Molecular mechanisms of gut microbiota dysbiosis and metabolites in Alzheimer’s disease pathogenesis: implications for precision therapeutics

The gut and brain are directly connected via the vagus nerve, which carries microbial information—SCFAs and LPS—to the CNS. Such Vagal control, limited to transcutaneous stimulation, has shown promising effects in reducing β-amyloid burden in models and in modulating BDNF levels in AD models [32].

Microbial dysbiosis leads to increased gut permeability ("leaky gut"), enabling the translocation of endotoxins, such as lipopolysaccharide (LPS), into the systemic circulation. These endotoxins induce peripheral inflammation and trigger central microglial activation, thereby promoting chronic neuroinflammation—a hallmark of AD pathology [12].

Key gut metabolites produced by microbes include SCFA—butyrate, propionate, and acetate—along with tryptophan metabolites and secondary bile acids. SCFAs have been shown to play protective roles at tight junctions, as well as anti-inflammatory and neuroprotective roles, in animal models by inhibiting tau phosphorylation [33, 34]. Indole compounds derived from tryptophan can modulate microglial reactivity and serotonergic signaling and, therefore, can imply additional therapeutic targets [8]. Having established the key anatomical and molecular components of the gut-brain axis—including the microbiome composition, vagal neural pathways, immune barrier integrity, and metabolite signaling—we now turn to the empirical evidence linking gut dysbiosis directly to AD pathogenesis. The following section examines human cohort studies and preclinical models that demonstrate how alterations in these components translate into Alzheimer's pathology, providing the translational foundation for therapeutic intervention.

According to meta-analyses and clinical datasets, patients diagnosed with MCI and AD have a different gut microbiome than control subjects [35, 36]. Changes that occur early in the gut microbiome are predictive. These include a decrease in taxa that produce SCFA (such as Faecalibacterium and Roseburia) and an increase in the pro-inflammatory abundance of Escherichia and Bacteroides spp. [35]. However, differences across studies indicate the need for harmonized metagenomic approaches. However, the differences across studies highlight the need for harmonized metagenomic approaches.

AD patients 'FMT into germ-free mice exacerbates cognitive decline, Aβ deposition, and tau aggregation [36]. In contrast, in transgenic AD models, FMT from young or healthy donors improves synaptic plasticity and reduces inflammatory markers [37]. The depletion of microbiomes by antibiotics alters tau pathology in APOE4 carriers, suggesting that host genes interact with the microbiome [38]. According to compelling evidence from human and animal studies, gut dysbiosis has been identified as a feature of Alzheimer's disease. Creating a correlation is just the first step. A better understanding of how changes in the gut lead to damage in the central nervous system is needed to develop targeted therapies. The following subsection examines how the dysbiotic gut microbiome contributes to AD development by exploring its pathological mechanisms: neuroinflammation, amyloid-β and tau pathology, metabolic dysfunction, and oxidative stress.

Microbial dysbiosis results in the release of systemic cytokines (IL-6, TNF-α), which subsequently activate microglia into a pro-inflammatory state [39]. Microbial metabolites and LPS cross the gut and blood–brain barriers, triggering neuroinflammatory cascades that lead to synaptic loss and neuronal death [11].

Bacterial amyloids (e.g., curli fibers from E. coli) may mimic or seed host Aβ aggregation via molecular mimicry, promoting cerebral amyloidogenesis [31]. Gut-derived SCFAs modulate γ-secretase activity and enhance Aβ clearance through microglial phagocytosis pathways [40]. In parallel, SCFA supplementation in tauopathy models reduces tau hyperphosphorylation and improves cognitive performance [41].

The microbiota influences glucose metabolism and insulin signaling, both of which are related to AD risk. According to SCFA, it can enhance insulin sensitivity and mitochondrial bioenergetics. In addition, it can help restore neuronal energy balance in mouse models of AD [36]. Disturbances in the gut flora contribute to peripheral insulin resistance and impose additional metabolic strain on the aging brain.

