Front. Immunol. Frontiers in Immunology Front. Immunol. 1664-3224 Frontiers Media S.A. 10.3389/fimmu.2025.1739329 Mini Review The gut microbiota influences neurodegenerative diseases through the gut-brain axis: molecular mechanisms and effects on immune function YangJiaheng 1 Writing – review & editing Writing – original draft Conceptualization SongXiangzhun 2 Writing – review & editing Conceptualization YanSu 2 Formal analysis Writing – review & editing LiQianxun 2 Writing – review & editing Formal analysis YangWenying 2 * Writing – review & editing Clinical College of Medicine, Changchun University of Chinese Medicine, Changchun, China Department of Gastroenterology, Jilin Province People’s Hospital, Changchun, Jilin, China Correspondence: Wenying Yang, 1332041932@qq.com 12 01 2026 2025 16 1739329 04 11 2025 15 12 2025 12 12 2025 Copyright © 2026 Yang, Song, Yan, Li and Yang. 2026 Yang, Song, Yan, Li and Yang https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

The pathogenesis of neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is complex and multifactorial. Recent studies indicate that the microbiota-gut-brain axis (MGBA) plays a crucial role in the development and progression of NDDs. The MGBA concept reveals a complex bidirectional regulatory network between the gut microbiota and the central nervous system (CNS), linking them through immune, neural, endocrine, and metabolic pathways. This review summarizes the components of the MGBA, communication pathways between gut microbiota and the brain, and mechanisms by which gut microbiota influence the onset and progression of NDDs. Finally, preclinical therapeutic approaches for NDDs are discussed, evaluating preclinical trial data for probiotics, prebiotics, and fecal microbiota transplantation.

 AD fecal microbiota transplantation gut-microbiota-brain axis NDDs PD The author(s) declared that financial support was not received for this work and/or its publication. section-at-acceptance Multiple Sclerosis and Neuroimmunology Introduction

Neurodegenerative diseases (NDDs) represent a complex class of disorders characterized by progressive loss of neuronal function or structure, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) (1). A common feature of these diseases is protein misfolding and aggregation, leading to neuronal death and dysfunction, which in turn causes impairment of cognitive, motor, or autonomic functions (2). In recent years, with the acceleration of global aging, the incidence of NDDs has significantly increased, becoming a major social and economic burden. Although traditional research has made some progress in the pathological mechanisms and therapeutic strategies of NDDs, their complex etiology and multifactorial interactions remain incompletely elucidated. The pathogenesis of NDDs involves multiple pathways, including pathological protein aggregation, synaptic dysfunction, protein homeostasis imbalance, mitochondrial dysfunction, neuroinflammation, ferroptosis, and interactions between genetic and environmental factors (3–5). With advances in biology, the role of gut microbiota in NDDs has garnered widespread attention. Research indicates that gut microbiota influence brain function through multiple pathways, including neural, endocrine, immune, and metabolic systems. Their dysregulation is closely associated with the pathological processes of NDDs such as AD and PD (6). Specifically, the gut microbiota communicates bidirectionally with the CNS via the gut-brain axis (GBA), a mechanism involving multifaceted regulation of endocrine, immune, and neural signaling (7).

The Microbiota-Gut-Brain Axis (MGBA) theory reveals a complex bidirectional regulatory network between the gut microbiota and the CNS, offering new insights into the pathological mechanisms of NDDs (8). Dysregulation of the MGBA is considered a key component in the pathogenesis of NDDs. Research indicates that the gut microbiota directly influences CNS function and homeostasis by modulating immune responses, neurotransmitter synthesis, metabolite production, and blood-brain barrier (BBB) permeability (9). For example, short-chain fatty acids (SCFAs) and neuroactive metabolites (e.g., 5-Hydroxytryptamine and dopamine) produced by the gut microbiota can be transported to the brain via the GBA, regulating neuronal activity and microglial function (10). Furthermore, gut microbiota dysbiosis (i.e., gut microbial imbalance) can induce systemic inflammation and oxidative stress, thereby promoting the pathological progression of NDDs (11, 12). Research indicates that dysbiosis of the gut microbiota may compromise the integrity of the BBB by inducing systemic chronic inflammation (SCI) and abnormal immune responses, ultimately leading to neuroinflammation and neurodegeneration (13, 14).

Therefore, this paper introduces the gut microbiota and its metabolites, and reviews the effects of gut microbes on the nervous system via the GBA. Subsequently, it highlights the effects of gut microbiota on the immune system in NDDs such as AD, PD, and ALS, and explores interventions targeting the gut microbiota as potential therapeutic targets for NDDs. This aims to enhance understanding of the pathogenesis of NDDs and provide new targets and therapeutic approaches for their treatment.

 Gut microbiota-gut-brain axis

The core components of the MGBA include the gut microbiota, intestinal epithelial barrier, enteric nervous system (ENS), immune system, endocrine system, and CNS. It not only regulates digestive system functions but also profoundly influences brain development and the onset and progression of various neurological disorders (15).

Components of the gut microbiota-gut-brain axis

The gut microbiota refers to the vast microbial community residing within the human gastrointestinal tract, comprising bacteria, viruses, fungi, and archaea, numbering in the trillions (16). These microorganisms not only participate in digestion, nutrient absorption, and vitamin synthesis but also interact with the host’s immune, nervous, and metabolic systems through complex signaling networks, forming the so-called “gut-microbiota-host axis” (17). Through symbiosis with the host, gut microbes interact via metabolites, neurotransmitters, and immune signals. Metabolic products of gut microbes include short-chain fatty acids (SCFAs), secondary bile acids, indole compounds, trimethylamine N-oxide (TMAO), and various gas molecules (e.g., H2S, NO, and CO) (18, 19). In addition to metabolic roles, the gut microbiota is essential for immune regulation. It guides the differentiation and function of immune cells—including T cells and dendritic cells-thereby upholding systemic immune homeostasis (20). Furthermore, by reinforcing the integrity of the intestinal epithelial barrier, the microbiota helps prevent translocation of pathogenic organisms and harmful agents, playing a critical role in host defense and overall health (21).

The intestinal epithelial barrier constitutes the primary physical and immunological line of defense, selectively restricting the passage of harmful agents into systemic circulation while actively communicating with the gut microbiota via chemosensory receptors and tight junction proteins (22). Its structural and functional integrity is essential for sustaining a stable host-microbiota relationship and preventing aberrant immune activation (23).

A second critical component is the ENS, a subdivision of the peripheral nervous system composed of intrinsic neurons and glial cells that autonomously regulate gut motility, secretion, and absorption (24). The ENS maintains bidirectional communication with the CNS through vagal and spinal pathways, forming a key neural relay within the MGBA (25). The CNS, encompassing the brain and spinal cord, receives and integrates signals from the gut through neural, endocrine, and immune pathways, thereby influencing behavior and cognitive function (26). Simultaneously, the gut-resident immune system engages in continuous interaction with commensal microbiota, deploying cytokines and inflammatory mediators that influence both local intestinal function and central nervous integrity. Dysregulation of this crosstalk has been associated with the pathophysiology of several neuropsychiatric conditions, including anxiety, depression, Major Depressive Disorder (MDD), and bipolar disorder (BD) (27, 28). Furthermore, systemic immune and endocrine pathways contribute to gut–brain signaling through circulating cytokines, hormones, and neuropeptides, collectively enabling multi-level communication across the MGBA (26).

 Functions of the gut microbiota-gut-brain axis

The MGBA exerts broad influence on neurodevelopment, behavioral modulation, and disease susceptibility through multiple interconnected pathways. One primary mechanism involves the microbial production of signaling molecules—such as short-chain fatty acids (e.g., butyrate), neurotransmitters (e.g., serotonin and GABA), and indole-derived metabolites—that directly or indirectly shape neuronal plasticity and synaptic function (29). Research indicates that the gut microbiota influences serotonin synthesis by regulating the tryptophan metabolic pathway, thereby modulating mood and cognitive function (30).

Additionally, the gut microbiota regulates neuroinflammatory tone and neuroprotective mechanisms through vagus nerve activation and immune modulation. For example, in AD models, altered gut microbiota reduced neuroinflammation and cognitive impairment by increasing indole-3-acetic acid levels (31). The microbiota also contribute to neurodegenerative pathology by dynamically regulating BBB permeability, thereby controlling the CNS exposure to circulating metabolites and neurotransmitters (32).

When the composition of the gut microbiota changes-a condition known as dysbiosis-it may trigger a series of pathophysiological responses (33). This process promotes systemic immune activation (21, 34). Inflammatory signals are then relayed to the CNS via immune and neuroendocrine routes, ultimately driving neuroinflammation and neurodegeneration (33). Accumulating evidence underscores a strong association between gut microbiome dysbiosis and the pathogenesis of several neurodegenerative disorders, including AD, PD, and multiple sclerosis (MS) (35).

 Core communication pathways

MGBA constitutes a complex bidirectional communication network that facilitates information exchange between gut microbiota and the CNS through multiple pathways (Figure 1). These core pathways include neural, immune, metabolic, and endocrine mechanisms, which together mediate gut-brain crosstalk.

The communication pathway of gut microbiota-gut-brain axis in healthy status and the effect of gut microbial Dysbiosis on nerves in neurodegenerative diseases.

Infographic contrasting health status and neurodegenerative disease status, showing pathways like immune, metabolic, and endocrine. Illustrates effects on the gut-brain axis, including neurotransmitter and cytokine interactions, alongside depictions of intestinal barriers, neuronal pathways, and blood vessels. Highlights conditions such as inflammation, dysbiosis, leaky gut, and blood-brain barrier disruption. Includes various cells, metabolites, and bacteria types, depicting their roles in maintaining health or contributing to disease. Neural pathways

Current research suggests that the neural pathways of the MGBA predominantly consist of the vagus nerve pathway, spinal cord afferent pathways, and local neural circuits mediated by the ENS (36). The vagus nerve serves as the most direct neural link between the gut and the brain. Gut microbes activate the vagus nerve via metabolites, thereby influencing brain functions including emotional regulation and cognitive performance (37). Additionally, the ENS—intrinsically organized with local neural networks—interacts with gut microbes and relays signals centrally, indirectly influencing brain activity and behavior (38). The spinal afferent pathways transmit mechanical and chemical stimuli from the distal gut, including the colon, to the central nervous system via dorsal root ganglion (DRG) neurons (39). The characteristic of the DRG whereby a single neuron innervates multiple targets allows the same sensory neuron to integrate heterogeneous signals from multiple levels of the intestine and affect visceral perception and cognitive function via the spinal cord - thalamus - cortex pathway (39, 40).

 Immune pathways

Gut microbes regulate the activity of intestinal immune cells to release cytokines. These cytokines affect BBB permeability and brain inflammatory states via the bloodstream (22). Furthermore, microbial metabolites are capable of directly shaping microglial maturation and function, thereby influencing neurodevelopmental and neuroinflammatory processes (16, 41).

 Metabolic pathways

Short-chain fatty acids (e.g., butyrate, propionate) produced by gut microbes fermenting dietary fiber reach the brain via the bloodstream, regulating neuroinflammation and neurotransmitter synthesis (8). Gut microbes also synthesize or modulate neurotransmitter precursors (e.g., tryptophan, 5-hydroxytryptophan), which subsequently influence central neurotransmission via humoral or neural routes (42).

