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Review

The Gut–Brain Axis and Neurodegenerative Diseases: The Role of Nutritional Interventions Targeting the Gut Microbiome—A Systematic Review

by
Despoina Koumpouli
1,
Varvara Koumpouli
2 and
Antonios E. Koutelidakis
3,*
1
Laboratory of Microbiology, University General Hospital of Ioannina, Stavrou Niarchou Avenue, 45500 Ioannina, Greece
2
Laboratory of Hematology, University General Hospital of Ioannina, Stavrou Niarchou Avenue, 45500 Ioannina, Greece
3
Unit of Human Nutrition, Laboratory of Nutrition and Public Health, Department of Food Science and Nutrition, University of the Aegean, Leoforos Dimokratias 66, 81400 Myrina, Greece
*
Author to whom correspondence should be addressed.
Appl. Sci. 2025, 15(10), 5558; https://doi.org/10.3390/app15105558
Submission received: 26 February 2025 / Revised: 28 April 2025 / Accepted: 14 May 2025 / Published: 15 May 2025
(This article belongs to the Special Issue Innovations in Microbiome Research for Functional and Sustainable Food Systems)
Versions Notes

Abstract

:
The gut–brain axis (GBA) comprises bidirectional communication connecting the gut and brain. Many neurodegenerative disorders (NDDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), are characterized by a dysfunction of the GBA, indicating its possible role in disease pathogenesis. This systematic review was performed according to PRISMA guidelines, mainly using the following keywords: gut–brain axis, gut microbiota, gut dysbiosis, neurodegenerative disorders, prebiotics, and probiotics. The most recent scientific articles were searched from the PubMed, Google Scholar, and Scopus databases. The main components and communication pathways of the GBA are discussed in this study, and the aim was to investigate if therapeutic approaches, through dietary intervention targeting the gut microbiota, could ameliorate NDDs. The gut microbiota is a crucial constituent of the GBA, and an unbalanced microbiota, known as dysbiosis, has been related to GBA impairment and neurodegeneration. In most of the studies discussed, the modulation of the microbial constitution through nutritional intervention and probiotic and prebiotic supplementation showed promising outcomes. Although promising, further research is essential to fully elucidate the mechanisms involved and confirm the therapeutic potential of gut microbiota modulation in NDDs.

1. Introduction

Recent studies emphasize the impact of the gut microbiota via the gut–brain axis (GBA) on neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) [1,2,3,4]. NDDs are a heterogeneous group of diseases; their main clinical characteristic is the impairment of the central and peripheral nervous systems [3,5]. Older people are mostly affected by NDDs, which are an important cause of mortality and comorbidities [1].
The World Health Organization (WHO) reports that by 2040, NDDs will become the second cause of mortality globally [5,6]. NDDs present a pathological aggregation of deficient proteins in the brain, like toxic Tau proteins, extracellular amyloid β-protein (Aβ), and α-synuclein (α-Syn), that lead to the progression of AD and PD, respectively [3,7]. These accumulated proteins, stimulating astrocytes and microglia, cause damage and influence synaptic activity [3]. These pathogenic proteins enter the brain through the vagus nerve. The gut microbiota can influence vagus nerve activation, potentially leading to the accumulation of these toxic proteins in the brain [3].
The GBA is a two-way communication pathway between the gut and brain [2,3,5,8,9]. NDDs present as a dysfunction of the GBA, suggesting the probable involvement of GBA in disease pathogenesis [3]. In this bidirectional pathway, the gut microbiota interacts with the immune system, enteric nervous system (ENS), and enteroendocrine system, supporting signal transmission via the vagus nerve and the blood circulation to the central nervous system (CNS) [3]. This involves various microorganism metabolites, neurotransmitters, hormones, and cytokines, indicating the crucial role of the gut microbiota in keeping this communication in equilibrium [3,5,10].
The gut microbiota interacts with its host in a symbiotic relationship [3]. The intestinal microbiota has crucial functions, such as the development and maturation of the immune system [1], the integrity of the gut barrier, the permeability of the blood–brain barrier (BBB), the homeostasis of the endocrine system, and the development of astrocyte cells and microglia [1,2,3,5]. The gut microbiota is a very important constituent of the GBA, and an unbalanced gut microbiota, known as dysbiosis, contributes to the increased permeability of both the intestinal barrier and the BBB. Furthermore, dysbiosis leads to a state of toxic inflammation [11] that causes oxidative stress, pathological protein accumulation, neuroinflammation, neuronal death, and alteration of the brain architecture, contributing to the etiopathogenesis of NDDs [12].
The type of diet is a very important factor that can modify the constitution of the gut microbiota [9,13]. In this way, dietary interventions modulating gut microbiota could offer probable therapeutic strategies for controlling the pathology of NDDs [1]. This review aims to investigate the most recent literature regarding the impact of gut microbiota through GBA on NDDs. In addition, it examines potential therapeutic approaches through nutritional interventions targeting gut microbiota. The review also investigates the potential role of factors that ameliorate the constitution of the gut microbiota, such as prebiotics and probiotics.

2. Methodology

The literature review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the search engines PubMed, Scopus, and Google Scholar. The keywords used were GBA, gut microbiota, gut dysbiosis, NDDs, prebiotics, probiotics, and interventional studies. The research articles used were published between 2011 and 2024, and only research articles written in the English language were taken into consideration. Articles that included the above-mentioned keywords in the abstract or title were further studied. The selection criteria included research conducted in the last decade in which there was an estimation of the influence of prebiotics and probiotics on NDDs through the gut microbiome. Studies with inaccurate findings and evidence were excluded to avoid citing invalid research data. Articles that did not enclose information about prebiotics and probiotics regarding the intestinal microbiome were also excluded.

