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7 January 2026

Targeting the Gut Microbiota: Mechanistic Investigation of Polyphenol Modulation of the Gut–Brain Axis in Alzheimer’s Disease

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School of Basic Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
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First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming 650500, China
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Authors to whom correspondence should be addressed.
Int. J. Mol. Sci.2026, 27(2), 604;https://doi.org/10.3390/ijms27020604
This article belongs to the Special Issue Nutrition in Neurodegenerative Diseases: Molecular Perspectives
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Abstract

Alzheimer’s disease (AD) represents an increasingly severe global health challenge. Recently, the role of the gut–brain axis in AD pathogenesis has garnered significant attention. Dysbiosis of the gut microbiota can exacerbate core pathologies such as neuroinflammation, amyloid beta (Aβ) deposition, and tau hyperphosphorylation through neural, endocrine, and immune pathways. Polyphenolic compounds have emerged as a focal point in neuroprotective research owing to their pronounced anti-inflammatory and antioxidant properties. Notably, polyphenols exert effects not only by directly influencing the central nervous system (CNS) but also through indirectly modulating the composition and function of the gut microbiota, thereby impacting bidirectional gut–brain communication. This dual mechanism offers a potential avenue for their application in the prevention and treatment of AD. This review aims to compile recent research on the relationship between polyphenols and the gut microbiota. We assessed the literature from PubMed, Google Scholar, and Web of Science databases, published from the establishment of the database to 24 November 2025. The keywords used include “Polyphenols”, “Gut–brain axis”, “Gut microbiota”, “Alzheimer’s disease”, “Epigallocatechin gallate”, “Quercetin”, “Curcumin”, “Ferulic acid”, “Resveratrol”, “Anthocyanin”, “Myricetin”, “Chlorogenic acid”, etc. This review discusses the various mechanisms by which polyphenols influence AD through modulating the gut microbiota. Polyphenols and gut microbiota exhibit critical bidirectional interactions. On one hand, the bioavailability and activity of polyphenols are highly dependent on metabolic conversion by gut microbiota. On the other hand, polyphenols selectively promote the proliferation of beneficial bacteria such as bifidobacteria and lactobacilli like prebiotics, while inhibiting the growth of pathogenic bacteria. This reshapes the intestinal microecology, enhances barrier function, and regulates beneficial metabolites. Utilizing a nanotechnology-based drug delivery system, the pharmacokinetic stability and brain targeting efficacy of polyphenols can be significantly enhanced, providing innovative opportunities for the targeted prevention and management of AD.

