The gut-brain axis relies on anatomical connections that facilitate bidirectional communication between the gastrointestinal tract and the CNS (19). The vagus nerve, a major component of the parasympathetic nervous system, serves as a direct neural pathway between the gut and the brain. It transmits signals from the gut to the brainstem and vice versa, influencing functions such as appetite, digestion and stress responses (3). The spinal cord also plays a role in this communication, processing sensory information from the gut and sending motor commands that regulate gastrointestinal motility and secretion (20). Additionally, brain-gut peptides such as ghrelin, leptin and peptides are released in response to nutrient intake and act on distant targets in the brain to regulate feeding behavior, energy balance and metabolic processes (21). These anatomical connections form the structural basis for the complex interactions that occur within the gut-brain axis.

The gut microbiota, comprising trillions of microorganisms, plays a crucial role in shaping the gut environment and influencing both local and systemic immune responses (22). Microbiota-gut-brain communication occurs through several pathways. Metabolites produced by gut bacteria, such as short-chain fatty acids (SCFAs), secondary bile acids and tryptophan metabolites, can enter the bloodstream and affect brain function (23). These metabolites have been shown to influence neuroinflammation, neurotransmitter synthesis and blood-brain barrier (BBB) integrity (24). The immune system also serves as a key communication pathway, with gut-resident immune cells producing cytokines and chemokines that can modulate CNS function (25). Furthermore, neural pathways, including the vagus nerve, transmit signals from the gut to the brain and vice versa, allowing for rapid communication and coordinated responses to internal and external stimuli (3) (Fig. 1). This intricate network of communication pathways enables the gut microbiota to exert profound effects on neurological health.

Endocrine and neuroendocrine mechanisms further contribute to the bidirectional communication between the gut and the brain (23). Gut hormones such as ghrelin, leptin and peptides are released into the bloodstream and act on receptors in the brain to regulate appetite, energy expenditure and metabolic processes (26). These hormones can influence neurotransmitter release and affect brain regions involved in reward, motivation and stress responses (27). Additionally, the HPA axis, a key neuroendocrine system, plays a significant role in stress response and regulation of the gut-brain axis. Stress-induced activation of the HPA axis leads to the release of corticotropin-releasing hormone and subsequent increases in cortisol levels, which can modulate gut motility, secretion and barrier function (28) (Fig. 1). Conversely, signals from the gut can feedback to the HPA axis, creating a dynamic interplay that impacts both gastrointestinal and neurological health (29). This complex web of endocrine and neuroendocrine interactions underscores the intimate connection between the gut and the brain in maintaining overall homeostasis and health.

The human gut microbiota comprises a complex community of microorganisms, including bacteria, archaea, viruses and eukaryotic microbes, with bacterial species being the most predominant and diverse (30). The composition of gut microbiota varies significantly among individuals and is influenced by factors such as genetics, diet, age, geographical location and lifestyle (31). The gut microbiota is established at birth, with the initial microbial colonization influenced by the mode of delivery and breastfeeding (32). During infancy and childhood, the microbiota continues to develop and diversify, reaching a relatively stable state in adulthood. However, this stability can be disrupted by various factors, including antibiotics, stress and changes in diet, leading to dysbiosis, which is associated with numerous health issues, including neurological disorders (33).

Gut microbiota produces a wide range of metabolites that play crucial roles in host physiology and pathology. Tryptophan metabolites-indole derivatives (for example, indole-3-lactic acid, indole-3-acetic acid) and kynurenine pathway metabolites (kynurenine, kynurenic acid, 3-hydroxykynurenine)-are synthesized by gut bacteria (for example, Clostridium sporogenes, Lactobacillus spp.) via tryptophanase or indoleamine-2,3-dioxygenase. Dysbiosis-induced accumulation of neurotoxic kynurenine metabolites (3-hydroxykynurenine, quinolinic acid) and reduction of neuroprotective indole-3-lactic acid have been implicated in neurological disorders. In patients with AD, reduced serum indole-3-lactic acid correlates with cognitive decline (34), while elevated 3-hydroxykynurenine levels are associated with neuroinflammation in PD (35). SCFAs, including acetate, propionate and butyrate, are the primary metabolites produced by the fermentation of dietary fiber by gut bacteria (36). SCFAs have been shown to modulate neuroinflammation, reinforce the integrity of the BBB, and regulate neurotransmitter synthesis (37). Secondary bile acids, such as deoxycholic acid and lithocholic acid, are generated by the microbial transformation of primary bile acids and have been implicated in influencing neuroinflammation and cognitive function through interactions with specific receptors (38). Tryptophan metabolites, including indole derivatives and kynurenine, are another important group of microbiota-derived metabolites that impact serotonin production and immune responses, potentially affecting neuropsychiatric conditions (39).