3. The Gut–Brain Axis (GBA) and Gut Microbiome

GBA, as mentioned before, facilitates bidirectional communication connecting the gut and the brain [3,9,14]. It consists of neural, immune, and hormonal communication pathways between the gastrointestinal (GI) tract and the CNS and maintains the equilibrium inside the GI tract, CNS, and gut microbiome [4,8,9,15,16]. Some of the most significant characteristics of the GBA are given below.

3.1. Human Gut Microbiota

The gut microbiota contains up to 100 trillion bacteria, fungi, archaea, parasites, and viruses, with the majority being bacteria [2,4,9,17], and it consists of about 22,000,000 genes, including 1000 times more genes than our cells. There are four major phyla: Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria; there are two minor phyla: Verrucomicrobia and Fusobacteria. Firmicutes and Bacteroidetes represent almost 90% of the gut microbiota [2,3,5,16].
A healthy microbiome is related to the high diversity and balance of bacteria and consists of bacteria that produce short-chain fatty acids (SCFAs). Bacteria considered negative are potential pathogens or bacteria that produce bacterial toxins like lipopolysaccharide (LPS) [18,19,20]. The Firmicutes/Bacteroidetes ratio is an indicator of gut microbiota health. The Firmicutes/Bacteroidetes ratio has been related to maintaining homeostasis, and its disruption leads to dysbiosis [21]. Reduced levels of Bacteroidetes and high levels of Firmicutes have been associated with obesity, diabetes, and dementia [14]. The gut microbiota plays a crucial role in the modulation of the activity of the GBA [3,4].

3.2. Autonomic Nervous System Communication Pathway

The autonomic nervous system (ANS) consists of the sympathetic (SNS) and parasympathetic nervous systems (PNS); GBA’s components interact with each other via this network [1,5,16].
Afferent signals from the GI tract are sent to the CNS, and efferent signals occur from the CNS to the lumen through both the SNS and the PNS. The ANS regulates the integrity of the intestinal barrier, intestinal motility, and immune responses. Gut microbiota metabolites, which interact with gut ANS synapses, such as catecholamines, serotonin, and precursors of tryptophan and γ-aminobutyric acid (GABA), trigger gut autonomic nerves to send sensory messages to the brain. These neurotransmitters can interact with the CNS [22].

3.3. Vagus Nerve

The vagus nerve is a crucial constituent of the PNS and has a very important role in the GBA. [4,16]. It is made up of 80% afferent and 20% efferent neurons, which transmit information from visceral organs like the GI to the CNS and from the CNS to the viscera [4]. Vagal afferents consist of an abundance of receptors that can detect bacterial products, intestinal hormones, and neurotransmitters. Consequently, they respond to chemical, hormonal, and mechanical signals [16].

3.4. Enteric Nervous System

A crucial constituent of the ANS is the ENS situated in the GI tract. It is made of 200 to 600 million neurons. The ENS regulates gut activity, secretion and absorption, immune defense, and motor activity and preserves gut equilibrium and communication with the gut microbiota [5]. The ENS interacts with the CNS via the SNS (prevertebral ganglia) and the PNS (the vagus nerve) [14,15]. The gut microbiota controls the functions and development of the ENS by stimulating toll-like receptors (TLRs), which can identify microbial peptidoglycan, LPS, and viral RNA. Furthermore, gut microbiota controls the ENS by producing metabolites and neurotransmitters such as SCFAs, catecholamines, GABA, and acetylcholine [3,15]. On the other hand, the ENS exhibits an influence on the gut microbiota [15].

3.5. Hypothalamic–Pituitary–Adrenal Axis Communication Pathway

The hypothalamic–pituitary–adrenal (HPA) axis is a neuroendocrine pathway crucial for GBA communication that regulates adaptation to stress. In conditions of stress, the corticotropin-releasing hormone (CRH) is released and stimulates the release of the adrenocorticotropic hormone (ACTH) into the blood circulation. ACTH triggers the production and release of glucocorticoids (cortisol) [15,23].
On the other hand, the microbial impact on the HPA axis also regulates glucocorticoid concentrations [15]. Glucocorticoid receptors are allocated in multiple organs, such as the CNS and the GI tract [23]. Adequate levels of glucocorticoids are vital for neurodevelopment and cognitive mechanisms like memory and learning [15]. Glucocorticoids are important for gut and brain function via endocrine, metabolic, neural, and immunological pathways. Extended periods of stress lead to HPA dysregulation. Elevated levels of cortisol lead to cognitive dysregulation and elevated AD risk [23].

3.6. Neurotransmitters

Neurotransmitters control signal transportation through neuronal and glial cells, influencing memory, learning, and movement activity. Their production and modulation are controlled by neurons and glial cells with the assistance of enzymes, and their impairment is related to NDDs, including AD, PD, anxiety, and depression. Microbiome enzymes and metabolites promote the production of neurotransmitters and their precursors, so in this mode, they regulate brain activity [3,4,5,10,16,17].

3.7. Immune System Communication Pathway

Enterocytes have immune receptors and can release cytokines and chemokines. TLRs identify microorganism-associated molecular patterns (MAMPs), LPS, polysaccharide A (Gram-negative bacteria), and peptidoglycan (Gram-positive bacteria), and that is how immune system cells identify and react to microorganisms, identify alterations in microbial balance, and preserve gut equilibrium [24].
Immune cell stimulation promotes the intercommunication between the immune system, gut microbiota, and CNS. Appropriate intestinal cytokine production maintains intestinal equilibrium and microbial abundance under control [25]. So, the gut microbiota can regulate neuroinflammation [25,26].