1. Introduction

Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder (NDD), with advancing age serving as the primary risk factor for its pathogenesis [1]. Approximately 18.2% of the elderly population aged 65 and above are diagnosed with AD, with prevalence increasing to 33.4% among those aged 85 and older [1]. The global prevalence of AD has been increasing annually. By 2010, the estimated worldwide population of dementia patients had surpassed 55 million [2]. The principal phenotypic presentations of AD encompass gradual neurocognitive deterioration, amnestic deficits, language and visuospatial impairments, as well as neuropsychiatric and personality alterations, eventually culminating in mortality. The principal neuropathological features of AD include the extracellular accumulation of amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, both contributing to neuronal degeneration [1]. Current therapeutic interventions for AD predominantly involve cholinesterase inhibitors, such as donepezil, and N-Methyl-D-Aspartate receptor antagonists, exemplified by memantine. However, these pharmacological interventions only mitigate cognitive deterioration and enhance functionality in activities of daily living; they do not fundamentally inhibit the pathological progression of the disease [3].
The gut–brain axis (GBA) functions as a bidirectional communication network connecting the enteric nervous system (ENS) with the central nervous system (CNS). The main pathways encompass neural routes primarily involving the vagus nerve (VN) and the nucleus tractus solitarius, immunological pathways where microbiota-derived metabolites activate immune cells that subsequently modulate neuroinflammatory processes within the CNS through cytokine and chemokine signaling, and endocrine pathways in which microbiota-secreted compounds directly enter the systemic circulation to influence neuroregulatory functions. The total commensal microbiome within the human colon is estimated to consist of approximately 100 trillion microorganisms [4], encoding over 22 million functional genes [5]. This “second genome” is integral to host metabolic processes, immune system maturation, and neurodevelopmental pathways. The gut microbiome serves as a crucial component of the gut–brain axis, regulating neurodevelopment and modulating synaptic plasticity [6]. Therefore, intestinal microbiota dysbiosis has been identified as a substantial modifiable etiological factor in the pathogenesis of diverse neurodegenerative and neuropsychiatric conditions, such as depression, Parkinson’s disease (PD), and AD [7].
Polyphenols are phenylpropanoid secondary phytochemicals intrinsic to vegetal organisms. Polyphenols are a category of phytochemical secondary metabolites characterized by one or more aromatic benzene rings fused with multiple hydroxyl functional groups [8]. They predominantly consist of two principal phytochemical classes: flavonoids and non-flavonoids [9]. Polyphenols, owing to their distinctive bioactive properties—including antioxidant, anti-inflammatory, neuroprotective, and gut microbiota-modulating effects—are posited to have therapeutic and prophylactic potential in NDD such as AD and PD [10]. Data suggest that polyphenol extracts derived from fruits may mitigate age-related cognitive decline in senior populations [11]. Despite their high dietary prevalence, polyphenols exhibit limited bioavailability in vivo. Predominantly, their absorption is contingent upon biotransformation mediated by gut microbiota, which subsequently amplifies their bioactive potential [12].
The authors’ research expertise has focused on constructing animal models of neuropsychiatric diseases and conducting prevention and treatment with the combination of traditional Chinese Medicine and Western medicine. For example, we have published a review article that focuses on the efficacy of polyphenols on ischemic stroke, Parkinson’s disease. It is emphasized that polyphenols exert neuroprotective effects primarily through inhibiting the production of oxidative stress [13]. Furthermore, the therapeutic benefits of polyphenols on autism-spectrum disorders, anxiety disorders, depression, and sleep disorders were also investigated [14]. This review consolidates existing evidence on the interactions between polyphenolic compounds and the gut microbiota in AD, encompassing the following domains: (I) the modulatory effects of polyphenols on AD pathogenesis; (II) the role of the gut–brain axis in AD progression; (III) microbiota-mediated biotransformation of polyphenols; (IV) polyphenol-induced modulation of commensal and pathogenic microbial populations; (V) microbial metabolites’ impact on intestinal barrier integrity; (VI) nanotechnology-based delivery systems to enhance polyphenol bioavailability and targeted CNS delivery. Collectively, these insights underpin the potential for microbiome-guided, nanomedicine-enhanced polyphenol interventions for precision prophylaxis and therapeutics in AD.

2. The Gut Microbiota–Gut–Brain Axis and Its Connection to Alzheimer’s Disease

The human gastrointestinal tract hosts a diverse microbial consortium predominantly consisting of bacteria, accompanied by viruses, fungi, protozoa, and parasitic nematodes, collectively designated as the microbiota [15,16]. The “microbiota–gut–brain axis” has become a central area of investigation in NDD research. Researchers administered intracorpuscular injections of Aβ1-42 oligomers into the gastric mucosa of murine models. Over a 12-month period, they documented retrograde translocation of Aβ peptides from the gastrointestinal epithelium to the CNS. These findings imply that gut-to-brain Aβ oligomer transport may be a critical pathway in the etiopathogenesis of AD and related neuroinflammatory processes [17]. The microbial composition of individuals with AD exhibits significant alterations. A minimum of 11 phyla, 15 classes, 14 orders, 38 families, 137 genera, and 51 species (comprising 9.77%) [18]. Among these, the taxonomic groups Enterobacteriaceae, Lachnospiraceae, Ruminococcus, and the genera Bifidobacterium and Bacteroides were recognized as exhibiting significant variations in relative abundance [18].