The gut microbiota significantly influences neurodevelopment, with animal studies demonstrating that germ-free mice exhibit altered brain development and behavior compared with conventionally raised animals (40). The microbiota also plays a vital role in neurotransmission, as gut bacteria are capable of producing or stimulating the production of neurotransmitters such as serotonin, dopamine and gut luminal GABA) (41,42). In total, ~90% of the body's serotonin is synthesized by enterochromaffin cells in the gut, and this peripheral serotonin can influence both gut function and brain activity (43). Furthermore, the gut microbiota is a key regulator of neuroinflammation, modulating the host's immune response and influencing the activation of microglia, the resident immune cells of the CNS (44,45). Dysbiosis has been associated with increased neuroinflammatory responses, which are implicated in the pathogenesis of various neurological disorders, including AD, PD and MS (46-48).

In PD, research has shown that gut microbiota dysbiosis precedes motor symptoms and may contribute to neuroinflammation and α-synuclein aggregation (49). Sampson et al (50) demonstrated that gut microbiota regulates motor deficits and neuroinflammation in a PD model, with antibiotic treatment reducing motor dysfunction and microglial activation. Perez-Pardo et al (51) further explored the role of Toll-like receptor 4 (TLR4) in the gut-brain axis in PD, suggesting that TLR4 signaling may be a therapeutic target. Additionally, Srivastav et al (52) found that a probiotics mixture increases butyrate, rescuing nigral dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone-induced neurotoxicity.

In PD, α-synuclein pathology is closely linked to gastrointestinal dysbiosis; increased α-synuclein expression correlates with reduced Lachnospiraceae and elevated Enterobacteriaceae, accelerating neurodegeneration via gut-derived inflammation (53). Homogeneously, emerging evidence suggests that gut microbiota alterations may contribute to amyloid-β plaque formation and neuroinflammation. Honarpisheh et al (54) observed dysregulated gut homeostasis prior to brain amyloid-β accumulation in Tg2576 mice. Kim et al (55) found that transplantation of gut microbiota from mouse models with AD impairs memory function and neurogenesis in recipient mice. Shi et al (56) demonstrated that a fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites. Furthermore, chronic PD progression is associated with gut microbiota-driven protection of dopaminergic neurons. Clostridium butyricum supplementation increased butyrate-producing taxa, suppressed substantia nigra inflammation, and improved motor deficits in mice with MPTP-induced PD (57).

Recent advances have highlighted the potential therapeutic role of probiotics and prebiotics in neurodegenerative diseases (57). Castelli et al (58) discussed the emerging role of probiotics in PD, suggesting new therapeutic possibilities. Yuan et al (59) explored the ApoE-dependent protective effects of sesamol on high-fat diet-induced behavioral disorders through regulation of the microbiome-gut-brain axis. Additionally, prebiotics such as microbiota-accessible carbohydrates (a class of prebiotics), have been shown to prevent neuroinflammation and cognitive decline by improving the gut microbiota-brain axis in diet-induced obese mice (60). While these preclinical studies are encouraging, a recent randomized controlled trial (RCT) in early PD reported no motor benefit from multi-strain probiotics after 12 weeks (14), underscoring the need for larger, longer-duration trials that stratify patients by baseline microbiota profiles.

In MS, research has identified specific gut commensals that modulate neuroinflammation. Bianchimano et al (61) utilized microbiota profiling to pinpoint gut bacteria influencing MS-like disease in mice, revealing potential therapeutic targets within the gut microbiota. Similarly, in TBI, the gut-brain axis plays a pivotal role in neuroinflammatory responses. Celorrio and Friess (62) highlighted the impact of gut microbiota dysbiosis on neuroinflammation following TBI, suggesting that targeting the gut microbiota could mitigate post-injury inflammation. Furthermore, first-episode psychosis (FEP) exhibits gut dysbiosis characterized by decreased Faecalibacterium prausnitzii and elevated Enterococcus, correlating with increased kynurenine/tryptophan ratios and peripheral inflammation (63). These findings implicate microbial tryptophan metabolism in FEP pathophysiology.

Environmental factors also contribute to neuroinflammation through the gut-brain axis (64). Lee et al (65) demonstrated that exposure to polystyrene microplastics impairs hippocampus-dependent learning and memory in mice, with gut microbiota alterations preceding neuroinflammatory changes. Exercise has shown promise in modulating the gut microbiota to reduce neuroinflammation. Yuan et al (66) found that treadmill exercise modulates intestinal microbes and suppresses lipopolysaccharide (LPS) displacement, alleviating neuroinflammation in APP/PS1 mice.

