In a review published in the Experimental & Molecular Medicine journal, researchers discussed the current evidence of the role of gut microbiota in Alzheimer’s disease (AD) pathogenesis.
Additionally, they reviewed potential microbiota-based therapies that could help with AD management in the future.
Study: Current understanding of the Alzheimer’s disease-associated microbiome and therapeutic strategies. Image Credit: TopMicrobialStock/Shutterstock.com
Background
AD is a progressive neurodegenerative disease characterized by early extracellular deposition of the amyloid-beta (Aβ) plaques and intracellular formation of neurofibrillary tangles of hyperphosphorylated tau protein in the brain.
Its other pathophysiological hallmarks are neuroinflammation, synaptic dysfunction, and metabolic dysregulation.
Given the lack of understanding of the complex biological processes involved in AD, significant challenges remain in developing its effective treatments.
Studies reporting the association between the gut microbiome and AD in human subjects and animal models emerged in the past decade.
They proposed multiple mechanistic hypotheses to explain the role of microbiota in AD, for instance, their involvement in the production and clearance of Aβ plaques.
Yet, several knowledge gaps remain, and this complex interaction is not fully understood.
Thus, while it might be feasible to target the gut microbiota as a therapeutic strategy for AD, its real-world application in clinical settings would require more rigorous research efforts in the future.
The gut microbiota and AD pathology
In 2017, two studies analyzed fecal samples of patients with AD and without a diagnosis of dementia due to AD.
Cattaneo et al. measured the abundance of six types of bacteria using quantitative PCR, while Vogt et al. used 16S rRNA gene sequencing.
The former study results revealed a significant decline in the abundance of pro-inflammatory bacteria, such as Escherichia/Shigella, in the stool of AD patients and a lower number of anti-inflammatory bacteria, specifically Eubacterium rectale, compared to controls.
Vogt et al. discovered a decreased diversity of gut microbiota in AD patients compared to controls. Accordingly, Firmicutes phyla were less, and Bacteroidetes were more abundant in the gut microbiome of AD patients.
Recent studies have also shown that individuals with mild cognitive impairment (MCI) and in the preclinical stage of AD can have distinct gut microbiota compositions compared to controls.
These findings, including from studies using AD animal models, have remained inconsistent given the differences in study design, patient populations, lifestyles, dietary habits, and the techniques used for RNA sequencing.
Future research efforts should focus on standardizing methodologies, using larger sample sizes to increase the statistical power and reliability of the findings, especially the taxonomic signature of microorganisms associated with AD.
It could help understand the functional activities and interactions of the gut microbiota in AD patients beyond their taxonomic composition, which involves studying the small molecules produced by the microorganisms and their impact on AD pathologies.
The role of the microbiota in AD has progressed in two directions:
(1) Direct microbial infection in the central nervous system (CNS)
It is challenging to prove the infectious hypothesis of AD due to the long period between Aβ deposition and dementia onset.
However, studies suggest CNS infections can originate from the gut, contributing to AD pathologies.
For instance, peripheral amyloid protein may promote its accumulation in the brain through retrograde transport via the vagal nerve or bloodstream.
(2) Indirect pathways
These involve the peripheral immune and metabolic systems. For instance, aberrant glial cell activity accelerates AD progression by disrupting brain homeostasis.
Nonglial mechanisms, such as amyloid-clearing enzymes and disrupted gut permeability, may also contribute to the interaction between gut microbiota and brain innate immunity.
Notably, short-chain fatty acids (SCFAs), derived from the fermentation of dietary fibers by gut bacteria, play a role in these interactions.
In healthy humans, SCFAs regulate brain innate immunity, the production of cytokines by immune cells, provide energy to cells, and support the intestinal barrier.
SCFAs also function indirectly via peripheral immune cells and directly modulate microglial cellular functions through epigenetic and mitochondrial mechanisms.
In neurological diseases like AD, SCFAs can promote neuroinflammation and disease progression, with each type of SCFA having a unique effect and mechanism of action.
In addition to SCFAs, trimethyl-amine N-oxides (TMAO), lipopolysaccharides (LPS), tryptophan, and bile acids have been implicated in AD clinical studies; however, their specific role in AD pathology remains elusive.
The apolipoprotein (APOE) genotype, a genetic risk factor for AD, likely influences the gut microbiota composition.
Moreover, environmental factors and diets may contribute to its variations across APOE isoforms.
Future studies should investigate the specific mechanisms by which APOE alleles modulate the gut microbiome.
Studies have also shown how antibiotic-induced disturbances in the gut microbiota reduced AD pathologies in male but not in female animals (sex-related differences); however, its underlying mechanisms are not well-understood.
Effect of other microbes on AD pathology
Recent studies have indicated that the lung and oral cavity inhabiting microbes might influence AD pathology.
For instance, Maurer et al. observed that P. gingivalis was more frequent in the oral cavity of AD patients with periodontitis than controls.
Another recent study revealed that LPS-producing lung microbiota exacerbated multiple sclerosis, an autoimmune disease of the CNS, in animal models.
Thus, understanding the impact of specific antibiotic treatments on non-GI microbiota is also crucial.
Moreover, other microorganisms in the gut, such as fungi, protozoa, archaea, and viruses, have received less attention, given they are less abundant than bacteria, and studies focused on microbiome analysis used bacterial 16SrRNA gene sequencing. They likely affect AD pathology by interacting with the bacterial communities.
Therapeutic strategies for AD
The use of antibiotics after the onset of AD pathology is not very effective. However, an epidemiological study conducted recently in Germany by Rakusa et al. found a decreased likelihood of dementia with prior antibiotic use.
Studies have shown that fecal microbiota transplantation (FMT) can reduce the formation of Aβ plaques and tau pathology, improve cognitive impairment, and delay cognitive decline in AD patients.
There was a case report where an 82-year-old male AD patient with Clostridioides difficile infection (CDI) underwent a single FMT infusion and showed improvement in AD symptoms within two months.
The potential benefits of probiotics in AD are in the nascent stages of investigation.
However, several preclinical studies have explored the effects of probiotics (e.g., Bifidobacterium breve) in animal models and AD patients, showing promising improvements in cognitive function and reduction in amyloid-β plaques.
However, high levels of SCFAs, which may be used as postbiotics, may be detrimental to AD patients rather than beneficial.
Future studies should focus on finding the specific effects of dietary fiber pre-, pro-, and post-biotics on AD pathologies.
Conclusions
Different individuals share approximately 10–20% of the gut microbiome; however, even microbial species from distinct phylogenetic lineages can contribute to similar functional activities within the gut network.
This functional redundancy raises the importance of studying the functional activity of the gut microbiota and their overall composition, diversity, stability, and interactions.
A comprehensive understanding of the mechanistic pathways connecting the gut microbiota to AD pathology is crucial to ensure the safety and efficacy of treatments such as antibiotics, prebiotics, probiotics, postbiotics, and FMT.
The effect of microbiota on host physiology, immunology, metabolism, and biological factors, such as genes and sex, must also be considered.
Therefore, it remains challenging to identify one pathway in the “microbiota-gut-AD brain” axis.
Nonetheless, approaches involving microbial encapsulation, bacteriophages, microbial enzyme modulators, and other bioengineered microbes are emerging and could lead to more targeted AD interventions in the future.
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