 Endocrine pathways

Gut microbiota influence the hypothalamic-pituitary-adrenal (HPA) axis by regulating the secretion of gut peptides and hormones, thereby modulating stress responses and mood (43). Additionally, microbial metabolites such as bile acids and ammonia may alter BBB permeability, further enabling direct modulation of CNS function (44).

 Microbial metabolites

Gut microbes directly synthesize a range of neuroactive molecules, including gamma-aminobutyric acid, which can influence CNS activity upon reaching the brain via circulation or neural pathways (45). Additionally, bacterial structural components such as lipopolysaccharide (LPS) act as potent immunostimulants; their systemic translocation can provoke immune activation and sustained neuroinflammation, thereby accelerating the progression of NDDs (44).

 Barrier function

The integrity of the intestinal barrier function is fundamental to MGBA communication. Dysbiosis of gut microbiota can lead to impaired intestinal barrier function, known as “leaky gut.” Leaky gut allows bacteria and their metabolites to enter the systemic circulation via the bloodstream, subsequently affecting the integrity of the BBB, triggering neuroinflammation and neuronal damage (46). Disruption of these barriers is closely associated with various neurological disorders, including autism and AD (47). In AD research, gut dysbiosis is significantly correlated with intestinal permeability, which accelerates neuroinflammation and Aβ deposition through BBB disruption (48).

 Gut microbiota dysbiosis in neuroinflammation and immune dysfunction

Gut microbiota dysbiosis is considered a key driver of neuroinflammation and immune dysfunction in NDDs (49). For example, mutations in the GBA1 gene can induce microbial imbalance, which in turn exacerbates PD pathology through neuroimmune activation (50). Supporting this, preclinical studies show that microbiota depletion markedly reduces neuroinflammation and ameliorates motor deficits in disease models (51).

In NDDs, the gut microbiota influences the immune system through multiple pathways. First, gut microbiota directly shape the phenotype and function of immune cells (52, 53). Furthermore, the gut microbiota influences neuronal survival and function by modulating the activity of myeloid cells such as macrophages and microglia (54). These cells play critical roles in clearing neurotoxic substances like amyloid plaques and regulating neuroinflammation (55). Studies have demonstrated that microglia, as the primary immune effector cells in the central nervous system, display an over - activated phenotype under conditions of intestinal flora imbalance. This results in the release of a substantial quantity of pro - inflammatory factors (e.g., IL - 1β, TNF - α), which in turn leads to neuronal damage and the specific loss of dopaminergic neurons (56). For example, in AD, amyloid proteins secreted by the gut microbiota can cross-aggregate with Aβ in the brain via a molecular mimicry mechanism, which exacerbates neuroinflammation and synaptic damage (57, 58).

From an immunological perspective, dysbiosis of the gut microbiota can result in the impairment of intestinal barrier function, which facilitates the translocation of bacteria and their metabolic products (e.g., lipopolysaccharides) into the circulatory system. Subsequently, this activates peripheral immune cells and initiates a systemic inflammatory response. These inflammatory mediators can impact the central nervous system through multiple pathways. Firstly, the disruption of the integrity of the BBB enables cytokines and immune cells to infiltrate the brain parenchyma. Secondly, peripheral immune signals can be transmitted to the central nervous system via the vagus nerve or directly act on brainstem circumventricular organs (e.g., the area postrema) (59). For example, in PD, the age-associated decline in immune system function, combined with long-term exposure to environmental factors like pesticides or pathogens, can be further aggravated by gut microbiota dysbiosis, creating an ideal situation that facilitates the pathological spread of α-synuclein (49). It is noteworthy that the gut microbiota also influences the production of kynurenine through the regulation of the tryptophan metabolic pathway. This metabolic product can not only exert an effect on the enteric nervous system, leading to intestinal dysfunction, but also cross the BBB to directly modulate the immune balance of the central nervous system (50, 60).

The gut microbiota also modulates bile acid and tryptophan metabolism, with downstream effects on neurotransmitter synthesis and neuronal viability (61). Specific tryptophan metabolites such as indole-3-acetaldehyde (I3AA) have been shown to regulate TGFβ signaling and CD4+ T cell differentiation, thereby exacerbating intestinal and neuroinflammation (62).

Collectively, the gut microbiota influences the MGBA through multiple core communication pathways-encompassing neural, immune, metabolic, endocrine, microbial metabolite, and barrier functions. These pathways are highly interconnected, forming an integrated network that collectively regulates bidirectional gut–brain communication and ultimately shapes host physiology and disease susceptibility. A deeper understanding of these mechanisms will not only help clarify the pathogenesis of NDDs but also provide a scientific rationale for developing novel microbiota-targeted therapeutic strategies.

 The role of the gut microbiota in neurodegenerative diseases

The MGBA, a bidirectional communication system, tightly links the gut microbiota with the CNS through neural, endocrine, and immune pathways, thereby playing a pivotal role in the pathogenesis of NDDs (31, 35, 63).

Alzheimer’s disease

As a NDDs, AD involves a complex pathogenesis encompassing multiple factors such as chronic neuroinflammation, Aβ, and abnormal tau phosphorylation. In AD, the gut microbiota influences disease progression by regulating Aβ deposition and tau hyperphosphorylation (55, 64). Gut microbiota dysbiosis has been demonstrated to be closely associated with AD pathogenesis. In AD patients, the abundance of Firmicutes and Bifidobacteria in the gut is reduced, while the abundance of Bacteroidetes and Proteobacteria is increased (65). This imbalance may induce “Leaky Gut” syndrome, allowing pathogen-associated molecular patterns (PAMPs) such as LPS to enter the bloodstream and trigger systemic low-grade inflammation (66). Research indicates that gut dysbiosis-induced intestinal permeability facilitates bacterial LPS and Aβ entry into the bloodstream, further activating microglia and exacerbating AD-associated neuroinflammation (67). Microglia, the primary immune cells of the CNS, exhibit dysfunction that constitutes a core pathological feature of AD. Certain gut microbial metabolites may induce abnormal activation of microglia and cross-seeding of amyloid through molecular mimicry mechanisms, further exacerbating AD pathology (68). Additionally, gut dysbiosis can cause astrocyte dysfunction, thereby impairing neuronal energy metabolism and antioxidant capacity, promoting neuronal degeneration (20). Microbial metabolites-including SCFAs, LPS, and trimethylamine N-oxide (TMAO)-also contribute to AD progression by enhancing systemic inflammation, disturbing cerebral Aβ clearance, and directly activating microglia, which intensifies neuroinflammation and neuronal injury (69–72). Moreover, gut microbes influence cognitive function in AD through the regulation of glutamate metabolism. Specific bacteria, such as Bacteroides vulgatus and Campylobacter jejuni, can lower levels of the glutamate metabolite 2-ketoglutarate, potentially altering NMDA receptor function and synaptic plasticity (73). Other microbiota-derived molecules, including secondary bile acids and tryptophan metabolites, may also modulate brain function and immune activity, thereby shaping AD trajectory (74).

Additionally, the interaction between the gut microbiota and the immune system constitutes a key mechanism in the onset and progression of AD. Research indicates that the efficacy of AD immunotherapies may partially depend on the regulatory role of the gut microbiota. For example, in AD mouse models, tau-targeted immunotherapy significantly alters the composition of the gut microbiota, thereby influencing treatment outcomes (75).

 Parkinson’s disease

Dysbiosis of the gut microbiota has been demonstrated to be closely associated with PD. In the research on biodiversity, the Simpson’s Index and the Species Evenness Index are frequently employed for assessment (76). Specifically, the Simpson’s Index is utilized to quantify the concentration or dominance within a community (77), while the Species Evenness Index is designed to measure the uniformity of the distribution of individual numbers of various species within a community (78). Studies report reduced Simpson and species evenness indices in PD patients, reflecting decreased microbial diversity and ecological imbalance (79). Characteristic shifts include a decline in Firmicutes abundance with concomitant increases in Bacteroidetes and Proteobacteria. The expansion of pro-inflammatory taxa can elevate circulating lipopolysaccharide (LPS), promoting systemic inflammation and potentially accelerating PD pathology (80, 81). These alterations may compromise intestinal barrier function, thereby promoting gut inflammation and systemic inflammatory responses that ultimately affect the CNS via the gut-brain axis (82). Indirectly, they regulate BBB permeability and neuroinflammatory responses, thereby affecting neuronal survival. For instance, probiotic supplementation with Bifidobacterium lactis MH-022 has been shown to improve motor function and neuronal integrity in PD models by enhancing antioxidant defenses and suppressing neuroinflammation (83). A central pathological feature of PD is the aggregation of α-synuclein. Gut dysbiosis may promote the misfolding and aggregation of α-synuclein in the ENS (84, 85). These pathological forms can potentially propagate to the CNS via the vagus nerve, leading to Lewy body formation and PD-related neurodegeneration (86, 87).

Microbial metabolites-including SCFAs, H2S, and tryptophan derivatives-also contribute to PD progression. SCFAs exhibit anti-inflammatory and neuroprotective effects; for instance, propionic acid exerts neuroprotection by activating the FFAR3 receptor, alleviating motor dysfunction and dopaminergic neuron loss in PD models (88). However, their levels are significantly reduced in PD patients, potentially diminishing their inhibitory effect on neuroinflammation (89). Other microbial metabolites, including H2S, Adenosine (ADO) and Quinolinic acid (QA) may promote oxidative stress and mitochondrial dysfunction, exacerbating neuronal injury (90–95).

Immune regulation represents another key mechanism by which the gut microbiota influences PD. Research indicates that in PD, the gut microbiota affects immune responses and neuronal function by regulating amino acid metabolism (e.g., branched-chain amino acids and aromatic amino acids) (96). Alterations in microbial composition can activate innate and adaptive immunity, leading to sustained neuroinflammation and neuronal damage (83). For example, certain gut bacteria (e.g., Ruminococcaceae) can enhance immune responses by activating dendritic cells (DCs) and CD8+ T cells (97). Furthermore, dysbiosis may promote α-synuclein aggregation and propagation by modulating Toll-like receptor (TLR) signaling pathways (98).

 Amyotrophic lateral sclerosis

ALS is a progressive NDDs characterized by the selective loss of motor neurons. Its pathogenesis is multifactorial, involving a complex interplay of genetic, epigenetic, and environmental influences (99). In recent years, the gut microbiota has emerged as a key modulator in ALS pathophysiology, primarily through its role in the bidirectional GBA that links the gastrointestinal tract with the CNS (100).

Patients with ALS exhibit decreased gut microbial diversity and significant compositional shifts, including an increased abundance of Enterobacteriaceae and reduced levels of beneficial genera such as Bifidobacterium and Clostridium sensu stricto (101–103). This dysbiotic state can trigger non-cell-autonomous neuroinflammation by activating microglia and astrocytes, thereby accelerating motor neuron injury (99). Furthermore, impaired intestinal barrier integrity-driven by microbial imbalance-facilitates the systemic translocation of bacterial metabolites and pro-inflammatory mediators, which may subsequently compromise CNS immune homeostasis (104).