FMT represents a novel therapeutic approach. Hu et al (67) showed that FMT inhibits neuroinflammation following TBI in mice by regulating the gut-brain axis, indicating its potential as a treatment for neuroinflammatory conditions. Additionally, specific probiotics have demonstrated neuroprotective effects. Li et al (68) revealed that Lactobacillus rhamnosus GG ameliorates noise-induced cognitive deficits and systemic inflammation in rats by modulating the gut-brain axis.

Recent research has also focused on the role of microbial metabolites in neuroinflammation. Wei et al (69) showed that butyrate ameliorates chronic alcoholic CNS damage by suppressing microglia-mediated neuroinflammation and modulating the microbiome-gut-brain axis. Similarly, Zhu et al (70) demonstrated that Bifidobacterium breve HNXY26M4 attenuates cognitive deficits and neuroinflammation in APP/PS1 mice through gut-brain axis regulation.

In ASD, research has identified specific gut microbiota alterations associated with disease severity. De Theije et al (71) demonstrated intestinal inflammation in a murine model of ASD, suggesting a potential link between gut dysfunction and behavioral abnormalities. Stilling et al (72) found that absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala, highlighting the role of gut microbiota in neurodevelopmental programming. Kantarcioglu et al (73) identified specific yeast species in the stool samples of children with ASD, suggesting a potential role of fungal microbiota in disease pathogenesis. Furthermore, recent comparative analyses revealed significant differences in gut microbiota composition between children with ASD and their neurotypical siblings, with reduced Bifidobacterium and Akkermansia abundance in ASD cohorts (74). These alterations correlated with increased serum zonulin levels, suggesting compromised intestinal barrier integrity as a mechanistic link to neuroinflammation.

In addition to ASD, gut microbiota dysbiosis has been implicated in schizophrenia and bipolar disorder. In schizophrenia, patients show reduced microbial diversity and decreased abundance of SCFA-producing taxa such as Faecalibacterium and Roseburia, which correlates with cognitive deficits and negative symptoms (75). A systematic review by Bioque et al (76) further highlighted the role of the microbiome-gut-brain axis in schizophrenia, emphasizing its potential as a therapeutic target (75-77). Similarly, in bipolar disorder, gut dysbiosis is characterized by decreased Bifidobacterium and increased pro-inflammatory Enterobacteriaceae, which may exacerbate neuroinflammation via kynurenine pathway activation and cognitive dysfunction (63). A pilot study by Reininghaus et al (78) demonstrated that probiotic supplementation improved cognitive parameters in patients with euthymic bipolar disorder, suggesting a modulatory role of gut microbiota in psychiatric outcomes.

Recent research has focused on the therapeutic potential of targeting the gut microbiota in ASD. Pulikkan et al (79) reported gut microbial dysbiosis in Indian children with ASD, with specific bacterial taxa correlating with disease severity. Bojović et al (80) found altered production of SCFAs in children with neurodevelopmental disorders, suggesting a potential metabolic link between gut dysbiosis and neurological symptoms.

In attention-deficit hyperactivity disorder (ADHD), emerging evidence suggests that gut microbiota dysregulation may contribute to disease development. Slob et al (81) found an association between early-life antibiotic use and the risk of ADHD and ASD in a discordant twin study, indicating that gut microbiota perturbations during critical developmental windows may have long-term neurological consequences. Bundgaard-Nielsen et al (82) reported distinct microbiota compositions in children and adolescents with ADHD and ASD, suggesting shared and unique gut microbiota signatures across neurodevelopmental disorders. Nevertheless, a meta-analysis of 14 pediatric ASD cohorts found no consistent taxonomic signature after adjusting for diet and antibiotic exposure, highlighting the risk of over-interpreting small, uncontrolled studies (83).

Environmental factors and their impact on the gut-brain axis in neurodevelopmental disorders have also been explored. Gonçalves et al (84) demonstrated that exposure to high doses of amoxicillin causes behavioral changes and oxidative stress in young zebrafish, suggesting potential developmental consequences of antibiotic use. Volkova et al (85) found that early-life penicillin exposure alters frontal cortex and amygdala gene expression, highlighting the sensitivity of the developing brain to gut microbiota perturbations.

Research has shown that gut microbiota dysbiosis is associated with increased risk and severity of stroke. Benakis et al (86) demonstrated that commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells, highlighting the role of gut immunity in stroke pathogenesis. Dou et al (87) found that resveratrol exerts neuroprotection against focal cerebral ischemia/reperfusion injury in mice through a mechanism targeting the gut-brain axis. Bonsack et al (88) discussed the active role of the gut-brain axis in homeostasis and dysbiosis related to stroke. A review highlighted that cerebral ischemia-reperfusion injury triggers gut dysbiosis-mediated neuroinflammation via TLR4/NF-κB signaling and elevated IL-6/TNF-α levels (89). FMT from healthy donors restored Lactobacillus abundance and attenuated microglial activation in rodent stroke models.