A dysbiotic gut flora leads to increased reactive oxygen species and decreased antioxidant capacity in the brain. After urolithins are produced through microbial metabolism of ellagic acid, research has shown that these compounds reduce oxidative stress and improve mitochondrial turnover in AD mice [42]. Sect. "The gut-brain axis: mechanisms and relevance to AD" establishes the GBA as a bidirectional communication network fundamentally altered in Alzheimer's disease. Evidence from human cohorts, preclinical models, and mechanistic studies indicates that gut dysbiosis is not merely a peripheral consequence of AD but an active contributor to disease pathogenesis through multiple interconnected pathways. Microbial dysbiosis drives neuroinflammation through systemic immune activation, promotes amyloid-β aggregation and tau hyperphosphorylation via bacterial amyloids and metabolite imbalances, impairs metabolic homeostasis by disrupting insulin signaling, and accelerates neuronal damage through oxidative stress and mitochondrial dysfunction [43, 44]. These insights validate the gut microbiome as a therapeutically actionable target and lay the groundwork for examining how individual gut-derived factors influence AD pathology. In Sect. "Mechanistic pathways: how the gut influences the AD brain", these specific molecular pathways are discussed in detail, further building on the foundations established above.

SCFAs, including acetate, propionate, and butyrate, are microbial fermentation products derived from dietary fiber that play a critical neuromodulatory role in AD. In AD, gut dysbiosis alters patterns of SCFA production, typically leading to decreased butyrate-producing taxa, such as Faecalibacterium prausnitzii, and increased acetate concentrations, which correlate with β-amyloid (Aβ) aggregation and tau hyperphosphorylation [70, 71]. SCFAs cross the BBB via monocarboxylate transporters (MCTs) and modulate gene expression through epigenetic mechanisms, particularly by inhibiting histone deacetylase (HDAC). Butyrate is a potent class I and IIa HDAC inhibitor that increases neurotrophic factor (BDNF) transcription and improves synaptic plasticity and memory performance [72]. In rodent models of Alzheimer's disease (e.g., APP/PS1 and 5xFAD), butyrate administration has been shown to reverse Aβ-induced cognitive impairment by restoring hippocampal BDNF expression and activating downstream CREB/TrkB signaling pathways [73]. However, elevated systemic SCFAs, mainly acetate, in specific-pathogen-free (SPF) mice have been associated with disease exacerbation. Acetate can induce a pro-inflammatory microglial phenotype characterized by MGnD-like transitions and upregulated ApoE, impairing Aβ clearance [74].

This context-dependent duality—in which microbial composition, host genotype (e.g., APOE4), and metabolite concentrations determine SCFA effects—underscores the need for precision microbiome therapeutics. Interventions such as targeted probiotics (Clostridium butyricum, Lactobacillus plantarum) and dietary prebiotics have been shown in both preclinical and early clinical studies to normalize SCFA levels and reduce neuroinflammation [57, 71].

Tryptophan (Trp), the essential aromatic amino acid, is an important substrate at the Gut Microbiome (GM)–brain axis level. It is degraded via three main pathways: (1) the kynurenine pathway (KP), which leads to neuroactive and neurotoxic metabolites such as quinolinic acid (QA); (2) the serotonin/melatonin pathway, which is responsible for neuroprotection and mood regulation; and (3) the indole pathway, in which intestinal microorganisms produce immunomodulatory and antioxidant compounds such as indole-3-propionic acid (IPA) [56, 75]. A skewing of Trp metabolism toward the KP occurs in AD, where increased activity of indoleamine 2,3-dioxygenase (IDO1) converts Trp to quinolinic acid, a recognized NMDA receptor agonist and oxidant, thereby increasing tau phosphorylation and neuroinflammation [48, 76]. This imbalance is consistent with decreased serotonin levels and leads to cognitive and neuropsychiatric symptoms often associated with AD [77]. On the other hand, microbial-derived indole derivatives, including IAA, indole-3-aldehyde, and IPA, inhibit NF-κB signaling and reduce microglial activation by interacting with the AhR, thereby preventing hippocampal neurodegeneration [78]. In addition, both IPA and its analogs have been shown to inhibit Aβ fibrillization and increase neuronal antioxidant capacity [58]. Certain gut bacteria, including Bifidobacterium longum, can convert tryptophan into tryptamine, an agonist of the serotonin receptor that promotes hippocampal neurogenesis and synaptic plasticity in 5xFAD mouse models [59, 75]. Clinical and preclinical evidence increasingly suggests that therapy focusing on Trp metabolism through probiotics, Trp supplementation, or IDO1 inhibitors is a viable strategy for rebalancing the GBA and modulating neuroinflammation in early AD.

