The gut microbiota plays a critical role in the maturation of the immune system, particularly during the early stages of human development (Pantazi et al., 2023). From birth, the infant immune system evolves alongside changes in the microbiota, which are shaped by dietary and environmental factors (Zhang H. et al., 2022). Maternal influences and environmental exposures during pregnancy and lactation significantly impact the development of the infant’s intestinal microbiota (Nyangahu and Jaspan, 2019). By the age of three, the microbiota typically stabilizes, adopting a composition similar to that of an adult (Derrien et al., 2019; Yatsunenko et al., 2012). However, alterations during these critical early stages may have long-term health implications, predisposing individuals to inflammatory, immunological, and neurological disorders (Maciel-Fiuza et al., 2023; Sittipo et al., 2022). These disruptions can persist into old age, exacerbated by stress and contributing to dysbiosis (Zhao M. et al., 2023).

Dysbiosis, defined as an imbalance between beneficial and pathogenic microorganisms within the gut microbiota (Petersen and Round, 2014), is closely linked to the MGBA and associated with neurodegenerative diseases such as Parkinson’s disease (PD) (Cersosimo and Benarroch, 2012; Scheperjans et al., 2015). A notable example of this connection is constipation, affecting up to 80% of PD patients and often preceding the onset of motor symptoms (Edwards et al., 1992; Klann et al., 2021). Similarly, individuals with IBS characterized by dysbiosis face an increased risk of developing dementia, including AD (Chen et al., 2016). Intriguingly, certain bacteria, such as BaGBcillus subtilis and Escherichia coli, produce beta-amyloid proteins, which are implicated in Alzheimer’s pathology (Asti and Gioglio, 2014; Hill and Lukiw, 2015). These proteins may penetrate the intestinal barrier, enter the bloodstream, and potentially contribute to neurodegenerative processes (Friedland and Chapman, 2017).

Maintaining a stable gut microbiota is essential for host protection against pathogens and for preserving homeostasis, including immune regulation (Wu and Wu, 2012). Disruptions in gut microbiota—induced by factors such as dietary changes, antibiotic use, aging, or infections—can lead to a spectrum of inflammatory, metabolic, and pathogenic conditions, including neurodegenerative diseases (Giau et al., 2018). These disturbances affect the MGBA through mechanisms involving the VN, the neuroendocrine system, and metabolites like short-chain fatty acids (SCFAs), which are carboxylic acids with aliphatic tails of 1 to 6 carbon atoms, which collectively influence mood, cognition, and overall neurological health (Ullah et al., 2023) (Figure 1).

Given the gut microbiota’s profound influence on multiple physiological systems, therapeutic interventions such as fecal microbiota transplants, probiotics, prebiotics, and postbiotics offer promising avenues for improving gut health and reducing the risk of neurological disorders. Further research is essential to understand their mechanisms and potential applications in clinical practice.

The human microbiota consists of an estimated 10 to 100 trillion symbiotic microbial cells, primarily residing in the intestine, where bacteria predominate. In contrast, the term “microbiome” encompasses the collective genomes of these microbial communities (Ursell et al., 2012; Zhu et al., 2010). Global research efforts have sought to decipher the intricate roles these microorganisms play and their profound impact on human health.

The intestinal microbiota is essential for various physiological processes, including nutrient absorption, fermentation, host metabolism, and vitamin synthesis (de Vos et al., 2022). Additionally, it serves a protective role by competing with pathogens for resources and modulating the immune system (Belkaid and Hand, 2014). Beyond these core functions, the microbiota is a key regulator of oxidative and inflammatory processes and acts as a mediator in the bidirectional communication between the gut and the brain, forming the MGBA (Goyal et al., 2021; Shandilya et al., 2022).

Inflammation, the body’s response to harmful stimuli, is a critical mechanism for restoring homeostasis (Chen et al., 2018). However, chronic inflammation in various organs has been implicated in the progression of degenerative diseases (Baechle et al., 2023; Zhang W. et al., 2023). In particular, systemic inflammation involving the MGBA can lead to neuroinflammation, potentially linking the intestinal microbiota to neurodegenerative disorders.

Recent studies have highlighted the role of the microbiota in AD, emphasizing the importance of dietary intervations and the use of prebiotics, probiotics, and postbiotics (Peddinti et al., 2024; Seo and Holtzman, 2024). These approaches have demonstrated promise in modulating inflammation and enhancing the function of glial cells in the CNS.

Dietary interventions targeting the gut microbiota—including prebiotics, probiotics, and postbiotics—have demonstrated potential in modulating inflammation and enhancing glial cell function in the CNS.

Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) relative to the antioxidant defenses of the organism. This phenomenon is a hallmark of various neurodegenerative diseases, with AD being particularly notable (Li et al., 2013; Patten et al., 2010). The accumulation of ROS and RNS triggers signaling pathways that lead to cell death through apoptosis, necrosis, or autophagy.

In AD, Aβ aggregates have been shown to interact directly with lipid and cholesterol components of cell membranes. This interaction disrupts membrane integrity and permeability, forming channels that perturb intracellular calcium (Ca²⁺) homeostasis. These disruptions inhibit long-term potentiation (LTP), induce oxidative and nitrosative stress, and ultimately lead to neuronal death (Bode et al., 2019; De Felice et al., 2007; Mattson and Chan, 2003; Shankar et al., 2007; Townsend et al., 2007; Yasumoto et al., 2019). Additionally, Aβ binds to the NR2B subunit of the NMDA receptor, further deregulating intracellular Ca²⁺ levels, causing synaptic dysfunction and neuronal degeneration (Alberdi et al., 2010; Rönicke et al., 2011; Shankar et al., 2007). These processes collectively exacerbate oxidative and nitrosative stress, driving neuronal degeneration.