Recent studies have focused on the therapeutic potential of targeting the gut microbiota in stroke (89). Park et al (90) reported that reproductive senescence and ischemic stroke remodel the gut microbiome and modulate the effects of estrogen treatment in female rats. Sadler et al (91) found that SCFAs improve poststroke recovery via immunological mechanisms, suggesting a potential therapeutic avenue. Aswendt et al (92) demonstrated that the gut microbiota modulates brain network connectivity under physiological conditions and after acute brain ischemia, indicating its role in both health and disease states.

Environmental factors and their impact on the gut-brain axis in stroke have also been explored (93). Henry et al (94) found that SCFAs taken at the time of thrombectomy in patients with acute ischemic stroke are associated with inflammatory markers and worse symptoms at discharge, suggesting complex interactions between gut metabolites and clinical outcomes. Jiang et al (95) reported alterations in the gut microbiome and correlated lipid metabolism in post-stroke depression, indicating potential metabolic links between gut dysbiosis and neurological symptoms.

Research has shown that gut microbiota dysbiosis is associated with increased risk and severity of epilepsy. Huang et al (96) demonstrated distinct gut microbiota composition and functional categories in children with cerebral palsy and epilepsy, suggesting a potential link between gut dysfunction and seizure activity. Lindefeldt et al (97) reported that the ketogenic diet influences the taxonomic and functional composition of the gut microbiota in children with severe epilepsy, indicating that dietary interventions can modulate gut microbiota to reduce seizure frequency.

Previous studies have focused on the therapeutic potential of targeting the gut microbiota in epilepsy. He et al (98) described a pediatric case where FMT cured epilepsy in a patient with Crohn's disease, highlighting the potential of microbiota-based therapies. Avorio et al (99) found that functional gastrointestinal disorders are common in patients with epilepsy and may influence seizure occurrence, suggesting that targeting gut dysfunction could improve seizure control.

The mechanism underlying the gut-brain axis in epilepsy has also been explored. Citraro et al (100) provided the first evidence of altered microbiota and intestinal damage in a genetic animal model of absence epilepsy, the WAG/Rij rat, indicating a potential pathway linking gut dysfunction to seizure activity (100). Gallucci et al (101) proposed that gut metabolites may modulate neuronal excitability and contribute to epileptogenesis, suggesting new therapeutic targets.

Emerging evidence highlights that dysregulation of the gut-brain axis contributes to neuroinflammation and systemic immune activation in neurological diseases. For instance, alcohol-induced intestinal hyperpermeability in rats promotes systemic endotoxemia, characterized by elevated LPS levels. This activates TLR4 signaling in peripheral immune cells and the brain, exacerbating neuroinflammatory cascades (102). TLR4 activation has been directly implicated in PD pathogenesis, as demonstrated by elevated TLR4 expression in both human patients and murine models with PD, driving microglial activation and dopaminergic neuron loss (51).

Gut microbiota-derived metabolites play dual roles in modulating neuroimmune responses. SCFAs, such as propionate, exhibit protective effects by reinforcing the BBB and suppressing pro-inflammatory cytokine production (for example, IL-6 and TNF-α) through histone deacetylase inhibition (103). Conversely, dysbiosis-associated reductions in SCFA-producing bacteria (for example, Faecalibacterium) correlate with increased CNS immune activation, as observed in HIV-associated neurocognitive disorders (104). Notably, sex-specific differences in gut-immune interactions have been reported; early-life adversity in mice induces persistent gut dysbiosis and neuroinflammation in males but not females, linked to altered IL-10/IL-17A balance and microglial priming (105,106).

The gut microbiome also influences peripheral immune cell trafficking to the brain. In a mouse model of ASD, prepubertal microbiota depletion alters T helper cell polarization, leading to aberrant IFN-γ and IL-17A levels in the prefrontal cortex, which disrupts synaptic plasticity and exacerbates behavioral deficits (107). Similarly, neonatal immune challenges in rodents induce gut-mediated Th1/Th2 imbalances, promoting hippocampal microglial activation and anxiety-like behaviors in adulthood (106). Therapeutic interventions targeting gut-immune crosstalk, such as high-dose probiotics, have shown efficacy in attenuating CNS inflammation by restoring regulatory T cell (Treg) function and reducing monocyte activation (104,108).

Recent studies further implicate gut-derived extracellular vesicles and bacterial amyloid proteins in priming peripheral immune cells to cross-react with CNS antigens, potentially initiating autoimmune-driven neuroinflammation (109,110). For example, microbiome-induced molecular mimicry between microbial peptides and α-synuclein may contribute to PD pathogenesis by eliciting cross-reactive T cell responses (51,111). Additionally, gut dysbiosis in AD correlates with increased cerebral LPS levels and NLRP3 inflammasome activation, suggesting a feedforward loop between peripheral inflammation and neurodegenerative processes (111,112).