The gut microbiome influences cholesterol metabolism and bile acid (BA) conversion, with implications for systemic and neuroimmune responses relevant to AD. The liver produces classical bile acids, including cholic acid and chenodeoxycholic acid, which are metabolized into secondary bile acids (such as deoxycholic and lithocholic acid) via microbial 7α-dehydroxylation. These microbial metabolites can cross the BBB and further regulate brain physiology, directly and indirectly via nuclear receptor activation [61, 64].

In AD, gut dysbiosis alters bile acid pools, notably reducing Bacteroides-driven transformation, leading to elevated neurotoxic deoxycholic acid, which increases BBB permeability by downregulating tight junction proteins such as claudin-5 and occludin. Simultaneously, this BA activates astrocytes and microglia via FXR signaling, exacerbating neuroinflammation [62, 65].

Conversely, tauroursodeoxycholic acid (TUDCA), a conjugated secondary BA with neuroprotective properties, can enhance Aβ clearance by upregulating insulin-degrading enzyme (IDE) and reducing reactive gliosis in APP/PS1 mouse models [67, 68]. Recent findings also implicate FXR not only in inflammation control but also in lipid metabolism and neuronal autophagy regulation, indicating a multifaceted involvement in AD pathophysiology [69, 78].

Interventions such as FXR agonists, BA sequestrants, or microbiome engineering are under investigation as methods to rebalance the BA pool and restore BBB function. These approaches aim to normalize BA signaling cascades, thereby modifying the GBA in early and prodromal AD stages [61, 64, 68].

Trimethylamine N-oxide (TMAO) is a microbiome product formed when trimethylamine (TMA) undergoes hepatic oxidation. TMA is made in the gut from your food (e.g., choline, carnitine, and betaine). Microbial enzymes make TMA from supplements and food. TMAO levels are significantly elevated in AD patients, and studies demonstrate that plasma TMAO concentrations greater than five μM correlate with faster hippocampal atrophy, cognitive deficits, and microglial activation in humans and in APP/PS1 mouse models [60, 79]. In APP/PS1 mice, the microbiota showed a greater abundance of TMA-producing species with age, and plasma TMAO levels increased markedly. NLRP3 inflammasome activation leads to IL-1β production by microglia and astrogliosis in the hippocampus, worsening neuroinflammation [76]. TMAO also crosses the BBB and induces oxidative stress via mitochondrial dysfunction in microglia, thereby impairing Aβ clearance [80]. Investigations conducted found that Lactobacillus plantarum administration and exercise reduced TMAO levels and restored hippocampal synaptic plasticity by altering the gut microbiota composition to fewer TMA-producing microbes [36, 81]. Importantly, TMAO has recently been identified as a biomarker of early cognitive impairment, underscoring the need for clinical risk stratification [39].

The microbes in the gut produce proteins and harmful substances that affect brain health. Curli fibers produced by E. coli exhibit structural homology with host β-amyloid (Aβ) and have been shown to override Aβ aggregation both in vitro and in vivo. Curli amyloids do the following: They activate TLR2-mediated NF-κB signaling, thereby activating neuroinflammatory cascades and tau phosphorylation [63, 82].