The primary ROS and RNS implicated in oxidative stress include singlet oxygen (O₂), superoxide anion (O₂^•-), hydroxyl anion (HO^•), hydrogen peroxide (H₂O₂), nitric oxide (NO⁻), and peroxynitrite anion (ONOO⁻). The brain is particularly susceptible to oxidative stress due to its high metabolic rate and substantial O₂ consumption. Neurons, unlike other cell types, depend heavily on oxygen for mitochondrial ATP production, but mitochondria are also significant sources of ROS and RNS (Lambert and Brand, 2009). Furthermore, neuronal membranes, rich in polyunsaturated fatty acids and low in antioxidant defenses, are highly prone to lipid peroxidation (Floyd and Hensley, 2002; Mattson et al., 2002).

Elevated levels of Aβ_1-40 and Aβ_1-42 peptides correlate with increased oxidative damage to proteins, lipids, and nucleic acids in the hippocampus and cortex of AD patients (Butterfield and Lauderback, 2002). Biomarkers of oxidative stress, such as oxidized proteins, lipids, DNA, and RNA, have been extensively studied in AD (Butterfield et al., 2007). The most critical free radicals involved in oxidative stress are O₂^•-, HO^•, and NO⁻. Neurotoxic mechanisms of oxidative/nitrosative stress mediated by Aβ involve the activation of nitric oxide synthases (NOS), which increase NO⁻ production (Halliwell, 2007). The NOS family comprises three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Notably, nNOS and eNOS are Ca²⁺-dependent, whereas iNOS functions independently of Ca²⁺. NO⁻ plays crucial roles in central nervous system functions, including learning and memory (Zhou and Zhu, 2009). However, excessive NO⁻ reacts with O₂^•- to form ONOO⁻, inducing nitrosative stress through protein modifications.

ONOO⁻ also promotes lipid peroxidation, damaging cell membranes and generating markers such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) (Di Domenico et al., 2017; Mark et al., 1997; Niedzielska et al., 2016). Lipid peroxidation propagates a chain reaction that alters dendritic and axonal morphology, including myelin sheath damage. Oxidative stress similarly affects DNA, with 8-oxo-2′-deoxyguanosine (8-OHdG) serving as a marker of oxidative DNA damage. Such damage disrupts the cell cycle, protein synthesis, and promotes mutagenesis (Lovell et al., 1999; Nunomura et al., 1999).

The long-term effects of oxidative stress significantly impair cell survival in the CNS. Structures such as the hippocampus, amygdala, and prefrontal cortex are particularly vulnerable. The hippocampus, crucial for spatial learning and memory, is profoundly affected in AD patients, with CA1 neurons and the dentate gyrus exhibiting heightened susceptibility to oxidative damage (Cruz-Sánchez et al., 2010). Additionally, oxidative stress is closely linked to neuroinflammation, as ROS and RNS activate inflammatory pathways in astrocytes, triggering the release of inflammatory mediators like interleukins. This cascade contributes to reactive astrogliosis and microgliosis, further exacerbating neuronal damage (Sudo et al., 2015).

The inflammatory response is intricately modulated by oxidative stress. Under conditions of redox balance, this response functions as a self-limiting defense mechanism that facilitates tissue repair. However, when redox equilibrium is disrupted, the signaling pathways governing the immune system become altered, favoring proinflammatory responses—a hallmark of neurodegenerative diseases (Jayaraj et al., 2017). In the CNS, glial cells, including microglia, oligodendrocytes, and astrocytes, as well as non-glial resident myeloid cells (macrophages and dendritic cells) and peripheral leukocytes, play pivotal roles in mediating the inflammatory response.

Microglia, the resident macrophages of the CNS, constitute approximately 10% of total glial cells in the human brain and are particularly immunologically active in the hippocampal region (Ochocka and Kaminska, 2021; Smith et al., 2012). These cells exhibit a ramified morphology in a healthy brain, indicative of a resting but active state involved in environmental surveillance. Upon activation during pathological conditions, microglia undergo morphological transformations, adopting an amoeboid shape characterized by a larger soma and reduced, retracted processes (Kettenmann et al., 2011; Ransohoff and Perry, 2009; Stence et al., 2001). Activation can be identified by specific surface markers, including Iba-1, IB4, CD11b, F4/80, CD14, CD45, CD80, CD115, and CD68 (Fadini et al., 2013; Jenkins et al., 2013; Jeong et al., 2013; Lin et al., 2005; Rice et al., 2017; Yun et al., 2018; Zanoni et al., 2011). Reactive microglia release cytotoxic factors such as ROS and RNS, which can induce inflammation and transform astrocytes into neurotoxic phenotypes (Liddelow et al., 2017).

Astrocytes, the most abundant glial cells in the brain, are essential for maintaining cerebral homeostasis. They exhibit complex morphologies, with extended processes that interact with neighboring cells (Bélanger and Magistretti, 2009), contacting between 250,000 and 2 million synapses in the human brain (Oberheim et al., 2006). Key astrocytic functions include regulating blood flow, maintaining ionic (e.g., Ca²⁺) and neurotransmitter homeostasis, and serving as the brain’s primary glycogen reserve. These roles are critical for neuronal survival and functionality; thus, astrocytic dysregulation can precipitate neurodegeneration.