The gut microbiota exerts profound influence over central and peripheral neurotransmitter systems, modulating behaviors and disease progression through bidirectional gut-brain communication. For example, Bifidobacterium dentium colonization in mice elevates GABA levels by upregulating glutamate decarboxylase activity, correlating with reduced anxiety-like behaviors and altered hippocampal GABA receptor expression (113). Similarly, gut-resident Escherichia coli strains producing pyrroloquinoline quinone mitigate oxidative stress-induced dopamine depletion in rodent models of neurotoxicity, preserving striatal dopaminergic function (114).

Dysbiosis-driven neurotransmitter imbalances are increasingly implicated in neurological disorders. In a MPTP-induced PD mouse model, gut microbiota disruption precedes dopaminergic neuron degeneration, accompanied by diminished colonic serotonin (5-HT) and elevated cerebral norepinephrine, suggesting microbiota-dependent regulation of monoamine metabolism (115). Notably, Lactiplantibacillus plantarum supplementation restores CUMS-induced depressive behaviors in mice by normalizing gut microbial diversity and increasing prefrontal cortical 5-HT and brain-derived neurotrophic factor (BDNF) levels, highlighting therapeutic potential (116).

Dietary factors further shape neurotransmitter dynamics via microbiota-mediated pathways. High-sugar/high-fat diets reduce fecal Lactobacillus abundance, impairing tryptophan metabolism and lowering hippocampal 5-HT synthesis, which disrupts synaptic plasticity and memory consolidation (117). Conversely, melatonin attenuates caffeine-induced zebrafish hyperactivity by rescuing gut microbial diversity and rebalancing dopamine/GABA ratios in the brain, underscoring diet-microbiota-neurotransmitter interplay (118).

Emerging evidence links environmental toxins to gut-mediated neurotransmitter dysregulation. Methylmercury exposure alters Bacteroidetes-to-Firmicutes ratios, suppressing colonic dopamine and 5-HT synthesis while elevating glutamate in the hippocampus, a phenotype reversible by Akkermansia-enriched probiotics (119). Aluminum oxide nanoparticles, commonly used in food additives, accumulate in juvenile rat brains, reducing striatal dopamine and serotonin while increasing pro-inflammatory cytokines, effects exacerbated by gut barrier leakage (120).

Advanced multi-omics approaches reveal novel microbiota-neurotransmitter networks in disease. In arteriosclerotic cerebral small vessel disease, decreased gut Roseburia and Faecalibacterium correlate with disrupted tryptophan-kynurenine pathways and reduced cortical GABA, implicating microbial regulation of neurovascular coupling (121). Similarly, Salvia officinalis extracts ameliorate neuroinflammation by modulating gut microbial bile acid metabolism, which enhances hypothalamic dopamine signaling and suppresses TNF-α-driven neuronal apoptosis (122).

Indole-3-lactic acid, a tryptophan metabolite produced by Lactobacillus spp., protects against neuroinflammation by activating aryl hydrocarbon receptor signaling in microglia (34). Conversely, dysbiotic expansion of Eggerthella lenta increases kynurenine/tryptophan ratios, exacerbating neurotoxicity via quinolinic acid production in MS models (35). These findings underscore microbial tryptophan catabolism as a key regulator of neurotransmitter balance (serotonin depletion) and neurodegeneration in neurological disorders (34).

The gut microbiota plays a critical role in modulating oxidative stress within the gut-brain axis, with dysbiosis exacerbating reactive oxygen species (ROS) accumulation and impairing antioxidant defenses in neurological diseases. For instance, Lactobacillus rhamnosus-derived exopolysaccharides mitigate D-galactose-induced brain aging in mice by activating nuclear factor erythroid 2-related factor 2 (NRF2), thereby upregulating superoxide dismutase (SOD) and glutathione peroxidase activity while reducing hippocampal lipid peroxidation (123). Similarly, heat-eliminated Levilactobacillus brevis KU15152 attenuates H₂O₂-induced oxidative damage in neuronal cells by enhancing SOD1 expression, highlighting strain-specific antioxidant properties (124).

Gut barrier dysfunction amplifies systemic oxidative stress via microbial translocation. In a rotenone-induced zebrafish model of PD, intestinal hyperpermeability promotes ROS overproduction in the brain, which is reversed by caprylic acid through restoration of tight junction proteins and suppression of NADPH oxidase 2 activity (125). Notably, Lactiplantibacillus plantarum GOLDGUT-HNU082 alleviates MPTP-induced dopaminergic neuron loss by reducing colonic LPS leakage and inhibiting NLRP3 inflammasome-driven oxidative stress in the substantia nigra (126).

