Could a Mediterranean Diet Modulate Alzheimer’s Disease Progression? The Role of Gut Microbiota and Metabolite Signatures in Neurodegeneration

An essential component of maintaining general health, including brain function, is the gut flora, through its interactions with the immune, metabolic, and nervous systems [13]. However, in individuals with Alzheimer’s disease and dementia, significant alterations in gut microbial composition, referred to as dysbiosis, have been observed [14]. These changes often involve reduced beneficial bacteria and increased pathogenic or pro-inflammatory microbial species, which can contribute to neurodegenerative processes [15]. Research has indicated that those who have Alzheimer’s typically possess lower microbial diversity than healthy individuals. A balanced microbiome, rich in various bacterial species, is essential for producing beneficial metabolites like SCFAs, which help regulate neuroinflammation and maintain the integrity of the blood–brain obstruction [16]. However, in Alzheimer’s patients, a decrease in SCFA-producing bacteria, such as Faecalibacterium sp., Bifidobacterium sp., and Akkermansia sp., has been reported. This reduction can lead to increased neuronal injury, inflammation, and oxidative stress, all contributing to neurocognitive dysfunction [17]. Also, specific bacterial taxa are more abundant in individuals with neurodegenerative diseases. For example, increased levels of Proteobacteria and Bacteroides have been linked to higher production of lipopolysaccharides (LPS), a bacterial endotoxin known to trigger systemic inflammation and disrupt blood–brain barrier function [18]. The presence of these harmful microbial metabolites in circulation can promote neuroinflammation, exacerbate amyloid-beta accumulation, and accelerate the progression of dementia. The observed differences in gut microbiota between healthy individuals and those with Alzheimer’s highlight the potential role of the gut–brain axis in disease pathology [19]. These microbial alterations might offer information about new diagnostic markers and therapeutic targets for neurodegenerative conditions. Further research is needed to determine whether dietary interventions, probiotics, or microbiome-based therapies could restore microbial balance and potentially slow the progression of Alzheimer’s disease. The gut–brain axis has been linked to neurodegeneration through various microbial and metabolic pathways (Figure 1).

The gut microbiota profoundly influences neurodegenerative processes by producing bioactive metabolites that modulate the central nervous system (CNS) function. These metabolites can cross the blood–brain barrier (BBB) or signal through neuroimmune and neuroendocrine pathways [20]. Among the most extensively studied are short-chain fatty acids (SCFAs), tryptophan-derived metabolites, and bile acids, which have been implicated in the pathophysiology of Alzheimer’s disease (AD) [21]. Dysregulation of these metabolic pathways contributes to neuroinflammation, BBB disruption, oxidative stress, and the accumulation of neurotoxic proteins.

The gut microbiota modulates neuroinflammatory pathways by producing microbial metabolites that influence immune responses. Among these, SCFAs, LPS, and tryptophan metabolites can significantly impact the central nervous system (CNS) by regulating crucial inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB) [40]. These cytokines and transcription factors are central to neuroinflammatory processes and are implicated in the development and advancement of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease [41]. IL-6 is a pleiotropic cytokine that can exert pro-inflammatory and anti-inflammatory effects depending on the context. Microbial metabolites, particularly LPS from Gram-negative bacteria, can trigger IL-6 secretion by activating toll-like receptor 4 (TLR4) signaling in microglia and astrocytes [42]. This activation contributes to neuroinflammation, exacerbating neuronal damage and synaptic dysfunction. Similarly, SCFAs such as butyrate and propionate can modulate IL-6 expression, either dampening or amplifying inflammation based on their concentration and the host’s immune status [43]. TNF-α, another vital inflammatory cytokine, is upregulated in response to microbial-derived molecules, particularly in conditions of gut dysbiosis. Dysregulated TNF-α levels contribute to the BBB, allowing peripheral immune cells to pass through due to increased permeability and inflammatory mediators to infiltrate the CNS [44]. This cascade can amplify neuroinflammation and neuronal injury, further linking gut microbial composition to neurodegenerative disease progression. NF-κB is a master DNA-binding protein that orchestrates inflammatory responses and is activated by microbial signals. LPS and specific bacterial metabolites can stimulate NF-κB pathways via TLR signaling, producing IL-6, TNF-α, and other pro-inflammatory cytokines [45]. Chronic NF-κB activation in glial cells sustains neuroinflammation and contributes to neurodegeneration by promoting oxidative stress and apoptosis. However, specific microbial metabolites, such as indole derivatives from tryptophan metabolism, can counteract NF-κB activation and provide neuroprotective effects [46]. The interplay between gut microbial metabolites and neuroinflammatory mediators indicates the critical role of the gut–brain axis in neurological health. The realization of these molecular crosstalk mechanisms could pave the way for microbiome-targeted therapies aimed at modulating neuroinflammation and mitigating neurodegenerative diseases [47]. As shown in Table 1, primary microbiota-derived metabolic byproducts, including SCFAs, lipopolysaccharides, and tryptophan metabolites, play significant roles in modulating neuroinflammation and influencing the progression of neurodegenerative diseases. Microbiome-derived metabolites are essential for neurodegeneration through modulation of neuroinflammatory pathways and neurotransmitter balance (Figure 2).