Astrocytes exist in either a resting or reactive state. Resting astrocytes vary in morphology depending on their location: fibrous astrocytes, found in white matter, possess long, slender processes, while protoplasmic astrocytes in gray matter have highly branched processes that interface with synapses and blood vessels. Reactive astrocytes, characterized by astrogliosis, exhibit hypertrophic morphology and upregulation of glial fibrillary acidic protein (GFAP). These cells secrete proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1β (IL-1β) (Giovannoni and Quintana, 2020), as well as ROS. Myoinositol, another astrocytic activation marker, increases during normal aging and in neuroinflammatory conditions (Cabezas et al., 2019; Liddelow et al., 2017; Sofroniew, 2005; Sofroniew, 2009). GFAP and myoinositol serve as reliable indicators of astrocyte activation.

In AD, both microglia and astrocytes contribute significantly to neuroinflammation, which exacerbates neuronal dysfunction and cell death. The bidirectional interactions between these glial cells and their environment underscore the complexity of neuroinflammatory processes and their pivotal role in neurodegenerative diseases.

Glial cells, particularly microglia, play a crucial role in neuroprotection in AD by mediating the clearance of Aβ plaques through phagocytosis. This process prevents the cytotoxic accumulation of Aβ, a hallmark of AD-associated neurodegeneration (Lee and Landreth, 2010; Wyss-Coray et al., 2003; Yoon and Jo, 2012). Microglia recognize and engulf Aβ deposits via receptors such as TLRs, CX3C chemokine receptor 1 (CX3CR1), and CD36, which facilitate the detection of pathogen-associated molecular patterns (Malm et al., 2015).

A recently identified subset of disease-associated microglia (DAM) has been characterized through single-cell transcriptional analysis. These microglia cluster around Aβ plaques and express genes related to phagocytosis and lipid metabolism, thereby limiting Aβ spread and mitigating its neurotoxic effects. However, chronic exposure to Aβ leads to microglial dysfunction, characterized by a decline in phagocytic capacity and an increase in pro-inflammatory cytokine production, both of which exacerbate neurodegeneration (Wang et al., 2015).

The efficiency of microglia-mediated Aβ clearance declines with aging and chronic inflammation, partly due to the reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of phagocytosis and inflammation. Notably, genetic variants of TREM2 are associated with an increased risk of AD (Thomas et al., 2022). Recent findings using single-nucleus RNA sequencing have identified both TREM2-dependent and independent microglial responses, underscoring the complexity of microglial activation beyond a simplistic pro- or anti-inflammatory paradigm (Zhou et al., 2020). Additionally, peripheral and perivascular macrophages may contribute to Aβ clearance; however, their effectiveness depends on BBB permeability, which regulates their access to the brain parenchyma (Wen et al., 2024).

While microglia exhibit neuroprotective functions, they can also contribute to neurotoxicity in AD. The DAM phenotype, initially characterized by its role in Aβ phagocytosis has been linked to genes associated with lipid metabolism, proliferation, and immune activation (Keren-Shaul et al., 2017). Although the existence of a similar microglial phenotype in the human brain remains unclear, several components of the signaling pathways involved in the transition between pro-inflammatory M1 and anti-inflammatory M2 states have been implicated in AD pathophysiology (Gerrits et al., 2021; Guo et al., 2022; Valiukas et al., 2025).

Aβ interacts with pattern recognition receptors (PRRs) such as TREM2, TLR4, and CD14, triggering microglial activation and initiating neurotoxic processes (Colonna and Butovsky, 2017; Heneka et al., 2015). TLR4 activation by Aβ induces downstream signaling cascades, including NF-κB and mitogen-activated protein kinases (MAPKs), leading to the transcription of pro-inflammatory genes and sustaining chronic neuroinflammation (Guo et al., 2024). Additionally, DAM activation amplifies microglial reactivity, reinforcing inflammatory cycles in AD (Wei and Li, 2022).

As pro-inflammatory cytokines and chemokines accumulate, microglial dysfunction results in impaired Aβ clearance, increased Ca²⁺ influx, complement activation, and sustained NF-κB signaling (Muzio et al., 2021; Qie et al., 2020; Wang et al., 2018). These processes not only exacerbate neuronal damage but also compromise the integrity of the CNS microenvironment, including the BBB (Erickson et al., 2012). The BBB, composed of astrocytes, pericytes, microglia, endothelial cells, tight junctions, and a basement membrane, is particularly vulnerable to microglia-driven inflammation. Elevated cytokine levels and microglial phagocytosis of BBB-associated cells have been implicated in its disruption, further aggravating AD pathology (Haruwaka et al., 2019; Mayer and Fischer, 2024).

Astrocytes also play a dual role in AD. Initially, they exert neuroprotective effects, promoting recovery from oxidative stress and inflammation. However, under chronic conditions, their activity shifts, hindering repair mechanisms and exacerbating damage through the release of reactive oxygen species and pro-inflammatory cytokines. The A1 astrocytic phenotype has been specifically associated with the activation of classical complement cascade genes, contributing to synaptic deterioration. Activated microglia induce A1 astrocytes, impairing their physiological functions and promoting neurotoxic activities, ultimately accelerating neuronal and oligodendrocyte loss.

Notably, inhibiting A1 phenotype formation before neuronal injury has been shown to prevent neuronal death, underscoring the critical role of reactive astrocytes in AD pathogenesis. Targeting glial interactions may represent a promising therapeutic strategy to mitigate neuroinflammation and slow neurodegeneration in AD.

