The gut microbiota plays a critical role in modulating immune responses through microbial metabolites and neuroinflammatory pathways.¹⁷ Dysbiosis is linked to altered gut homeostasis and facilitates the invasion of bacteria and their metabolite products, LPS, into circulation. LPS, an endotoxin derived from gram-negative bacteria, is a potent activator of neuroinflammation. Lipopolysaccharides binding protein (LBP), an acute phase protein, is also identified as an inflammatory biomarker of bacterial translocation from the gut in AD.¹⁸ Persistent exposure to LPS and dysregulated LBP activity result in BBB disruption, and their infiltration into the CNS by inflammatory mediators increases neurodegeneration. In mice models, a demonstration of systemic LPS administration showed the activation of the microglial cells by binding to the TLR4 receptor. This interaction triggered the downstream signaling of nuclear factor kappa B (NF-κB) and the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 by promoting Aβ deposition and tau phosphorylation.¹⁹ Both human and murine studies showed a positive correlation between elevated LPS levels and neuronal damage, memory deficits, and cognitive decline.²⁰ Numerous studies have shown a higher abundance of Bacteroides fragilis, Escherichia coli, and Firmicutes-associated species (e.g., Clostridium perfringens) in AD patients, contributing to elevated serum LPS levels and cognitive decline (Figure 1).^21,22

In contrast, beneficial microbes such as Lactobacillus and Bifidobacterium produce metabolites, particularly SCFAs butyrate, acetate, and propionate that exhibit anti-inflammatory functions. Studies have shown that supplementation with Lactobacillus and Bifidobacterium inhibited microglial activation and release of pro-inflammatory cytokines through SCFA production.²³ Similar studies also found butyrate attenuated neuroinflammatory markers by decreasing NF-kB signaling and preventing neurodegeneration in AD.²⁴ Disruption of dysbiosis not only enhances systemic inflammation but also accelerates amyloid plaque deposition and tau phosphorylation. Immune cells over and under-activation by microbial imbalance is proposed as a critical pathway in the AD progression.

Aβ plaques and tau tangles accumulation in the brain are directly correlated with the severity of dementia.³⁰ Recent studies suggest microbiomes and their metabolite’s potential role in regulating the production and deposition of these pathological proteins.³³ A study was done on gut microbiota-derived metabolites, phenyl-γ-valerolactones, which significantly inhibited proteasome activity and enhanced autophagy by decreasing levels of intra and extracellular Aβ (1-42) peptides in cultured neuronal cells.³⁴ Another study showed a shift in gut microbiota composition and diversity and a reduction in Aβ plaque deposition after long-term broad-spectrum antibiotic treatment in the APP_SWE/PS1_ΔE9 mouse model of AD. Furthermore, microbiome changes were linked with altered levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, as well as chemokines such as C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 10 and reduced glial reactivity, suggesting dysbiosis can impact Aβ amyloidosis and neuroinflammation by regulating host immunity.³⁵ It supports the notion that frequent antibiotic usage may increase the risk of AD development. SCFAs (butyrate, acetate, and propionate) are produced by gut bacteria during the metabolism of dietary fibers such as inulin, resistant starch, and pectin. These SCFAs have been shown to have neuroprotective effects against AD by interfering with the formation of soluble toxic Aβ aggregates in vitro.³⁶

Similarly, in rTg4510 mice (expressing the TauP301L mutation), LPS significantly ameliorated tau phosphorylation at Ser 199/202 and Ser396 but did not affect mature tangle formation and simultaneously cleared pre-existing Aβ deposits.³⁷ The dual effect of LPS could explain the limited efficacy of anti-inflammatory therapies in treating dementia.³⁸ A recent study highlighted a relationship between specific gut metabolites and tau pathology by employing advanced system biology to analyze 1.09 million metabolite protein pairs involving 408 human G-protein-coupled receptors (GPCRs) and 335 metabolites.³⁹ Results demonstrated that gut microbial metabolites phenethylamine and agmatine are potential modulators of tau pathology via GPCR interaction, reducing tau hyperphosphorylation in AD-derived neurons.⁴⁰ Agmatine has also been shown to have neuroprotective effects through NOS inhibition and NMDA receptor modulation, reducing oxidative stress and neuroinflammation associated with tau aggregation.⁴¹ As a neuromodulator, it is believed that PEA interacts with TAAR1 receptors, modulating dopaminergic and serotonergic pathways to regulate tau phosphorylation through a cAMP/PKA pathway.⁴² Though these findings suggest a gut-brain connection with tau accumulation, the exact molecular mechanisms of neuronal damage connecting dysbiosis to tau-related neurodegeneration remain underexplored.

Probiotics are live-active organisms that maintain or restore the natural balance of the gut microbiome when consumed in adequate amounts. Prebiotics, on the other hand, are non-digestible fibers or oligosaccharide substrates that promote the growth, survival, and function of beneficial gut bacteria.⁴³ Probiotics such as Lactobacillus rhamnosus GG and Bifidobacterium breve and prebiotics like fructooligosaccharides (FOS) and galactooligosaccharides (GOS) have attracted significant attention as a potent therapeutic tool in AD by suppressing neuroinflammation.⁴⁴ However, evidence demonstrating pro/prebiotics therapeutic efficacy in mitigating AD symptoms is not widely available.