In Tg2576 AD mice, colonization with curli-producing E. coli significantly increases ileal expression of PGP9.5 + neuroendocrine cells, stimulating afferent vagal pathways that relay pro-inflammatory signals to the nucleus tractus solitarius (NTS), resulting in enhanced hippocampal Aβ burden (Tić, 2022). This gut-to-brain relay exemplifies the bottom-up inflammatory signaling that may precede central amyloidosis. Bacillus subtilis, another common spore-forming commensal, secretes surfactin (a cyclic lipopeptide). This molecule acts as a potent neurotoxin, disrupting the mitochondrial membrane potential and damaging neurons. The toxicity of surfactin is enhanced by conditions that disrupt BBB permeability, which is frequently observed in AD [83].

Fermented meals containing Bacillus subtilis or E. coli can either harm or remedy AD pathology, depending on the amyloid, metabolic context, and immune tone [82, 83]. These findings underscore the need for strain-level characterization and urge caution against the blanket use of live biotherapeutics in neurodegeneration. This gut-to-brain amyloid relay exemplifies how structural mimicry between microbial and host proteins can initiate pathological cascades, highlighting the need for strain-specific microbiome characterization in AD risk assessment [84].

Collectively, these microbial metabolites function as an integrated signaling network that converges on common molecular targets, including nuclear receptors (FXR, AhR), G-protein-coupled receptors (GPR43, GPR41, GPR109A), inflammasome complexes (NLRP3), and epigenetic regulators (HDACs). Recent systems biology approaches reveal extensive crosstalk between metabolite-activated pathways: for instance, SCFAs and bile acids synergistically regulate BBB permeability through complementary effects on tight junction proteins; tryptophan-derived indoles and SCFAs converge on microglial polarization via AhR and GPR43 co-activation; and TMAO amplifies inflammatory cascades initiated by bacterial LPS. This mechanistic integration underscores the rationale for multi-targeted therapeutic approaches—including synbiotic formulations combining SCFA-producing and indole-producing strains, dietary interventions that simultaneously modulate multiple metabolite pathways, and precision medicine strategies that account for individual variation in metabolite production, receptor expression, and host genotype (particularly APOE4 status). The context-dependent effects of these metabolites—protective versus pathogenic depending on concentration, timing, microbial community structure, and host factors—emphasize the need for personalized microbiome-based diagnostics and therapeutics in AD management. While gut-derived metabolites represent critical biochemical mediators of gut-brain communication in AD, these molecular signals do not act in isolation. Instead, they converge on and are amplified through systemic and central immune activation—the second major mechanistic axis linking the gut to the Alzheimer's brain. The following section examines how microbial products trigger peripheral inflammatory cascades, reprogram microglial phenotypes, and perpetuate chronic neuroinflammation, thereby accelerating disease progression.

MAMPs, such as lipopolysaccharide and polysaccharide A, play a central role in the development of neuroinflammation via the gut-brain-immune axis. In AD, increased systemic concentrations of LPS from Gram-negative bacteria overcome the leaky gut-BBB and activate TLR4 on microglia and perivascular macrophages, leading to pro-inflammatory signaling and overproduction of TNF-α and IL-6 [85, 86].

This LPS-TLR4 axis causes microglial priming, synaptic pruning, and accelerated Aβ deposition in transgenic AD models such as 5xFAD. Mice aged 5xFAD exhibit increased gut permeability, allowing leakage of LPS that activates glia in the hippocampus [87].

In contrast, polysaccharide A (PSA), which is produced by Bacteroides fragilis, activates Tregs, particularly IL-10–secreting Foxp3⁺-Tregs. These cells cross the BBB and inhibit the activity of reactive astrocytes and the release of pro-inflammatory cytokines in the CNS. Treatment with PSA restores the immune system's balance in the aged AD brain, making it a potential next-generation postbiotic therapy. The difference between LPS, which triggers inflammation, and PSA, which prevents inflammation, shows how gut-derived MAMPs can affect the immune response in both directions. This means that the effect of microbes in AD is reversible. However, the microbes must be administered precisely for modulation of AD to occur [86].