2.1. Endocrine Pathway

The impact of bacterial metabolic signaling on CNS functionality is an emerging research focus. Bioactive microbial metabolites, including gamma-aminobutyric acid (GABA), serotonin, histamine, and dopamine, act as neurotransmitters or their precursors, playing a pivotal role in modulating neurochemical pathways involved in emotion, behavior, and cognition [19,20]. Bacteroides, Bifidobacterium and Lactobacillus strains possess glutamate decarboxylase enzymatic genes responsible for the decarboxylation of glutamate to GABA [21,22]. Abnormal levels of gamma-aminobutyric acid are present in the CNS and cerebrospinal fluid of AD patients [23,24]. Animal models demonstrate that reactive astrocytes neighboring Aβ deposits upregulate gamma-aminobutyric acid production, thereby perturbing synaptic plasticity and contributing to deficits in cognitive function and memory [25,26,27]. These findings indicate that microbiota-derived GABA could influence neurodegenerative mechanisms implicated in AD pathology.
Bile acids synthesized by gut microbiota can enhance the permeability of the blood-brain barrier (BBB) [28,29]. Following its direct association with cholesterol in neuronal cell membranes, the amyloid precursor protein (APP) demonstrates increased affinity for the phospholipid monolayer of lipid rafts, thereby facilitating enzymatic processing and the production of Aβ [30]. Short-chain fatty acids (SCFAs), functioning as endogenous ligands, selectively activate the extensively expressed free fatty acid receptors (FFARs) and hydroxycarboxylic acid (HCA) receptors. Through modulation of intracellular signaling pathways involving cyclic adenosine monophosphate (cAMP) and calcium flux, they regulate endocrine hormone secretion, immune responses, and [31]. Interestingly, bacterial amyloid proteins exhibit structural and functional parallels with Aβ, including curli fibers generated by Escherichia coli, phenol-soluble modulins produced by Staphylococcus aureus [32]. It can promote heterotypic crystallization and aggregation of host amyloid-beta via molecular mimicry [33].

2.2. Neurotransmission

The VN, emerging from the medulla oblongata, projects extensively along the gastrointestinal mucosa, facilitating bidirectional communication between the gut and the CNS. This system incorporates diverse chemoreceptors and mechanoreceptors capable of detecting signals generated by the gut microbiota and transmitting them to the CNS [34,35]. Particular strains of Lactobacillus influence the gene expression of GABA receptor mRNA within the prefrontal cortex and hippocampal areas; however, this modulatory effect is abolished after vagotomy [36]. VN transection also resulted in reduced neurogenesis and cell survival within the dentate gyrus of the mouse hippocampus [37]. While the VN does not traverse the epithelial barrier [38], intestinal epithelial cells and enteric glial cells located within the mucosal and muscular layers can form direct synaptic junctions with vagal afferent fibers, thereby enabling afferent signal transmission to the CNS [39]. Intestinal glial cells are also capable of modulating the permeability of the intestinal epithelial barrier through neuroglial synapses, relaying alterations in the gut microbiome to the CNS [40]. Therefore, changes in the gut microbiome are believed to potentially disrupt hippocampal-dependent memory processes through VN-mediated pathways, consequently contributing to cognitive impairments associated with dementia [41].

2.3. Immunomodulation

The gastrointestinal tract hosts a complex and abundant community of immune effector cells. Interactions between the microbiome and the immune system can trigger the release of pro-inflammatory cytokines and chemokines, thereby affecting systemic neuroimmunological homeostasis [42]. Gut microbiota dysbiosis disrupts intestinal barrier integrity. When the gut-vascular barrier is compromised, microbes, their antigens, and inflammatory mediators infiltrate the systemic circulation [43]. The neuroinflammatory response concomitantly induces BBB disruption, thereby amplifying neuroinflammation and β-amyloid aggregation [44]. Additionally, gut microbiota-derived metabolites modulate the ontogeny, phenotypic differentiation, and activation of microglial cells and astrocytes [45]. Microglia play a critical role in maintaining cerebral homeostasis and mediating neuroprotection against insults, including Aβ and tau aggregation. Dysregulation of microglial activity leads to persistent secretion of chemokines, pro-inflammatory cytokines, and reactive oxygen species (ROS), thereby initiating and amplifying neuroinflammatory responses that exacerbate neuronal degeneration and accelerate the progression of AD pathology [46].
Endocrine, neurophysiological, and inflammatory signaling cascades intricately cross-communicate, collectively orchestrating the bidirectional neuro-gastroenteric axis. SCFAs are capable of penetrating the BBB, modulating neurophysiological processes, and regulating cerebral perfusion, thereby impacting neuroinflammatory responses. Afferent fibers of the VN are capable of directly sensing microbe-associated molecular patterns and metabolic derivatives, relaying nociceptive signals to central pain processing pathways [47]. VN influences neuroinflammatory mechanisms within CNS regions such as the hippocampus by modulating both intestinal and systemic inflammatory responses [48]. In conclusion, the gut microbiome contributes to the development of the GBA via endocrine, neural, and immune pathways, collectively impacting the initiation and progression of AD.