The BBB serves as a critical defense mechanism, regulating the passage of substances between the bloodstream and the CNS. It comprises endothelial cells that form tight junctions, protecting the brain from potentially harmful substances, including pathogens and toxins [61]. Recent research has uncovered a complex relationship between the microbiota of the gut and the BBB, with gut-derived metabolites playing a significant role in maintaining or disrupting BBB integrity. The microbiota produces various metabolites, such as SCFAs, tryptophan derivatives, and bile acids, which can influence endothelial cell function and modulate the permeability of the BBB [21]. SCFAs, especially butyrate, have been shown to promote the expression of tight junction proteins in endothelial cells, thereby enhancing BBB integrity and protecting the brain from inflammatory insults. On the other hand, dysbiosis, or an imbalance in the gut microbiota, can disrupt this delicate equilibrium and negatively affect BBB function [62]. When the gut microbiota is disrupted, the production of beneficial metabolites like SCFAs can decrease, while the abundance of harmful microbial components such as LPS can increase. LPS, a potent endotoxin derived from the outer membrane of Gram-negative bacteria, can enter the bloodstream when the intestinal barrier is compromised [63]. Gut dysbiosis is often triggered by factors such as aging, a Western-style diet, or the overuse of antibiotics. This reduces beneficial SCFAs like butyrate, which are critical for maintaining tight junction integrity within the BBB [64]. It is essential to distinguish between the structural role of tight junction proteins in maintaining the physical barrier of the BBB and the functional role of microbial metabolites like SCFAs and LPS in modulating its permeability and immune response [65]. A healthy gut microbiota supports BBB tight junctions through SCFA production. Still, when dysbiosis occurs, the resulting decrease in SCFAs is coupled with an increase in harmful microbial components, particularly lipopolysaccharides (LPS) [66]. Once in the bloodstream, LPS triggers systemic inflammation and contributes to endothelial dysfunction by upregulating inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). This inflammatory state increases BBB permeability, allowing peripheral immune cells and neurotoxic molecules to infiltrate the brain [67].

The sequence typically follows this cascade: gut dysbiosis → ↑ LPS and inflammatory cytokines → BBB disruption → neuroinflammation [26].

Once in circulation, LPS triggers systemic inflammation and can directly affect the BBB by increasing its permeability. This compromised barrier allows immune cells and inflammatory mediators to infiltrate the brain, promoting neuroinflammation and contributing to the development and progression of neurodegenerative diseases [65]. Increased BBB permeability due to dysbiosis leads to a cascade of events that exacerbate neuroinflammation. The infiltration of peripheral immune cells, including macrophages and T-cells, into the brain triggers the activation of the CNS-resident immune cells known as microglia [68]. Once activated, the release of pro-inflammatory cytokines, including IL-6 and TNF-α, by microglia amplifies the brain’s inflammatory response. This inflammatory cascade is detrimental to neuronal health and can accelerate neurodegenerative processes, as seen in disorders like Alzheimer’s and Parkinson’s diseases [69]. A leaky BBB allows the entry of neurotoxic molecules, including amyloid-beta, which can directly promote neuronal damage and synaptic dysfunction. Overall, gut microbiota plays a crucial role in regulating the integrity of the BBB [70]. A balanced microbiota helps maintain a robust BBB, protecting the brain from external insults. At the same time, dysbiosis disrupts this protective barrier, leading to increased permeability, neuroinflammation, and an elevated risk of neurodegeneration [71]. Interpreting the mechanisms by which gut microbiota influence BBB function opens the door for potential therapeutic strategies to restore gut health and prevent or mitigate the detrimental effects of BBB dysfunction in neurodegenerative diseases.

Chronic inflammation is a central factor in the development and progression of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and multiple sclerosis. A growing body of evidence suggests that gut microbiota is pivotal in initiating and perpetuating systemic inflammation that impacts the brain [72]. Microbial metabolites derived from gut bacteria can influence immune responses by activating principal inflammatory pathways, including the upregulation of inflammatory cytokines, such as interleukin-6 and TNF-alpha [73]. These cytokines are central to the inflammatory cascade and contribute to neuronal damage, synaptic dysfunction, and the neuroinflammatory environment observed in neurodegenerative diseases. Dysbiosis, or an imbalance in the gut microbiota, can exacerbate this inflammatory response, leading to the activation of chronic inflammation within the CNS [74]. The activation of inflammatory pathways, mainly through IL-6, TNF-α, and nuclear factor kappa B (NF-κB), is closely linked to neurodegenerative processes. IL-6 and TNF-α are potent pro-inflammatory cytokines produced by various immune cells, including microglia and astrocytes, in response to microbial signals [75]. These cytokines can activate NF-κB, a transcription factor that governs the expression of numerous genes involved in inflammation, cell survival, and apoptosis. The continuous stimulation of NF-κB in the brain amplifies neuroinflammation and results in neuronal injury, contributing to the progressive nature of neurodegeneration [76]. Thus, the microbiota-induced activation of these pathways plays a vital role in maintaining the chronic inflammatory state that accelerates neurodegenerative disease progression. One of the most significant microbial factors that drive systemic inflammation is LPS, a component of the outer membrane of Gram-negative bacteria [77]. LPS can enter the bloodstream through an impaired intestinal barrier, particularly in gut dysbiosis. Once in the circulation, LPS acts as a potent endotoxin, triggering systemic inflammation by activating immune cells through toll-like receptor 4 (TLR4). This releases pro-inflammatory cytokines, including IL-6 and TNF-α, which can reach the brain via the bloodstream, exacerbating neuroinflammation [78]. The gut-derived LPS-mediated systemic inflammation is particularly relevant in neurodegenerative diseases, as it has been shown to increase BBB permeability, permitting the entry of immune cells and inflammatory mediators to penetrate the brain more efficiently [79]. This breakdown of the BBB facilitates further neuroinflammation and neuronal damage, reinforcing the vicious cycle of chronic inflammation and neurodegeneration. Chronic inflammation, driven by microbiota-derived factors such as IL-6, TNF-α, and LPS, is a leading mechanism in the pathogenesis of neurodegenerative diseases [80]. The gut microbiota influences local gut immune responses and profoundly affects the central nervous system, exacerbating neuroinflammation and accelerating neurodegeneration. Recognizing these mechanisms paves the way for new therapeutic approaches to modulate the microbiota to reduce chronic inflammation and its detrimental effects on brain health [81]. BBB dysfunction is a critical factor in neurodegeneration, influenced by inflammatory cytokines, microbial metabolites, and oxidative stress (Figure 3).