3.8. Enteroendocrine Communication Pathway

Enteroendocrine cells (EECs) are situated in the GI tract. They constitute a large endocrine organ and exhibit a regulatory function on the GBA. EECs exhibit transporters and specific G protein-coupled receptors (GPCRs) that permit the EECs to identify alterations in the gut lumen nutrients, gut microbiota, and metabolites [27,28].
After neural or mechanical stimulation, there is a release of gut molecules through the basolateral membrane into the outer environment, where these peptides trigger vagal afferent neurons [5]. Many gut hormones, such as GLP-1, are associated with the activity of GBA. GLP-1 ameliorates memory, learning, and motor activity and displays potential neuroprotective function in NDDs such as AD and PD. Gut microbiota regulates the release of GLP-1 [29].
Bacterial metabolites trigger EECs to produce neuropeptides that pass into the blood circulation and affect the ENS. The consequent stimulation of the immune system provokes the release of cytokines or the stimulation of the vagal nerve. This process affects neurotransmission and neurogenesis and can be involved in neuroinflammation [3,5].

3.9. Intestinal Barrier

The intestinal barrier is a selective barrier that promotes the absorption of nutrients and immune supervision and limits the entry of pathogenic microorganisms [30]. The intestinal barrier consists of the external mucus layer and the internal lamina propria.
Intestinal epithelial cells beneath the mucus layer are linked to each other with firm junctional structures. They consist of transmembrane proteins, occludins, claudins, and membrane proteins, zonula occludens (ZO). Adherent junctions are situated under tight junctions to form adhesion links and guarantee the integrity of the intestinal barrier [30].
When intestinal permeability rises (leaky gut), microbiome metabolites and toxins can enter the blood circulation, induce the production of pro-inflammatory cytokines, and initiate an inflammatory cascade [13]. Gut dysbiosis allows bacterial toxins like LPS to enter the blood circulation and induce the production of pro-inflammatory cytokines as well [13]. A leaky gut is associated with various human diseases, like irritable bowel, obesity, depression, AD, PD, and diabetes [31].

3.10. Blood–Brain Barrier

The BBB subdivides the CNS from systemic circulation and preserves brain homeostasis. The BBB is a selective barrier that allows oxygen, vital nutrients, and waste metabolites to enter while impeding entry to pathogens and harmful products. The impairment of the BBB’s integrity is involved in the pathology and development of NDDs. The BBB consists of endothelial cells that cover cerebral vessels, tight junction proteins, and basement membranes [32].
Endothelial cells in the CNS are characterized by a low level of transcytosis and display many enzymes and transporters. In this mode, there is a selective translocation of elements in and out of the CNS parenchyma, maintaining an equilibrium for optimal neuronal function [32,33]. Additionally, tight junction proteins preserve the stability of the BBB. Tight junction proteins are membrane-associated cytoplasmic proteins like ZO and transmembrane proteins like claudins and occludins. Alterations in tight junction proteins lead to BBB damage and the development of NDDs [34].

4. Neurodegenerative Diseases

NDDs are a heterogeneous group of diseases; their main clinical characteristic is the impairment of the central and peripheral nervous systems [3,5]. Many NDDs, such as AD, PD, and MS, are characterized by dysfunctions of the GBA, indicating their possible role in disease pathogenesis. Recent studies emphasize the impact of the gut microbiota via the GBA on NDDs [1,2,3,4].

4.1. Alzheimer’s Disease

AD is the most common type of dementia, more frequent in old age, and was discovered in 1907. Almost 50 million people are affected by dementia, and this figure is predicted to quadruple by 2050 [7,35]. AD is an irreversible and developing disorder characterized by memory loss, personality modification, behavioral matters, and an impairment in thinking capacity [7,36]. AD brains display the extracellular gathering of insoluble Aβ peptides and intraneuronal neurofibrillary tangles produced by pathological alterations of the tau protein [4,7,8,35,36].
Gut microbiota, due to its ability to produce pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α, IL-18, IL-1β) and metabolites that pass through the BBB, provokes neuroinflammation in the AD brain. High levels of IL-6 lead to the hyperphosphorylation of tau and neuronal degeneration. [37]. Furthermore, gut microbiota produces insoluble amyloids that could increase the development of plaque and contribute to the pathogenesis of AD [38,39].
AD patients display in their feces great amounts of Escherichia spp. and Shigella spp., which are pro-inflammatory bacteria, and low concentrations of Eubacterium rectale, known as anti-inflammatory bacteria [4,9,10,16]. The bacteria found in AD patients are Actinobacteria, Bacteroides, Lachnospiraceae, and Ruminococcus, with lower levels of Firmicutes and Bifidobacterium and higher levels of Bacteroidetes [10].
The dysbiosis of gut microbiota may be one of the major causes of AD pathogenesis [4,5,16]. The ENS can be triggered to create and aggregate Aβ proteins by various bacteria such as Escherichia coli, Klebsiella pneumoniae, Streptococcus, Staphylococcus aureus, Salmonella, and Mycobacterium [40]. Metabolites produced from pro-inflammatory bacterial species increase brain neuroinflammation and worsen AD [10]. Furthermore, a leaky gut allows bacterial amyloids to pass into the blood circulation and intensify the brain’s neuroinflammation [10].
On the other hand, the age-related decline in gut microbiota diversity is correlated with AD, with a decrease in Bifidobacterium spp. and an increase in Proteobacteria influencing lipid metabolism and memory function [5,10]. All these results discussed above indicate a relationship between GBA, microbial metabolism, and the progress of AD.