SCFAs are revealed as crucial mediators that stimulate microglial activation in AD and mediate both protective and deleterious effects [47]. Microglia, the brain's resident immune cells, can shift between anti-inflammatory (homeostatic/M2-like) and pro-inflammatory (neurodegenerative/MGnD) phenotypes in response to microbial metabolites [88]. Microglia, the brain's immune cells, can switch between anti-inflammatory (homeostatic/M2-like) and pro-inflammatory phenotypes.

In particular, butyrate induces microglial homeostasis through mechanisms independent of direct GPR43 receptor activation, as primary microglia do not express FFAR2 (GPR43) [47, 89]. Instead, SCFAs modulate microglial function through histone deacetylase (HDAC) inhibition and monocarboxylate transporter-mediated uptake, subsequently inhibiting the NLRP3 inflammasome by decreasing ASC oligomerization and IL-1β release [41, 89]. Butyrate supplementation restores microglial phagocytic capacity in germ-free APP/PS1 mice, associated with upregulation of TREM2 and CD33, two important receptors involved in Aβ clearance and AD risk [63].

Conversely, acetate—another SCFA—has been shown to promote a neurodegenerative microglial (MGnD) transcriptional profile, increasing Apo E expression and promoting a disease-associated signature that impairs Aβ phagocytosis and accelerates plaque accumulation [41]. This emphasizes the metabolically specific and context-dependent nature of gut-derived SCFAs' effects on CNS immunity. Modulating the SCFA–microglial axis through diet, targeted prebiotics, or SCFA analogs represents a promising strategy to rebalance immune tone in early-stage AD.

The gut microbiome contributes to and influences AD through gut-brain exchanges and the systemic inflammatory response. Serum amyloid A (SAA) is one of this axis's most important molecular mediators. It is an acute-phase reactant that increases intestinal dysbiosis. SAA binds to the receptor for advanced glycation end products on cerebral endothelial cells, allowing the influx of β-amyloid (Aβ) into the brain parenchyma (i.e., brain cells) and activating astrocytic and microglial cytokine cascades [90].

At the same time, gut immune cells, especially Th17 cells, are influenced by specific microbial groups, such as segmented filamentous bacteria (SFB). Interleukin-17A (IL-17A) is a cytokine that enters the CNS and stimulates C1q expression at synapses to initiate complement-mediated synaptic pruning, which is pathologically accelerated in early AD [91, 92]. C1q activity is too much. When this happens, it leads to accelerated synapse loss. This is particularly true in the hippocampus and cortex [92].

Recent studies demonstrate that manipulating Th17 expansion via diet, probiotics, or RORγt inhibition can reduce IL-17A levels and preserve synaptic integrity, suggesting that peripheral immune control may offer upstream leverage over central pathology [90, 93]. Beyond metabolite diffusion and systemic immune signaling, the gut communicates with the brain through a third, anatomically discrete pathway: direct neural transmission via the vagus nerve. This bidirectional neural highway enables rapid, real-time communication between gut microbiota and central nervous system structures, offering unique therapeutic opportunities for neuromodulation. We now examine the vagal mechanisms through which microbial signals are transduced into neurophysiological responses relevant to AD pathogenesis. While vagal neural signaling provides rapid, direct communication between gut and brain, the microbiota also influences central nervous system function through hormonal and neurotransmitter pathways that operate on slower timescales but exert profound regulatory control. The neuroendocrine system, particularly through modulation of the hypothalamic–pituitary–adrenal axis and microbial neurotransmitter production, represents a fourth critical mechanism linking gut dysbiosis to AD pathology.

The vagus nerve is a primary bidirectional communication pathway between the gut microbiota and the brain. It transmits microbial signals that influence the neuroimmune and neuroendocrine pathways involved in AD [32].