Dietary interventions targeting the microbiota-gut-brain axis demonstrate therapeutic potential. Soy protein supplementation enhances cognitive function in mice by increasing hippocampal nerve growth factor levels and reducing ROS, effects mediated by Lactobacillus-enriched gut microbiota and upregulated fecal butyrate production (127). Conversely, high-dose amoxicillin exposure in zebrafish depletes Bifidobacterium, disrupts glutathione metabolism, and induces behavioral deficits linked to cerebral oxidative damage. Intriguingly, calorie restriction combined with spinach thylakoids in obese women with polycystic ovary syndrome lowers serum 8-OHdG (a DNA oxidative marker) and rescues gut Akkermansia abundance, suggesting microbiota-dependent redox balance (128). Emerging evidence implicates microbial metabolites in redox signaling. Butyrate rescues oxidative stress-induced tryptophan transport deficits in intestinal epithelial cells, preserving serotonin synthesis and mitigating depressive-like behaviors in mice (129). In AD models, hydrogen-rich water restores gut Roseburia levels, which correlates with reduced hippocampal malondialdehyde and enhanced SOD2 activity via the BDNF/TrkB pathway (130). Furthermore, Lactobacillus supernatants suppress microglial ROS production by modulating NRF2-SOD1 crosstalk, offering a novel anti-inflammatory strategy for neuroprotection (131).

Clinical studies underscore translational relevance. Probiotic supplementation in patients with AD reduces plasma 8-isoprostane (a lipid peroxidation marker) and elevates BDNF, correlating with improved cognitive scores (132,133). Similarly, Agaricus mushroom-enriched diets in mice lower cortical ROS and normalize gut Bacteroides populations, highlighting diet-microbiota interactions in antioxidant defense (134).

Gut microbiota-derived metabolites regulate BBB permeability through structural and functional adaptations. For instance, microbial SCFAs, such as propionate, enhance BBB integrity by upregulating tight junction proteins (for example, occludin and claudin-5) and reducing systemic inflammation (103,135). Similarly, the microbial co-metabolite p-cresol glucuronide strengthens BBB function in vivo by suppressing pro-inflammatory cytokines and preserving endothelial cell junctions (136). Conversely, dysbiosis-induced uremic toxins, such as indoxyl sulfate, compromise BBB tightness by activating oxidative stress pathways, a mechanism attenuated by polyphenol-rich dietary interventions that restore microbial balance (137,138).

BBB disruption is increasingly recognized in neurodevelopmental and neurodegenerative disorders. In ASD, dual impairment of the BBB and intestinal epithelial barrier correlates with elevated circulating neuroinflammatory markers, suggesting a 'leaky gut-leaky brain' axis (139). Furthermore, gut microbiome depletion via antibiotics exacerbates BBB permeability, facilitating monocyte infiltration into the brain-a process linked to post-infection cognitive deficits (140). In hypertension-related stroke models, gut dysbiosis promotes BBB breakdown through systemic endotoxemia and endothelial activation, underscoring microbiota-driven vascular pathology (141).

Therapeutic modulation of the gut-BBB axis shows promise. Microbial-derived metabolites, such as butyrate, induce actin cytoskeletal rearrangements in brain endothelial cells, enhancing barrier resilience against inflammatory insults (142). Non-invasive vagus nerve stimulation mitigates ischemia-induced BBB damage by regulating mast cell degranulation via the microbiota-gut-brain axis, highlighting neuro-modulatory approaches (143). Additionally, precocious gut maturation through dietary interventions stabilizes BBB development in early life by shaping microbiota-host metabolic crosstalk (144).

However, not all gut signals permeate the BBB. Phoenixin-14, a neuropeptide implicated in stress responses, fails to cross in vitro BBB models, emphasizing selective transport mechanisms (145). This selectivity underscores the need for targeted delivery strategies when leveraging gut-derived molecules for neurological therapies. In summary, the BBB serves as both a gatekeeper and a sensor of gut-derived mediators, with its permeability dynamically shaped by microbial metabolites, systemic inflammation and host-microbe interactions. Restoring BBB integrity via microbiota-centric interventions represents a novel avenue for treating neurological diseases characterized by barrier dysfunction.