Diet plays a pivotal role in regulating the microbiota–brain interaction, the exchange network across the gut–brain interface, influencing cognitive function, mood, and even neurodegenerative disease emergence. The composition of the diet can profoundly impact the gut microbiota, which in turn affects brain health [82]. Two commonly studied dietary patterns are the Western and Mediterranean diets, each of which has distinct effects on gut microbiota and cognitive function. The Western diet, characterized by a high intake of processed foods, sugars, unhealthy fats, and low fiber, has been associated with detrimental effects on gut health and cognitive function [83]. This dietary pattern promotes the growth of pathogenic bacteria in the gut, leading to a disruption of the microflora, or dysbiosis, which is associated with increased inflammation and impaired brain health. Research suggests that individuals who adhere to a Western diet can experience accelerated cognitive decline and a higher risk of developing neurodegenerative diseases such as Alzheimer’s and Parkinson’s [84]. The high levels of processed sugars and fats in this diet contribute to an inflammatory environment in the gut and the brain, promoting neuroinflammation and altering brain function [85]. In contrast, the Mediterranean diet, rich in fruits, vegetables, yam [86], whole grains, legumes, healthy fats (mainly olive oil), lean proteins, and pepper soup [87], has been consistently associated with better cognitive function and a reduced risk of neurodegenerative diseases [88]. This diet promotes a more diverse and balanced gut microbiota, supporting the growth of beneficial bacteria that produce metabolites like SCFAs, which are known for their anti-inflammatory and neuroprotective properties [89]. The Mediterranean diet’s emphasis on polyphenols, antioxidants, and healthy fats helps reduce oxidative stress and inflammation in the brain, contributing to improved cognitive health. Studies have shown that individuals following a Mediterranean diet experience slower cognitive decline and demonstrate better cognitive performance in aging [90]. The diet’s positive effects on intestinal microbes and their anti-inflammatory properties are critical in enhancing cognitive function and protecting the brain from age-related neurodegenerative diseases [91]. Furthermore, high-fat, low-fiber diets, often a hallmark of the Western diet, have been shown to promote microbiota dysbiosis. These diets foster the overgrowth of Firmicutes bacteria, which are associated with inflammation and an imbalance in gut health, while decreasing the concentration of Bacteroidetes in fiber fermentation and SCFA production [92]. Reduction in fiber intake in high-fat, low-fiber diets directly impacts SCFA synthesis, which is essential to support gut barrier integrity and regulate immune responses. The imbalance between beneficial and pathogenic microbes leads to increased gut permeability, or “leaky gut”, which facilitates the translocation of harmful bacterial products like LPS into the bloodstream [93]. These microbial products can trigger systemic inflammation, subsequently impacting the brain and leading to neuroinflammation and neuronal damage. This inflammation in the brain is a chief factor during the onset of neurodegenerative diseases [94]. Therefore, the lack of fiber and the dominance of unhealthy fats in high-fat diets exacerbate microbiota dysbiosis and contribute to cognitive decline and brain dysfunction. Dietary patterns, particularly the Western and Mediterranean diets, significantly influence the gut–brain axis and cognitive function [95]. The typical Western diet, rich in unhealthy fats and sugars and low in fiber, fosters microbiota dysbiosis, leading to neuroinflammation and cognitive decline. In contrast, the Mediterranean diet promotes a healthy, balanced microbiota and has neuroprotective effects, supporting cognitive function and reducing the risk of neurodegenerative diseases [96]. These findings mark the importance of dietary choices in maintaining gut health and brain function, indicating that nutritional interventions might be decisive in preventing neurodegeneration.

Bioactive dietary compounds in various foods have garnered increasing attention for their potential neuroprotective effects. These compounds can influence brain health through multiple mechanisms, including anti-inflammatory properties and modulation of the gut microbiota [97]. Among these bioactive compounds [98], polyphenols and omega-3 fatty acids stand out for their promising roles in neuroprotection. Polyphenols, such as resveratrol and curcumin, are widely recognized for their powerful antioxidant and anti-inflammatory effects, which can help protect the brain from neurodegenerative diseases and cognitive decline [99]. Resveratrol, a polyphenol found in red wine, grapes, and berries, has been shown to exert anti-inflammatory effects by modulating several signaling pathways involved in inflammation. It inhibits the activation of pro-inflammatory cytokines and enzymes, such as TNF-α and COX-2, which play a central role in the inflammatory response in the brain [100]. Resveratrol also activates the SIRT1 pathway, which has been associated with cellular stress resistance and promoting neuronal survival. These effects contribute to reducing neuroinflammation, which is a hallmark of many neurodegenerative conditions, including Alzheimer’s and Parkinson’s diseases [101]. Similarly, curcumin, the active compound in turmeric, has been extensively studied for its anti-inflammatory and antioxidant properties. Curcumin can cross the blood-brain barrier and suppress the activation of microglia, the brain’s innate immune cells, thus preventing excessive inflammation in the CNS [102]. It also reduces oxidative stress by scavenging free radicals and promoting the expression of antioxidant enzymes. Both resveratrol and curcumin are potent modulators of inflammatory pathways, making them valuable dietary components for reducing neuroinflammation and supporting brain health. Omega-3 fatty acids, particularly those found in fatty fish, flaxseeds, and walnuts, are another group of bioactive compounds with significant neuroprotective potential [103]. Omega-3 fatty acids, including EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), have been shown to exert neuroprotective actions through various pathways, including the regulation of the gut flora [104]. These fatty acids are critical components of neuronal membranes and are vital in maintaining brain structure and function. Omega-3 fatty acids also exhibit anti-inflammatory activity, helping to decrease the activation of cytokines that induce inflammation and immune cells in the brain [105]. Furthermore, omega-3 fatty acids promote the growth and function of beneficial gut bacteria, which can positively influence the gut–brain axis. By enhancing the diversity of the gut microbiota and supporting the production of anti-inflammatory metabolites like SCFAs, omega-3 fatty acids help to maintain gut health, reduce systemic inflammation, and protect the brain from neurodegenerative damage [106]. In addition to their direct effects on brain health, both polyphenols and omega-3 fatty acids have the potential to influence the gut microbiota, which is increasingly recognized as a crucial mediator of brain function. The modulation of gut microbiota composition through diet can impact the synthesis of neuroactive metabolic products, the control of inflammation, and the integrity of the blood–brain barrier [107]. In this way, these bioactive compounds protect the brain through their inflammation-reducing and antioxidant properties and help maintain the delicate balance of the gut–brain axis. As such, including polyphenols, like resveratrol and curcumin, and omega-3 fatty acids in the diet could be a powerful strategy for preventing or mitigating neurodegenerative diseases and supporting overall cognitive health [108]. Bioactive dietary compounds such as polyphenols (resveratrol and curcumin) and omega-3 fatty acids possess significant neuroprotective potential [109]. These compounds exert their effects through anti-inflammatory and antioxidant mechanisms and by modulating the gut microbiota [110]. By incorporating these compounds into their diet, individuals can support brain health, reduce neuroinflammation, and protect against the onset of neurodegenerative diseases.