Curli amyloids produced by Escherichia coli are involved in the crucial interaction. Toll-like receptor 2 (TLR2) on enteroendocrine and immune cells of the intestinal epithelium is activated by these extracellular fibers. Curli, which activates vagal afferents, sends signals to the NTS and locus coeruleus that alter the release of noradrenergic (NE) in the hippocampus and increase the expression of IGF-1 [93, 94]. According to the APP/PS1 mouse model (80, 81), both NE and IGF-1 can promote Aβ clearance. Consequently, these agents can either enhance microglial activation or upregulate IDE [95, 96].

The composition of the gut microbiota also influences the overall degree of vagal tone and the intensity of afferent signaling. A lack of the right bacteria impairs vagal A system function, whereas the appropriate bacterium, Lactobacillus rhamnosus, restores system responses and improves memory in animal brains [97].

These results emphasize that afferent vagal activation by microbial products may serve as a neuroprotective feedback loop that counteracts AD pathology by modulating neurotransmitters and growth factors.

Vagus nerve stimulation (VNS) has developed into a neuromodulatory treatment modality with anti-inflammatory potential in AD, which it exerts essentially by engaging the α7 nicotinic acetylcholine receptor (α7nAChR) on microglia and astrocytes. Activation of α7nAChRs results in inhibition of pro‐inflammatory cytokines, notably IL‐1β and TNF‐α, and a return toward microglia homeostasis [98, 99]. Transcutaneous VNS significantly improved spatial memory performance in 5xFAD mice and diminished hippocampal plaque burden. This was concomitant with enhanced α7nAChR expression in microglia and activation of anti-inflammatory signaling pathways, such as the JAK2/STAT3 pathway [32]. Electrophysiological studies demonstrate that α7nAChR activation also modulates synaptic plasticity, particularly in the hippocampus, a region critically affected in AD [100].

Pharmacologic enhancement of α7nAChRs or targeted VNS results in neuroprotective effects, including reductions in oxidative stress, restoration of long-term potentiation (LTP), and improved cholinergic transmission in AD models [101]. The cholinergic anti-inflammatory reflex, centrally mediated via the vagus nerve, offers a bidirectional therapeutic target with both peripheral and central anti-inflammatory impact [102].

Recent findings reveal that Lactobacillus rhamnosus JB-1 communicates with the brain via extracellular vesicles (EVs) that carry small RNAs and miRNAs, which engage host neuroimmune networks. These EVs can modulate vagal nerve activity by acting on enteroendocrine cells and primary afferent neurons, thereby transmitting signals to the brainstem and hippocampus [103, 104].

In preclinical studies, L. rhamnosus JB-1 has been shown to influence central neurotransmitter systems and reduce neuroinflammatory markers in the brain via vagus nerve–dependent mechanisms, although direct validation in AD models is still limited. One proposed mechanism involves miR-155–containing EVs, which may downregulate pro-inflammatory genes, such as BACE1, a β-secretase involved in Aβ production [105].

While specific confirmation in APP/PS1 or 5xFAD models is pending, mechanistic extrapolations from major depressive disorder (MDD) and stress-related neuroinflammation studies strongly support a role for microbiota-derived miRNAs and EVs in the modulation of CNS targets by the vagus [106, 107].

The GBA is closely linked to the HPA axis. HPA refers to the hypothalamic–pituitary–adrenal axis. It is a neuroendocrine structure, according to some researchers. HPA observes personality types. HPA is associated with AD. In APP/PS1 mouse models, gut microbiota depletion increases circulating corticosterone levels, the murine analog of cortisol. This leads to increased transcription of β-secretase 1 (BACE1), mediated by glucocorticoid receptor (GR) binding to its promoter. This ultimately leads to accelerated Aβ42 deposition [108, 109].