Notably, microbial metabolites play a dual role in ALS progression. SCFAs such as butyrate exert anti-inflammatory and neuroprotective effects, yet their levels are often diminished in ALS patients (105). Similarly, SCFAs can directly stimulate the vagus nerve, thereby regulating inflammatory responses and neuroprotective mechanisms within the CNS (106). The gut microbiota further influences ALS by shaping peripheral immune responses. Dysregulation promotes the infiltration and skewed differentiation of T cell populations-such as an imbalance between Th17 and Treg cells-which amplifies neuroinflammation and motor neuron damage (99).

Metagenomic analyses also reveal marked alterations in microbial metabolic pathways in ALS, particularly those involved in neurotransmitter synthesis and neuroprotection (107). For instance, tryptophan metabolites produced by the gut microbiota-such as serotonin and kynurenine-exhibit dysregulation in ALS patients, with elevated kynurenine levels closely linked to neuroinflammation and oxidative stress (108).

In summary, the gut microbiota contributes to NDDs pathogenesis through metabolite signaling, immune modulation, and gut-brain communication. However, given the rapid progression and heterogeneity of NDDs, the precise causal role of microbial communities remains incompletely defined. Future studies should focus on elucidating the specific mechanisms underlying gut-brain interactions in NDDs and evaluating the translational potential of microbiota-targeted interventions.

 Therapeutic measures based on gut microbiota

Based on the cognitive advancement that gut microbiota influences NDDs via the MGBA, the treatment regimens for NDDs have gradually broadened from single neural therapy to the regulation of gut microbiota. Probiotics (beneficial live microorganisms) and prebiotics (dietary components that stimulate the growth of beneficial bacteria) for regulating the intestinal flora have emerged as a highly promising novel treatment and prevention strategy (109, 110). Specific strains, including Lactobacillus and Bifidobacterium, have the potential to restore the equilibrium of the intestinal flora, decrease the concentrations of pro - inflammatory factors (e.g., IL - 6, TNF - α), and enhance the expression of brain - derived neurotrophic factor (BDNF), consequently improving cognitive function (19, 111). Clinical trials have demonstrated that probiotic mixtures can notably delay cognitive decline in patients with AD (111).

Probiotics, including Lactobacillus and Bifidobacterium, regulate the MGBA via multiple pathways. Initially, they are capable of restoring the equilibrium of the intestinal flora, curbing the excessive proliferation of pathogenic bacteria such as Akkermansia (whose population is significantly elevated in patients with AD and PD), and augmenting the population of SCFAs - producing bacteria (e.g., Faecalibacterium). These SCFAs - producing bacteria can inhibit the over - activation of microglia through the BBB and mitigate neuroinflammation (112, 113). Secondly, probiotics directly secrete neuroactive substances (e.g., GABA, 5 - hydroxytryptamine) and influence brain function through the vagus nerve or the circulatory system (114). For example, clinical research has demonstrated that supplementation with Lactobacillus rhamnosus can notably reduce Aβ plaque deposition in the hippocampus of AD model mice and enhance the phagocytic activity of microglia (115). Moreover, probiotics can also fortify the tight junctions of the intestinal epithelium, diminish the entry of endotoxins (such as LPS) into the bloodstream, thus reducing the damage to the BBB induced by systemic inflammation (20).

Prebiotics, classified as indigestible dietary fibers (e.g., inulin and fructooligosaccharides), selectively stimulate the proliferation of probiotics and produce SCFAs (e.g., butyric acid and propionic acid) via fermentation (116). A randomized controlled trial conducted on patients with PD indicated that prebiotic intervention notably elevated the concentration of butyric acid in feces and enhanced motor symptom scores (Unified Parkinson’s Disease Rating Scale, UPDRS). The effect was positively associated with the abundance of butyrate - producing bacteria, such as Roseburia, in the gut microbiota (117). Moreover, prebiotics can modulate the tryptophan metabolic pathway, mitigate the accumulation of neurotoxic metabolites (e.g., QA), and augment the levels of 5 - hydroxytryptamine precursors, thereby indirectly alleviating depression and cognitive impairment (118). The combined utilization of probiotics and prebiotics (synbiotics) demonstrates a synergistic effect. For example, in an ALS model, synbiotic intervention not only rectified gut microbiota dysbiosis but also postponed motor neuron degeneration by reducing plasma interleukin - 6 (IL - 6) and tumor necrosis factor - α (TNF - α) levels (119).

Fecal microbiota transplantation (FMT): The transplantation of intestinal microbiota from healthy donors to patients suffering from NDDs can reshape their microbial composition and mitigate the deposition of pathogenic proteins. For example, subsequent to FMT, patients diagnosed with PD have demonstrated enhancements in both motor symptoms and intestinal permeability (120, 121). In PD models, the transplantation of microbiota from healthy donors can substantially reverse motor deficits induced by MPTP in mice, suppress microglial/astrocyte activation in the substantia nigra - striatum region, and alleviate mitochondrial oxidative stress via the AMPK/SOD2 pathway (122). Clinical investigations have further verified that following FMT, PD patients exhibit ameliorated constipation symptoms and a reduced intestinal transit time, also display notable improvements in subjective motor and non - motor symptoms, such as cognitive function (123).

 Discussion and conclusion

In recent years, the mechanism by which gut microbiota influence NDDs via the gut-brain axis has garnered widespread attention. This paradigm underscores that the pathogenesis of NDDs extends beyond the brain, with gut microbes modulating CNS function through metabolite secretion, neurotransmitter synthesis, and immunomodulatory signaling (124). Microbial metabolites-such as SCFAs-participate in NDDs pathology by regulating the function of microglia, astrocytes, and oligodendrocytes (16). Additionally, gut bacteria produce neurotransmitters (e.g., serotonin, GABA) and gut hormones (e.g., glucagon-like peptide-1), which transit the MGBA to influence neuronal excitability and synaptic plasticity, thereby shaping disease progression in AD and other NDDs (6, 7, 125, 126).

The immune system represents another critical mediator through which gut microbes participate in NDDs. Dysbiosis can compromise both intestinal and BBB integrity, facilitating the translocation of microbial components and inflammatory mediators into the CNS. This process exacerbates neuroinflammation and accelerates neuronal injury (104, 127, 128).

Despite substantial advances in delineating the role of the MGBA in NDDs, important limitations remain. Current evidence is largely correlative, and definitive causal links have yet to be fully established (16). Moreover, the gut microbiota exhibits considerable interindividual variation in composition and functional output, which challenges the generalizability and reproducibility of findings across studies (7, 9, 104, 129). Future research should prioritize longitudinal and interventional studies to clarify causative mechanisms, alongside efforts to standardize methodologies and account for host confounding factors.

Building on advances in MGBA research, gut microbes and their metabolites have emerged as promising targets for diagnosing and treating NDDs. Therapeutic strategies such as probiotics, prebiotics, dietary interventions, and FMT have shown encouraging results in both preclinical and clinical settings (Table 1). For instance, probiotic interventions (e.g., Lactobacillus plantarum and Bifidobacterium breve) can restore gut microbial balance, also improve cognitive function and neuroinflammation by modulating gut-brain axis signaling pathways (177). Another notable example is GV-971, a recently developed oligosaccharide derived from marine algae, which has been shown to significantly improve cognitive function in patients with mild-to-moderate AD by targeting gut microbiota dysbiosis and dampening neuroinflammation (178).

Clinical studies on the role of microbiota-gut-brain axis (MGBA) disruption in neurodegenerative diseases.