The role of diet in modulating the gut microbiota and its potential to slow the progression of Alzheimer’s disease has been the focus of several human trials in recent years. These studies aim to determine whether specific dietary patterns or bioactive compounds can positively influence cognitive function and delay the onset or progression of Alzheimer’s by affecting the gut–brain axis [111]. Evidence from human trials suggests that dietary interventions can significantly impact cognitive performance and brain health. For instance, the Mediterranean diet, rich in fruits, vegetables, whole grains, and healthy fats, has been shown to reduce the risk of developing Alzheimer’s and slow cognitive decline in aging populations [112]. Several clinical studies have indicated that individuals following this diet exhibit improved cognitive function, reduced neuroinflammation, and a healthier gut microbiota composition compared to Western diets. Similarly, clinical trials examining the effects of specific nutrients, such as omega-3 fatty acids and polyphenols, on Alzheimer’s progression have yielded promising results [113]. Omega-3 supplementation, particularly DHA, is found to enhance cognitive performance and decrease markers of neuroinflammation in elderly individuals at risk for Alzheimer’s. Polyphenols, such as those found in berries, green tea, and turmeric, have also demonstrated potential cognitive benefits, possibly by reducing oxidative stress and inflammation in the brain [114]. These dietary interventions can exert their effects by modulating gut microbiota, which influences systemic inflammation and brain health. Furthermore, a recent systematic review and meta-analysis has strengthened the link between gut microbiota composition and cognitive function in individuals with Alzheimer’s disease, indicating that the gut microbiome may act both as a contributor to disease progression and a promising therapeutic target [115].

The connection between diet and neuroinflammation is increasingly being understood through molecular mechanisms that link dietary components to cellular and epigenetic processes in the brain. One of the critical pathways through which diet impacts neuroinflammation is the production of SCFAs [116]. SCFAs, such as butyrate, propionate, and acetate, are produced by the fermentation of dietary fiber by gut bacteria and have been shown to play a crucial role in regulating the immune system and modulating inflammation. SCFAs can enter the bloodstream and reach the brain, where neuroinflammatory pathways are influenced by activating specific receptors, such as G-protein-coupled receptors (GPCRs) [22]. One of the most notable effects of SCFAs is their ability to modulate gene expression through epigenetic mechanisms. SCFAs can inhibit histone deacetylases (HDACs), enzymes involved in chromatin remodeling, which leads to activating anti-inflammatory genes [117]. This epigenetic modulation helps to reduce neuroinflammation in the brain, a significant driver of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. By promoting the expression of anti-inflammatory cytokines and reducing the levels of pro-inflammatory mediators, SCFAs contribute to a neuroprotective environment that can help slow the progression of these diseases [118]. Another molecular pathway linking diet to neuroinflammation involves polyphenols, bioactive compounds in plant-based foods like fruits, vegetables, and tea. Polyphenols, such as curcumin and resveratrol, have been shown to modulate neuroinflammation by influencing autophagy in neuronal cells [119]. Autophagy is a cellular process that removes damaged or dysfunctional components from cells, including misfolded proteins implicated in neurodegenerative diseases [120]. Polyphenols can stimulate autophagy by activating essential signaling pathways, such as the AMPK-mTOR pathway, which enhances the degradation of damaged proteins and reduces cellular stress. This process protects neurons from oxidative damage and helps to maintain neuronal homeostasis and function [121]. In neuroinflammation, polyphenol-induced autophagy can also promote the clearance of neurotoxic substances and inflammatory cytokines, further reducing inflammation and supporting brain health. By influencing both epigenetic mechanisms through SCFAs and cellular processes such as autophagy through polyphenols, diet can play a pivotal role in mitigating neuroinflammation and offering neuroprotective effects against advancing neurodegenerative disorders [122]. Diet is critical in modulating neuroinflammation through various molecular pathways. SCFAs synthesized by gut microbiota from dietary fiber fermentation regulate immune responses and gene expression via epigenetic modulation, contributing to a reduction in neuroinflammation [123]. Conversely, polyphenols influence neuronal autophagy, promoting the clearance of damaged proteins and reducing oxidative stress. These dietary mechanisms support brain health and offer promising strategies for slowing the progression of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, by targeting the underlying processes of neuroinflammation [124]. As shown in Table 2, dietary components can significantly affect the intestinal microbial community, influencing the growth of microflora and the balance of microbial diversity. Dietary patterns significantly influence the gut–brain axis, with the Western diet exacerbating neuroinflammation, while the Mediterranean diet promotes neuroprotection (Figure 4).

Dysbiosis, a disruption in the balance of the gut microbiota, has been increasingly associated with the pathogenesis of Alzheimer’s disease, particularly concerning tau pathology. Tau proteins are critical for maintaining the structure of neurons, but in neurodegenerative diseases like Alzheimer’s, tau can become hyperphosphorylated, forming abnormal protein aggregates in the brain [134]. These abnormal proteins disrupt neuronal activity and play a role in cognitive decline. One main factor contributing to tau hyperphosphorylation is bacterial endotoxins, such as LPS, which are released by pathogenic bacteria in the gut. When the gut microbiota becomes dysbiotic, the overgrowth of harmful bacteria can lead to the increased release of LPS into the bloodstream, a condition known as endotoxemia [135]. LPS can cross the blood–brain barrier, triggering inflammation and oxidative stress in the brain. This inflammation can activate several signaling pathways that contribute to tau hyperphosphorylation, including the activation of kinases such as glycogen synthase kinase 3 beta (GSK-3β) and cyclin-dependent kinase 5 (CDK5), which are involved in tau phosphorylation [136]. Oxidative stress induced by LPS can produce reactive oxygen species (ROS), further exacerbating tau pathology and promoting neurofibrillary tangles’ formation. The relationship between gut dysbiosis, bacterial endotoxins, and tau hyperphosphorylation conveys the importance of maintaining a balanced gut microbiota to protect against neurodegenerative diseases [137]. Handling dysbiosis through dietary interventions or probiotic supplementation can help reduce endotoxin release and oxidative stress, potentially mitigating tau pathology and slowing the progression of Alzheimer’s disease. Both SCFAs, particularly butyrate, and gut dysbiosis play significant roles in the pathophysiology of Alzheimer’s [138]. Butyrate helps to activate microglia, facilitating the clearance of amyloid-β plaques. At the same time, dysbiosis and the release of bacterial endotoxins like LPS contribute to tau hyperphosphorylation and the progression of neurodegeneration [139]. These findings highlight the critical connection between gut health, microbiota composition, and brain function, emphasizing the potential for dietary interventions to modulate the connection between the gut and brain, and provide treatment benefits for conditions related to neurodegenerative diseases.