3. Polyphenol Alleviates Pathology of Alzheimer’s Disease

Polyphenols are bioactive phytochemicals prevalent in fruits, vegetables, and cereals, demonstrating antioxidant, anti-inflammatory, and metabolic modulation activities. These polyphenols can be classified into flavonoid subclasses and non-flavonoid phytochemicals [9]. Flavonoids comprise subclasses such as flavanols and anthocyanins [49]; non-flavonoids encompass phenolic acids, lignans, and others [50]. Its structural heterogeneity defines its multi-modal therapeutic mechanism in AD management (Figure 1).
Figure 1. Polyphenol alleviates the pathology of Alzheimer’s disease.

3.1. Polyphenols Alleviate β-Amyloid Deposition in AD

Polyphenolic compounds potentially attenuate β-amyloid accumulation in AD pathology. Aberrant conformations of APP promote overproduction and aggregation of Aβ peptides, resulting in amyloid plaque formation and tangle development, which ultimately induce neurodegeneration and synaptic dysfunction [3]. Myricetin potentially engages in intermolecular hydrogen bonding with the carbonyl functionalities of β-sheet secondary structures through its hydroxyl moieties, thus impeding Aβ fibrillogenesis [51]. Research demonstrates that myricetin at specific concentrations (10 μM, IC50 = 2.8 μM) can upregulate α-secretase expression and enzymatic activity, inhibit β-secretase (BACE-1) activity, and promote the non-amyloidogenic pathway to diminish amyloid-beta (Aβ) production [52].
Epigallocatechin gallate (EGCG) facilitates non-amyloidogenic pathways through inhibition of the extracellular signal-regulated kinase (ERK)/NF-κB signaling cascade, augmentation of α-secretase enzymatic activity, and downregulation of β- and γ-secretase complexes [53,54]. Moreover, EGCG inhibits the nucleation and fibrillogenesis of Aβ-laden protofibrils through binding interactions with intrinsically disordered peptide conformations [54]. EGCG facilitates the disassembly of mature Aβ protofibrils by degrading their structured aggregates into inert, non-toxic amorphous microaggregates [53].

3.2. Polyphenols Inhibit Tau Protein Phosphorylation in AD

Excessive hyperphosphorylation of tau protein significantly contributes to AD pathogenesis. Tau, a microtubule-associated protein primarily localized within neuronal axons, is integral to microtubule polymerization, stabilization, and axonal cytoskeletal integrity, playing a crucial role in axonal development and neuronal maturation [55]. The hyperphosphorylation of tau proteoforms is intricately controlled by various kinases, notably AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3 beta (GSK3β) [56,57].
Quercetin attenuates tau hyperphosphorylation through the modulation of GSK3β enzymatic activity [58]. It concurrently mitigates oxidative stress-triggered apoptosis and caspase-3 activation, primarily through modulation of the MAPK and PI3K/Akt/GSK3β signaling cascades [58,59]. In addition to quercetin, naringenin modulates the PI3K/Akt/GSK3β signaling pathway, thereby attenuating tau hyperphosphorylation [60]. Furthermore, Sonawane et al. [61], elucidated that EGCG exhibits time- and concentration-dependent efficacy in disaggregating preformed tau fibrils and destabilizing their oligomeric assemblies.