Despite converging evidence that gut-brain axis disruption participates in neurological disease, several mechanistic questions remain contentious. First, the temporal and causal relationship between dysbiosis and disease phenotype is unresolved: Mendelian randomization studies yield conflicting signals-some supporting a causal role of reduced SCFA-producers in MS, others finding no causal link in AD-highlighting the need for longitudinal, diet-controlled human cohorts and gnotobiotic humanized-mouse validation. Second, the therapeutic window and inter-individual heterogeneity of SCFA supplementation are unclear; butyrate attenuates neuro-inflammation in AD models yet exacerbates inflammatory markers in a subset of post-stroke patients with high baseline LPS, underscoring the necessity for baseline microbiome/metabolome stratification in future RCTs. Third, extrapolation from germ-free rodent data is limited by the absence of human-equivalent mucosal immunity and dietary complexity; therefore, human intestinal organoid-microbiota co-cultures and phase-0 micro-dosing trials are required. Finally, the 'microbial amyloid' hypothesis-where bacterial curli fibers seed α-synuclein aggregation-remains correlative; targeted metagenomic surveys and CRISPR knock-out of curli operons in gnotobiotic mice are proposed as definitive tests. These challenges emphasize the need for standardized multi-omics protocols and precision-medicine frameworks to reconcile associative evidence with causality.

Dietary interventions have emerged as a promising approach to modulate the gut-brain axis and improve neurological health. The Mediterranean diet, rich in vegetables, fruits, whole grains, legumes and olive oil, has been associated with beneficial effects on cognitive function and a reduced risk of neurodegenerative diseases. This diet promotes a healthy gut microbiota composition, increasing the abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus, which produce SCFAs that exert anti-inflammatory effects and enhance gut barrier function. For example, Solch et al (146) found that adherence to the Mediterranean diet was associated with a lower risk of AD. The mechanisms underlying this effect may involve the production of SCFAs, which can modulate neuroinflammation, reinforce the BBB, and regulate neurotransmitter synthesis.

The ketogenic diet, high in fats and low in carbohydrates, has also gained attention for its neuroprotective effects, particularly in epilepsy and neurodegenerative disorders. By inducing ketosis, this diet alters the metabolic landscape of the brain, providing alternative energy substrates and reducing oxidative stress. Lussier et al (147) demonstrated that the ketogenic diet could inhibit tumor growth in a mouse model of glioblastoma multiforme. In addition to its direct metabolic effects, the ketogenic diet can also influence gut microbiota composition, increase the relative abundance of beneficial bacteria and reduce pathogenic species. This modulation of the gut microbiota may contribute to the diet's therapeutic effects on neurological diseases.

Fiber supplementation and prebiotics represent another avenue for targeting the gut-brain axis. Berding et al (148) demonstrated that supplementing with microbiota-accessible carbohydrates can prevent neuroinflammation and cognitive decline by improving the gut microbiota-brain axis in diet-induced obese mice. This evidence underscores the potential of fiber supplementation and prebiotics in modulating the gut-brain axis for neurological health. Alcohol addiction exacerbates gut dysbiosis in patients with minimal hepatic encephalopathy, further impairing cognitive function through increased gut-derived ammonia and systemic inflammation (149).

Specific probiotic strains have been investigated for their effects on neurodegenerative and neuroinflammatory diseases. For instance, Lactobacillus and Bifidobacterium strains have demonstrated the ability to produce neurotransmitters such as GABA, serotonin and dopamine, which can influence brain function and behavior. Bravo et al (150) found that administration of Lactobacillus rhamnosus to mice reduced anxiety-like behavior and altered GABA receptor expression in the brain. In animal models of AD, probiotic supplementation with strains such as Lactobacillus plantarum and Bifidobacterium longum has been shown to reduce amyloid-beta pathology and improve cognitive performance. Srivastav et al (52) demonstrated that a probiotics mixture increased butyrate levels, which rescued nigral dopaminergic neurons from MPTP and rotenone-induced neurotoxicity.

Clinical trials in humans have also provided encouraging results. An RCT by Chong et al (151) found that Lactobacillus plantarum DR7 alleviated stress and anxiety in adults. Lew et al (152) showed that Lactobacillus plantarum P8 alleviated stress and anxiety while enhancing memory and cognition in stressed adults. In patients with major depressive disorder, probiotic supplementation has been associated with improvements in mental status, inflammation and intestinal barrier function. Karakula-Juchnowicz et al (153) evaluated the effect of probiotic supplementation on the mental status, inflammation and intestinal barrier in patients with major depressive disorder using a gluten-free or gluten-containing diet. The results showed that probiotic supplementation improved mental status and reduced inflammation in both groups.

FMT, the transfer of microbiota from a healthy donor to a recipient, has gained interest as a therapeutic approach for neurological diseases. FMT aims to restore a healthy gut microbiota composition and function, potentially reversing dysbiosis-associated neurological pathology. Preclinical studies have shown promising results in various neurological disease models. Cheng et al (154) investigated the efficacy of FMT in patients with PD. The results showed that FMT improved motor symptoms and quality of life in patients with PD. These preliminary data (n=47) lack blinding and showed transient engraftment (<8 weeks) in 30% of recipients. Adverse events including bloating (23%) and transient delirium (4%) further caution against uncritical adoption outside controlled trials.

