Alzheimer's Disease 19 Mar, 2024 Read Time: 10 mins

Association between the Gut Microbiome & Alzheimer’s Disease

The most prevalent type of dementia, Alzheimer's disease (AD), is a neurodegenerative disorder with several pathological and clinical features. Though the burden on global health is increasing, the development of efficient treatments is hindered by the incomplete understanding of the mechanisms causing disease pathology. The importance of microglia and inflammation in brain function has led to the discovery that neuroinflammation is a crucial aspect of AD1.

The onset and development of AD have been connected to neuroinflammation. It has been demonstrated that the gut microbiome (GMB), which is made up of trillions of bacteria, viruses, archaea, protozoa, and fungi, may control neuroinflammation in several neurological disorders, including AD2. There is evidence linking the progression of AD to the gut microbiota3. It has been claimed that the microbiota-gut-brain axis (MGBA), a two-way communication mechanism linking neurological, immunological, endocrine, and metabolic pathways, is how the human gut microbiota influences behavior and brain function1.

The onset and development of AD have been connected to neuroinflammation. It has been demonstrated that the gut microbiome (GMB), which is made up of trillions of bacteria, viruses, archaea, protozoa, and fungi, may control neuroinflammation in several neurological disorders, including AD2.

Association Between the Gut Microbiome and Alzheimer's Disease

Microbiome Diversity and Composition

In numerous neurological and psychiatric illnesses, the shifts in the diversity and equilibrium of GMB have drawn significant attention in recent times. Unbalanced GMB composition results from aberrant changes to the gut ecology (dysbiosis). This dysbiotic pattern induces the host to form a microbial community associated with the disease, which can result in bacterial translocation, leaky gut, and the blood-brain barrier (BBB)4. Studies on animals have shown that gut dysbiosis has a role in the etiology of AD5,6. Research conducted in clinical settings has also investigated the composition of GMB in individuals with AD spectrum conditions, such as AD and mild cognitive impairment (MCI)7,8,9,10. It has been reported that several GMB strains are linked to cognitive abilities and neuropsychiatric symptoms in AD patients11.
 

It has been reported that several GMB strains are linked to cognitive abilities and neuropsychiatric symptoms in AD patients11.

The fact that GMB composition varies by nation is a fascinating observation. For example, a prior U.S. study revealed that patients with AD had changed GMB, with reduced Actinobacteria and increased Bacteroidetes at the phylum level10. Zhuang et al., on the other hand, showed the reverse outcomes in Chinese AD patients (that is, decreased Bacteroidetes and increased Actinobacteria 12. Furthermore, it has been noted that people with AD and MCI have differing levels of intestinal dysbiosis. The majority of the research to date has shown that, in comparison to older persons in good health, patients with AD—but not MCI—exhibited noticeably lower GMB diversity9,10,11. Nonetheless, a study found that patients with MCI and AD had comparable GMB diversity and abundance8.

Inflammation and Immune Response

By releasing bacterial toxins and producing metabolites, the gut microbiome has been demonstrated to interact with both the innate and adaptive immune systems13. A growing quantity of evidence suggests that the gut microbiota may be a major factor in oxidative stress and "neuro"-inflammation14. Also, in addition to possibly having direct impacts on cognition and behavior, lower levels of neurotrophic metabolites and the production of psychotropic substances have also been linked to altered microbiota compositions and may play a role in the pathogenesis of AD15. The gut microbiota's homeostasis is primarily regulated by immune cells, and exposure to the wide range of soluble mediators generated there—mostly cytokines and microbiota-related toll-like receptors (TLRs) ligands—causes notable alterations in the host mononucleate phenotype16. By encouraging an inflammatory "inclination" that is most likely a component of the process known as "inflammaging", these modifications contribute to the pathophysiology of AD13.

 

Role of Microbial Metabolites

It has been documented that immunological, endocrine, and metabolic processes connected to the genesis of AD are impacted by changes in the gut microbiota. According to Xi J. et al., substances secreted or affected by bacteria may cause systemic inflammatory reactions known as secondary metabolites, which might damage the blood-brain barrier and accelerate neurodegeneration17.