3.3. Polyphenols Reduce Oxidative Stress Levels in AD

Consequently, oxidative stress is widely recognized as a pivotal contributor to NDD, such as AD [62]. Oxidative stress has been posited as the primary pathogenic trigger initiating tau protein aggregation [63].
Flavonoids mitigate oxidative stress caused by reactive oxygen species via multiple biochemical pathways. One such mechanism involves direct neutralization of free radicals, where the hydroxyl moieties in flavonoids undergo oxidation by reactive species, thereby stabilizing the radicals and diminishing their cytotoxic reactivity [64]. For example, the eight hydroxyl functionalities on EGCG efficiently neutralize reactive oxygen species, thereby exhibiting exceptional antioxidant activity [65] Another antioxidative pathway of flavonoids pertains to the suppression of reactive ROS generation, primarily through the inhibition of critical oxidative enzymes such as xanthine oxidase and the chelation of pro-oxidant metal ions, including Fe2+ and Cu2+ ions, which catalyze radical formation [66]. Quercetin may promote the phosphorylation and activation of the downstream p53 protein by inhibiting the activity of the ERK1/2 and AKT pathways [67]. Under mild oxidative stress conditions, p53 functions as an antioxidant regulator by transcriptionally activating downstream target genes such as TP53-Induced Glycolysis and Apoptosis Regulator, sestrin1/2, and p21. These proteins mitigate reactive oxygen species (ROS) accumulation by modulating glycolytic flux and preserving mitochondrial integrity. Furthermore, proteins like sestrin1/2 and p21 facilitate the dissociation of Keap1 from Nrf2, thereby enhancing Nrf2-mediated endogenous antioxidant responses and systematically reducing intracellular oxidative stress [68]. Furthermore, quercetin and naringenin upregulate glutathione (GSH) synthesis in hippocampal neurons and stimulate the transcription of key antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) [69,70]. In addition to regenerating antioxidant enzymes such as SOD, CAT, and GSH as previously described, myricetin also exhibits inhibitory effects on the Fenton reaction through chelation of transition metal ions like Cu2+ and Fe2+, thereby attenuating ROS generation and markedly augmenting its antioxidant efficacy [71,72].
Non-flavonoid phytochemicals also exhibit significant antioxidant properties, contributing to the attenuation of oxidative stress and neutralization of free radicals. Specifically, ferulic acid, a phenolic acid, mitigates reactive ROS generation by upregulating SOD enzymatic activity and suppressing malondialdehyde concentrations [73,74]. Butylated ferulic acid—a highly lipophilic ester—has been shown to inhibit Aβ1-42 oligomerization, diminish ROS generation, and concurrently enhance endogenous antioxidant defense by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway [75]. The antioxidative response regulated by Nrf2 represents a vital component of the cellular defense arsenal in mammals. It has been documented that Nrf2 activation can be effectively triggered by natural polyphenolic compounds such as curcumin, EGCG, resveratrol, ferulic acid, puerarin, and quercetin [76].

3.4. Polyphenols Alleviate Neuroinflammation in AD

Neuroinflammation, an immune response within the CNS, is identified as a pivotal etiological factor in AD and is perceived as a downstream effect of its neuropathological progression [77]. In age-related chronic neuroinflammatory conditions, glial cells undergo phenotypic polarization towards a pro-inflammatory state, resulting in elevated secretion of cytokines such as IL-1β, IL-6, and TNF-α, which further intensifies neuroinflammatory processes [78]. Clinically, neuroinflammatory responses have been inversely associated with cognitive decline in AD patients [63].
The polyphenolic constituents of pomegranates, including punicalagin and ellagic acid, upregulate IL-10 anti-inflammatory cytokine expression and suppress IL-1β pro-inflammatory cytokine secretion in an Aβ1-42-induced neuroinflammatory model. This modulation appears to be mediated through downregulation of CD86 and upregulation of CD163, promoting the polarization of microglia and macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype [79]. Similarly, quinic acid (QA) exhibits neuroprotective effects by mitigating neuroinflammation via suppression of the retinoic acid-induced protein 3/iκB kinase complex/NF-κB signaling cascade, mediated through modulation of gut microbiota-derived metabolites such as indole-3-acetic acid and kynurenic acid [80]. NF-κB, a central transcription factor modulated by diverse inflammation-associated signaling cascades, plays a pivotal role in the regulation of inflammatory responses. Phytochemical polyphenols—including naringin, myricetin, and icariin—demonstrate anti-inflammatory properties through the suppression of NF-κB activation [81,82,83].

