Gut Microbiota and its Metabolites: Bridge of Dietary Nutrients and Alzheimer's Disease

Alzheimer's disease (AD) is characterized by β-amyloid and tau pathologies leading to progressive cognitive impairment and neuroinflammation. With more than 55 million people living with dementia globally and costs projected to reach $2 trillion by 2030, there is urgent need for disease-modifying strategies. Although anti-amyloid therapeutics (e.g., lecanemab) have emerged, no approach halts disease progression. Converging evidence from gut-brain axis research indicates that the gut microbiota, immune system, and host metabolism influence brain development and function and are modifiable by environmental factors, particularly diet. Advances in sequencing and metabolomics now enable dissection of microbiota–gut–brain associations. This review asks how gut microbiota and their metabolites link dietary nutrients to AD pathophysiology, synthesizing animal and human evidence, mechanistic pathways (neuronal, immune, metabolic), and the potential of dietary and microbiome-targeted interventions to prevent or slow AD progression.

The review compiles evidence that gut microbiome alterations are associated with AD across animal models and human cohorts. In transgenic AD mice (e.g., APP/PS1, 5xFAD), microbiota composition shifts appear as early as 3 months and evolve with age, often with decreased butyrate-producing taxa and links to amyloid and tau pathology; microbiota transfer experiments suggest causal contributions (e.g., aged or AD-donor fecal microbiota exacerbate Aβ, while young-donor microbiota improve cognition). In humans, multiple cross-sectional cohorts from the United States, China, Japan, and Turkey report distinct β-diversity profiles in AD versus controls, with mixed findings on α-diversity. Frequently reported changes include increased Bacteroidetes, Blautia, and Bacteroides, and decreased Firmicutes and Actinobacteria, with taxa correlating to CSF AD biomarkers. Some studies note higher Firmicutes/Bacteroidetes ratios in dementia or reduced butyrate-producing species by shotgun metagenomics; machine-learning models integrating microbiome and clinical data highlight pathways such as P-glycoprotein linked to inflammation. A systematic review/meta-analysis reports increased Proteobacteria, Bifidobacterium, and Phascolarctobacterium in AD, with decreases in Firmicutes, Clostridiaceae, Lachnospiraceae, and Rikenellaceae. Overall, literature supports an association between gut dysbiosis and AD, but longitudinal, causal, and strain-resolved evidence remains limited.

This is a narrative review. The authors synthesize findings from animal models, human observational cohorts, randomized controlled trials, and meta-analyses on gut microbiota composition, microbial metabolites, gut–brain communication pathways, and diet- or microbiome-targeted interventions related to AD. No formal systematic search strategy or risk-of-bias assessment is reported.

- Animal models: AD transgenic mice show early and progressive gut microbiota alterations. Antibiotic perturbation, germ-free status, and fecal microbiota transplantation experiments indicate microbiota can exacerbate or ameliorate amyloid/tau pathologies and cognition. Transferring young-donor microbiota to aged mice attenuates age-associated cognitive deficits. - Human cohorts: Consistent β-diversity differences between AD/MCI and controls; taxa shifts commonly include increases in Bacteroidetes, Blautia, Bacteroides and decreases in Firmicutes/Actinobacteria and butyrate producers; some taxa correlate with CSF AD biomarkers. Shotgun metagenomics reveals reduced key butyrate-producing species and links to the P-glycoprotein anti-inflammatory pathway in AD. - Mechanisms of gut–brain interaction: Neuronal (vagus nerve, ENS), immune-mediated (cytokines crossing a more permeable BBB; T helper 1 activation; microglial M1 polarization), and metabolic signaling (microbial metabolites) converge to influence neuroinflammation, amyloid/tau, synaptic plasticity, and behavior. - Microbial metabolites: • SCFAs (acetate, propionate, butyrate) regulate host gene expression (e.g., HDAC inhibition), cross the BBB, and reduce neuroinflammation; butyrate supplementation improved memory and reduced amyloid in AD mice; SCFA-enhancing probiotics (e.g., B. breve CCFM1025) improved behavior and inflammation. • Amino acids: AD is associated with altered serum AAs (e.g., phenylalanine, isoleucine, arginine); tryptophan metabolism (serotonin and kynurenine pathways) relates to cognition and inflammation; peripheral 5-HTP can cross BBB; effects may be causal or biomarker-related. • Polyphenols: Poorly absorbed parent compounds are metabolized by microbiota into bioactive metabolites that reach the brain; grape seed extract, EGCG, resveratrol, and other polyphenols reduce amyloid/tau aggregation and improve cognition in models; a human RCT with EGCG plus cognitive training improved outcomes in Down syndrome. • Bile acids: Secondary bile acids (microbiota-modified) are detected in AD brains; altered bile acid profiles correlate with cognitive decline and AD/MCI biomarkers; bile acids act via nuclear and GPCR receptors and can cross the BBB. • Neurotransmitters and polyamines: Microbiota modulate 5-HT and GABA; altering neurotransmitter levels via probiotics can affect behavior and cognition in models; polyamines (putrescine, spermidine, spermine) rise in AD brains and can be modulated by probiotics and diet to influence inflammation and memory. - Dietary components and patterns: • Fats: Omega-3 PUFAs enrich beneficial/SCFA-producing taxa and protect against AD-related pathology in models; cohort and interventional data suggest benefits, though effects may vary by APOE ε4 status, dose, and duration. • Carbohydrates: High sugar associates with dysbiosis and cognitive decline; dietary fibers increase SCFAs and benefit cognition via microbiota fermentation. • Proteins: Animal proteins may increase neurotoxic metabolites and cognitive risk; plant proteins associate with lower AD prevalence and promote beneficial taxa. • Vitamins: A, D, E, and B vitamins relate to microbiota composition and cognitive outcomes; evidence is mixed for vitamin D in AD progression; mechanisms include immune modulation and antioxidant effects. • Polyphenol-rich foods (blueberries, grape seed, green tea) modulate microbiota and reduce inflammation; resveratrol upregulates BDNF and reduces Aβ burden in models. • Dietary patterns: Mediterranean, DASH, MIND, and ketogenic diets show associations with better cognition or slower decline. Meta-analyses report that high adherence to the Mediterranean diet associates with 17% lower MCI and 40% lower AD risk; MIND diet shows strong, sometimes superior, associations. Ketogenic interventions (including kMCT ~30 g/d for 6 months) improved cognition in MCI; microbiome changes (e.g., Akkermansia, Parabacteroides) link to increased hippocampal GABA/glutamate in seizure models and improved CSF AD biomarkers in MCI. - Microbiome-targeted interventions: • Probiotics: RCTs/meta-analyses indicate cognitive benefits particularly in MCI, with strain-specific effects and inconsistent microbiome shifts. • Prebiotics: Inulin, FOS, mannan-oligosaccharides, and others improved cognition, reduced Aβ, and modulated microbiota/SCFAs in AD models; human trials are lacking. • Synbiotics: Small RCTs suggest cognitive and anti-inflammatory benefits (e.g., kefir in AD).