Over the years, the gut-resorting neuroprotective effects of numerous probiotics have been investigated. A multi-strain probiotic, VSL#3 is composed of a mix of eight species of bacteria—Lactobacillus species (Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus), Bifidobacterium species (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis), and Streptococcus thermophilus. This particular formulation of seven strains has been shown to restore the balance of gut microbiota, maintain the integrity of the intestinal barrier, and also decrease systemic inflammation.⁴⁵ The different strains in VSL#3 are believed to synergistically enhance the gut-brain interaction, providing a therapeutic advantage for neurodegenerative diseases such as AD.⁴⁶

SLAB51, one specific strain of probiotics, has been explored for its potential neuroprotective effects in models of AD. It is a strain of Lactobacillus that was originally isolated from human gut microbiota and has been shown to impact the balance of the gut microbiome. SLAB51 can also affect neuroimmune interactions that play a central role in AD pathology.⁴⁷ Previous studies showed the utility of SLAB51 probiotics in reducing brain damage in 3xTg-AD mice by increasing gut microbiota homeostasis, lowering Aβ plaque, and enhancing cognitive symptoms.⁴⁸

A systematic review of the role of Lactiplantibacillus plantarum in AD animal models and its use in humans showed a limited number of studies.⁴⁹ Overall, L. plantarum supplementation attenuated neuroinflammation, influenced gut microbiota composition with a rise in numerous beneficial Lactobacillus and Bifidobacterium populations, increased beneficial gut bacteria, restored balance of gut microbiota, and decreased Escherichia coli and Clostridium perfringens. This microbial shift resulted in lesser production of LPS along with enhancements in memory and learning abilities.⁵⁰ Multiple studies found that Bifidobacterium longum breve A1 probiotic consumption is useful for ameliorating AD symptoms. A clinical study of elderly patients with mild cognitive impairment showed that memory function, especially immediate and delayed recalling of tasks, significantly improved after Bifidobacterium longum breve A1 supplementation (12 weeks) compared with the placebo group. Further, supplementation was linked to decreased amounts of inflammatory cytokines, indicating a neuroprotective function in A D pathology.⁵¹

Many prebiotic dietary fibers, such as FOS, inulin, GOS, and resistant starches, have been shown to produce neuroprotective effects in AD.⁵² In pre-clinical AD models, the administration of inulin—a prebiotic mediator for beneficial bacteria such as Bifidobacteria and Lactobacilli—in female APOE4 mice showed a decrease in Escherichia coli and inflammation pathways by restoring alpha diversity. Contrarily, male APOE4 mice showed less pronounced improvement in SCFAs-producing bacteria, suggesting a sex-specific dietary response to inulin.⁵³ Additionally, studies found the positive effect of synbiotic treatment (a combination of Lactiplantibacillus plantarum and inulin) in the AD model by improving Aβ clearance, reducing tau proteins, and boosting cognitive functions (Figure 3).⁵⁴

Building on these findings, researchers are now exploring advanced genetic approaches to enhance gut microbiome modulation. Furthermore, investigations are also in progress for applying CRISPR-Cas9 technology to edit specific bacterial species of the microbiome to combat dysbiosis in AD.⁵⁵ Future studies should employ CRISPR-Cas9 to enhance the production of beneficial microbes, improve gut integrity, and possibly reduce neuroinflammation.⁵⁶ Such genetic modification also has the potential as an adjunct-based non-drug therapeutic approach to restore microbiome balance in the gut that can help effectively alleviate AD symptoms.^57,58

FMT is an ancient treatment method that involves transferring fecal material from a healthy donor into the GI tract of a recipient in order to restore dysbiosis.⁵⁹ Since 1958, after the application of FMT in treating Clostridioides difficile infection-associated enterocolitis, researchers are increasingly investigating its potential in AD therapeutics.^60,61

Pre-clinical studies have demonstrated that FMT done from healthy wild-type mice into ADLP_APT transgenic models showed restoration of gut homeostasis and reduction in the formation of Aβ plaques and neurofibrillary tangles, leading to cognitive improvement.³³ Mechanistically, this was associated with upregulation of tight junction proteins (e.g., occludin and claudin-5), reduced expression of pro-inflammatory cytokines (e.g., TNF-α, IL-1β), and modulation of microglial activation. A pilot study of human patients with cognitive decline showed that FMT normalized gut microbial composition with a decrease in Proteobacteria and Bacteriodetes and an increase in protective bacteria such as Firmicutes and Actinobacteria. These changes were associated with lower levels of systemic inflammation, lower pro-inflammation cytokines (TNF-α, IL-6), and improved cognition and quality of life.⁶² Clinical trials exploring the effectiveness of FMT, particularly targeting AD dysbiosis, are in the early stages, but preliminary data is encouraging.