inflammatory taxa, whereas consumption of plant proteins and fermentable carbohydrates promotes proliferation of commensal bacteria and increased SCFA production [207,208]. These data highlight the critical role of dietary factors in regulating microbial metabolic pathways and justify the need to develop precision dietary strategies integrated analysis of the baseline microbiome, genetic potential, and dietary habits, as standardized approaches demonstrate limited efficacy due to the marked heterogeneity of individual responses.

Precision nutrition is based on the identification and validation of reproducible biomarkers that can predict individual metabolic responses to dietary interventions. Recent advances in high-throughput technologies have enabled the identification of molecular signatures associated with nutrient metabolism, gut microbiota composition, and metabolic health.

Biomarkers are objective and measurable indicators that play a key role in assessing health status, identifying nutrient deficiencies, and taking into account individual metabolic characteristics. In the context of precision nutrition aimed at preventing neurodegenerative diseases, the analysis and use of biomarkers in dietary interventions helps to accurately determine the physiological needs of the body, minimizing the subjectivity of interpretation and providing evidence-based interventions [209].

Nutritional biomarkers are biochemical indicators determined in biological fluids of the body that allow an objective and specific assessment of micronutrient status. They are of particular importance in the diagnosis of micronutrient deficiency, when clinical symptoms may be absent, which excludes the possibility of using traditional screening methods on anthropometric measurements [210].

Unlike traditional approaches based on average nutrient intake rates, the use of biomarkers allows identifying specific metabolic disorders and nutrient deficiencies associated with an increased risk of neurodegenerative diseases. This opens up opportunities for targeted and safe correction, which is especially important in the context of pathogenetic mechanisms associated with oxidative stress, neuroinflammation and mitochondrial dysfunction.

Recommended nutritional biomarkers for precision therapy of neurodegenerative diseases are presented in Table 5.

The main feature of key processes that determine health status, such as lipid and carbohydrate metabolism, systemic inflammation, oxidative stress and microbiota status, if their ability to reflect different, but also interconnected aspects of metabolism [219]. These processes can be described in the form of biomarkers listed in Table 5, including metabolites and proteins. Integration of these and other biomarkers through data analysis algorithms and machine learning methods allows us to quantitatively assess the state of each of the key processes that determine cognitive health.

Modern advances in genetic testing and bioinformatics have significantly expanded the possibilities for identifying genetic biomarkers associated with predisposition to diseases, the dynamics of their progression and response to therapy [220]. Of particular importance is the development of molecular rapid tests for use in point-of-care tests (POCT). Such systems use microfluidic technologies and modern amplification methods, which ensures real-time genetic testing directly in clinical practice. This area promotes the active implementation of the principles of personalized medicine and precision nutrition [221].

Proteomic and metabolomic approaches to precision nutrition can be non-targeted (covering a wide range of biomolecules and reflecting multiple metabolic pathways) of targeted, aimed at studying specific hypothetical mechanisms linking nutritional status with cognitive health.

Recent studies in this area have identified disturbances in markers of immune function, lipid metabolism, and cellular bioenergetics that can potentially be modulated by diet [222,223]. Other studies have also found specific metabolic and proteomic signatures in the blood associated with cognitive impairment, risk of dementia, of Alzheimer's disease biomarkers in the cerebrospinal fluid. These biomarkers are amino acids and their derivatives associated with mitochondrial function and regulation of glutamatergic transmission (branched amino acids, acyclarnites, glutamate, taurine), as well as lipids involved in maintaining the structural integrity of neuronal membranes and modulating neuroinflammation (individual subfractions of high-density lipoproteins, phospholipids, and long-chain omega-3 polyunsaturated fatty acids) [224,225,226].

Another promising direction in the prevention of neurodegenerative diseases is the use of parameter analysis using artificial intelligence (AI) in precision nutrition. This approach provides a more accurate and targeted correction of dietary factors compared to traditional universal recommendations. Machine learning methods, in particular deep learning models, allow the analysis of clinical laboratory data and potential biomarkers to predict cognitive status assessed by standardized scales as the Mini-Mental State Examination (MMSE) [227]. Such algorithms demonstrate high accuracy in identifying individual metabolic abnormalities, which makes them a valuable tool for objective quantitative monitoring of cognitive risk, as well as for assessing the effectiveness of preventive interventions.

An important advantage of artificial intelligence (AI) models based on routine biochemical indicators if their applicability for mass screening of cognitive impairment without the need for expensive neuroimaging of molecular diagnosis [228]. This opens up prospects for the widespread implementation of this approach in clinical practice, healthcare systems and preventive health insurance programs.

Nutrigenomic, epigenetic and transcriptomic approaches have significant potential for identifying the molecular mechanisms underlying precision nutrition in the context of maintaining cognitive health. However, despite the promise of these areas, their particular application currently remains limited [229].

Modern precision nutrition strategies go beyond simply taking into account the genetic and metabolic characteristics of an individual, integrating the timing of nutritional interventions to optimize their effectiveness. Chrononutrition, as a rapidly developing field, studies the influence of circadian rhythms of nutrient absorption, energy metabolism, and physiological processes associated with various diseases. This approach is based on the understanding that synchronization of dietary interventions with endogenous biological rhythms can enhance their preventive and therapeutic potential [230].

Recent studies have demonstrated that circadian regulation disorders, including desynchronosis, can initiate oxidative stress [231], neuroinflammation [232], and mitochondrial dysfunction [233]—key pathogenetic mechanisms of neurodegenerative diseases. In this regard, optimization of meal timing, macro- and micronutrients is of particular importance for the correction of metabolic disorders and maintenance of cognitive health. For example, time-restricted feeding (TRF) has been shown to improve metabolic plasticity, reduce insulin resistance, and modulate the activity of key regulators of cellular longevity and neuroprotection [234].