The compiled evidence supports a bidirectional relationship between gut microbiota/metabolites and AD-related brain processes. Microbiota disruptions in AD correlate with immune activation, BBB permeability, and neuronal dysfunction; manipulating microbial composition and metabolites through diet, probiotics, prebiotics, synbiotics, and specific dietary patterns can modulate neuroinflammation, amyloid/tau dynamics, and synaptic/behavioral outcomes. SCFAs, tryptophan derivatives, bile acids, neurotransmitters, and polyamines emerge as plausible mediators linking diet and microbiota to brain function. Although much of the mechanistic and interventional evidence arises from animal models, early human data (dietary patterns, ketogenic interventions, selected probiotics, and metagenomics) indicate translational potential. These findings address the review’s central question by delineating pathways that connect dietary nutrients to AD via the microbiota, highlighting targets (e.g., butyrate producers, bile acid signaling, tryptophan metabolism) for preventive or adjunctive strategies. The clinical significance lies in the prospect of accessible, modifiable interventions that could delay cognitive decline, especially in at-risk or early-stage populations (e.g., MCI), while acknowledging the need for personalization (e.g., APOE genotype) and rigorous trials.

Dietary nutrients and microbiome-derived metabolites are key modulators of brain function relevant to AD. The review consolidates evidence that gut dysbiosis is associated with AD in animals and humans and that multiple gut–brain pathways (neuronal, immune, metabolic) mediate effects on cognition and neuropathology. It identifies promising avenues for intervention through dietary components (fibers, omega-3 PUFAs, vitamins, polyphenols), dietary patterns (Mediterranean, DASH, MIND, ketogenic), and microbiome-targeted strategies (probiotics, prebiotics, synbiotics). Future research should prioritize: longitudinal, strain-resolved, multi-omics human studies to establish causality; mechanistic trials targeting specific metabolites (e.g., SCFAs, bile acids, tryptophan derivatives, polyamines); personalized approaches considering host genetics (e.g., APOE) and disease stage; standardized dosing, duration, and outcome measures; and well-powered RCTs to translate preclinical findings into clinical guidelines.

- Predominance of cross-sectional human studies limits causal inference; few longitudinal, large-scale cohorts exist. - Geographic concentration of cohorts (e.g., China, United States) may limit generalizability across populations and diets. - 16S rRNA studies lack strain-level resolution; functional effects may be strain-dependent, necessitating shotgun metagenomics and multi-omics. - Heterogeneity in analytical pipelines (α/β-diversity metrics, sequencing platforms) complicates comparisons across studies. - Many mechanistic insights derive from animal models; human translational evidence remains sparse for specific metabolites and pathways. - Interventional variability (strain selection, dosing, duration, disease severity) and microbiome resilience can attenuate or obscure effects. - Unclear necessity for generalized versus personalized microbiome-based interventions (e.g., APOE genotype, inflammatory status). - Compliance challenges for long-term dietary interventions; safety and tolerability (e.g., ketogenic diet adverse events) require careful monitoring. - Mixed findings for certain interventions (e.g., vitamin D), underscoring need for standardized, well-designed RCTs.