3.5. Clinical Research on Polyphenol Therapy for Alzheimer’s Disease

We have compiled clinical trial data examining the efficacy of polyphenol-based interventions for AD. Findings demonstrate that polyphenol isolates and extracts derived from specific botanical sources can enhance cognitive function and memory deficits in patients. Furthermore, these compounds facilitate the enhancement of AD-related biomarkers in both serum and cerebrospinal fluid (Table 1). However, certain empirical investigations have demonstrated that polyphenol supplementation does not produce a statistically significant divergence from placebo controls [84,85]. The causes of this paradoxical result may be attributable to various determinants, such as sample population size, patient adherence to therapy, and pharmacokinetic properties of the medication.
Table 1. Clinical trials of polyphenols for the treatment of Alzheimer’s disease.
Table 1. Clinical trials of polyphenols for the treatment of Alzheimer’s disease.
Intervention DrugsTest SubjectsTest TypeIntervention TimeCognitive and Memory FunctionsAD-Related BiomarkersReferences
Spirulina maxima Extract80 patients with mild cognitive impairment (average age 68.26 ± 4.68 years)Randomized, placebo-controlled, double-blind study12 weeksVisual learning and visual working memory are enhanced. (p < 0.05)BDNF and Aβ showed no significant intergroup differences.[86]
Resveratrol119 patients with AD (aged ≥ 49 years)Randomized, placebo-controlled, double-blind study52 weeksThere was no significant difference between the treatment group and the placebo group.Compared with the placebo serum group, the decrease in Aβ40 in cerebrospinal fluid was more pronounced (p < 0.05).[87]
Dietary flavonoidsHealthy elderly individuals aged 60 and aboveRandomized, placebo-controlled, double-blind study3 yearsMemory function improved in individuals with low dietary quality and low flavonoid intake. (p < 0.01) [88]
Resveratrol119 patients with mild to moderate ADRandomized, placebo-controlled, double-blind, multi-site study52 weeksThe placebo group exhibited a significant decline in MMSE scores (p < 0.01); the resveratrol group showed no significant decline.Cerebrospinal fluid Aβ42 and Aβ40 levels decreased in both groups. However, the placebo group exhibited a greater downward trend than the resveratrol group (Aβ42 downward trend, p = 0.0618). Tau levels showed no significant change.[89]
Ginkgo biloba leaf extract EGb 761333 patients with AD (aged ≥ 50 years)Randomized, placebo-controlled, double-blind study24 weeksSKT score: Compared with the placebo group, the treatment group demonstrated improved cognitive function (p < 0.001). [90]