The gut microbiota is crucial in metabolizing various neurotransmitters, which are essential for maintaining brain function and regulating mood, cognition, and behavior. Among the neurotransmitters influenced by gut microbiota are serotonin, dopamine, and acetylcholine, all of which are involved in neuropsychiatric disorders such as depression, anxiety, and Parkinson’s disease [140]. The gut is a primary site for synthesizing serotonin, with approximately 90–95% of the body’s serotonin produced in the gastrointestinal tract. Microbial populations within the gut can influence serotonin levels by affecting the synthesis and breakdown of this neurotransmitter [141]. Certain gut bacteria, such as Lactobacillus sp. and Bifidobacterium sp., have been shown to enhance serotonin production through the action of specific enzymes. By modulating its absorption and metabolism, gut bacteria can influence the availability of tryptophan, the precursor for serotonin synthesis [33]. The gut microbiota’s modulation of serotonin levels can directly impact brain serotonin signaling, influencing mood and behavior. Similarly, the gut microbiome influences dopamine metabolism, which plays a pivotal role in motivation, reward, and motor control [142]. Particular bacterial species in the gut, such as Bacteroides, can influence the production of dopamine precursors, which can subsequently impact dopamine signaling in the brain. In Parkinson’s disease, a condition characterized by the degeneration of dopamine-producing neurons in the brain, the gut microbiota has been implicated in regulating dopaminergic signaling and modulating neuroinflammation [143]. Furthermore, gut microbiota influences acetylcholine metabolism, a neurotransmitter vital to learning, memory, and muscle function. Research suggests that gut bacteria can modulate choline levels, the precursor for acetylcholine, thereby affecting its synthesis [144]. Dysbiosis, or imbalances in the gut microbiota, can lead to altered neurotransmitter metabolism, contributing to various neurological and psychiatric disorders [145]. Therefore, appreciating the intricate relationship between the gut microbiota and neurotransmitter metabolism is crucial for exploring potential therapeutic approaches to modulate brain function and treat diseases like depression, Parkinson’s disease, and Alzheimer’s.

The gut microbiota is increasingly recognized for regulating cellular processes beyond the gastrointestinal system, including clearing misfolded proteins that accumulate in neurodegenerative diseases. Misfolded proteins, such as amyloid-β in Alzheimer’s and α-synuclein in Parkinson’s disease, can aggregate and form toxic plaques that disrupt cellular function and contribute to neurodegeneration [146]. One of the mechanisms by which the body clears these misfolded proteins is through the proteasomal degradation system and autophagy, both of which are critical cellular processes for maintaining protein homeostasis. The gut microbiota can influence these processes by modulating systemic inflammation, oxidative stress, and the production of metabolites that directly impact cellular pathways involved in protein degradation [147]. Proteasomal degradation, a process in which damaged or misfolded proteins are tagged for destruction by ubiquitin and then degraded by the proteasome, may be modulated by microbial metabolites like SCFAs. SCFAs, including butyrate, have been shown to promote proteasomal activity, thereby enhancing the clearance of misfolded proteins [148]. Autophagy, a cellular process encompassing the intake and degradation of misfolded proteins within lysosomes, is also influenced by the gut microbiota. Particular bacterial species can stimulate autophagy by producing metabolites such as SCFAs, which activate major signaling pathways such as the mTOR and AMPK pathways [149]. By promoting autophagic clearance, the gut microbiota helps reduce the accumulation of toxic misfolded proteins and mitigates the neurodegenerative processes associated with diseases like Alzheimer’s and Parkinson’s. Moreover, the gut microbiome can influence the immune system, which plays a significant role in the clearance of misfolded proteins [150]. Dysbiosis, a disruption in gut microbial balance, can result in chronic low-grade immune response and the activation of the brain’s immune cells, the microglia. When microglia are overactivated, neuroinflammation occurs, hindering the clearance of misfolded proteins [151]. Thus, a balanced gut microbiota that promotes anti-inflammatory pathways can support the brain’s ability to clear toxic protein aggregates, reducing the risk of neurodegenerative processes. The role of the gut microbiota in influencing proteasomal degradation, autophagy, and immune modulation highlights its essential role in maintaining protein homeostasis and protecting the brain from accumulating misfolded proteins contributing to neurodegenerative diseases [152]. Through dietary interventions or probiotic supplementation aimed at restoring gut health, it is possible to enhance these cellular clearance processes and slow the progression of neurodegeneration. As shown in Table 3, several clinical trials have investigated diet–microbiota interventions in Alzheimer’s, exploring the impacts of various eating habits, supplements, as well as probiotics on mental function and gut health. Gut microbiota play a pivotal role in modulating amyloid-β aggregation and tau pathology, influencing neurodegenerative progression through microbial metabolites and immune signaling (Figure 5).