Both microglia and astrocytes exhibit profound functional plasticity in response to pathological stimuli, transitioning from protective to neurotoxic states depending on disease stage and microenvironmental cues. While intrinsic CNS signals such as Aβ accumulation are established drivers of glial reactivity, increasing evidence highlights the role of extrinsic factors, particularly those derived from the gut microbiome, in modulating glial activation and cytokine expression.

It suggests that gut microbiota dysbiosis contributes to glial reprogramming and neuroinflammation through systemic immune signaling and microbial metabolites. Disruption of the MGBA facilitates the translocation of microbial products, such as LPS, peptidoglycans, and SCFAs, into circulation, where they interact with peripheral immune cells and can penetrate the central nervous system via a compromised blood–brain barrier (Ashique et al., 2024; Honarpisheh et al., 2022; Solanki et al., 2023).

LPS activates TLR4 expressed on microglia and astrocytes, leading to the activation of NF-κB and MAPK signaling cascades, which in turn induce the transcription and release of pro-inflammatory cytokines including IL-1β, TNF-α, and IL-6 (Guijarro-Muñoz et al., 2014). These cytokines perpetuate a state of chronic neuroinflammation, contributing to synaptic dysfunction, oxidative stress, and neuronal apoptosis—hallmarks of Alzheimer’s pathology (Zhang W. et al., 2023). SCFAs, under homeostatic conditions, exert anti-inflammatory effects through GPR41/GPR43 signaling and histone deacetylase inhibition; however, in dysbiotic states, their concentrations and systemic distribution may become imbalanced, failing to restrain glial inflammation (Du et al., 2024; Li et al., 2018).

Additionally, dysbiosis-induced systemic inflammation may increase circulating cytokines that further prime glial cells toward a pro-inflammatory state, lowering the threshold for activation in response to CNS stressors (Solanki et al., 2023). This peripheral-to-central signaling loop underscores the importance of gut microbial composition in shaping the neuroimmune landscape of the AD brain (Anand et al., 2022).

By modulating glial phenotypes and cytokine profiles, the gut microbiota emerges as a key extrinsic regulator of neuroinflammation in AD, offering new insights into therapeutic strategies that target both central and peripheral inflammatory mechanisms.

Prebiotics are non-digestible carbohydrates, primarily polysaccharides and oligosaccharides, that the human body lacks the enzymes to break down (Holscher, 2017). Instead, they reach the intestine intact, where they are fermented by the colonic microbiota. This fermentation process selectively promotes the growth of beneficial bacteria, particularly Lactobacillus and Bifidobacterium, while inhibiting the proliferation of pathogenic microorganisms (Olveira and González-Molero, 2016; van der Beek et al., 2017; Śliżewska and Chlebicz-Wójcik, 2020) (Figure 2).

Key prebiotics include inulin, FOS, GOS, and xylooligosaccharides (XOS), which differ in their degree of polymerization, ranging from 2 to 10 monomeric units (Broekaert et al., 2011; Marín-Manzano et al., 2013; van de Wiele et al., 2007). Their fermentation enhances the production of SCFAs, such as acetate, which is metabolized in the liver, muscles, kidneys, heart, and brain; butyrate, utilized by commensal bacteria in the colon; and propionate, which is metabolized in the liver and regulates lipid metabolism (Erny et al., 2021; Frampton et al., 2020; Murashige et al., 2020; Song et al., 2019; Tong et al., 2015; Zhao et al., 2020) (Figure 2).

SCFAs play a crucial role in gut health by stimulating mucus production, maintaining optimal pH, accelerating intestinal epithelial healing, and promoting anti-inflammatory responses (den Besten et al., 2013; Fukuda et al., 2011; Vieira et al., 2017). Additionally, they modulate the immune system by reducing pro-inflammatory cytokine production and increasing regulatory T cell populations (Li et al., 2021; Olsson et al., 2021; Sartor, 2014). Given that helper T cells, macrophages, B lymphocytes, and mast cells are major cytokine producers, prebiotics can significantly influence immune regulation. Studies have demonstrated that prebiotic supplementation reduces the levels of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-12, TNF-α, and IFN-γ (Cani et al., 2009; Dehghan et al., 2014; Lecerf et al., 2012).

Neuroinflammation is a key driver of amyloid accumulation and disease progression in AD. However, no effective therapy has been developed to halt its progression. Various factors contribute to AD pathogenesis, including aging, immunosenescence, chronic inflammation, lifestyle habits (diet, exercise, and cognitive engagement), infections, and sleep disorders (Lourida et al., 2013; Ozawa et al., 2014; Sochocka et al., 2019).

Numerous studies highlight the neuroprotective potential of prebiotics. For instance, FOS enhances probiotic survival in the gastrointestinal lumen and exhibits protective effects against Aβ_25-35 neurotoxicity in PC12 cells. Pretreatment with 10–40 μM Bajijiasu (β-D-fructofuranosyl-(2–2)-β-D-fructofuranosyl) significantly reversed Aβ_25-35-induced reductions in cell viability and decreased oxidative stress, inflammation, and apoptosis markers (Chen et al., 2013).

Lactulose, a simple prebiotic widely used in commercial formulations, has also shown neuroprotective effects. In a study using an Aβ_25-35 oligomeric toxicity model in mice, lactulose administration mitigated short-term memory impairment and improved learning ability. The observed neuroprotection was associated with reduced neuroinflammation and enhanced autophagic pathway activation, suggesting lactulose as a potential preventative and/or therapeutic agent for AD (Lee et al., 2021). Similarly, fructooligosaccharides from Morinda officinalis (OMO) have demonstrated protective effects against Aβ_1-42 and Aβ_25-35-induced cognitive deficits. OMO supplementation improved performance in the Morris water maze, reduced oxidative stress and neuroinflammation, and regulated neurotransmitter release (Chen et al., 2017; Deng et al., 2020).