5. Enhancing Polyphenol Bioavailability Through Nanodelivery Technology

Polyphenolic compounds provide neuroprotection through the modulation of gut microbiota; however, their clinical application is limited by poor bioavailability. This primarily arises from their intricate chemical structures, poor aqueous solubility, hydrophobic nature, and vulnerability to hydrolytic degradation within the gastrointestinal environment, leading to suboptimal absorption and limited systemic availability [173].
To address the aforementioned issues, nanocarrier systems have emerged as a significant strategy. Such systems typically refer to solid colloidal drug delivery nanocarriers, with at least one dimension within the nanoscale range (1–100 nanometers). They are primarily categorized into organic nanoparticles—including natural polysaccharides, lipids, and proteins—and inorganic nanoparticles, such as metal and metal oxide nanoparticles, carbon-based nanomaterials, and calcium-based nanostructures [174]. Their nanometric scale and extensive surface area enhance optimal drug encapsulation and precise targeting, while concurrently accommodating both hydrophilic and hydrophobic agents [175]. Nanoencapsulation safeguards polyphenols against enzymatic hydrolysis in the gastric environment, facilitating controlled-release and targeted delivery within the gastrointestinal tract. This markedly improves their bioaccessibility and maximizes their modulation of the gut microbiome [124,142,143].
Polyglutamic acid is a water-soluble, biodegradable multivalent polypeptide with high loading capacity. Bisdemethoxycurcumin conjugated with spherical crosslinked self-assembled star-shaped polyglutamic acid demonstrates efficient BBB penetrance and CNS cellular uptake, mitigating Aβ-induced neurotoxicity in transgenic AD models and promoting neurotrophic activity in hippocampal organoid systems [176]. Furthermore, β-lactoglobulin-EGCG nanoencapsulates demonstrate a notable resilience to gastric fluid, rendering them effective as natural bioactive compound delivery systems for sustained release of EGCG [177]. In addition to protein carriers, polysaccharide matrices can critically improve polyphenol bioavailability: the binding of polyphenols to plant cell wall components directly affects their release kinetics and intestinal absorption. Positively charged chitosan, owing to its low cytotoxicity, biodegradability, and excellent biocompatibility, is extensively employed in the synthesis of polyphenol-chitosan conjugates. These conjugates significantly improve mucoadhesive properties within the gastrointestinal epithelium, facilitating targeted, controlled release of polyphenolic compounds [173]. An experimental study in AD murine models revealed [142] that resveratrol encapsulated within selenium and chitosan nanoparticle delivery systems modulates the composition of gut microbiota, including Enterococcus spp., Escherichia coli, Rickettsia spp., and Candidatus Saccharimonas—microbial taxa implicated in oxidative stress, inflammatory responses, and lipid accumulation. This methodology attenuated LPS secretion and neuroinflammatory responses, concomitantly modulating gut microbiota by decreasing Firmicutes and elevating Bacteroidetes populations. It also mitigated tau hyperphosphorylation and Aβ deposition within neural tissue through the modulation of the c-jun N-terminal kinase/AKT/GSK3β signaling cascade. Additionally, the evidence indicates that intranasal delivery of lipid nanostructures markedly surpassed oral routes in therapeutic outcomes. These findings suggest that intranasally administered lipid nanocarriers exhibit considerable promise regarding treatment efficacy for AD, safety profiles, and patient adherence [178].
Within the field of inorganic nanomaterials, selenium-core nanoparticles have been predominantly examined in AD pathogenesis studies. For example, Li et al. [124], developed selenium nanoparticle-based nanodelivery systems (TGN-Res@SeNPs) capable of traversing the BBB. Their findings demonstrated that these nanocarriers inhibit Aβ aggregation, attenuate neuroinflammation via modulation of NF-κB, MAPK, and Akt signaling pathways, reduce ROS levels, and remodel oxidative stress-associated microbiota—including Alistipes and Helicobacter species—leading to a significant decrease in hippocampal Aβ accumulation and enhancement of cognitive performance. Similarly, chlorogenic acid encapsulated within selenium nanocarriers (TGN-CGA@SeNCs) demonstrates comparable bioactivity, effectively enhancing the relative abundance of probiotic genera such as Turicibacter and Ruminococcus [179]. Both nanoplatforms demonstrate dose reduction of therapeutic agents, improved bioavailability, and multifaceted mitigation of AD pathology via a tripartite mechanism involving BBB penetration, intracerebral targeting, and modulation of gut microbiota. This constitutes an innovative nanotherapeutic strategy for precision brain intervention in AD.
Nano-delivery platforms facilitate enhanced bioavailability of polyphenolic phytochemicals in AD therapeutics, markedly improving their physicochemical stability, solubility, and cellular uptake, thus augmenting their pharmacodynamic efficacy in metabolic pathologies such as AD. Nonetheless, further optimization of formulation methodologies is required, along with comprehensive safety assessments and longitudinal clinical trials to substantiate the enduring therapeutic efficacy in AD pathology. Collectively, this strategy establishes a robust framework for fully harnessing the neuroprotective potential of polyphenolic compounds in the management of AD.