4.2. Parkinson Disease

PD is the second most frequent NDD globally [1,8]. There is an increasing prevalence of PD as age advances, and is predicted to increase to 12.9 million in 2040 globally. Furthermore, it is not common before the age of 50, and it is more frequent in men than women between 50 and 59 years old [16].
In PD, there is an accumulation of misfolded α-Syn proteins (known as Lewy bodies) in dopaminergic neurons of the substantia nigra, considered a biomarker in PD [8,14,16]. The accumulation of α-Syn protein leads to motor symptoms (bradykinesia, postural instability, resting tremors, and stiffness) [14,41] and non-motor symptoms in the GI tract, like constipation, which affects 80% of individuals [1,7,9,14,16,35], cognitive deficits, urinogenital complications, and olfactory damage (hyposmia). Hyposmia often anticipates diagnosis by years, suggesting an early accumulation of the α-Syn protein in the olfactory bulb [14].
The ENS could be a way of communicating between the gut microbiota and the CNS and could contribute to the development of PD [14,16]. GI impairment anticipates motor symptoms, suggesting that α-Syn accumulation first takes place in the ENS and then advances to the CNS [14], indicating a potential connection to the GBA [2,16]. Furthermore, in vivo studies evidenced that α-Syn is disseminated from the intestine via the vagus nerve to the brain [5,9,14].
In addition, PD patients present modifications of the gut microbiota as well as an increased permeability of the intestinal barrier [2,5], permitting access to toxins that may impair the neuroendocrine system and GBA [5,14,16]. Dysbiosis has been suggested as being an early marker in PD because the aggregation of α-Syn in the ENS anticipates the symptoms of PD [16].
PD patients present low quantities of Prevotellaceae [4,14], which are SCFA producers that contribute to intestinal barrier impairment, and low quantities of Lachnospiraceae (SCFA producers as well), such as Ruminococcus, Roseburia, and Blautia. On the other hand, PD patients present increased Enterobacteriaceae that increase levels of LPS, lead to neuroinflammation, and are related to postural instability [4,16] and increased pro-inflammatory genera such as Proteobacteria [16].

4.3. Multiple Sclerosis

MS is a chronic demyelinating inflammatory disease of the CNS, where the immune system’s impairment plays a crucial role [1,16,17,35,36,42]. With the knowledge that gut microbiota is very important for the growth and development of the immune system, we can comprehend why gut microbiota is involved in the pathogenesis of MS [9,43].
Globally, it is more common in women than in men [16,43], with a ratio of women to men of 4:1. Worldwide, MS affects about 2.3 million people [1,16,43].
The principal symptoms are diplopia associated with optic neuritis, gastrointestinal symptoms such as dysphagia, constipation, or incontinence (gastrointestinal impairment modifies the composition of gut microbiota), motor sensory symptoms, vestibular symptoms like vertigo, memory impairment, and even psychiatric symptoms like anxiety and depression [42]. MS displays the demyelination of neurons, axonal impairment, and impairment in neurological activity [1,16,17,36,43,44]. MS presents inflammation, BBB impairment, and neurodegeneration [9,16].
GF mice resist neuroinflammation, and this information has triggered an interest in analyzing the relationship between the gut microbiota and MS [44]. The gut microbiota takes part in the etiopathogenesis of MS because it modulates the immune system, modifies the permeability of the BBB, and is implicated in autoimmune demyelination [9,16]. MS patients may more frequently display dysbiosis than healthy controls [1,4,13]. Examining 16S rRNA gene sequencing revealed that MS patients have a more diverse microbiome than healthy controls [44].

5. Microbiome Modification as a Therapeutic Target for Neurodegenerative Diseases

The gut microbiota is a significant constituent of the GBA, and an unbalanced gut microbiota, known as dysbiosis, contributes to the etiopathogenesis of NDDs [11,12]. Several studies suggest that the gut microbiota plays a crucial role in the neuropathogenesis of NDDs by modulating the activity of the GBA [3,4]. The type of diet is a very important factor that can modify the constitution of the gut microbiota [9,13]. Thus, we investigate the effects of prebiotics and probiotics on the gut microbiota as a therapeutic target for NDDs.

5.1. Prebiotics

Prebiotics were first presented in 1995 [45,46]. In 2008, prebiotics were reported as a fermented constituent that led to specific modifications of the composition and activity of the gut microbiota for the benefit of the host’s health [45,47,48]. Prebiotic fermentation by the gut microbiota induced the production of SCFAs and lactic acid. SCFAs, mainly butyrate, affect barrier function and present anti-inflammatory effects. Inulin and fructo-oligosaccharides (FOSs) induce the growth of Bifidobacteria that lead to the production of acetic and lactic acids, produce antimicrobial substances that remove pathogens, and trigger the development of the immune system [48,49,50].

5.1.1. Types of Prebiotics

Fructans

This category includes FOS or oligofructose and inulin. Fructans can selectively stimulate lactic acid bacteria [45,47]. FOS is included in many fruits and vegetables and can be produced by microbial fermentation [47].

Galacto-Oligosaccharides (GOSs)

GOSs stimulate Bifidobacteria and Lactobacilli. GOS also stimulates Bacteroidetes, Firmicutes, and Enterobacteria. There is a type of starch, named resistant starch (RS), that resists upper gut digestion. RS produces high levels of butyrate, contributing to health, and so it is classified as a prebiotic [45].

Non-Carbohydrate Oligosaccharides

There are some constituents that do not belong to carbohydrates but are proposed to be classified as prebiotics, like cocoa flavanols. In vivo and in vitro studies showed that flavanols stimulate lactic acid bacteria [45].