Metabolic dysfunction has been implicated as a predisposition factor for AD, with some researchers referring to the disease as “type 3 diabetes” due to its links with insulin resistance, neuroinflammation, and cognitive decline (Nguyen et al., 2020; Peng et al., 2024). Early consumption of prebiotics such as inulin may help mitigate this risk. Studies indicate that inulin enhances gut microbiota composition and improves intestinal and brain metabolism in transgenic mice carrying the APOE4 gene. Additionally, inulin reduces hippocampal expression of inflammatory genes, including CCL4, CCL10, and Fcgr4, which are associated with Aβ accumulation, vascular damage, and neurodegeneration (Fuller et al., 2014; Tavares et al., 2020; Zhu et al., 2014).

In APP/PS1 transgenic mice, supplementation with FOS, GOS, and a combination of FOS + GOS improved spatial memory and novel object recognition. Among these treatments, GOS was the most effective, followed by FOS + GOS, whereas FOS alone showed no significant effects. Additionally, both the GOS and FOS + GOS groups exhibited reduced expression of Iba-1 and GFAP, markers of microglial and astrocytic activation, respectively. This reduction correlated with lower levels of IL-1β and IL-6, key mediators of neuroinflammation (Zhang S. et al., 2023). Furthermore, these prebiotics modulated the TLR4-Myd88-NF-κB pathway in the colon and cortex. MyD88, a critical adaptor protein, mediates downstream inflammatory signaling, leading to the activation of NF-κB-dependent genes, including those encoding IL-1β, TNF-α, IFN-γ, and IL-6 (Cucos et al., 2022) (Figure 2).

XOS have been shown to alleviate cognitive dysfunction and gut microbiota imbalances in APP/PS1 mice undergoing partial hepatectomy. XOS administration reduced peripheral and central levels of IL-1β and IL-6, accompanied by decreased Iba-1 expression in the brain. Moreover, XOS treatment preserved blood–brain barrier integrity by upregulating tight junction proteins such as ZO-1 and occludin (Han et al., 2020).

Another promising prebiotic is mannan oligosaccharide (MOS), which has been found to remodel gut microbiota and increase neuroprotective SCFAs. In a study using 5xFAD transgenic mice, MOS supplementation significantly inhibited neuroinflammation and oxidative stress. Researchers observed a reduction in Iba-1 expression in the prefrontal cortex, hippocampus, and amygdala, as well as microglial morphology changes from an amoeboid to a branched form, indicative of decreased activation. Consequently, MOS treatment reduced TNF-α and IL-6 levels (Liu et al., 2021).

The administration of prebiotics and probiotics to maintain or restore gut microbiota composition is emerging as a promising nutraceutical strategy to prevent or mitigate AD symptoms. Recent studies suggest that these compounds can attenuate neuroinflammation and oxidative stress, reducing neurodegeneration in different AD models. Notably, an increase in phagocytic microglia (CD68+, CX3CR1+) has been observed in APP/PS1 mice following prebiotic administration, suggesting a neuroprotective effect through enhanced Aβ clearance and immune modulation (Deng et al., 2022; Lana et al., 2024).

The human gut hosts a diverse array of bacterial species and strains, with Firmicutes and Bacteroidetes being the predominant phyla (Buffington et al., 2016). An imbalance in the gut microbiota, known as dysbiosis, has been linked to the development of various diseases, including AD (Vogt et al., 2018). Evidence from germ-free APP/PS1 transgenic mice supports this connection, as these mice exhibit significantly reduced brain Aβ protein levels compared to their conventionally raised counterparts. This finding suggests that the gut microbiota plays a crucial role in neurodegenerative processes (Harach et al., 2017). Moreover, intestinal barrier dysfunction and increased permeability allow microbial metabolites to enter the bloodstream, triggering systemic and central inflammatory pathways. The subsequent disruption of the BBB facilitates the infiltration of proinflammatory cytokines, which activate glial cells and contribute to neuronal damage (Rutsch et al., 2020; Tang et al., 2020). Given their critical role in immune surveillance, microglia are responsible for eliminating pathogens, cellular debris, and Aβ peptides. Studies indicate that probiotic interventions, whether involving single- or multi-strain formulations, can mitigate cognitive deficits in AD animal models by modulating glial cell activity (Lee et al., 2019).

Probiotics are live microorganisms that confer health benefits to their host. They produce antimicrobial compounds, such as bacteriocins, which inhibit pathogenic colonization and enhance the integrity of the intestinal barrier by stimulating mucus production. Additionally, probiotics influence the release of cytokines from epithelial cells, thereby strengthening the immune response (Ohland and Macnaughton, 2010).

In APP/PS1 transgenic mice, a four-week intragastric administration of Clostridium butyricum demonstrated significant neuroprotective effects. This probiotic treatment reduced cognitive decline, Aβ deposition, and microglial activation while decreasing TNF-α and IL-1β levels in the brain. Furthermore, C. butyricum restored gut microbiota composition and normalized butyrate levels. Notably, butyrate therapy inhibited Aβ-induced NF-κB p65 phosphorylation in BV2 microglia, thereby reducing CD11b and COX-2 expression (Sun et al., 2020). Similarly, in a D-galactose-induced AD model, oral administration of Lactobacillus plantarum MTCC 1325 improved cognitive function by restoring acetylcholine (ACh) levels in the hippocampus and cerebral cortex, highlighting the potential of probiotics in modulating gut-brain axis communication (Nimgampalle and Kuna, 2017).