Microbial metabolites exert neuroprotective effects by interacting with various molecular targets and signaling pathways involved in neuroinflammation, neuronal survival, and cognitive function [20]. Short-chain fatty acids (SCFAs) such as butyrate, acetate, and propionate influence inflammation, intestinal barrier integrity, and the sympathetic nervous system by activating G-protein-coupled receptors like GPR41 and GPR43, which play a significant role in neurodegeneration [159]. Butyrate inhibits histone deacetylases (HDACs), leading to epigenetic changes that promote anti-inflammatory gene expression and support neuronal plasticity. This process enhances the production of brain-derived neurotrophic factor (BDNF), which is crucial for cognitive function [160]. Bile acids activate the farnesoid X receptor (FXR) and TGR5, which regulate both metabolic and immune responses, helping to reduce neuroinflammation and improve neuronal health [161]. Tryptophan-derived metabolites from the gut microbiota engage the aryl hydrocarbon receptor (AhR), impacting immune responses and oxidative stress. Some of these metabolites also contribute to serotonin production, linking microbiota activity to neurotransmitter balance and mood regulation [33]. These molecular mechanisms provide potential targets for microbiome-based therapies that could slow or prevent neurodegenerative diseases, such as Alzheimer’s disease.

Probiotics, prebiotics, and postbiotics have garnered attention for their potential neuroprotective effects, particularly concerning neurodegenerative conditions like Alzheimer’s disease. Probiotics, which are live beneficial bacteria, are crucial in maintaining gut health and influencing the gut–brain axis [162]. Certain strains of probiotics have been shown to have direct neuroprotective effects. For instance, Lactobacillus sp. and Bifidobacterium species are among the most studied probiotics positively affecting brain health. These strains can modulate the immune system, reduce gut inflammation, and influence the synthesis of neuroactive compounds, including serotonin [163]. These probiotics have been shown to enhance the integrity of the blood–brain barrier, which can help protect the brain from neuroinflammation and oxidative damage. The neuroprotective effects of probiotics are thought to be mediated through their ability to modulate gut microbiota composition, thereby improving gut health and reducing systemic inflammation, contributing to cognitive function and neuroprotection [164]. Prebiotics, which are food components that resist digestion and support the proliferation and function of beneficial gut microbes, also play a significant role in neuroprotection. One of the core benefits of prebiotics is their ability to enhance the production of SCFAs like butyrate [165]. SCFAs are manufactured by gut bacteria during the breakdown of dietary fibers through fermentation and are known to have multiple beneficial effects on brain health. Butyrate, in particular, has neuroprotective properties because of its capacity to reduce neuroinflammation, enhance mitochondrial function, and promote the removal of harmful proteins, like amyloid-β [166]. SCFAs can improve cognitive function by influencing gene expression in the brain through epigenetic modifications, such as histone acetylation. Together, probiotics and prebiotics present a promising approach to improving mental health in potentially slowing the progression of neurodegenerative diseases like Alzheimer’s [167]. Postbiotics, the bioactive compounds produced by probiotics during fermentation, have also been shown to have neuroprotective effects. These include metabolites such as SCFAs, antimicrobial peptides, and other signaling molecules that can modulate inflammation, promote neuronal survival, and enhance cognitive function [168]. By acting on the gut and the brain, postbiotics offer a novel and complementary approach to supporting brain health. Emerging research suggests that postbiotics could be combined with probiotics and prebiotics to optimize neuroprotective outcomes, providing a multi-faceted strategy for managing neurodegenerative diseases.

FMT is a procedure that involves transferring gut microbiota from a healthy donor into a recipient, is gaining attention as a potential therapeutic approach for Alzheimer’s disease and other neurodegenerative conditions. The goal of FMT is to restore a healthy microbiome in patients with dysbiosis, which has been linked to several chronic diseases, including neurodegenerative disorders [169]. For Alzheimer’s disease, the idea is that restoring a balanced gut microbiota could improve cognitive function, reduce neuroinflammation, and slow disease progression. Preclinical studies in animal models have shown that FMT can have beneficial effects on brain health, including improved memory, reduced amyloid plaque accumulation, and decreased neuroinflammation [170]. Additional research has shown that FMT can enhance cognitive function in animal models by modulating the gut–brain axis, which influences neuroinflammation and synaptic plasticity [171]. Butyrate, a short-chain fatty acid produced by gut microbiota during the fermentation of dietary fiber, plays a key role in maintaining brain health. It regulates microglial activity, which is crucial for managing neuroinflammation [172]. Preclinical studies indicate that butyrate inhibits histone deacetylases (HDAC), triggering changes in gene expression that foster a neuroprotective environment. Through HDAC inhibition, butyrate promotes histone acetylation, leading to the activation of anti-inflammatory genes and the suppression of pro-inflammatory cytokines in microglia, thus reducing neuroinflammation and improving cognitive function [173]. These mechanisms are extensively documented in studies exploring the relationship between gut-derived metabolites and brain function, particularly in Alzheimer’s disease and other neurodegenerative diseases.

These findings have led researchers to hypothesize that FMT could be a viable treatment for Alzheimer’s patients by promoting a healthier gut microbiome that positively influences the brain. The potential of FMT as a therapy for Alzheimer’s disease is based on the concept that gut microbiota imbalances contribute to neuroinflammation and the progression of amyloid-β and tau pathologies, both of which are central to Alzheimer’s [174]. By restoring the gut microbiota, FMT could reduce systemic inflammation and promote a healthier environment for neuronal function. Several clinical trials are currently investigating the effectiveness of FMT in individuals with Alzheimer’s disease, focusing on outcomes such as cognitive improvement, gut microbiota composition, and biomarkers of neuroinflammation [175]. However, while early studies show promise, the clinical application of FMT for Alzheimer’s is still in its infancy. There are several difficulties to consider, including identifying appropriate donor microbiota, the standardization of procedures, and the long-term safety and efficacy of the treatment [176]. Despite these obstacles, FMT remains an exciting potential therapy that could help modulate the gut–brain axis and provide a novel approach to treating Alzheimer’s disease and similar neurodegenerative conditions.