5.1.2. Effects of Prebiotics on the Microbiome Modification

In a randomized, double-blind, placebo-controlled, three-period, cross-over trial, 29 healthy adults 20–40 years old received 0, 5.0, or 7.5 g of Agave inulin/day for 21 days. This in vitro study proved that Agave inulin is fermented by Bifidobacteria and Lactobacilli. Fecal actinobacteria and Bifidobacterium increased 3- and 4-fold after 5.0 and 7.5 g of Agave inulin/d, respectively, in comparison to the control, while Desulfovibrio was diminished by 40% with Agave inulin compared to the control. Dietary fiber consumption was related to fecal butyrate, tended to be related to Bifidobacterium, and was negatively associated with Desulfovibrio abundance. Four species in the Bifidobacterium genera were highly increased after the intake of 5.0 and 7.5 g Agave inulin/d compared with the control: B. adolescentis, B. breve, B. longum, and B. pseudolongum [48].
In another open-label, non-randomized study, the participants affected by PD consumed prebiotics for 10 days. This intervention reduced the pro-inflammatory phyla Proteobacteria and Escherichia coli and increased SCFA-producing species like Fusicatenibacter saccharivorans and Parabacteroides merdae, Bifidobacterium adolescentis, Faecalibacterium prausnitzii, and Ruminococcus bicirculans, with a simultaneous increase in plasma SCFA. The prebiotic intervention also diminished plasma zonulin, a marker of intestinal barrier integrity, and calprotectin, a marker of neutrophils in the intestinal mucosa [51].
A randomized, double-blind, placebo-controlled, cross-over study included 34 healthy participants 19–65 years old, divided into two groups: low dietary fiber (LDF) and high dietary fiber (HDF) consumers. After 3 weeks of daily prebiotic consumption or a placebo, gut microbiota constitution (16S rRNA bacterial gene-sequencing) and SCFA concentrations were investigated. The aim of this study was to examine whether LDF versus HDF consumption modifies the gut microbiota reaction to an insulin-type fructan prebiotic. In the LDF group, the prebiotic consumption increased Bifidobacterium. In the HDF group, the prebiotic consumption increased Bifidobacterium and Faecalibacterium and diminished Ruminococcus, Dorea, and Coprococcus. This study found that HDF consumers had a higher gut microbiota reaction and a greater benefit from the insulin-type fructan prebiotic compared to LDF consumers [50].
In a double-blind, placebo-controlled clinical trial, 35 sedentary constipated adults were given 10 g GOS and sugar gummies for 30 days. The aim of the study was to investigate the effect of GOS gummy consumption on gut health and depression in constipated subjects. After 30 days of GOS consumption, increased Lactobacillus, Bifidobacterium, and Bacteroides considerably diminished the phyla Bacteroidetes, Firmicutes, and the genus Clostridium. The Firmicutes to Bacteroidetes (F/B) ratio was also ameliorated in the GOS group. The F/B ratio is an indicator of gut dysbiosis. GOS consumption ameliorated the SCFA profile. Increased levels of acetic acid, butyric acid, and propionic acid were found in the experimental group in comparison to the placebo. In conclusion, the daily consumption of 10 g of GOS for 30 days improves gut dysbiosis, constipation, and depression in subjects with functional constipation [49].
A cross-sectional study recruited 41 adult patients (25 males, 16 females) who were receiving exclusive enteral nutrition for at least 12 days. In total, 25 patients consumed FOS/fiber-enriched formulae, and 16 patients consumed standard formulae (no fiber or FOS). Fluorescent in situ hybridization was utilized to examine fecal samples for the main groups of microbiotas, and gas–liquid chromatography was utilized to examine SCFA concentrations. There were low concentrations of the main bacterial groups, including Bifidobacteria, in all patients. Nevertheless, fecal butyrate concentrations were higher in patients consuming the FOS/fiber-enriched formula in comparison to the standard formula [52].
A 24 h in vitro culturing method was used to investigate if FOS could provoke a different effect in three diverse adult age groups. Gut microbial communities were cultured to investigate whether FOS can alter microbial communities and how it can change communities based on age. The cultures were analyzed using 16S rRNA sequencing analysis, qPCR analysis, and gas chromatography–flame ionizing detection to identify modifications in their structure and activity. Fecal samples were collected from 18 adults. Consequently, with FOS addition, the genus Odoribacter diminished in the adult and older adult age groups after the consumption of FOS. The genus Bilophila decreased significantly in all age groups after 24 h of incubation with FOS. Bilophila stimulates the production of LPS and leads to inflammation. After 24 h of incubation, there was an increment in Bifidobacterium in all groups, which is very important because Bifidobacterium decreases as we become older and is related to the good health of the gut microbiota. Bifidobacterium also supports an adequate immune system. This study demonstrates that the great amount of SCFAs, butyrate, propionate, and acetate, is influenced by the consumption of this prebiotic [53].
The aim of the following randomized, double-blind, placebo-controlled, cross-over trial was to examine the impact of chicory-derived inulin on bowel activity in healthy subjects with constipation. This study observed a modest impact on microbiota constitution and specific changes after inulin supplementation in relative abundances of Bifidobacterium, Bilophila, and Anaerostipes. The decrease in Bilophila abundances leads to softer stools and the amelioration of constipation. The reduction in Bilophila, a genus containing pathobionts, is associated with good host health [46].
Summarizing some of the results of all the studies mentioned above, prebiotic consumption increased fecal Actinobacteria and Bifidobacterium, diminished the pro-inflammatory phyla Proteobacteria and Escherichia coli, and increased SCFA-producing species. Prebiotic consumption also reduced plasma zonulin, a marker of intestinal barrier integrity, and calprotectin, a marker of neutrophils in the intestinal mucosa [51]. The Firmicutes to Bacteroidetes (F/B) ratio was also ameliorated in the GOS group [49]. In addition, insulin consumption had a modest impact on microbiota constitution and specific alterations in relative abundances of Bifidobacterium, Bilophila, and Anaerostipes. The decrease in Bilophila abundance leads to softer stools and the amelioration of constipation [46].
Table 1 summarizes the results of prebiotics’ effects on the human microbiome. A lot of studies indicate the possible effect of prebiotics on the development of a healthy gut microbiome and increased bacteria with possible health benefits. However, more studies are needed to exact safer results due to the plethora of parameters that influence gut microbiota.