Another study examined the effects of Lactobacillus pentosus var. plantarum (C29) in a D-galactose-induced aging model. After 5 weeks of administration, C29 reduced cognitive impairment and restored the expression of key neurogenic and anti-inflammatory markers, including brain-derived neurotrophic factor (BDNF), doublecortin (DCX), and cAMP response element-binding (CREB). Notably, C29 significantly suppressed the expression of iNOS, COX-2, p-FOXO3a, p-p65, and the senescence marker p16, suggesting that CREB regulates inflammatory gene expression (Woo et al., 2014). Additionally, C29, when administered in the form of fermented defatted soybeans (FDS DW2009) to 5XFAD transgenic mice, improved cognitive function and modulated microglial activation. This was evidenced by reduced levels of neuroinflammatory markers such as NF-κB, CD11b, and CD11c. Furthermore, C29 favorably altered gut microbiota composition, reinforcing the link between gut health and cognitive function (Lee et al., 2018).

In AD models induced by intracerebroventricular injection of Aβ_25–35 and Aβ_1–40, oral administration of Bifidobacterium breve A1 (B. breve A1) reversed cognitive decline. Gene expression profiling revealed that B. breve A1 downregulated inflammation-related genes in the hippocampus and suppressed the transcription of Aβ-induced genes (Kobayashi et al., 2017).

Interestingly, microbial infections, gut dysbiosis, and bacterial byproducts such as LPS have been implicated in AD progression (Fülöp et al., 2020; Kim et al., 2021). A study demonstrated that oral administration of Lactobacillus mucosae NK41 and Bifidobacterium longum NK46 exerted anti-inflammatory effects on LPS-stimulated macrophages by reducing TNF-α levels and increasing IL-10, an anti-inflammatory cytokine. The combination of these probiotics (NKc) exhibited an even stronger suppression of the TNF-α to IL-10 ratio. In LPS-treated mice, NK41, NK46, and NKc reduced NF-κB + Iba1-positive microglia in the hippocampus, decreased Aβ accumulation, and increased BDNF and IL-10 expression (Ma X. et al., 2023). Additionally, in 5xFAD transgenic mice, these probiotics improved cognitive performance in behavioral tests such as the Y-maze, novel object recognition (NOR), and the Barnes maze. This correlated with lower TNF-α and IL-1β levels, alongside increased IL-10 and BDNF expression in the hippocampus (Ma X. et al., 2023). These findings suggest that NK41, NK46, and NKc can alleviate systemic inflammation and neuroinflammation, thereby mitigating cognitive decline.

Probiotics are widely recognized as a safe and effective natural intervention. However, while their health benefits are well-documented, the U. S. Food and Drug Administration (FDA) mandates further safety studies before approving probiotics for medicinal use.

Postbiotics and probiotics confer similar benefits through comparable mechanisms, a phenomenon known as the “probiotic paradox” (Adams, 2010). As a result, studies often explore both postbiotics and probiotic secretomes in the context of the MGBA (Figure 3).

One notable study evaluated the effects of heat-killed Enterococcus faecalis EF-2001 on inflammatory bowel disease (IBD)-like symptoms and depressive-like behavior in dextran sulfate sodium (DSS)-treated mice. DSS exposure induced significant inflammation and depressive behaviors, characterized by increased TNF-α and IL-6 levels in the rectum and hippocampus, caspase-3 activation, and reduced hippocampal neurogenesis. E. faecalis administration reversed these effects by lowering inflammatory cytokine levels and enhancing NFκB-p65 and XIAP expression in the hippocampus. Interestingly, E. faecalis increased NFκB-p65 activation in hippocampal astrocytes and microglia, underscoring the crucial role of glial cells in mediating its effects (Takahashi et al., 2019). β-Glucans have been linked to NFκB p65 activation via TLR2 (Aizawa et al., 2018), and E. faecalis was found to activate hippocampal TLR2 across multiple cell types. By attenuating DSS-induced neuroinflammation and regulating apoptosis via the NFκB p65/XIAP pathway, E. faecalis may offer neuroprotective benefits, particularly through its interaction with hippocampal microglia (Takahashi et al., 2019).

A separate study investigated the effects of different doses of live and inactivated Streptococcus thermophilus MN-ZLW-002 in APP/PS1 male mice, demonstrating significant cognitive improvements, including enhanced learning and memory. These benefits were associated with increased hippocampal mRNA levels of superoxide dismutase (SOD) and BDNF. Additionally, S. thermophilus administration altered gut microbiota composition, promoting colonic propionic acid-producing bacteria. However, increased systemic inflammation, evidenced by elevated serum inflammatory markers, may have contributed to heightened gliosis in the hippocampus (Zhang et al., 2024). The observed rise in colonic propionic acid-producing bacteria suggests a potential microbiome-gut-brain axis interaction, given that S. thermophilus produces SCFAs, which influence BDNF expression and downstream signaling pathways(Church et al., 2023).