In addition, time-restricted eating (TRE/TRF) has a complex effect on the pathogenetic mechanisms of Alzheimer's disease. The results of studies in this area induce that this nutritional approach helps to normalize circadian rhythms, reduce the accumulation of β-amyloid 42 (A β42), modulate anti-inflammatory cytokines, and positively change the composition of the intestinal microbiota, including an increase in its α-diversity and a decrease in the proportion of pathogenic bacteria [235]. The data obtained indicate the potential effectiveness of TRE/TRF as a preventive strategy for Alzheimer's disease, but further studies are needed to confirm the clinical significance and clarify the molecular mechanisms (Figure 4).

Preclinical studies suggest that TRE, independent of dietary macronutrients composition, significantly improves cognitive function in aging rats compared to ad bitum-fed controls, as assessed by biconditioned associative learning tests without the influence of motivational and sensorimotor factors [236]. TRE is associated with significant changes in gut microbiota composition, including an increase in Allobaculum species, which correlates with cognitive performance in rats, suggesting a potential role for microbiota in modulating cognitive health during aging.

Another study in 5xFAD mice demonstrated that TRE significantly improves cognitive function, reduces β-amyloid deposition, and reduces neuroinflammation, with these effects mediated by changes in gut microbiota composition, in particular an increase in Bifidobacterium pseudolongum abundance and propionic acid levels [237]. The obtained results are confirmed in a clinical study, where a four-month TRE regimen resulted in a significant improvement in cognitive performance in patients with Alzheimer's disease, with a positive correlation between fecal propionic acid levels and the degree of cognitive improvement. The neuroprotective effect of TRE is realized through the gut–brain axis by a microbiome-dependent increase in the production of propionic acids, which, penetrating the BBB, activates the FFAR3 receptor, which opens up new prospects for the development of therapeutic strategies for neurodegenerative diseases.

Intermittent fasting (IF), being a form of chrononutrition, can also significantly affect the composition and functional activity of the intestinal microbiota, which, in turn, has an indirect effect on the course of neurodegenerative diseases. A recent study demonstrated that IF induces significant restructuring of microbial communities, accompanied by an increase in α-diversity and enrichment of taxa with anti-inflammatory and neuroactive properties [238]. In particular intermittent fasting is associated with increased abundance of Akkermansia muciniphila, Lactobacillus, Faecalibacterium prausnitzii and Bifidobacterium longum bacteria capable of producing bioactive metabolites and modulating the immune response.

Another study showed that IF not only increases microbial diversity but also stimulates the growth of SCFA-producing bacteria such as Eubacterium rectale, Roseburia spp., and Anaerostipes spp., which are involved in the synthesis of propionate and acetate [239]. Notably, propionate, through its interaction with free fatty acid receptors (FFAR2/3), modulates vagal signaling and affects neuropeptide balance in the hypothalamus, while acetate is involved in appetite regulation and energy homeostasis [240]. In addition, intermittent fasting promotes an increase in the abundance of Bacteroides spp., which synthesize propionate via the succinate pathway, indicating a complex effect of chrononutrition on the metabolic profile of the microbiota [241].

Under conditions of food restriction, a metabolic shift occurs from glucose to ketone bodies, primarily β-hydroxybutyrate, which penetrates the BBB and is used by neurons as an energy source, reducing oxidative stress and stimulating the production of key neurotrophic factors [242]. The main molecular targets and effects of IF include: increased levels of BDNF, which enhances neuroplasticity, activation of SIRT3, which reduces neuroinflammation, stimulation of PGC1α, which is involved in mitochondriogenesis, an increase in GABA and ghrelin, which affect neurotransmission, induction of growth hormone and IGF-1 with neurotrophic effects, suppression of mTOR and activation of autophagy, which promotes the removal of pathological proteins and modulation of the gut microbiota, which improves cognitive function [243].

Preclinical studies in animal models indicate positive effects of intermittent fasting on cognitive functions, including improved memory performance, stimulation of neurogenesis, and reduction in neuroinflammatory processes [244,245]. Clinical studies, including observational and limited interventional studies, have shown that in elderly individuals, adherence to IF regimens, in particular limiting the time window of food intake to 8–10 h per day, is associated with improved cognitive performance and a reduced risk of developing cognitive impairment [246,247].

In addition, chrononutritive strategies involve taking into account the circadian dynamics of absorption and metabolism of bioactive compounds. The effectiveness of some neuroprotective nutrients depends on the time of their consumption, due to fluctuations in the activity of enzymes and transport systems [248]. Integrating data on circadian patterns of gene expression, hormonal profiles, and metabolic processes allows the development of personalized nutritional regimens aimed at enhancing the synergism between diet and endogenous rhythms of the body.

Another promising direction is the combination of chrononutritive interventions with real-time monitoring technologies, including wearable devices and mobile applications, which opens up new possibilities for dynamic nutritional adjustments taking into account individual circadian characteristics [249]. The introduction of these approaches into clinical practice requires further research to validate optimal nutrient intake windows and develop unified algorithms for different patients.

Thus, chrononutritive interventions represent a promising direction in precision nutrition, combining advances in nutritional science and cognitive health. Further research should be aimed at clarifying the molecular mechanisms, developing standardized protocols, and assessing the long-term effectiveness of the strategies in different patient groups.