5.2. Probiotics

Probiotics are live microorganisms that have a profitable effect on the body when consumed in adequate abundance [54,55]. These microorganisms cannot colonize the gut permanently and must survive through the digestive system. Probiotics modulate the constitution of the gut microbiota and the production of healthful products that derive from fermentation [56]. The main probiotic genera are Bifidobacterium and Lactobacillus [54]. Examples of probiotic bacteria, mainly included in dairy products, are Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium. Antagonistic attachment to epithelium and mucosa by pro-inflammatory microbes ameliorates the intestinal barrier’s integrity and activity via SCFA production [54,55].

Effects of Probiotics

In a 12-week multicenter, parallel, randomized, double-blind, and placebo-controlled clinical trial, the impact of probiotic supplementation was investigated on the cognitive situation of 90 older adults aged 50–90 years suffering from AD.
Probiotic consumption, compared with taking a placebo, had a positive impact on the anxiety, cognitive status, and instrumental daily functions of patients suffering from AD [57].
In another randomized, double-blind, placebo-controlled clinical trial, the aim was to examine the impact of the consumption of probiotics and vitamin D on the inflammatory features of PD and its complications. The Gastrointestinal Symptom Rating Scale (GSRS), Beck Anxiety Inventory (BAI), and Unified Parkinson’s Disease Rating Scale (UPDRS) were estimated at the beginning and the end of the trial. The supplementation of probiotics and vitamin D induced the reduction in inflammatory cytokines TNF-α, IFN-γ, and IL-1β and increased anti-inflammatory cytokines such as IL-10. BAI, GSRS, and UPDRS determined that the supplementation of probiotics and vitamin D significantly diminished the variables compared to the placebo group [58].
In the following animal study, the aim was to observe the anti-Alzheimer impact of acetylcholine-producing L. plantarum MTCC1325 against D-galactose-provoked AD in albino rats via its antioxidant features and GBA. L. plantarum MTCC1325 has the capacity to produce acetylcholine neurotransmitters. During the AD induction period, the body weight of rats progressively diminished when compared to the control group. The protective group exhibited elevated body weight when compared with the AD-model group. AD-model rats exhibited significantly diminished activity in comparison to the control group. L. plantarum MTCC 1325-treated groups showed amelioration in the activity of rats. The ACh load was diminished in the cortex and hippocampus of the AD-model group rat brain. Treatment with L. plantarum MTCC 1325 exhibited an important augmentation of ACh in both the cerebral cortex and hippocampus [59].
In another animal study, a genetic MitoPark PD mouse model was used. The MitoPark PD mouse has characteristics of PD, such as degeneration in dopaminergic neurons at an older age and the evolving impairment of motor activity, GI impairment, and gut microbiome modification. The aim of this study was to examine whether the daily consumption of probiotics can reduce motor impairment in a PD mouse model. This study showed that the daily consumption of probiotics for 16 weeks has a neuroprotective impact and mitigates the progressive impairment of motor activity in MitoPark PD mice. In addition, immunohistochemical staining demonstrated more intact dopamine neurons in the probiotic-treated group than in the sham probiotic-treated group, indicating the neuroprotective impact of probiotics. These results together indicate that probiotic supplementation may not only delay a decline in motor dysfunction but also have a neuroprotective impact against the progressing degeneration of dopaminergic cells [60].
A randomized, double-blind, placebo-controlled, multicenter clinical trial investigated the impact of probiotics on the brain and intestinal health of 63 individuals over the age of 65. The Consortium to Establish a Registry for AD (CERAD-K) was used to estimate cognitive function, which is a validated test for the screening of AD. The Geriatric Depression Scale (GDS-K) was used to estimate the level of depression. Probiotic supplementation ameliorated cognitive function and mental stress. BDNF, a neurotrophic factor very important for learning, memory, and stress, in contrast to the placebo group, was elevated at week 12 in the probiotics group. The frequency of abdominal distention and gas passage exhibited improvements in the probiotics group in comparison to the placebo group. Lastly, at the genus level, the study found important alterations in the diversity of gut microbiota in the probiotics group and no changes in the control group [61].
The following study included 20 patients (9 females and 11 males, aged 76,7 ± 9.6 years old) with AD. The high production of neopterin and increased breakdown of tryptophan are implicated in cognitive decline in patients affected by AD and other forms of dementia. The kynurenine-to-tryptophan ratio (Kyn/Trp) was measured as an indicator of tryptophan breakdown. The elevation of kynurenine was found after probiotic consumption. Zonulin concentrations (a marker of intestinal barrier integrity) declined after 4 weeks of supplementation with the probiotic [62].
Summarizing some of the results of all the studies mentioned above, probiotic consumption had a positive impact on anxiety, diminished inflammatory cytokines, and increased anti-inflammatory cytokines and GI symptoms. Probiotic consumption also delayed the decrease in motor dysfunction and had a neuroprotective impact against the progressing degeneration of dopaminergic cells, as shown in animal studies, and provoked important changes in the gut microbiota diversity.
Table 2 summarizes the results of probiotic effects. We can observe that many studies have concluded the possible effect of several probiotic bacteria on the gut and overall human health. Nevertheless, in several cases, the results are controversial, and more studies are needed to ensure the existence of data for positive effects.