TrkB receptors, expressed in neurons, astrocytes, and microglia, are pivotal in BDNF signaling, which is essential for CNS function. Upon BDNF binding, TrkB activation triggers intracellular pathways such as PI3K/Akt, MAPK/ERK, and PLCγ, leading to enhanced cell survival, differentiation, and synaptic plasticity (Rosso et al., 2020; Wang et al., 2022; Wang et al., 2024). SCFAs, generated through the anaerobic fermentation of dietary fiber by gut microbiota, have emerged as key mediators of gut–brain communication. Increasing evidence indicates that SCFAs contribute significantly to the maintenance of blood–brain barrier (BBB) integrity, particularly under pathological conditions (Fock and Parnova, 2023; Liu et al., 2015). Additionally, SCFAs can cross the BBB and promote neuroprotective mechanisms, further supporting cognitive function (Church et al., 2023; Zhao T. et al., 2023). By modulating inflammation and enhancing neuroprotection, postbiotics could improve neuronal health and cognitive function.

Reduced expression of tight junction proteins, including claudin-5 and occludin, has been observed in germ-free mice, indicating compromised BBB integrity. This phenotype is reversible upon colonization with defined bacterial consortia containing SCFA producing strains (Braniste et al., 2014). The presence of free fatty acid receptor 3 (FFAR3) in brain endothelial cells further suggests a mechanism through which butyrate may regulate BBB structure and function (Hoyles et al., 2018). SCFAs are primarily absorbed via co-transport with Na⁺ or K⁺ ions (Stumpff, 2018). Their ability to cross the BBB was demonstrated by carotid artery injection of radiolabeled 14C-SCFAs in rats, with detectable levels in brain tissue (Oldendorf, 1973). Among these, butyrate exhibited the highest brain uptake, followed by propionate and acetate. Transport across the BBB is mediated predominantly by monocarboxylate transporters (MCTs), particularly MCT1 and MCT4, members of the SLC16 family (Pellerin et al., 2005; Pierre and Pellerin, 2005; Terasaki et al., 1991). These proton-coupled transporters facilitate SCFA entry from circulation into the CNS (Halestrap and Price, 1999). MCT1, with higher substrate specificity, transports acetate and butyrate and is expressed in cortical and hippocampal astrocytes, endothelial cells, and pericytes (Baud et al., 2003; Gerhart et al., 1998; Hanu et al., 2000; Pellerin et al., 1998; Pierre et al., 2000; Vannucci and Simpson, 2003) (Figure 2). Although passive diffusion of SCFAs in their non-ionized form is possible, it is limited under physiological conditions due to their polarity, highlighting the essential role of transporter-mediated uptake.

Despite extensive research on the intestinal and neural effects of inactivated bacteria, data on their modulation of glial cells remain scarce. However, multiple studies have documented the health-promoting properties of postbiotics. For instance, the effects of heat-killed Lacticaseibacillus paracasei N1115 were tested in an antibiotic-induced dysbiosis (Abx) model in neonatal male mice. Over 84 days, L. paracasei treatment improved cognitive performance, anxiety, depressive-like behaviors, and locomotor activity. In the Morris Water Maze, N1115-treated mice exhibited reduced escape latency, while the Tail Suspension Test revealed shorter immobility periods, and the Open Field Test demonstrated increased motor activity compared to the Abx group. Moreover, L. paracasei administration was associated with normalized serum levels of IL-1, IL-6, and corticosterone, akin to control animals (Zhang Y. et al., 2022).

Previous studies have reported the anxiolytic and antidepressant effects of heat-inactivated bacteria, suggesting that postbiotics regulate stress hormones through modulation of the hypothalamic–pituitary–adrenal (HPA) axis (Kambe et al., 2020; Maehata et al., 2019; Warda et al., 2019). The exact mechanisms underlying these behavioral improvements remain unclear, yet they may involve neurochemical and neurotrophic factor regulation in the hippocampus and prefrontal cortex. L. paracasei treatment mitigated glucocorticoid receptor-induced stress, upregulated nerve growth factor (NGF) expression, and downregulated mineralocorticoid receptor (MR) levels, indicating restored neurotrophic support and balanced HPA axis signaling. Additionally, it counteracted dysbiosis-induced alterations in neurochemical signaling, reversing changes in GABAAα1, GABAB1, and BDNF expression (Zhang Y. et al., 2022).

One of the most consistent findings in postbiotic research is their ability to restore microbial eubiosis. This has been demonstrated in the bifidogenic properties of heat-killed Limosilactobacillus vaginalis in vitro (Giordani et al., 2023). This is particularly relevant in cesarean-section births, where neonates lack exposure to beneficial vaginal bacteria, resulting in reduced gut microbial diversity and increased susceptibility to diseases. Heat-killed L. vaginalis could potentially reinstate microbiome integrity by promoting Bifidobacterium spp. (Giordani et al., 2023), a key factor in neuroimmune regulation of glial cells (Erny et al., 2015).

Glial activation by the microbiome is mediated partly through the vagus nerve (Martin et al., 2018). Ultrasound-guided percutaneous vagus nerve stimulation has been shown to restore microglial and astrocyte morphology, reduce Aβ plaque deposition in the hippocampus, and modulate the autophagy-lysosomal pathway by upregulating transcription factor EB (TFEB) and lysosomal-associated membrane protein 1 (LAMP1) expression. Furthermore, microbiome integrity plays a crucial role in hippocampal neurogenesis (Ogbonnaya et al., 2015).

Bacterial extracellular vesicles (EVs) are also emerging as promising regulators of neuroinflammation (Pirolli et al., 2021). Lactobacillus-derived EVs (Lac-EVs) were found to suppress LPS-induced inflammation in microglia by downregulating iNOS (M1 phenotype marker) and upregulating Arg1 (M2 phenotype marker), shifting microglia toward an anti-inflammatory profile. Lac-EVs also reduced pro-inflammatory cytokine secretion (IL-1β, IL-6) while increasing IL-10 production (Yang et al., 2024).