Fecal microbiota transplantation (FMT) presents promising therapeutic potential for neurodegenerative disorders, as several ethical and logistical challenges must be resolved before it can be widely implemented [177]. One of the primary concerns is the absence of standardized protocols, which differ across institutions and regions, hindering consistent evaluation of safety and efficacy [178]. Despite comprehensive donor screening, there remains a risk of transmitting pathogenic or unidentified harmful microbes, which is an issue of particular concern in immunocompromised populations such as elderly patients with Alzheimer’s disease [179]. Patient acceptance is another critical factor, influenced by cultural norms and psychological discomfort associated with the nature of the procedure. Many individuals may view FMT as invasive or unappealing, leading to hesitation or outright refusal. These perceptions highlight the importance of thorough patient education and transparent informed consent processes [180]. In addition, regulatory ambiguity continues to challenge the integration of FMT into clinical practice. As FMT straddles the domains of biologics and procedural medicine, regulatory agencies are still working to define appropriate oversight mechanisms, particularly for use in high-risk or vulnerable patient groups [181]. While FMT holds considerable promise as a novel intervention for neurodegenerative diseases, its successful adoption depends on establishing standardized, safe procedures, more straightforward regulatory guidelines, and ethically sensitive strategies to improve patient understanding and acceptance.

A critical evaluation of FMT’s current experimental landscape reveals considerable variability in outcomes across clinical trials, raising concerns about the reproducibility of results and the influence of patient-specific factors [182]. The absence of standardized criteria for donor selection and microbiota profiling further complicates inter-study comparisons. The potential risks, such as adverse effects linked to the microbiome, long-term immune consequences, and microbiota instability, must not be overlooked. These concerns are especially pertinent in older populations, where immune aging and comorbidities may heighten the risks [183]. As such, there is a pressing need to establish standardized FMT protocols and robust regulatory oversight. Ethical considerations should also be given priority, including clear communication of potential risks, equitable treatment access, and careful patient selection to ensure safety and effectiveness, particularly in vulnerable groups like the elderly [184].

Personalized microbiome-based dietary strategies represent a promising approach to managing neurodegenerative diseases, including Alzheimer’s. These strategies are rooted in precision nutrition, where dietary recommendations are tailored based on an individual’s unique microbiome profile [185]. Advances in microbiome sequencing technology have made it possible to identify the specific composition and functional characteristics of an individual’s gut microbiota. This allows for a more targeted approach to diet and supplementation, resolving the unique microbial imbalances that can contribute to neuroinflammation and cognitive decline [186]. For instance, individuals with a gut microbiome that is low in probiotic bacteria, such as Bifidobacterium sp. and Lactobacillus sp., can benefit from dietary interventions that promote the growth of these microbes, such as increasing the intake of prebiotic fibers like inulin or fructooligosaccharides [187]. In contrast, individuals with an overgrowth of pro-inflammatory bacteria can benefit from diets focusing on anti-inflammatory foods, such as polyphenol-rich fruits and vegetables, to help restore balance in the microbiota and reduce neuroinflammation. By focusing on the gut–brain axis, personalized microbiome-based dietary strategies aim to optimize brain health by improving gut health [188]. This approach could help slow the progression of cognitive decline and potentially prevent neurodegeneration. For example, specific microbiome profiles have been associated with higher production of SCFAs, which are known to have neuroprotective effects. In contrast, others can be linked to the increased production of harmful metabolites that exacerbate neuroinflammation [189]. Personalized nutrition can, therefore, guide dietary changes that support healthy microbiota, promoting the production of beneficial metabolites like SCFAs and reducing the production of harmful substances. As research in this field continues to evolve, microbiome-based dietary strategies can become crucial in managing Alzheimer’s and other neurodegenerative diseases, offering a tailored, evidence-based approach to improving cognitive function [190].

Emerging therapies targeting the gut–brain connection represent a new frontier for treating neurodegenerative diseases, with metabolite-based drugs showing particular promise for neuroprotection [191]. One of the main aspects of these therapies is their ability to influence the microbiome, which modulates the brain through various biological processes, like immune modulation, inflammation reduction, and the production of neuroactive metabolites [192]. A growing body of research has shown that specific metabolites produced by gut bacteria, such as SCFAs, indoles, and bile acids, can benefit the brain, promoting neuroprotection, reducing neuroinflammation, and enhancing neuronal function [193]. For example, SCFAs like butyrate have been shown to support the integrity of the blood–brain barrier, modulate microglial activity, and protect against neurodegeneration by reducing the accumulation of toxic proteins like amyloid-β. Metabolite-based drugs are being developed to harness the therapeutic potential of these gut-derived compounds [194]. These drugs aim to either directly supply beneficial metabolites or promote their production through modulation of the gut microbiota [195]. For instance, drugs that increase the production of SCFAs in the gut could provide neuroprotective benefits by enhancing the anti-inflammatory effects of these metabolites on the brain [196]. Researchers are exploring probiotics, prebiotics, and postbiotics as adjunct therapies to improve gut health and, by extension, brain health. In particular, therapies that modulate the gut microbiota to reduce systemic inflammation and promote the production of neuroprotective metabolites offer a promising new avenue for treating Alzheimer’s and other neurodegenerative diseases. These emerging therapies are still in the early stages of development but hold significant potential for providing more targeted and effective treatments for neurodegeneration. Focusing on the gut–brain axis and leveraging the power of microbiome-derived metabolites can slow the progression of diseases like Alzheimer’s, improve cognitive function, and enhance overall brain health [197]. As clinical trials continue to explore the efficacy of these metabolite-based therapies, these therapies can offer a novel, more holistic approach to managing neurodegenerative diseases that incorporates both the gut and brain in a therapeutic context. As shown in Table 4, various probiotic and prebiotic strategies have been identified for promoting cognitive health through mechanisms such as modulating gut microbiota, enhancing gut barrier function, and reducing neuroinflammation.

While there has been significant progress in the grasp of the gut–brain axis and its implications for Alzheimer’s disease, there are still notable gaps in knowledge. One central area that requires further exploration is the need for large-scale, longitudinal microbiome studies. These studies would help clarify how changes in the gut microbiota over time contribute to the development and progression of Alzheimer’s [206]. Currently, most research is limited to cross-sectional studies, which provide only a snapshot of microbiota composition at a single point. Long-term studies are necessary to establish causal relationships between specific microbial populations, their metabolites, and the onset of neurodegenerative diseases [207]. Longitudinal studies could provide insights into how dietary interventions or microbiome-targeting therapies could prevent or slow the progression of Alzheimer’s, offering more personalized approaches to treatment. Another significant issue is knowing the complex, dynamic interactions between the gut microbiota, the immune system, and the brain [208]. While dysbiosis (microbial imbalance) and the resulting systemic inflammation contribute to neurodegeneration, the exact mechanisms remain unclear. More studies are required to pinpoint specific microbial signatures that could serve as biomarkers for early diagnosis and to understand how these microbial changes influence brain pathology [209]. Ultimately, overcoming these gaps in knowledge will pave the way for more targeted and effective interventions that can alter the microbiome to improve brain health and potentially prevent or treat Alzheimer’s.