6. Conclusions

This review presents evidence of the connection between the GBA and NDDs, which takes place via direct communication between the CNS and ENS through the vagus nerve and via indirect pathways like the immune system and microbial products [14,15]. Several studies suggest that gut microbiota play a crucial role in the neuropathogenesis of NDDs by modulating the activity of the GBA [3,4]. Dysbiosis can increase intestinal and BBB permeability and can lead to changes in intestinal mucus and the translocation of gut microbes and their metabolites. These alterations lead to a state of toxic inflammation [11]. Several factors can contribute to dysbiotic microbiomes, including a diet high in refined products with low fiber intake, excessive alcohol consumption, antibiotic use, bacterial or viral infections, and medical conditions such as diabetes and NDDs [12].
The correlation between gut dysbiosis and NDDs suggests that dietary interventions targeting gut dysbiosis could be an approach for treating symptoms and delaying the neuroinflammatory and degenerative processes in NDDs. Prebiotics are used by profitable gut microbes in the large bowel, ameliorating host health. During their fermentation, the production of by-products helps cross-feeding between microorganisms. Acidic fermentation products offer a favorable milieu for beneficial bacteria, like Lactobacilli and Bifidobacteria, and inhibit pathogenic bacteria [63]. The most valuable by-products produced by prebiotics are SCFAs that can enter into the blood circulation. Therefore, prebiotics have an impact not only on the GI tract but also on distant organs, including the brain [45].
The probiotics mostly used are Bifidobacterium, Lactobacillus, Enterococcus, Streptococcus, and Bacillus [64]. Studies have shown that probiotics regulate gut microbiota and diminish pathogen invasion and installation, promote epithelial cell development to fortify the intestinal barrier and diminish immunomodulation. Probiotics also produce healthy products like SCFAs, with anti-inflammatory and neuroprotective activity that enter the blood circulation and cross the BBB, and regulate CNS immune cell function, inflammatory cytokines, BBB integrity, and neurogenesis, thereby inducing brain health [64,65]. They trigger the production and release of neurotransmitters, affecting neuronal activity in NDDs [66].
The limitations of the cited studies are the sample size (many studies use small samples, which may compromise the generalizability of results), a lack of standardization in interventions (different types of prebiotics and probiotics were used, making comparisons between studies difficult), the duration of treatment (some interventions were short-term and may not reflect long-term effects), individual factors (variations in gut microbiota among individuals may influence the results), and the absence of robust clinical trials (many cited studies are experimental or based on animal models, requiring more randomized clinical trials to validate findings).
Continuous studies concerning the gut microbiome provide us with information about the connection between gut microbiota and its symbiotic correlation with humans. In the future, knowledge about the effects of gut microbiomes on NDDs like AD, PD, and MS will contribute to their prevention and therapy. Daily dietary interventions could have a therapeutic function. The development of functional foods containing prebiotics and probiotics holds potential, but further clinical trials are necessary to confirm their effectiveness. In addition, as our knowledge of gut microbiomes expands, predictive biomarkers for various NDDs and their outcomes can be developed. However, extensive studies are still required based on clinical evidence in humans. Moreover, new studies related to the modification of the human gut microbiome through dietary intervention should be performed.

Funding

This research received no external funding.

Data Availability Statement

The data are available after upon request.

Conflicts of Interest

The authors declare no conflicts of interest.