6. Discussion

6.1. Mechanisms of Polyphenol–Microbiota Interactions in AD

This review systematically synthesizes current evidence on the interactions between polyphenolic compounds and gut microbiota in AD, highlighting the pivotal role of the intricate “polyphenol–microbiota–gut–brain axis” network in the pathophysiological mechanisms of AD. Polyphenols do not function as standalone bioactive compounds; their pharmacological efficacy is predominantly contingent upon reciprocal interactions with the host gut microbiota. Structurally intricate polyphenols necessitate microbial bi-otransformation processes—such as deglycosylation—to produce metabolites with improved bioavailability, augmented bioactivity, or entirely novel chemical entities (e.g., tetrahydrocurcumin) [94]. Conversely, polyphenols modulate the composition of the gut microbiome, selectively enhancing the growth of commensal microbial taxa such as Bifidobacteria, Lactobacillus spp., and Akkermansia muciniphila [105,106,180] andattenuating the proliferation of pathogenic microorganisms, including Escherichia coli, Shigella species and Helicobacter pylori, via multi-modal mechanisms such as enzyme inhibition and disruption of microbial membrane integrity [96,97,132]. This re-configuration of the microbiome composition subsequently impacts concentrations of critical metabolites, including SCFAs, bile acids, and neuroactive compounds such as GABA. Via immune, neuroanatomical, and endocrine signaling pathways, it ultimately influences Aβ aggregation, tau protein hyperphosphorylation, neuroinflammatory responses, and oxidative stress within the CNS [31,99,181].

6.2. Research Gaps and Limitations

However, as mentioned earlier, fungi and viruses are also components of the gut microbiota. The interactions between bacteria and fungi play a role in maintaining the balance of microbial communities [182]. Unfortunately, we have found that research on gut fungi in AD remains relatively scarce compared to that on bacteria, primarily focusing on Candida, Saccharomyces, and Aspergillus species [183]. Moreover, in studies investigating the gut microbiota mechanisms of polyphenols in AD, whether in research articles or review papers, the primary focus has predominantly been on gut bacteria. Gut fungi and even viruses are often only briefly mentioned without in-depth discussion, or not addressed at all.
Additionally, to address the issues of low polyphenol activity and bioavailability, nanoscale systems have been introduced. However, in the field of AD, research on nanotechnology-related polyphenols remains incomplete. Current studies primarily focus on selenium-based and protein-based nanocarriers [124,176,177,178,184].

6.3. Future Directions

Therefore, to more effectively investigate the mechanisms through which polyphenols facilitate the restoration of gut microbiota homeostasis in AD, it is essential to comprehensively include microorganisms such as bacteria, fungi, and viruses as subjects of research. Investigate how polyphenols influence gut bacteria, fungi, and viruses, and examine the roles these factors play in maintaining gut homeostasis.
Moreover, the regulation of microbial abundance by polyphenols exhibits significant variations across different disease models. Future research and therapeutic strategies must account for the unique gut microbiome characteristics of individual hosts. Distinguishing differences between animal and human gut microbiota is essential for achieving better clinical therapeutic outcomes. Developing polyphenol-based nanomedicines from diverse materials for AD, whilst thoroughly investigating their therapeutic advantages and limitations.
Finally, the existing evidence primarily originates from animal models, necessitating the design of comprehensive randomized controlled trials to substantiate the therapeutic effectiveness and safety profile of these interventions in AD patients.

7. Conclusions

In conclusion, this research illustrates that integrating polyphenol-based therapy with gut microbiota modulation, augmented by nanotechnology to optimize bioavailability, constitutes a multi-faceted, systemic approach for the prophylaxis and management of AD. Advancing our comprehension of the intricate interplay among polyphenols, microbiota, and host physiology may reveal novel therapeutic pathways for AD intervention.

Author Contributions

This article was jointly authored by all contributors. Z.W. drafted the initial manuscript, S.B. and M.L. compiled the references, Y.W. (Yuanyuan Wei) and Y.W. (Yuenan Wang) contributed to the article’s framework, J.M. and Y.X. provided critical feedback, and D.Q. and C.Z. performed critical revisions of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the National Natural Science Foundation of China (82560898, 82060831) and the Yunnan Province-Yunnan University of Chinese Medicine Applied Basic Research Joint Special Project (202101AZ070001-034).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article. Data sharing is not applicable.

Conflicts of Interest

The author declares no other conflicts of interest.

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