Similarly, Lactobacillus paracasei-derived EVs (Lpc-EVs) demonstrated neuroprotective effects in an AD model (Kwon et al., 2023). Lpc-EVs mitigated Aβ-induced neurotoxicity in HT22 cells and APP/PS1 mice by upregulating neurotrophic factors (BDNF, Nt3, Nt4/5) and the TrkB receptor while modulating MeCP2 and Sirt1 expression. Additionally, Lpc-EVs restored Aβ-degrading proteases (Mmp-2, Mmp-9, Nep) and reduced Aβ accumulation and neuroinflammation, thereby improving cognitive function (Kwon et al., 2023).

SCFA depletion during aging disrupts the BBB and impairs microglial function, contributing to CNS damage (Knox et al., 2022). SCFAs are among the most studied postbiotic compounds, with evidence showing their ability to mitigate hypoxic–ischemic brain injury (HIBI) by reducing astrocyte activation and preserving oligodendrocyte precursor cells (OPCs). SCFAs also downregulate pro-inflammatory markers (NLRP3, IL-6, CCL2, IP-10) and regulate apoptosis-related proteins (Bax, Bcl-2), suggesting a protective role against neuroinflammation (Gao et al., 2022).

Certain strains of lactic acid bacteria produce menaquinones (vitamin K2) as part of their fermentation process (Morishita et al., 1999). These molecules play a crucial role in sphingolipid synthesis, which is essential for maintaining the structural integrity and stability of the myelin sheath, a key component in cell signal transduction. The synthesis of sphingolipids depends on vitamin K-dependent enzymes (Giussani et al., 2021).

In vitro studies have demonstrated that vitamin K2 derivatives can mitigate the amyloidogenic pathway by modulating genes involved in the toxic processing of the APP. This modulation results in the downregulation of beta-site APP cleaving enzyme 1 (BACE1) and presenilin 1 (PSEN1) expression, which encode for the active sites of β- and γ-secretases, respectively. In transgenic mouse models, these proteins are significantly upregulated, leading to excessive Aβ production and aggregation (Hampel et al., 2021). Interestingly, menaquinone treatment has been shown to enhance the expression of secretases involved in the non-amyloidogenic pathway, as evidenced by increased A Disintegrin And Metalloprotease 17 (ADAM17) levels compared to control groups (Orticello et al., 2023).

Another in vitro study investigated the effects of vitamin K2 on c-Myc-immortalized MG6 microglial cells, revealing a dose-dependent reduction in the mRNA expression of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6. This anti-inflammatory effect was observed in microglial cultures stimulated with LPS and TNF-α. Typically, these inflammation cascades are mediated by NF-κB, a transcription factor activated in response to toxic pro-inflammatory molecules (Bubici et al., 2006). The study suggested that menaquinones may inhibit NF-κB translocation by promoting p65 phosphorylation, thereby suppressing its transcriptional activity (Saputra et al., 2019). Similarly, bacterial EVs derived from Propionibacterium freudenreichii exhibit potential anti-inflammatory properties by modulating the NF-κB pathway. This effect appears to be partially mediated by surface-layer protein B (SlpB) and other cytoplasmic factors that interact with LPS-NF-κB signaling pathways (Rodovalho et al., 2020). However, it remains unclear whether P. freudenreichii EVs can cross the BBB to exert direct neuroprotective effects. Nevertheless, previous studies indicate that certain bacterial nanosized EVs can communicate with the brain (Pirolli et al., 2021), suggesting that their role in CNS modulation warrants further investigation.

Plasmalogens (Pls), another class of bacterial metabolic products, have been identified in postbiotic mixtures (Řezanka et al., 2012). Their therapeutic potential in AD is particularly relevant, as Pls levels are notably reduced in this pathology (Wood et al., 2010). Studies suggest that plasmalogen supplementation can mitigate cognitive decline in AD (Fujino et al., 2017; Hossain et al., 2018). For instance, in an LPS-induced neuroinflammation mouse model, 3 months of PLS treatment significantly improved memory performance compared to control animals. This cognitive recovery correlated with reduced GFAP and Iba-1 immunoreactivity, as well as lower Aβ burden in astrocytes and neurons within the prefrontal cortex and hippocampus (Hossain et al., 2018). Similar cognitive improvements were observed in a randomized, double-blind, placebo-controlled clinical trial involving mild AD patients who received plasmalogen supplementation (Fujino et al., 2017).

Other postbiotic metabolites, such as nicotinamide N-oxide (NAMO), equol, and linoleic acid derivatives, have also demonstrated neuroprotective and antioxidant properties. These compounds are known to modulate glial-cytokine interactions, which may contribute to their therapeutic potential in neurodegenerative diseases (Ikeguchi et al., 2018; Johnson et al., 2020; Li et al., 2022; Song et al., 2022). Increasing evidence supports the role of postbiotics in CNS health, and their mechanisms have been extensively reviewed elsewhere (Głowacka et al., 2024).

Emerging research highlights the significant potential of postbiotics in modulating neuroinflammation and enhancing cognitive function in neurodegenerative disorders. These effects are primarily mediated through the regulation of pro- and anti-inflammatory cytokines, neurotrophic support, and antioxidant activity. However, the precise interactions between postbiotics and glial cells remain largely unexplored, underscoring the need for further investigation to elucidate the complex cellular and molecular mechanisms underlying their neuroprotective effects.