Chronic activation of the HPA axis leads to phosphorylation of the GR in the hippocampus, impairing feedback inhibition, promoting persistent neuroinflammation, and decreasing synaptic plasticity [34]. Notably, probiotic interventions—particularly using Bifidobacterium infantis and Bifidobacterium longum—have shown promise in normalizing HPA axis activity, restoring hippocampal GR function, and reducing Aβ burden in transgenic models [110, 111]. These findings suggest that targeted microbiome modulation may serve as a therapeutic avenue to recalibrate neuroendocrine stress pathways in early-stage AD and attenuate downstream amyloidogenic signaling.

The gut microbiota influences the CNS by producing and modulating the neurotransmitters GABA and serotonin [103].

Lactobacillus spp. Including L. GABA-producing Lactobacillus strains, such as Rhamnosus, has been shown to help attenuate the cortical hyperexcitability seen in early AD and MCI. Research on GABA in mouse models of AD has shown that GABA inhibits glutamatergic excitotoxicity and restores neuronal network stability [112, 113]. In addition, tryptophan deficiency is caused by Candida albicans overgrowth. As a result, tryptophan is diverted from serotonin production. At the same time, this diversion leads to kynurenine pathways. The kynurenine pathways, therefore, produce neurotoxins that exacerbate depression-like behaviors and cognitive impairment [114].

Furthermore, gut-derived serotonin has been shown to regulate hippocampal neurogenesis and plasticity, and interventions that restore microbial tryptophan metabolism—such as administration of Bifidobacteria or polyphenol-rich diets—have reversed mood and memory deficits in experimental models [115, 116]. The metabolic, immune, neural, and neuroendocrine pathways we examined converge on a critical structure: the BBB. The BBB maintains brain homeostasis. Its integrity determines whether peripheral signals—beneficial or pathogenic—can reach the central nervous system. Next, we will explore how gut dysbiosis disrupts this neurovascular interface. This disruption creates a pathway for peripheral inflammation and microbial products to enter the brain parenchyma and contribute to Alzheimer's disease pathology.

The BBB and gut microbial signals are vital in health and disease. Mice raised in a germ-free environment do not develop a BBB. They have low claudin-5 and occludin, which are tight junction proteins. Giving them SCFA helps reverse this situation. SCFA supplementation can be achieved by adding an important fatty acid, butyrate [117, 118].

Butyrate enhances BBB integrity by activating the AMPK pathway, stabilizing TJ proteins, and inhibiting MLCK-mediated cytoskeletal destabilization. In models of AD, activation of AMPK decreased BBB permeability and inflammation-induced leakage, making it a potential therapy to prevent early-onset Aβ extravasation [119, 120]. These mechanisms directly affect endothelial cell gene expression through epigenetic rearrangements, while also indirectly reducing peripheral inflammation and maintaining the integrity of the neurovascular unit. Microbial metabolites induce the release of gut-brain signaling molecules that influence neuronal circuits in the brain and/or modulate the BBB workings.

Gut dysbiosis leads to BBB damage in AD by increasing systemic inflammation and enhancing the generation of microbial-derived toxins, including LPS [121]. LPS induces toll-like receptors in brain micro-vascular endothelium, which promotes the production of matrix metalloproteinase-9 (MMP-9). Type IV collagen and tight junction proteins (occludin and claudin-5) are enzymatically degraded by MMP-9, increasing BBB permeability and promoting Aβ40 extravasation into the brain parenchyma [122].