Treatment NCT number Brief summary Conditions Interventions Sex Age Phases Enrollment References
Prebiotics NCT06948929 A new synbiotic formula (SCV09) AD DIETARY_SUPPLEMENT: SCV09 ALL Adult, Older Adult NA 30 (130)
NCT04512599 A dietary bar PD OTHER: Prebiotic Bar ALL Child, Adult, Older Adult NA 20 (131)
NCT05576818 Lactobacillus acidophilus probiotic with prebiotic fibers as an adjuvant therapy PD DRUG: Lactobacillus acidophilus 10 billion colony forming unit (CFU) and prebiotic fibers ALL Adult, Older Adult PHASE3 66 (132)
NCT07127120 A prebiotic fiber blend PD DIETARY_SUPPLEMENT: Prebiotic fiber blend ALL Adult, Older Adult NA 20 (133)
NCT04451096 Multi-strain probiotic (Lactobacillus spp and Bifidobacterium spp at 30 X 109 CFU) with fructo-oligosaccaride (FOS) or placebo (fermented milk) PD DIETARY_SUPPLEMENT: Probiotics with prebiotic;DIETARY_SUPPLEMENT: Placebo ALL Adult, Older Adult PHASE3 48 (134)
Probiotics NCT05145881 Five strains of probiotics (Bifidobacterium breve Bv-889, B. Longum subspecies infantis BLI-02, B. Bifidum VDD088, B. Animalis subsp. Lactis CP-9, Lactobacillus plantarum PL-02) with anti-oxidant and anti-inflammatory functions. AD DIETARY_SUPPLEMENT: Low dose probiotics;DIETARY_SUPPLEMENT: Normal dose probiotics ALL Adult, Older Adult NA 40 (135)
NCT06019117 A probiotic preparation (Probiotic K10) PD; AD DIETARY_SUPPLEMENT: Probiotic K10;DRUG: Placebo ALL Adult, Older Adult NA 104 (136)
NCT06181513 Probiotics Neurodegenerative Diseases DRUG: Probiotic Blend Capsule ALL Older Adult EARLY_PHASE1 40 (137)
NCT05521477 A probiotic (SLAB51) AD DIETARY_SUPPLEMENT: SLAB51 ALL Adult, Older Adult NA 3 (138)
NCT06948929 A new synbiotic formula (SCV09) AD DIETARY_SUPPLEMENT: SCV09 ALL Adult, Older Adult NA 30 (130)
NCT03991195 The probiotic supplemented group with amci will take certain Bifidobacterium AD DIETARY_SUPPLEMENT: Probiotic supplemented intervention;DIETARY_SUPPLEMENT: Placebo ALL Adult, Older Adult NA 90 (139)
NCT05173701 The investigators developed a clinical trial protocol for the evaluation of probiotics' effects on the peripheral immune system profile in PD patients. PD DIETARY_SUPPLEMENT: Probiotics;DIETARY_SUPPLEMENT: Placebo ALL Child, Adult, Older Adult NA 88 (140)
NCT05576818 This study aims to investigate the possible efficacy and safety of synbiotic preparation of Lactobacillus acidophilus probiotic with prebiotic fibers as an adjuvant therapy in the treatment of PD PD DRUG: Lactobacillus acidophilus 10 billion colony forming unit (CFU) and prebiotic fibers ALL Adult, Older Adult PHASE3 66 (132)
NCT05568498 This study evaluates the use of an oral multi-strain probiotic in the treatment of depression in individuals with PD. PD DIETARY_SUPPLEMENT: Probiotic;DIETARY_SUPPLEMENT: Placebo ALL Adult, Older Adult PHASE2 60 (141)
NCT03968133 This study evaluates the use of an oral multi-strain probiotic in the treatment of anxiety in individuals with PD. PD DIETARY_SUPPLEMENT: Probiotic;DIETARY_SUPPLEMENT: Placebo ALL Adult, Older Adult PHASE2 61 (142)
NCT05146921 This is an exploratory study investigating the effects probiotic intervention (Symprove) on gut and general health in 60 patients with PD and constipation. PD DIETARY_SUPPLEMENT: Multi-strain probiotic;OTHER: Placebo ALL Adult, Older Adult NA 60 (143)
NCT03377322 This is a trial to evaluate the efficacy of probiotics in the treatment of constipation in PD. PD DRUG: Probiotic Capsule;DRUG: Placebo Capsule ALL Adult, Older Adult NA 72 (144)
NCT04871464 The improvement effect of bifidobacterium triad live bacteria capsules (BIFICO) on the motor symptoms, constipation and sleep conditions of patients with mild to moderate PD PD DRUG: Live Combined Bifidobacterium, Lactobacillus and Enterococcus Capsules;OTHER: Placebo ALL Adult, Older Adult PHASE4 240 (145)
NCT06487975 The aim of this study is to evaluate whether the administration of Bacillus Subtilis influences gut and blood biomarkers relevant to the proposed mechanism(s) of action, as well as being acceptable as a regular supplement for people with PD. PD DIETARY_SUPPLEMENT: Bacillus Subtilis;OTHER: Placebo ALL Adult, Older Adult NA 48 (146)
NCT04722211 This RCT study is designed to examine the extent to which L. Plantarum PS128 can improve symptoms in PD patients. PD DIETARY_SUPPLEMENT: PS128;DIETARY_SUPPLEMENT: placebo ALL Adult, Older Adult NA 120 (147)
NCT04293159 The aim of the study is to collect data for the assessment of the Lactobacillus casei DG (Enterolactis ®duo) effect on constipation and on neuropsychological performance. PD DIETARY_SUPPLEMENT: Lactobacillus casei DG (Enterolactis ®duo) ALL Adult, Older Adult NA 30 (148)
NCT06548256 This is a study to assess the efficacy of Clostridium Butyricum Miyairi on the motor and non-motor symptoms of PD. PD DRUG: Miyarisan-BM (Clostridium Butyricum Miyairi) ALL Adult, Older Adult NA 400 (149)
NCT03324399 New Biotic, LLC has submitted an Orphan Drug Designation Application for an investigational probiotic. ALS DIETARY_SUPPLEMENT: probiotic ALL Adult, Older Adult NA 5 (150)
NCT06051123 The aim of this study is to assess the impact of a probiotic formulation on participants with ALS-FTDSD. ALSFTD DIETARY_SUPPLEMENT: Probiotic;DIETARY_SUPPLEMENT: Placebo ALL Adult, Older Adult NA 150 (151)
Dietary intervention NCT03691519 The aim is to evaluate the efficacy of omega-3(DHA+EPA) supplementation on cognitive decline in older adults with low DHA/EPA status and subjective memory complaints or family history of AD. AD DRUG: Omega-3 treatment;DIETARY_SUPPLEMENT: Placebo ALL Older Adult PHASE3 774 (152)
NCT06705517 This study assesses whether an MD can improve motor and non-motor symptoms in PD patients. PD BEHAVIORAL: Mediterranean Diet ALL Adult, Older Adult NA 44 (153)
NCT02274324 To evaluate the role of dietary modifications of 3 different diets on clinical outcomes in patients with PD. PD DIETARY_SUPPLEMENT: different diets ALL Adult, Older Adult NA 20 (154)
NCT03851861 Mediterranean diet PD OTHER: Mediterranean Diet ALL Adult, Older Adult NA 8 (155)
NCT07213856 The goal of this clinical trial is to evaluate whether a dietitian-guided nutritional intervention can improve constipation symptoms in people with PD. Parkinsons Disease BEHAVIORAL: Dietitian-Guided Nutritional Intervention ALL Adult, Older Adult NA 54 (156)
NCT05469997 This study aims to investigate the safety of modified Mediterranean-ketogenic interventions, as it relates to the gut microbiome health in patients with PD. PD BEHAVIORAL: Mediterranean-Ketogenic Diet;DIETARY_SUPPLEMENT: Mediterranean diet supplemented with medium-chain triglyceride oil ALL Adult, Older Adult NA 50 (157)
NCT00906763 This study aims to investigate the effects of high cocoa content (85%) dark chocolate and chocolate without any cocoa components (white chocolate) on the motor symptoms of PD patients (measured through the third part of the UPDRS (motor score)). PD DIETARY_SUPPLEMENT: Chocolate ALL Adult, Older Adult NA 23 (158)
NCT06207136 The goal of this pilot study is to examine the feasibility and effects of an 18-month intervention diet compared to an active control diet (standard diet) in those living with PD, without dementia. PD OTHER: Mediterranean-style diet ALL Adult, Older Adult NA 40 (159)
NCT04683900 The aim is to explore the impact of Mediterranean diet intervention on the gastrointestinal function of patients with PD. PD OTHER: Standard of care + Mediterranean diet (intervention);OTHER: Standard of care (control) ALL Adult, Older Adult NA 46 (160)
NCT06463769 Compared with the ordinary German diet, the "new Nordic oligosaccharide diet" (a culturally adapted diet rich in fermentable fibers and phytochemicals) will have a beneficial effect on the intestinal microbiota of patients with PD. PD BEHAVIORAL: predominantly plant-based New Nordic LPF-diet program ALL Adult, Older Adult NA 75 (161)
NCT07178067 This observational study explored the connection between the gut microbiota and the brain in patients with ALS, specifically the modulation of short-chain fatty acids during disease progression and after following a Mediterranean diet for 6 months. ALS OTHER: Mediterranean diet ALL Adult, Older Adult 44 (162)
NCT04172792 The investigators seek to investigate whether an ultra-high caloric diet (UHCD), featuring the double amount of calories compared to LIPCAL-ALS, will be well tolerated by ALS patients and may serve as an intervention for a potential LIPCALII study. ALS DIETARY_SUPPLEMENT: high-caloric fatty diet;DIETARY_SUPPLEMENT: ultra-high-caloric fatty diet;DIETARY_SUPPLEMENT: ultra-high-caloric carbohydrate-rich diet ALL Adult, Older Adult PHASE1 64 (163)
NCT02306590 This is a trial comparing placebo with high caloric fatty diet for drinking as add-on therapy to 100 mg RILUZOLE in ALS in 200 enrolled patients. ALS DIETARY_SUPPLEMENT: Calogen;DIETARY_SUPPLEMENT: Placebo ALL Adult, Older Adult NA 207 (164)
NCT02152449 The aim of this study is to determine whether early oral nutritional supplementation (ONS) is effective in treating patients with ALS. ALS DIETARY_SUPPLEMENT: Oral nutritional supplementation ALL Adult, Older Adult NA 229 (165)
Fecal Microbiota Transplant (FMT) NCT03998423 The goal of this study is to assess the safety and feasibility of an oral FMT intervention for AD. AD BIOLOGICAL: Fecal Microbiota Transplant ALL Adult, Older Adult PHASE1 5 (166)
NCT06920212 To investigate the clinical safety and efficacy of FMT in AD patients, as well as the changes in the gut microbiota of AD patients before and after FMT. AD PROCEDURE: FMT capsule ALL Adult, Older Adult NA 30 (167)
NCT04854291 Patients with PD receive treatment through fecal microbiota transplantation from donors or by directly infusing their own feces into the rectum. PD OTHER: Administration of donor FMT;OTHER: Administration of placebo ALL Adult, Older Adult NA 51 (168)
NCT06388863 Patients undergoing FMT intervention PD DRUG: Healthy donor-derived FMT capsule;DRUG: Placebo capsule ALL Adult, Older Adult NA 76 (169)
NCT03808389 Determine the impact of FMT on the symptoms and progression of PD in patients. PD OTHER: Donor FM;OTHER: Autologous FMT ALL Adult, Older Adult NA 49 (170)
NCT03876327 This study aims to further explore the potential application of fecal microbiota transplantation in treating constipation and possibly improving the motor symptoms of patients with PD. PD PROCEDURE: FMT ALL Adult, Older Adult PHASE2|PHASE3 10 (171)
NCT07038226 The aim of this clinical trial is to assess the impact of FMT delivered via oral capsules in patients with PD who suffer from refractory constipation. PD BIOLOGICAL: Placebo;BIOLOGICAL: Oral capsule-delivered FMT ALL Adult, Older Adult NA 16 (172)
NCT06647277 The study investigated the effect of FMT on reducing the severity of symptoms in patients with PD. PD COMBINATION_PRODUCT: FMT ALL Adult, Older Adult PHASE1 10 (173)
NCT04837313 This study aims to evaluate the efficacy and safety of fecal microbiota transplantation in treating constipation symptoms in PD patients who are taking a stable dose of levodopa. PD PROCEDURE: FMT ALL Adult, Older Adult NA 30 (174)
NCT03766321 This study aims to evaluate the effects of FMT on patients with ALS in terms of biology and disease improvement. ALS BIOLOGICAL: FMT;BIOLOGICAL: Placebo ALL Adult, Older Adult NA 42 (175)
NCT07017946 A study on intestinal microbiota transplantation for patients with ALS. ALS DRUG: MTP-101C ALL Adult, Older Adult PHASE1|PHASE2 20 (176)

Nevertheless, most clinical studies conducted to date are limited by small sample sizes, and there remains a need for standardized intervention protocols as well as longer-term efficacy evaluations. The long - term safety of microbiota transplantation, the optimal donor screening criteria, and the dosage regimens remain to be clarified (179). The integration of multi-omics approaches with artificial intelligence-based analytics holds considerable potential to elucidate the gut microbiota’s role in NDDs more systematically and to guide the development of targeted therapeutic interventions.

In summary, the MGBA plays a critical role in the initiation and progression of NDDs, functionally linking central pathology to peripheral metabolic and immune processes. Understanding the involvement of gut microbes in NDDs provides novel mechanistic insights into their complex etiology and opens new avenues for therapeutic innovation. Future studies should focus on delineating the precise causal mechanisms underlying gut-brain communication and refining microbiota-based strategies to facilitate their successful translation into clinical practice.

 Author contributions

JY: Writing – review & editing, Writing – original draft, Conceptualization. XS: Writing – review & editing, Conceptualization. SY: Formal analysis, Writing – review & editing. QL: Writing – review & editing, Formal analysis. WY: Writing – review & editing.

 Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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 References Boland B Yu WH Corti O Mollereau B Henriques A Bezard E . Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat Rev Drug Discov. (2018) 17:660–88. doi: 10.1038/nrd.2018.109, PMID: 30116051 Peng C Trojanowski JQ Lee VM . Protein transmission in neurodegenerative disease. Nat Rev Neurol. (2020) 16:199–212. doi: 10.1038/s41582-020-0333-7, PMID: 32203399 Wilson DM 3rd Cookson MR Van Den Bosch L Zetterberg H Holtzman DM Dewachter I . Hallmarks of neurodegenerative diseases. Cell. (2023) 186:693–714. doi: 10.1016/j.cell.2022.12.032, PMID: 36803602 Chang A Xiang X Wang J Lee C Arakhamia T Simjanoska M . Homotypic fibrillization of tmem106b across diverse neurodegenerative diseases. Cell. (2022) 185:1346–55.e15. doi: 10.1016/j.cell.2022.02.026, PMID: 35247328 Nguyen TPM Alves F Lane DJR Bush AI Ayton S . Triggering ferroptosis in neurodegenerative diseases. Trends Neurosci. (2025) 48(10):750–65. doi: 10.1016/j.tins.2025.06.008, PMID: 40695640 Zhang H Chen Y Wang Z Xie G Liu M Yuan B . Implications of gut microbiota in neurodegenerative diseases. Front Immunol. (2022) 13:785644. doi: 10.3389/fimmu.2022.785644, PMID: 35237258 Ghezzi L Cantoni C Rotondo E Galimberti D . The gut microbiome-brain crosstalk in neurodegenerative diseases. Biomedicines. (2022) 10(7):1486. doi: 10.3390/biomedicines10071486, PMID: 35884791 Margolis KG Cryan JF Mayer EA . The microbiota-gut-brain axis: from motility to mood. Gastroenterology. (2021) 160:1486–501. doi: 10.1053/j.gastro.2020.10.066, PMID: 33493503 Li S Cai Y Wang S Luo L Zhang Y Huang K . Gut microbiota: the indispensable player in neurodegenerative diseases. J Sci Food Agric. (2024) 104:7096–108. doi: 10.1002/jsfa.13509, PMID: 38572789 Schaible P Henschel J Erny D . How the gut microbiota impacts neurodegenerative diseases by modulating cns immune cells. J Neuroinflamm. (2025) 22:60. doi: 10.1186/s12974-025-03371-0, PMID: 40033338 Xu X Wei S Lin M Chen F Zhang X Zhu Y . The relationship between acrylamide and neurodegenerative diseases: gut microbiota as a new intermediate cue. Crit Rev Food Sci Nutr. (2024) 65(29):6428–40. doi: 10.1080/10408398.2024.2440602, PMID: 39668759 Li S Zhao L Xiao J Guo Y Fu R Zhang Y . The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances. Mol Cell Biochem. (2024) 479:2217–43. doi: 10.1007/s11010-023-04853-6, PMID: 37787835 Mou Y Du Y Zhou L Yue J Hu X Liu Y . Gut microbiota interact with the brain through systemic chronic inflammation: implications on neuroinflammation, neurodegeneration, and aging. Front Immunol. (2022) 13:796288. doi: 10.3389/fimmu.2022.796288, PMID: 35464431 Uniyal A Tiwari V Rani M Tiwari V . Immune-microbiome interplay and its implications in neurodegenerative disorders. Metab Brain Dis. (2022) 37:17–37. doi: 10.1007/s11011-021-00807-3, PMID: 34357554 Morais LH Schreiber HLT Mazmanian SK . The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol. (2021) 19:241–55. doi: 10.1038/s41579-020-00460-0, PMID: 33093662 Loh JS Mak WQ Tan LKS Ng CX Chan HH Yeow SH . Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases. Signal Transduct Target Ther. (2024) 9:37. doi: 10.1038/s41392-024-01743-1, PMID: 38360862 Liu S Yin R Yang Z Wei F Hu J . The effects of rhein on D-galn/lps-induced acute liver injury in mice: results from gut microbiome-metabolomics and host transcriptome analysis. Front Immunol. (2022) 13:971409. doi: 10.3389/fimmu.2022.971409, PMID: 36389730 Hopper CP de la Cruz LK Lyles KV Wareham LK Gilbert JA Eichenbaum Z . Role of carbon monoxide in host-gut microbiome communication. Chem Rev. (2020) 120:13273–311. doi: 10.1021/acs.chemrev.0c00586, PMID: 33089988 Balakrishnan R Kang SI Lee JY Rho YK Kim BK Choi DK . Gut microbiota-immune system interactions in health and neurodegenerative diseases: insights into molecular mechanisms and therapeutic applications. Aging Dis. (2024) 16:3421–52. doi: 10.14336/AD.2024.1362, PMID: 39656490 Sorboni SG Moghaddam HS Jafarzadeh-Esfehani R Soleimanpour S . A comprehensive review on the role of the gut microbiome in human neurological disorders. Clin Microbiol Rev. (2022) 35:e0033820. doi: 10.1128/cmr.00338-20, PMID: 34985325 Fabi JP . The connection between gut microbiota and its metabolites with neurodegenerative diseases in humans. Metab Brain Dis. (2024) 39:967–84. doi: 10.1007/s11011-024-01369-w, PMID: 38848023 Aburto MR Cryan JF . Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota-gut-brain axis. Nat Rev Gastroenterol Hepatol. (2024) 21:222–47. doi: 10.1038/s41575-023-00890-0, PMID: 38355758 Dowling LR Strazzari MR Keely S Kaiko GE . Enteric nervous system and intestinal epithelial regulation of the gut-brain axis. J Allergy Clin Immunol. (2022) 150:513–22. doi: 10.1016/j.jaci.2022.07.015, PMID: 36075637 Cerantola S Caputi V Marsilio I Ridolfi M Faggin S Bistoletti M . Involvement of enteric glia in small intestine neuromuscular dysfunction of toll-like receptor 4-deficient mice. Cells. (2020) 9(4):838. doi: 10.3390/cells9040838, PMID: 32244316 Sharkey KA Mawe GM . The enteric nervous system. Physiol Rev. (2023) 103:1487–564. doi: 10.1152/physrev.00018.2022, PMID: 36521049 Ohara TE Hsiao EY . Microbiota-neuroepithelial signalling across the gut-brain axis. Nat Rev Microbiol. (2025) 23:371–84. doi: 10.1038/s41579-024-01136-9, PMID: 39743581 Mogor F Kovács T Lohinai Z Dora D . The enteric nervous system and the microenvironment of the gut: the translational aspects of the microbiome-gut-brain axis. Appl Sci. (2021) 11:12000. doi: 10.3390/app112412000 Stone TW Clanchy FIL Huang YS Chiang NY Darlington LG Williams RO . An integrated cytokine and kynurenine network as the basis of neuroimmune communication. Front Neurosci. (2022) 16:1002004. doi: 10.3389/fnins.2022.1002004, PMID: 36507331 Qu Z Tian P Wang L Jin X Guo M Lu J . Dietary nucleotides promote neonatal rat microbiota-gut-brain axis development by affecting gut microbiota composition and metabolic function. J Agric Food Chem. (2023) 71:19622–37. doi: 10.1021/acs.jafc.3c07349, PMID: 38014964 Hu J Johnson TA Zhang H Cheng HW . The microbiota-gut-brain axis: gut microbiota modulates conspecific aggression in diversely selected laying hens. Microorganisms. (2022) 10(6):1081. doi: 10.3390/microorganisms10061081, PMID: 35744601 Guo X Li C Zhang J Sun M Xu J Xu C . Chiral nanoparticle-remodeled gut microbiota alleviates neurodegeneration via the gut-brain axis. Nat Aging. (2023) 3:1415–29. doi: 10.1038/s43587-023-00516-9, PMID: 37946041 Kim NY Lee HY Choi YY Mo SJ Jeon S Ha JH . Effect of gut microbiota-derived metabolites and extracellular vesicles on neurodegenerative disease in a gut-brain axis chip. Nano Converg. (2024) 11:7. doi: 10.1186/s40580-024-00413-w, PMID: 38340254 Kustrimovic N Balkhi S Bilato G Mortara L . Gut microbiota and immune system dynamics in parkinson’s and alzheimer’s diseases. Int J Mol Sci. (2024) 25(22):12164. doi: 10.3390/ijms252212164, PMID: 39596232 Gong B Wang C Meng F Wang H Song B Yang Y . Association between gut microbiota and autoimmune thyroid disease: A systematic review and meta-analysis. Front Endocrinol (Lausanne). (2021) 12:774362. doi: 10.3389/fendo.2021.774362, PMID: 34867823 Cheng Y Chen C Zhang F . Immunity orchestrates a bridge in gut-brain axis of neurodegenerative diseases. Ageing Res Rev. (2023) 85:101857. doi: 10.1016/j.arr.2023.101857, PMID: 36669690 Wang X Wen X Yuan S Zhang J . Gut-brain axis in the pathogenesis of sepsis-associated encephalopathy. Neurobiol Dis. (2024) 195:106499. doi: 10.1016/j.nbd.2024.106499, PMID: 38588753 Agirman G Hsiao EY . Snapshot: the microbiota-gut-brain axis. Cell. (2021) 184:2524–.e1. doi: 10.1016/j.cell.2021.03.022, PMID: 33930299 Socała K Doboszewska U Szopa A Serefko A Włodarczyk M Zielińska A . The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacol Res. (2021) 172:105840. doi: 10.1016/j.phrs.2021.105840, PMID: 34450312 Spencer NJ Kyloh MA Travis L Dodds KN . Identification of spinal afferent nerve endings in the colonic mucosa and submucosa that communicate directly with the spinal cord: the gut-brain axis. J Comp Neurol. (2020) 528:1742–53. doi: 10.1002/cne.24854, PMID: 31909835 Cha Z Qiao Y Lu Q Wang Q Lu X Zhou H . Research progress and challenges of stem cell therapy for ischemic stroke. Front Cell Dev Biol. (2024) 12:1410732. doi: 10.3389/fcell.2024.1410732, PMID: 39040041 Haak BW Westendorp WF van Engelen TSR Brands X Brouwer MC Vermeij JD . Disruptions of anaerobic gut bacteria are associated with stroke and post-stroke infection: A prospective case-control study. Transl Stroke Res. (2021) 12:581–92. doi: 10.1007/s12975-020-00863-4, PMID: 33052545 Marano G Mazza M Lisci FM Ciliberto M Traversi G Kotzalidis GD . The microbiota-gut-brain axis: psychoneuroimmunological insights. Nutrients. (2023) 15(6):1496. doi: 10.3390/nu15061496, PMID: 36986226 Longo S Rizza S Federici M . Microbiota-gut-brain axis: relationships among the vagus nerve, gut microbiota, obesity, and diabetes. Acta Diabetol. (2023) 60:1007–17. doi: 10.1007/s00592-023-02088-x, PMID: 37058160 Honarpisheh P Bryan RM McCullough LD . Aging microbiota-gut-brain axis in stroke risk and outcome. Circ Res. (2022) 130:1112–44. doi: 10.1161/circresaha.122.319983, PMID: 35420913 Long-Smith C O’Riordan KJ Clarke G Stanton C Dinan TG Cryan JF . Microbiota-gut-brain axis: new therapeutic opportunities. Annu Rev Pharmacol Toxicol. (2020) 60:477–502. doi: 10.1146/annurev-pharmtox-010919-023628, PMID: 31506009 Zhang X Jia X Wang S Xin J Sun N Wang Y . Disrupted gut microbiota aggravates spatial memory dysfunction induced by high altitude exposure: A link between plateau environment and microbiome-gut-brain axis. Ecotoxicol Environ Saf. (2023) 259:115035. doi: 