One major problem in applying diet-based strategies for improving cognitive health is the variability in individual responses to dietary interventions. People have highly personalized gut microbiomes, influenced by genetics, lifestyle, environmental factors, and previous nutritional habits [210]. As a result, the same dietary intervention can affect each individual differently. For example, prebiotic fibers such as inulin or fructooligosaccharides (FOS) can promote the growth of beneficial bacteria in some individuals but not in others, depending on their baseline microbiota composition [211]. This variability complicates the development of one-size-fits-all dietary recommendations for cognitive health. Individual differences in metabolite production, such as SCFAs, can further impact the effectiveness of nutritional interventions. SCFAs, generated by gut bacteria through the fermentation of dietary fibers, have been shown to have neuroprotective effects [212]. However, not everyone produces the same amount of SCFAs, and this variability can influence how much a person benefits from a diet rich in prebiotics. Therefore, precision nutrition, which tailors dietary recommendations based on an individual’s unique microbiome profile, holds promise as a more practical approach for improving cognitive function and potentially slowing the progression of Alzheimer’s [213]. Research into personalized dietary strategies is essential to address this variability and optimize outcomes for individuals with neurodegenerative diseases.

Integrating microbiome science with precision medicine holds immense potential for advancing personalized interventions in the treatment of neurodegenerative diseases like Alzheimer’s. The application of multi-omics approaches, which combine genomics, transcriptomics, metabolomics, and proteomics, allows for a good grasp of how the microbiome interacts with various biological systems to influence health [214]. By profiling an individual’s microbiome alongside their genetic, metabolic, and proteomic data, researchers can gain deeper insights into how microbial imbalances affect disease pathways and identify tailored therapeutic strategies. Multi-omics data can also predict individual responses to specific dietary, probiotic, or pharmaceutical interventions, enabling clinicians to design more personalized, effective treatment plans [215]. Personalized interventions informed by multi-omics data could revolutionize how Alzheimer’s can be approached. For example, precision medicine could enable the identification of specific microbial signatures that predispose individuals to Alzheimer’s, allowing for early interventions targeting those microbial populations before neurodegeneration progresses [216]. These approaches could help predict which dietary interventions or probiotic strains would be most beneficial for each individual, optimizing their effects on cognitive function and overall brain health. Integrating microbiome science with precision medicine offers a promising avenue for developing more targeted, individualized therapies that could ultimately improve outcomes for people with neurodegenerative diseases.

As interest in microbiome-based therapies grows, it is essential to compare their effectiveness with conventional pharmaceutical interventions, particularly in treating Alzheimer’s. Diet-based strategies, which focus on modulating the gut microbiome through prebiotics, probiotics, and dietary fiber, are gaining attention for their potential to improve cognitive function and reduce neuroinflammation [217]. These strategies aim to restore balance in the microbiome [218], enhance gut–brain signaling, and reduce the systemic inflammation contributing to neurodegeneration. In contrast, conventional pharmaceutical interventions, such as cholinesterase inhibitors and glutamate regulators, primarily target symptoms of Alzheimer’s, such as memory loss and cognitive decline, but often fail to address the underlying causes of the disease [219]. While pharmaceutical treatments provide symptomatic relief, they do not halt or reverse the progression of the disease, and they are often associated with side effects. On the other hand, diet-based strategies that focus on the gut–brain axis offer a more holistic approach, potentially dealing with the root causes of Alzheimer’s by restoring gut health, reducing inflammation, and modulating neuroprotective pathways [220]. However, the effectiveness of diet-based therapies can vary depending on an individual’s unique microbiome composition. More research is needed to determine their long-term efficacy and safety. Comparatively, pharmaceutical therapies offer more immediate and standardized effects. Still, their inability to modify the disease’s progression highlights the need for adjunctive treatments, such as those targeting the microbiome, to enhance overall outcomes [221]. Ultimately, a combination of both microbiome-based and conventional therapies can offer the best approach for managing Alzheimer’s, improving both symptoms and underlying disease processes. As summarized in Table 5, there are several gaps in knowledge regarding the gut–brain connection in Alzheimer’s disease, with future studies focused on recognizing microbiome-drug interactions, identifying microbial biomarkers, and exploring personalized microbiome-based interventions.

Future research should prioritize large-scale, longitudinal human studies to establish clear causal relationships between gut microbial metabolites and neurodegenerative diseases. Overcoming challenges such as individual variability, non-standardized microbiome assessments, and clinical inconsistencies is critical for clinical application. A promising approach involves integrating multi-omics technologies such as metagenomics, metabolomics, and proteomics alongside personalized microbiome profiling, which could facilitate precision-targeted dietary interventions and microbial therapies. Furthermore, gut microbiota diversity is often reduced in Alzheimer’s patients, and nutritional strategies that support microbiota balance may help restore gut health and enhance cognitive function. Identifying specific microbial strains and dietary components with neuroprotective effects could lead to innovative treatments for neurodegenerative diseases.

In our view, well-controlled and long-term randomized controlled trials (RCTs) are crucial for clarifying the effects of microbiome-based interventions compared to conventional treatments. These trials could determine whether such interventions provide synergistic benefits or contribute to improved cognitive health. The neuroprotective roles of specific microbial strains and dietary components, particularly in restoring microbial diversity in Alzheimer’s patients, warrant further investigation. Research focused on diet-driven modulation of the gut microbiota holds considerable potential for slowing the progression of neurodegenerative diseases and enhancing cognitive health. Still, a more in-depth exploration of the underlying mechanisms is necessary to realize these therapeutic possibilities fully.

No new data were created or analyzed in this study.