Enhanced MMP-9 activity is also associated with decreased expression of zonula occludens-1 (ZO-1), a critical scaffolding protein necessary for the maintenance of TJ. This impairment results in the infiltration of neurotoxic proteins and peripheral cytokines into the brain and could exacerbate amyloidogenic and tau-related pathology [123]. By contrast, the gut bacterium A. muciniphila demonstrated neuroprotective effects on the BBB, including in APOE4 transgenic models. This defense is, at least in part, due to the released peptide P9, which induces ZO-1 preservation and stabilizes endothelial junctions. Therein, modulation of gut-derived peptides represents a potential therapeutic approach to reconstitute neurovascular integrity in dysbiosis-driven AD [124, 125]. Sect. "Mechanistic pathways: how the gut influences the AD brain" has dissected the multifaceted mechanistic architecture through which the gut microbiome influences Alzheimer's disease pathogenesis, revealing an integrated systems-level framework rather than isolated pathways. Five interconnected mechanisms collectively orchestrate gut-brain communication: (1) metabolic signaling through SCFAs, tryptophan derivatives, bile acids, TMAO, and bacterial amyloids that directly modulate neuronal function, epigenetic regulation, and amyloid aggregation; (2) immune system activation through MAMPs and microglial polarization that drives chronic neuroinflammation; (3) vagal neural transmission providing rapid bidirectional gut-brain signaling and neuromodulatory control; (4) neuroendocrine regulation via HPA axis dysregulation and microbial neurotransmitter production affecting stress responses and synaptic plasticity; and (5) BBB compromise enabling peripheral inflammatory mediators to infiltrate the CNS [40, 43].

Probiotic strains such as Lactobacillus acidophilus, L. casei, Bifidobacterium bifidum, and L. fermentum have neuroprotective properties in AD models and clinical populations. MMSE scores improved in a 12 week RCT with a multi-strain formulation, and IL-6 and MDA levels were reduced in Alzheimer's patients [120]. Prebiotics support the establishment of these probiotics, while synbiotics enhance SCFA production and gut-brain communication. In 3xTg-AD mice, females had a greater reduction in microglial activation and better neuron preservation than males after probiotic treatment [112].

FMT aims to restore eubiotic gut microbial communities. A pilot clinical trial in China showed FMT improved intestinal permeability and reduced plasma LPS in MCI subjects [135]. Despite early promise, standardization of donor selection, safety assurance, and long-term efficacy data remain significant hurdles. Recent reviews emphasize the need for personalized FMT protocols, accounting for host-microbiome compatibility [135].

The Mediterranean and MIND diets are associated with increased SCFA-producing bacteria (Roseburia, Faecalibacterium) and reduced Proteobacteria. These diets are linked to slower cognitive decline and reduced AD incidence [147]. Intermittent fasting enhances neuronal resilience by promoting microbial shifts and reducing oxidative stress. Polyphenols in berries and teas upregulate indoleamine 2,3-dioxygenase inhibitors and promote the production of neuroprotective indoles [152].

Microbiome-modulating drugs are emerging. Metformin, by activating AMPK, improves insulin signaling and rebalances gut flora, reducing Aβ and tau pathology [153]. Antibiotics have been trialed but may disrupt commensal taxa. Tight junction stabilizers and gut-derived cytokine inhibitors are in development [154].

Non-invasive VNS enhances cholinergic anti-inflammatory pathways, elevating norepinephrine and reducing tau phosphorylation. Preclinical models show VNS improves hippocampal synaptic plasticity and reduces microglial activation, making it a candidate for symptomatic relief [155, 156].

Machine learning-based algorithms now predict microbial response patterns, enabling personalized probiotic design and dietary regimens. Integration of host genomics, microbiomics, and plasma metabolomics allows identification of subgroups for tailored therapy. Postbiotic cocktails and targeted synbiotics are being trialed as part of individualized plans [157 –159]. Sect. "Potential therapeutic targets" has outlined a comprehensive therapeutic portfolio targeting the GBA in Alzheimer's disease, ranging from direct microbiome modulation to host-directed interventions and integrated precision medicine approaches. The evidence supports a multi-modal strategy rather than reliance on single interventions: microbiome-targeted therapies (probiotics, prebiotics, FMT, postbiotics) show promise in restoring beneficial microbial taxa and metabolite production; dietary interventions—particularly Mediterranean, ketogenic, and polyphenol-rich diets—provide synergistic benefits through multiple mechanisms, including SCFA enhancement and antioxidant protection; pharmacological approaches targeting specific receptors (FXR agonists, IDO1 inhibitors) and vagal neuromodulation offer complementary mechanistic leverage [44].