10.1016/j.ecoenv.2023.115035, PMID: 37224779 Wang Q Yang Q Liu X . The microbiota-gut-brain axis and neurodevelopmental disorders. Protein Cell. (2023) 14:762–75. doi: 10.1093/procel/pwad026, PMID: 37166201 Qu L Li Y Liu F Fang Y He J Ma J . Microbiota-gut-brain axis dysregulation in alzheimer’s disease: multi-pathway effects and therapeutic potential. Aging Dis. (2024) 15:1108–31. doi: 10.14336/ad.2023.0823-2, PMID: 37728579 Tansey MG Wallings RL Houser MC Herrick MK Keating CE Joers V . Inflammation and immune dysfunction in parkinson disease. Nat Rev Immunol. (2022) 22:657–73. doi: 10.1038/s41577-022-00684-6, PMID: 35246670 Aktas B Aslim B . Neuropathy in covid-19 associated with dysbiosis-related inflammation. Turk J Biol. (2021) 45:390–403. doi: 10.3906/biy-2105-53, PMID: 34803442 Bhattarai Y Si J Pu M Ross OA McLean PJ Till L . Role of gut microbiota in regulating gastrointestinal dysfunction and motor symptoms in a mouse model of parkinson’s disease. Gut Microbes. (2021) 13:1866974. doi: 10.1080/19490976.2020.1866974, PMID: 33459114 Yu L Pan J Guo M Duan H Zhang H Narbad A . Gut microbiota and anti-aging: focusing on spermidine. Crit Rev Food Sci Nutr. (2024) 64:10419–37. doi: 10.1080/10408398.2023.2224867, PMID: 37326367 Coretti L Buommino E Lembo F . The aryl hydrocarbon receptor pathway: A linking bridge between the gut microbiome and neurodegenerative diseases. Front Cell Neurosci. (2024) 18:1433747. doi: 10.3389/fncel.2024.1433747, PMID: 39175504 Merchak AR Bolen ML Tansey MG Menees KB . Thinking outside the brain: gut microbiome influence on innate immunity within neurodegenerative disease. Neurotherapeutics. (2024) 21:e00476. doi: 10.1016/j.neurot.2024.e00476, PMID: 39482179 Saaoud F Lu Y Xu K Shao Y Praticò D Vazquez-Padron RI . Protein-rich foods, sea foods, and gut microbiota amplify immune responses in chronic diseases and cancers - targeting perk as a novel therapeutic strategy for chronic inflammatory diseases, neurodegenerative disorders, and cancer. Pharmacol Ther. (2024) 255:108604. doi: 10.1016/j.pharmthera.2024.108604, PMID: 38360205 Cossu D Hatano T Hattori N . The role of immune dysfunction in parkinson’s disease development. Int J Mol Sci. (2023) 24(23):16766. doi: 10.3390/ijms242316766, PMID: 38069088 Haase S Wilck N Haghikia A Gold R Mueller DN Linker RA . The role of the gut microbiota and microbial metabolites in neuroinflammation. Eur J Immunol. (2020) 50:1863–70. doi: 10.1002/eji.201847807, PMID: 33188704 Cavaliere G Traina G . Neuroinflammation in the brain and role of intestinal microbiota: an overview of the players. J Integr Neurosci. (2023) 22:148. doi: 10.31083/j.jin2206148, PMID: 38176933 Kronsten VT Tranah TH Pariante C Shawcross DL . Gut-derived systemic inflammation as a driver of depression in chronic liver disease. J Hepatol. (2022) 76:665–80. doi: 10.1016/j.jhep.2021.11.008, PMID: 34800610 Prince N Peralta Marzal LN Markidi A Ahmed S Adolfs Y Pasterkamp RJ . Prebiotic diet normalizes aberrant immune and behavioral phenotypes in a mouse model of autism spectrum disorder. Acta Pharmacol Sin. (2024) 45:1591–603. doi: 10.1038/s41401-024-01268-x, PMID: 38589690 Jewell S Roper K Woodhouse H Adam R O’Sullivan J Gordon R . Lc-ms based urine metabolomic profiling indicate altered gut microbiome and host lipid metabolites in parkinson’s disease. FASEB J. (2022) 36. doi: 10.1096/fasebj.2022.36.S1.R2928 Wojciech L Png CW Koh EY Kioh DYQ Deng L Wang Z . A tryptophan metabolite made by a gut microbiome eukaryote induces pro-inflammatory T cells. EMBO J. (2023) 42:e112963. doi: 10.15252/embj.2022112963, PMID: 37743772 Zhang J Zhang Y Wang J Xia Y Zhang J Chen L . Recent advances in alzheimer’s disease: mechanisms, clinical trials and new drug development strategies. Signal Transduct Target Ther. (2024) 9:211. doi: 10.1038/s41392-024-01911-3, PMID: 39174535 Eslami M Alibabaei F Babaeizad A Banihashemian SZ Mazandarani M Hoseini A . The importance of gut microbiota on choline metabolism in neurodegenerative diseases. Biomolecules. (2024) 14(11):1345. doi: 10.3390/biom14111345, PMID: 39595522 Manfredi JN Gupta SK Vyavahare S Deak F Lu X Buddha L . Gut microbiota dysbiosis in alzheimer’s disease (Ad): insights from human clinical studies and the mouse ad models. Physiol Behav. (2025) 290:114778. doi: 10.1016/j.physbeh.2024.114778, PMID: 39672482 Qian XH Song XX Liu XL Chen SD Tang HD . Inflammatory pathways in alzheimer’s disease mediated by gut microbiota. Ageing Res Rev. (2021) 68:101317. doi: 10.1016/j.arr.2021.101317, PMID: 33711509 Chen Q Wu J Dong X Yin H Shi X Su S . Gut flora-targeted photobiomodulation therapy improves senile dementia in an aß-induced alzheimer’s disease animal model. J Photochem Photobiol B. (2021) 216:112152. doi: 10.1016/j.jphotobiol.2021.112152, PMID: 33610085 Pisa D Alonso R Carrasco L . Parkinson’s disease: A comprehensive analysis of fungi and bacteria in brain tissue. Int J Biol Sci. (2020) 16:1135–52. doi: 10.7150/ijbs.42257, PMID: 32174790 Tarawneh R Penhos E . The gut microbiome and alzheimer’s disease: complex and bidirectional interactions. Neurosci Biobehav Rev. (2022) 141:104814. doi: 10.1016/j.neubiorev.2022.104814, PMID: 35934087 Bano N Khan S Ahamad S Kanshana JS Dar NJ Khan S . Microglia and gut microbiota: A double-edged sword in alzheimer’s disease. Ageing Res Rev. (2024) 101:102515. doi: 10.1016/j.arr.2024.102515, PMID: 39321881 Fairley A Stewart CJ Cassidy A Woodside JV McEvoy CT . Diet patterns, the gut microbiome, and alzheimer’s disease. J Alzheimers Dis. (2022) 88:933–41. doi: 10.3233/jad-220205, PMID: 35634849 Chandra S Sisodia SS Vassar RJ . The gut microbiome in alzheimer’s disease: what we know and what remains to be explored. Mol Neurodegener. (2023) 18:9. doi: 10.1186/s13024-023-00595-7, PMID: 36721148 Chang CH Lin CH Lane HY . D-glutamate and gut microbiota in alzheimer’s disease. Int J Mol Sci. (2020) 21(8):2676. doi: 10.3390/ijms21082676, PMID: 32290475 Lista S Munafò A Caraci F Imbimbo C Emanuele E Minoretti P . Gut microbiota in alzheimer’s disease: understanding molecular pathways and potential therapeutic perspectives. Ageing Res Rev. (2025) 104:102659. doi: 10.1016/j.arr.2025.102659, PMID: 39800223 Dai CL Liu F Iqbal K Gong CX . Gut microbiota and immunotherapy for alzheimer’s disease. Int J Mol Sci. (2022) 23(23):15230. doi: 10.3390/ijms232315230, PMID: 36499564 Lan B He L Huang Y Guo X Xu W Zhu C . Tempo-spatial variations of zooplankton communities in relation to environmental factors and the ecological implications: A case study in the hinterland of the three gorges reservoir area, China. PLoS One. (2021) 16:e0256313. doi: 10.1371/journal.pone.0256313, PMID: 34407135 Alzahrani AS Kehail MA Almannaa SA Alkhalifa AH Alqahtani AM Altalhi MH . Seasonal occurrence and biodiversity of insects in an arid ecosystem: an ecological study of the king abdulaziz royal reserve, Saudi Arabia. Biol (Basel). (2025) 14(3):254. doi: 10.3390/biology14030254, PMID: 40136511 Parois SP Duttlinger AW Richert BT Lindemann SR Johnson JS Marchant-Forde JN . Effects of three distinct 2-week long diet strategies after transport on weaned pigs’ Short and long-term welfare markers, behaviors, and microbiota. Front Vet Sci. (2020) 7:140. doi: 10.3389/fvets.2020.00140, PMID: 32258069 Ji T Huang H Liu J Peng T Zhou X Tan Q . Leveraging sequence-based faecal microbial community survey data to identify alterations in gut microbiota among patients with parkinson’s disease. Eur J Neurosci. (2021) 53:687–96. doi: 10.1111/ejn.14952, PMID: 32865266 Choi JG Kim N Ju IG Eo H Lim SM Jang SE . Oral administration of proteus mirabilis damages dopaminergic neurons and motor functions in mice. Sci Rep. (2018) 8(1):1275. doi: 10.1038/s41598-018-19646-x, PMID: 29352191 Agrawal M Ajazuddin Tripathi DK Saraf S Saraf S Antimisiaris SG . Recent advancements in liposomes targeting strategies to cross blood-brain barrier (Bbb) for the treatment of alzheimer’s disease. J Controlled Release. (2017) 260:61–77. doi: 10.1016/j.jconrel.2017.05.019, PMID: 28549949 Chan DG Ventura K Villeneuve A Du Bois P Holahan MR . Exploring the connection between the gut microbiome and parkinson’s disease symptom progression and pathology: implications for supplementary treatment options. J Parkinsons Dis. (2022) 12:2339–52. doi: 10.3233/jpd-223461, PMID: 36278360 Tsao S-P Yeh T-H Lin Y-T Pan C-H Lee Y-K Wu C-H . Supplementation with bifidobacterium animalis subsp. Lactis mh-022 for remission of motor impairments in a 6-ohda-induced parkinson’s disease rat model by reducing inflammation, reshaping the gut microbiome, and fostering specific microbial taxa. Food Funct. (2024) 15:9368–89. doi: 10.1039/D4FO02039A, PMID: 39189385 Salim S Ahmad F Banu A Mohammad F . Gut microbiome and parkinson’s disease: perspective on pathogenesis and treatment. J Adv Res. (2023) 50:83–105. doi: 10.1016/j.jare.2022.10.013, PMID: 36332796 Bolliri C Fontana A Cereda E Barichella M Cilia R Ferri V . Gut microbiota in monozygotic twins discordant for parkinson’s disease. Ann Neurol. (2022) 92:631–6. doi: 10.1002/ana.26454, PMID: 35852145 Wallen ZD Stone WJ Factor SA Molho E Zabetian CP Standaert DG . Exploring human-genome gut-microbiome interaction in parkinson’s disease. NPJ Parkinsons Dis. (2021) 7:74. doi: 10.1038/s41531-021-00218-2, PMID: 34408160 Zhang X Tang B Guo J . Parkinson’s disease and gut microbiota: from clinical to mechanistic and therapeutic studies. Transl Neurodegener. (2023) 12:59. doi: 10.1186/s40035-023-00392-8, PMID: 38098067 Hou Y-F Shan C Zhuang S-Y Zhuang Q-Q Ghosh A Zhu K-C . Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of parkinson’s disease. Microbiome. (2021) 9:34. doi: 10.1186/s40168-020-00988-6, PMID: 33517890 Bi M Feng L He J Liu C Wang Y Jiang H . Emerging insights between gut microbiome dysbiosis and parkinson’s disease: pathogenic and clinical relevance. Ageing Res Rev. (2022) 82:101759. doi: 10.1016/j.arr.2022.101759, PMID: 36243356 Zheng S-Y Li H-X Xu R-C Miao W-T Dai M-Y Ding S-T . Potential roles of gut microbiota and microbial metabolites in parkinson’s disease. Ageing Res Rev. (2021) 69:101347. doi: 10.1016/j.arr.2021.101347, PMID: 33905953 Murros KE . Hydrogen sulfide produced by gut bacteria may induce parkinson’s disease. Cells. (2022) 11(6):978. doi: 10.3390/cells11060978, PMID: 35326429 Murros KE Huynh VA Takala TM Saris PEJ . Desulfovibrio bacteria are associated with parkinson’s disease. Front Cell Infect Microbiol. (2021) 11:652617. doi: 10.3389/fcimb.2021.652617, PMID: 34012926 Zhu W Hu Y Shi Y Bao H Cheng X Jiang M . Sleep deprivation accelerates parkinson’s disease via modulating gut microbiota associated microglial activation and oxidative stress. Microbiol Res. (2025) 293:128077. doi: 10.1016/j.micres.2025.128077, PMID: 39889629 Zhu Y Huan F Wang J Xie X Yu G Wang X . 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced parkinson’s disease in mouse: potential association between neurotransmitter disturbance and gut microbiota dysbiosis. ACS Chem Neurosci. (2020) 11:3366–76. doi: 10.1021/acschemneuro.0c00475, PMID: 32926778 Qiao CM Ma XY Tan LL Xia YM Li T Wu J . Indoleamine 2, 3-dioxygenase 1 inhibition mediates the therapeutic effects in parkinson’s disease mice by modulating inflammation and neurogenesis in a gut microbiota dependent manner. Exp Neurol. (2025) 385:115142. doi: 10.1016/j.expneurol.2025.115142, PMID: 39793693 Zheng W He R Yan Z Huang Y Huang W Cai Z . Regulation of immune-driven pathogenesis in parkinson’s disease by gut microbiota. Brain Behav Immun. (2020) 87:890–7. doi: 10.1016/j.bbi.2020.01.009, PMID: 31931152 Lin NY-T Fukuoka S Motooka D Shigeno Y Irie T Tourlousse DM . Abstract 6686: the mechanism of gut microbiome-mediated immune activation on the clinical efficacy of pd-1 blocking treatment in solid tumors. Cancer Res. (2024) 84:6686. doi: 10.1158/1538-7445.Am2024-6686 Yang Y Stewart T Zhang C Wang P Xu Z Jin J . Erythrocytic Α-synuclein and the gut microbiome: kindling of the gut-brain axis in parkinson’s disease. Movement Disord. (2024) 39:40–52. doi: 10.1002/mds.29620, PMID: 37798868 Calma AD Pavey N Menon P Vucic S . Neuroinflammation in amyotrophic lateral sclerosis: pathogenic insights and therapeutic implications. Curr Opin Neurol. (2024) 37:585–92. doi: 10.1097/wco.0000000000001279, PMID: 38775138 Anderson G . Gut microbiome and circadian interactions with platelets across human diseases, including alzheimer’s disease, amyotrophic lateral sclerosis, and cancer. Curr Top Med Chem. (2023) 23:2699–719. doi: 10.2174/0115680266253465230920114223, PMID: 37807406 Zeng Q Shen J Chen K Zhou J Liao Q Lu K . The alteration of gut microbiome and metabolism in amyotrophic lateral sclerosis patients. Sci Rep. (2020) 10:12998. doi: 10.1038/s41598-020-69845-8, PMID: 32747678 Yang EJ . The emerging role of the brain-gut axis in amyotrophic lateral sclerosis: pathogenesis, mechanisms, and therapeutic perspectives. Int J Mol Sci. (2025) 26(17):8419. doi: 10.3390/ijms26178419, PMID: 40943341 De Marchi F Mazzini L Mogna L Amoruso A Pane M Aloisio I . Potential role of gut microbiota in amyotrophic lateral sclerosis (Als) pathogenesis (P1.318). Neurology. (2018) 90:P1.318. doi: 10.1212/WNL.90.15_supplement.P1.318 Zheng Y Bonfili L Wei T Eleuteri AM . Understanding the gut-brain axis and its therapeutic implications for neurodegenerative disorders. Nutrients. (2023) 15(21):4631. doi: 10.3390/nu15214631, PMID: 37960284 Sun J Chen J Xie Q Sun M Zhang W Wang H . Sodium butyrate alleviates R97–116 peptide-induced myasthenia gravis in mice by improving the gut microbiota and modulating immune response. J Inflammation (Lond). (2023) 20:37. doi: 10.1186/s12950-023-00363-w, PMID: 37924056 Moțățăianu A Șerban G Andone S . The role of short-chain fatty acids in microbiota-gut-brain cross-talk with a focus on amyotrophic lateral sclerosis: A systematic review. Int J Mol Sci. (2023) 24(20):15094. doi: 10.3390/ijms242015094, PMID: 37894774 Chen L Chen Y Zhao M Zheng L Fan D . Changes in the concentrations of trimethylamine N-oxide (Tmao) and its precursors in patients with amyotrophic lateral sclerosis. Sci Rep. (2020) 10:15198. doi: 10.1038/s41598-020-72184-3, PMID: 32938991 Gupta R Advani D Yadav D Ambasta RK Kumar P . Dissecting the relationship between neuropsychiatric and neurodegenerative disorders. Mol Neurobiol. (2023) 60:6476–529. doi: 10.1007/s12035-023-03502-9, PMID: 37458987 Pluta R Ulamek-Koziol M Januszewski S Czuczwar SJ . Gut microbiota and pro/prebiotics in alzheimer’s disease. Aging (Albany NY). (2020) 12:5539–50. doi: 10.18632/aging.102930, PMID: 32191919 Romo-Araiza A Ibarra A . Prebiotics and probiotics as potential therapy for cognitive impairment. Med Hypotheses. (2020) 134:109410. doi: 10.1016/j.mehy.2019.109410, PMID: 31627123 Mincic AM Antal M Filip L Miere D . Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review. Clin Nutr. (2024) 43:1832–49. doi: 10.1016/j.clnu.2024.05.036, PMID: 38878554 You M Chen N Yang Y Cheng L He H Cai Y . The gut microbiota-brain axis in neurological disorders. MedComm (2020). (2024) 5:e656. doi: 10.1002/mco2.656, PMID: 39036341 Taghizadeh Ghassab F Shamlou Mahmoudi F Taheri Tinjani R Emami Meibodi A Zali MR Yadegar A . Probiotics and the microbiota-gut-brain axis in neurodegeneration: beneficial effects and mechanistic insights. Life Sci. (2024) 350:122748. doi: 10.1016/j.lfs.2024.122748, PMID: 38843992 Ma YY Li X Yu JT Wang YJ . Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside. Transl Neurodegener. (2024) 13:12. doi: 10.1186/s40035-024-00404-1, PMID: 38414054 Baldi S Mundula T Nannini G Amedei A . Microbiota shaping - the effects of probiotics, prebiotics, and fecal microbiota transplant on cognitive functions: A systematic review. World J Gastroenterol. (2021) 27:6715–32. doi: 10.3748/wjg.v27.i39.6715, PMID: 34754163 Nandwana V Nandwana NK Das Y Saito M Panda T Das S . The role of microbiome in brain development and neurodegenerative diseases. Molecules. (2022) 27(11):3402. doi: 10.3390/molecules27113402, PMID: 35684340 Liu X Liu Y Liu J Zhang H Shan C Guo Y . Correlation between the gut microbiome and neurodegenerative diseases: A review of metagenomics evidence. Neural Regener Res. (2024) 19:833–45. doi: 10.4103/1673-5374.382223, PMID: 37843219 Polito R Di Meo I Barbieri M Daniele A Paolisso G Rizzo MR . Adiponectin role in neurodegenerative diseases: focus on nutrition review. Int J Mol Sci. (2020) 21(23):9255. doi: 10.3390/ijms21239255, PMID: 33291597 Philip Mani A Balasubramanian B Mali LA Joseph KS Meyyazhagan A Pappuswamy M . The role of the gut microbiota in neurodegenerative diseases. Microbiol Res. (2024) 15:489–507. doi: 10.3390/microbiolres15020033 Wei W Wang S Xu C Zhou X Lian X He L . Gut microbiota, pathogenic proteins and neurodegenerative diseases. Front Microbiol. (2022) 13:959856. doi: 10.3389/fmicb.2022.959856, PMID: 36466655 Roy Sarkar S Banerjee S . Gut microbiota in neurodegenerative disorders. J Neuroimmunol. (2019) 328:98–104. doi: 10.1016/j.jneuroim.2019.01.004, PMID: 30658292 Xie Z Zhang M Luo Y Jin D Guo X Yang W . Healthy human fecal microbiota transplantation into mice attenuates mptp-induced neurotoxicity via ampk/sod2 pathway. Aging Dis. (2023) 14:2193–214. doi: 10.14336/AD.2023.0309, PMID: 37199590 DuPont HL Suescun J Jiang ZD Brown EL Essigmann HT Alexander AS . Fecal microbiota transplantation in parkinson’s disease-a randomized repeat-dose, placebo-controlled clinical pilot study. Front Neurol. (2023) 14:1104759. doi: 10.3389/fneur.2023.1104759, PMID: 36937520 Cryan JF O’Riordan KJ Cowan CSM Sandhu KV Bastiaanssen TFS Boehme M . The microbiota-gut-brain axis. Physiol Rev. (2019) 99:1877–2013. doi: 10.1152/physrev.00018.2018, PMID: 31460832 Guo B Zhang J Zhang W Chen F Liu B . Gut microbiota-derived short chain fatty acids act as mediators of the gut-brain axis targeting age-related neurodegenerative disorders: A narrative review. Crit Rev Food Sci Nutr. (2025) 65:265–86. doi: 10.1080/10408398.2023.2272769, PMID: 37897083 Khatoon S Kalam N Rashid S Bano G . Effects of gut microbiota on neurodegenerative diseases. Front Aging Neurosci. (2023) 15:1145241. doi: 10.3389/fnagi.2023.1145241, PMID: 37323141 Nie T You L Tang F Duan Y Nepovimova E Kuca K . Microbiota-gut-brain axis in age-related neurodegenerative diseases. Curr Neuropharmacol. (2025) 23:524–46. doi: 10.2174/1570159x23666241101093436, PMID: 39501955 Zhang Y Chen Y Yuan S Yu Q Fu J Chen L . Effect of gastrodin against cognitive impairment and neurodegeneration in app/ps1 mice via regulating gut microbiota-gut-brain axis. Exp Brain Res. (2023) 241:1661–73. doi: 10.1007/s00221-023-06632-7, PMID: 37199774 Toledo ARL Monroy GR Salazar FE Lee JY Jain S Yadav H . Gut-brain axis as a pathological and therapeutic target for neurodegenerative disorders. Int J Mol Sci. (2022) 23(3):1184. doi: 10.3390/ijms23031184, PMID: 35163103 A Pilot, Single-Arm Study on the Efficacy and Safety of the Use of a Synbiotic Formula (Scv09) in Alzheimer's Disease Patients [Internet]. (2025). Available from: https://clinicaltrials.gov/study/NCT06948929. Short Chain Fatty Acid Enhancing Prebiotics and Normalization of Parkinson's Disease Microbiome: A Pilot Tolerability Study [Internet]. (2020). Available from: https://clinicaltrials.gov/study/NCT04512599. Clinical Study Evaluating the Efficacy and Safety of Synbiotic as an Adjuvant Therapy in the Treatment of Parkinson's Disease [Internet]. (2022). Available from: https://clinicaltrials.gov/study/NCT05576818. A Single Arm, Open Label Study to Assess the Tolerability of a Prebiotic