However, translating these findings to clinical practice presents several challenges. The mechanisms underlying FMT's therapeutic effects remain incompletely understood, and there is a need for standardized protocols regarding donor selection, preparation of fecal microbiota, and administration routes. Additionally, safety concerns related to the transmission of pathogens or harmful metabolites necessitate rigorous screening of donors and donor materials. Despite these challenges, ongoing clinical trials are exploring the efficacy and safety of FMT in neurological conditions such as MS, AD and PD, which may provide valuable insights into its therapeutic potential in the near future.

Pharmacological strategies targeting microbiota-derived metabolites offer another avenue for modulating the gut-brain axis. SCFAs analogs and bile acid sequestrants represent two classes of agents with potential therapeutic applications in neurological diseases. Dalile et al (155) demonstrated that colon-delivered SCFAs attenuated the cortisol response to psychosocial stress in healthy men.

Bile acid sequestrants, such as cholestyramine, bind to bile acids in the gut, altering their enterohepatic circulation and potentially modulating bile acid signaling pathways. Recent research has shown that bile acids can influence gut microbiota composition and immune responses, suggesting that sequestrants may indirectly affect the gut-brain axis. In animal models of PD, cholestyramine treatment reduced alpha-synuclein pathology and improved motor function, highlighting the potential of this approach in neurodegenerative diseases. Lei et al (156) demonstrated that disulfiram ameliorated nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism.

Immune modulators and anti-inflammatory agents represent a broad category of pharmacological interventions with potential applications in targeting the gut-brain axis. For instance, anti-tumor necrosis factor (TNF) agents, such as infliximab and adalimumab, have been used in the treatment of IBD and have shown promise in ameliorating neurological symptoms in patients with comorbid IBD and neurological disorders. Similarly, interleukin (IL)-17 and IL-23 inhibitors are being investigated for their potential to modulate neuroinflammation in conditions such as MS and PD. Fleck et al (157) found that dietary conjugated linoleic acid links reduced intestinal inflammation to amelioration of CNS autoimmunity.

Recent clinical trials have explored the use of these agents in neurological diseases. A phase II trial of the IL-17 inhibitor secukinumab in patients with relapsing-remitting MS demonstrated a reduction in disease activity and MRI lesions, suggesting a potential role for targeting IL-17 signaling in this condition. Additionally, the TNF inhibitor etanercept has shown beneficial effects in patients with PD, with improvements in motor symptoms and quality of life. These findings highlight the potential of immune modulators in targeting gut-brain pathways for neurological health.

Advances in synthetic biology and genetic engineering have paved the way for the development of engineered microbiota with tailored functions for therapeutic applications. These engineered bacteria can be designed to produce specific metabolites, enzymes, or anti-inflammatory molecules that target key pathways in neurological diseases. Martin et al (158) demonstrated that metabolome-associated psychological comorbidities improved in patients with irritable bowel syndrome receiving a probiotic. Moreover, synthetic biology approaches allow for the creation of bacteria with sensing and responsive capabilities, enabling them to detect specific disease biomarkers and release therapeutic agents in a targeted manner. This precision medicine approach could enhance the efficacy and safety of microbiota-based therapies for neurological disorders. Mysonhimer et al (159) found that prebiotic consumption alters microbiota but not biological markers of stress and inflammation or mental health symptoms in healthy adults.

Nanomedicine and advanced drug delivery systems offer innovative strategies to enhance the targeting and efficacy of therapeutics aimed at the gut-brain axis. Nanoparticles can be engineered to encapsulate drugs, probiotics, or bioactive compounds, protecting them from degradation and enabling controlled release at specific sites along the gastrointestinal tract. For instance, chitosan nanoparticles loaded with curcumin, a polyphenol with anti-inflammatory and antioxidant properties, have shown enhanced bioavailability and therapeutic efficacy in animal models of AD and PD. These nanoparticles can traverse the BBB and deliver curcumin to the brain, where it exerts neuroprotective effects. Similarly, lipid-based nanoparticles have been used to deliver probiotics to the gut, improving their survival and colonization efficiency. Li et al (160) investigated the effects of Bifidobacterium breve 207-1 on regulating lifestyle behaviors and mental wellness in healthy adults based on the microbiome-gut-brain axis. The results showed that Bifidobacterium breve 207-1 improved mental wellness and regulated lifestyle behaviors in healthy adults.

Additionally, targeted drug delivery systems can be designed to specifically interact with gut microbiota or immune cells, modulating their function in a precise manner. For example, antibody-conjugated nanoparticles can target specific bacterial strains or immune cells, delivering therapeutic agents directly to the site of action. These approaches hold promise for improving the therapeutic index of existing drugs and developing novel interventions for neurological diseases by leveraging the gut-brain axis. Casertano et al (161) demonstrated that GABA-producing lactobacilli boost cognitive reactivity to negative mood without improving cognitive performance.