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Table 1. Summary of results of prebiotics and their effects on the human microbiome.
Table 1. Summary of results of prebiotics and their effects on the human microbiome.
Study TypeStudy Sample/DurationParticipantsProtocolSummary of ResultsStudy Reference
Randomized, double-blind, placebo-controlled, 3-period, cross-over trial.29 healthy adults/21 days.29 healthy adults of 20–40 years old.Participants received 0, 5.0, or 7.5 g of agave inulin/day for 21 days, and fecal samples were collected and analyzed by 16S Illumina sequencing.Fecal Actinobacteria and Bifidobacterium increased.[48]
Open-label, non-randomized study.20 PD participants.20 PD patients were newly diagnosed: 10 treated PD patients and 10 non-medicated PD patients.Participants consumed prebiotics in the form of a bar for 10 days daily during the first three days and then one bar twice a day for an additional seven days.This intervention diminished the pro-inflammatory phyla Proteobacteria and Escherichia coli, increased SCFA-producing species, and reduced plasma zonulin, a marker of intestinal barrier integrity, and calprotectin, a marker of neutrophils in the intestinal mucosa.[51]
Randomized, double-blind, placebo-controlled cross-over study.34 healthy participants/3 weeks.34 participants 19–65 years old.Participants were divided into 2 groups, LDF and HDF, and received 16 g/d of the inulin-type fructan prebiotic in two doses for 3 weeks or 16 g/d of placebo maltodextrin in two doses for 3 weeks.In the LDF group, the prebiotic consumption increased Bifidobacterium. In the HDF group, prebiotic consumption increased Bifidobacterium, Faecalibacterium, and diminished Ruminococcus, Dorea, and Coprococcus.[50]
Double-blind placebo control clinical trial.35 adults/30 days.35 sedentary, constipated adults, 25–62 years old.17 subjects in the experimental group and 18 subjects in the control group were given 10 g of GOS and sugar gummies, respectively, for 30 days.GOS consumption ameliorated the SCFA profile, increased Lactobacillus, Bifidobacterium, and Bacteroides, and considerably diminished the phyla Bacteroidetes, and Firmicutes and the genus Clostridium. The Firmicutes to Bacteroidetes (F/B) ratio was also ameliorated in the GOS group.[49]
Cross-sectional study.41 adult patients/12 days.25 males and 16 females.25 patients consumed FOS/-fiber-enriched formulae, and 16 patients consumed standard formulae.
The standard formulae included no fiber or FOS, and the FOS/fiber-enriched formulae included six dietary sources of non-digestible carbohydrates.		Fecal butyrate concentrations were higher in patients consuming the FOS/fiber-enriched formula in comparison to the standard formula.[52]
24 h in vitro culturing method.18 adults.3 age groups: young adults (25–35 years old), adults (36–50 years old), and older adults (51–70 years old), with 6 subjects in each group.Fecal samples were collected after 24 h of incubation with FOS. Gut microbial communities were cultured to investigate whether FOS can change microbial communities.After 24 h of incubation, there was an increment in Bifidobacterium in all groups; the genus Odoribacter diminished; and the genus Bilophila decreased significantly. SCFA levels were increased.[53]
Randomized, double-blind, placebo-controlled, cross-over trial.Healthy
adults/4 weeks.		Healthy subjects with constipation were investigated to
assess the effect of inulin consumption.		In two 4-week intervention periods, 12 g of inulin or maltodextrin (placebo control) was given daily for 2 weeks.A modest impact on microbiota constitution was found, and specific alterations after inulin consumption in relative abundances of Bifidobacterium, Bilophila, and Anaerostipes. The decrease in Bilophila abundance led to softer stools and amelioration of constipation.[46]
Table 2. Summary of results on probiotic effects.
Table 2. Summary of results on probiotic effects.
Study TypeStudy Sample/DurationParticipantsProtocolSummary of ResultsStudy Reference
Randomized double-blind and placebo-controlled clinical trial.90 older adults with mild and moderate AD/12 weeks.Aged 50–90 years old.The participants
were randomly divided into three groups: placebo,
(n = 30), L. rhamnosus (n = 30), and B. longum (n = 30). The cognitive function was evaluated using MMSE and CFT. The IADL scale and GAD-7 scale were used to estimate the ability to execute daily jobs and the levels of anxiety, respectively.		A 12-week
probiotic
consumption study
compared
with
placebo
had
positive
impact on the anxiety, cognitive status, and instrumental daily functions of patients suffering from AD.		[57]
Randomized double-blind, placebo-controlled clinical
trial.		46 patients with PD/12 weeks.Aged 18 to 80 years old.Patients were randomly divided into two groups: Group A was given probiotic/vitamin D supple-
mentation (n = 23) and Group B was given placebo capsules (n = 23) for 12 weeks. GSRS, BAI, and UPDRS were used to estimate the intensity of anxiety, the frequency and intensity of GI problems, and the severity and symptoms of PD, respectively.		Probiotic
consumption and vitamin D diminished
inflammatory cytokines,
IFN-γ, IL-1β, IL-6, and increased anti-
inflammatory cytokines such as IL-10 and diminished disease severity, anxiety, and GI symptoms
in PD patients.		[58]
Animal study.48 albino rats (Wistar strain)/60 days.48 albino rats were separated into 4 groups of 6 animals each.The control group was given normal saline (1 mL/kg body weight). The AD-Model group received an intraperitoneal injection of D-galactose (120 mg/kg body weight). The protective group was given both D-galactose and L. plantarum (10 mL/kg body weight; 12 × 108 CFU/mL) for 60 days. The L.P group was given L. plantarum for 60 days. Animal behavior was evaluated on the 30th and 60th days in all groups.Supplementation with L. plantarum MTCC1325
for 60 days ameliorated cognition problems; treated groups exhibited amelioration in the activity of rats, showed elevated body weight, and exhibited an important augmentation of ACh in both the cerebral cortex and hippocampus.		[59]
Animal study.Transgenic MitoPark PD mouse model/16 weeks.16 male
MitoPark PD mice, 8 weeks old.		8-week-old PD mice were randomly divided into a probiotic-treated group and a sham treatment group.
After daily oral supplementation with
probiotics for 16 weeks, the Beam Balance test was used to estimate the execution of motor skills and balance.		Probiotic consumption delays the decrease in motor dysfunction but also has a neuroprotective impact on the progressive degeneration of dopaminergic cells in MitoPark PD mice.[60]
A randomized, double-blind, placebo-controlled,
multicenter clinical trial.		63 participants/12 weeks.63 subjects/over 65 years old.In total, there were 31 and 32 subjects in the
placebo and probiotics groups, respectively. The probiotics or placebo group received their products twice a day for 12 weeks (1 × 109 CFU of Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI in soybean oil). In the placebo group, each capsule included 500 mg of soybean oil only.		Probiotic supplementation ameliorated cognitive function and mental stress, elevated BDNF and the frequency of abdominal distention and gas passage, exhibited benefits in the probiotics group and demonstrated important changes in gut microbiota diversity in the probiotics group.[61]
Explorative intervention study.20 patients/4 weeks.9 females, 11 males, aged 76.7 ± 9.6 years with AD.Supplements with probiotics were consumed daily
for 28 days. Gut inflammation markers, microbiota constitution in fecal specimens, and biomarkers of immune activation (serum neopterin and tryptophan breakdown) were estimated.		The elevation of kynurenine was found after probiotic consumption; Faecalibacterium prausnitzii increased; and zonulin concentrations declined after 4 weeks of supplementation with probiotics.[62]
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Koumpouli, D.; Koumpouli, V.; Koutelidakis, A.E. The Gut–Brain Axis and Neurodegenerative Diseases: The Role of Nutritional Interventions Targeting the Gut Microbiome—A Systematic Review. Appl. Sci. 2025, 15, 5558. https://doi.org/10.3390/app15105558

AMA Style

Koumpouli D, Koumpouli V, Koutelidakis AE. The Gut–Brain Axis and Neurodegenerative Diseases: The Role of Nutritional Interventions Targeting the Gut Microbiome—A Systematic Review. Applied Sciences. 2025; 15(10):5558. https://doi.org/10.3390/app15105558

Chicago/Turabian Style

Koumpouli, Despoina, Varvara Koumpouli, and Antonios E. Koutelidakis. 2025. "The Gut–Brain Axis and Neurodegenerative Diseases: The Role of Nutritional Interventions Targeting the Gut Microbiome—A Systematic Review" Applied Sciences 15, no. 10: 5558. https://doi.org/10.3390/app15105558

APA Style

Koumpouli, D., Koumpouli, V., & Koutelidakis, A. E. (2025). The Gut–Brain Axis and Neurodegenerative Diseases: The Role of Nutritional Interventions Targeting the Gut Microbiome—A Systematic Review. Applied Sciences, 15(10), 5558. https://doi.org/10.3390/app15105558

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