in Adults with Parkinson's Disease and Healthy Adults [Internet]. (2025). Available from: https://clinicaltrials.gov/study/NCT07127120. Probiotics-Prebiotic Fiber Therapy Improved Bowel Opening Frequency and Whole Gut Transit Time in Parkinson's Disease Patients with Constipation: A Randomised Controlled Study [Internet]. (2020). Available from: https://clinicaltrials.gov/study/NCT04451096. Evaluation of Clinical Effect of Probiotics in Alzheimer's Disease: A Randomized, Double-Blind Clinical Trial [Internet]. (2021). Available from: https://clinicaltrials.gov/study/NCT05145881. Effectiveness of a Probiotic K10 in Managing Health Outcomes in Parkinson's Disease and in Early Stage (Mild Cognitive Impairment to Mild Dementia) and Alzheimer's Disease [Internet]. (2023). Available from: https://clinicaltrials.gov/study/NCT06019117. Effect of Probiotics on Cognitive Functioning of Patients with Mild Alzheimer's Disease [Internet]. (2023). Available from: https://clinicaltrials.gov/study/NCT06181513. High Frequency Sampling to Study the Physiological Effect of Probiotics on Peripheral Markers of Alzheimer's Pathology: A Proof-of-Concept Study [Internet]. (2022). Available from: https://clinicaltrials.gov/study/NCT05521477. Regulatory Mechanism of Intestinal Microorganism in Intervening Mild Cognitive Impairment Based on Multi-Modal Neuroimaging Techniques [Internet]. (2019). Available from: https://clinicaltrials.gov/study/NCT03991195. Effects of Probiotics on Peripheral Immunity in Parkinson's Disease [Internet]. (2021). Available from: https://clinicaltrials.gov/study/NCT05173701. Probiotic Treatment for Depression and Associated Mood Disorders in Parkinson's Disease [Internet]. (2022). Available from: https://clinicaltrials.gov/study/NCT05568498. Treating Anxiety in Parkinson's Disease with a Multi-Strain Probiotic – a Randomized, Placebo-Controlled Trial [Internet]. (2019). Available from: https://clinicaltrials.gov/study/NCT03968133. Gut Health and Probiotics in Parkinson's (Sympd) [Internet]. (2021). Available from: https://clinicaltrials.gov/study/NCT05146921. A Randomized Double-Blinded Placebo-Controlled Trial of Probiotics for Constipation in Parkinson's Disease [Internet]. (2017). Available from: https://clinicaltrials.gov/study/NCT03377322. Role and Mechanism of Bifidobacterium Triple Viable Capsules in Improving Motor Symptoms in Patients with Mild to Moderate Parkinson's Disease: A Multicenter Randomized Clinical Study [Internet]. (2021). Available from: https://clinicaltrials.gov/study/NCT04871464. Effects of Bacillus Subtilis on Blood and Gut Biomarkers in Parkinson's Disease [Internet]. (2024). Available from: https://clinicaltrials.gov/study/NCT06487975. Effects of Lactobacillus Plantarum Ps128 on the Parkinsonian Symptoms in Parkinson's Disease [Internet]. (2021). Available from: https://clinicaltrials.gov/study/NCT04722211. Effect of Probiotic on Constipation and on Neuropsychological Performance in Patients with Parkinson's Disease [Internet]. (2020). Available from: https://clinicaltrials.gov/study/NCT04293159. The Clinical Application of Clostridium Butyricum Miyairisan for Motor and Non-Motor Symptoms in Parkinson's Disease [Internet]. (2024). Available from: https://clinicaltrials.gov/study/NCT06548256. A Study of Protein Metabolism, Microbiome and Investigational Probiotic Use in Patients with Amyotrophic Lateral Sclerosis (Als) [Internet]. (2017). Available from: https://clinicaltrials.gov/study/NCT03324399. Effects of Probiotics on Lipidomic Profile and Disease Evolution in Als-Ftdsd Patients: A Randomized Multicenter, Double-Blind, Phase Ii, Placebo-Controlled, Parallel Trial [Internet]. (2023). Available from: https://clinicaltrials.gov/study/NCT06051123. Prevention of Cognitive Decline in Older Adults with Low Dha/Epa Index in Red Blood Cells [Internet]. (2018). Available from: https://clinicaltrials.gov/study/NCT03691519. Mediterranean Diet Effects on Parkinson's Disease (Med-Park): A Randomized Controlled Trial [Internet]. (2024). Available from: https://clinicaltrials.gov/study/NCT06705517. Dietary Modifications Effect on Continuous Lcig Infusion Outcomes in Patient with Advanced Parkinson's Disease [Internet]. (2014). Available from: https://clinicaltrials.gov/study/NCT02274324. Dietary Intervention and Gastrointestinal Function in Patients with Parkinson's Disease [Internet]. (2019). Available from: https://clinicaltrials.gov/study/NCT03851861. Nutritional Intervention for Constipation Symptoms in Patients with Parkinson's Disease: A Randomized Clinical Trial [Internet]. (2025). Available from: https://clinicaltrials.gov/study/NCT07213856. Ketogenic Diet Interventions in Parkinson's Disease: Safeguarding the Gut Microbiome [Internet]. (2022). Available from: https://clinicaltrials.gov/study/NCT05469997. Effects of Chocolate on Motor Symptoms of Parkinson's Disease – a Monocenter, Prospective, Observer-Blinded Interventional Trial [Internet]. (2009). Available from: https://clinicaltrials.gov/study/NCT00906763. Canadian Parkinson's Microbiome Initiative: A Pilot Phase 2 Feasibility Randomized Controlled Trial of the Mind Diet in Parkinson's Disease [Internet]. (2024). Available from: https://clinicaltrials.gov/study/NCT06207136. Mediterranean Diet Intervention to Improve Gastrointestinal Function in Parkinson's Disease: A Randomized, Controlled, Clinical Trial [Internet]. (2020). Available from: https://clinicaltrials.gov/study/NCT04683900. Impact of Diet on the Microbiome-Immune-Brain Axis in Parkinson's Disease as Part of the Collaborative Research Center 1697 "Targeting the Microbiome-Immune-Brain Interaction in Neurodegeneration" [Internet]. (2024). Available from: https://clinicaltrials.gov/study/NCT06463769. Short Chain Fatty Acids Profiles in Amyotrophic Lateral Sclerosis: Longitudinal Effects of Disease and Mediterranean Diet Intervention [Internet]. (2025). Available from: https://clinicaltrials.gov/study/NCT07178067. Safety and Tolerability of Fat-Rich Vs. Carbohydrate-Rich High-Caloric Food Supplements in Patients with Amyotrophic Lateral Sclerosis (Als) [Internet]. (2019). Available from: https://clinicaltrials.gov/study/NCT04172792. [Internet]. (2014). Available from: https://clinicaltrials.gov/study/NCT02306590. Impact on Functional Status of Early Oral Nutritional Supplementation (Ons) in Amyotrophic Lateral Sclerosis (Als) Patients [Internet]. (2014). Available from: https://clinicaltrials.gov/study/NCT02152449. Oral Fecal Microbiota Transplant Feasibility Study in Alzheimer's Disease [Internet]. (2018). Available from: https://clinicaltrials.gov/study/NCT03998423. Clinical Safety and Efficacy of Fmt in the Treatment of Alzheimer's Disease [Internet]. (2025). Available from: https://clinicaltrials.gov/study/NCT06920212. A Randomized, Double Blind, Placebo Controlled Multicenter Trial of Fecal Microbiome Transplantation Safety and Efficacy for Parkinson's Disease Patients with Abnormal Gut Microbiota Composition [Internet]. (2021). Available from: https://clinicaltrials.gov/study/NCT04854291. Evaluation of the Efficacy and Safety of Fecal Microbiota Transplantation for Parkinson's Disease Patients with Constipation [Internet]. (2024). Available from: https://clinicaltrials.gov/study/NCT06388863. A Double-Blind, Placebo-Controlled, Randomized Clinical Trial Investigating Fecal Microbiota Transplantation for Parkinson's Disease and Its Effect on Symptoms and Disease Progression [Internet]. (2018). Available from: https://clinicaltrials.gov/study/NCT03808389. Fecal Microbiota Transplantation as a Potential Treatment for Parkinson's Disease: A Pilot Study [Internet]. (2019). Available from: https://clinicaltrials.gov/study/NCT03876327. Fecal Microbiota Transplantation Via Oral Capsule for Treating Refractory Constipation in Parkinson's Disease: A Double-Blind, Placebo-Controlled, Randomised Trial [Internet]. (2025). Available from: https://clinicaltrials.gov/study/NCT07038226. An Open-Label Phase I Clinical Trial of Vancomycin Followed by Fecal Microbiota Transplant for the Treatment of Parkinson's Disease [Internet]. (2024). Available from: https://clinicaltrials.gov/study/NCT06647277. Efficacy and Safety of Fecal Microbiota Transplantation in the Treatment of Parkinson's Disease with Constipation [Internet]. (2020). Available from: https://clinicaltrials.gov/study/NCT04837313. Interplay between Gut Microbiota and Adaptive Immunity in Amyotrophic Lateral Sclerosis: A Clinical Trial [Internet]. (2018). Available from: https://clinicaltrials.gov/study/NCT03766321. A Pilot Trial to Investigate the Safety and Efficacy of Intestinal Microbiome Transplant (Mtt) in People with Amyotrophic Lateral Sclerosis [Internet]. (2025). Available from: https://clinicaltrials.gov/study/NCT07017946. Sproten R Nohr D Guseva D . Nutritional strategies modulating the gut microbiome as a preventative and therapeutic approach in normal and pathological age-related cognitive decline: A systematic review of preclinical and clinical findings. Nutr Neurosci. (2024) 27:1042–57. doi: 10.1080/1028415x.2023.2296727, PMID: 38165747 Gates EJ Bernath AK Klegeris A . Modifying the diet and gut microbiota to prevent and manage neurodegenerative diseases. Rev Neurosci. (2022) 33:767–87. doi: 10.1515/revneuro-2021-0146, PMID: 35304983 Settanni CR Ianiro G Bibbo S Cammarota G Gasbarrini A . Gut microbiota alteration and modulation in psychiatric disorders: current evidence on fecal microbiota transplantation. Prog Neuropsychopharmacol Biol Psychiatry. (2021) 109:110258. doi: 10.1016/j.pnpbp.2021.110258, PMID: 33497754

Edited by: Amélia M. Sarmento, Fernando Pessoa University, Portugal

Reviewed by: Saima Khatoon, Jamia Hamdard University, India

Tobiloba S. Olajide, University of Medical Sciences, Nigeria