It has been documented that immunological, endocrine, and metabolic processes connected to the genesis of AD are impacted by changes in the gut microbiota.

The following compounds have been assessed in the pathophysiology of AD by gut microbiota: propionate, isobutyrate, butyrate, valerate, acetate, and formic acid18,19. These metabolites have been demonstrated to affect the pathogenesis of AD by regulating the activations of microglia and astrocytes, which helps to reduce inflammation and amyloid-beta and tau aggregations18,19. Without a doubt, the two most important markers of AD pathogenesis are tau and amyloid-beta depositions. It was investigated how short-chain fatty acids (SCFAs) affected amyloid-beta aggregation18. According to a study by Ho and colleagues using a photo-induced cross-linking of unmodified proteins protocol, amyloid-beta 40 oligomerization was reduced in a concentration-dependent manner by valerate, butyrate, and propionate28. A gamma-aminobutyric acid (GABA) homolog called valerate was described in order to identify the strongest inhibitory effect. However, research has demonstrated that acetic acid, isobutyric acid, and isovaleric acid had no noticeable impact on the synthesis of multimeric amyloid-beta peptide20.

 

Therapeutic Interventions and Biomarkers

Understanding the role of the gut microbiome in Alzheimer's disease opens new avenues for therapeutic intervention, including microbiome modulation through diet, probiotics, and fecal microbiota transplantation. It also highlights the importance of maintaining gut health as a preventive strategy against neurodegenerative diseases.
 

Understanding the role of the gut microbiome in Alzheimer's disease opens new avenues for therapeutic intervention, including microbiome modulation through diet, probiotics, and fecal microbiota transplantation. It also highlights the importance of maintaining gut health as a preventive strategy against neurodegenerative diseases.

Probiotics are live beneficial microbes, typically containing Lactobacillus and Bifidobacterium, aimed at improving gut microbiota dysbiosis and reducing illness severity when ingested orally21. Prebiotics, on the other hand, are non-digestible substrates that nourish beneficial gut bacteria. Both probiotics and prebiotics have shown effectiveness in Alzheimer's disease (AD) 2.

Probiotics and prebiotics show promise in AD models and some human trials.

Probiotics and prebiotics show promise in AD models and some human trials. In mouse models, prebiotic mannan oligosaccharide and prebiotic R13 improved cognitive deficits, reduced Aβ plaques, and altered gut microbiota22. Human trials with probiotics have shown mixed results: one trial reported cognitive improvement and reduced oxidative stress, while another did not show cognitive changes23. Probiotics like Bifidobacterium breve A1 improved cognition in patients with mild cognitive impairment24. Combined with selenium supplementation, probiotics enhanced cognitive scores and reduced inflammation markers in AD patients25,26.

Combined with selenium supplementation, probiotics enhanced cognitive scores and reduced inflammation markers in AD patients25,26.

Potential connections between the GMB and AD pathology include diet, sleep, and exercise: Diet significantly influences GMB composition and is associated with AD risk27,28. Mediterranean and ketogenic diets show promise in reducing AD pathology29,30,31. Sleep disturbances are common in AD and may affect AD progression32. Disrupted sleep patterns correlate with GMB changes, suggesting a bidirectional relationship33,34. Exercise is protective against AD-related cognitive decline and influences GMB composition35,36.

Conclusion

In conclusion, while the role of the gut microbiome in Alzheimer's disease is an area of intense research interest, it is still in its early stages. Continued research is necessary to unravel the complex interactions between the gut microbiome and the brain and to translate these findings into effective interventions for Alzheimer's disease prevention and treatment. Studying the interconnections between diet, sleep, exercise, and the GMB could offer insights into AD pathogenesis and aid in developing novel therapeutic strategies.

 

References

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Author

Amelia Nur Vidyanti, MD, PhD & Fitri Rahmawati, MD

Indonesia