Several studies have indicated that gut dysbiosis, which is defined as alterations in the gut microbiome, contributes to neurodegeneration and the pathogenesis of Alzheimer’s disease (AD). These studies have demonstrated the existence of a complex bidirectional relationship between AD and the intestinal microbiome, which also underlines the possibility of developing preventive strategies against the manifestation of the disease by altering the intestinal microbiome.
In a recent study in Neuroscience and Biobehavioral Reviews, scientists review the current literature associated with the role of the gut-brain axis in the pathogenesis of AD.
Study: The gut microbiome and Alzheimer’s disease: complex, bidirectional interactions. Image credit: Naeblys / Shutterstock.com
AD and the gut microbiome
AD is a neurodegenerative disease that mainly affects people over the age of 65. This condition causes behavioral changes, progressive memory loss, cognitive impairment and functional impairment.
AD arises due to abnormal aggregation of extracellular amyloid and neurofibrillary tangles, leading to synaptic dysfunction and neuronal death.
AD has become a global epidemic threat, especially among the elderly. This is due to the lack of effective treatments or preventive measures, as well as the aging of the world’s population. Recently, the onset of sporadic AD has been linked to complex genetic and environmental factors and lifestyle.
Animal and human-based studies have shown that changes in the gut microbiome influence the manifestation of AD pathology. Imbalances in the gut microbiome affect central nervous system (CNS) homeostasis and disease pathogenesis through the gut-brain axis. Imbalances in the gut microbiome can also lead to impairments in neuronal and synaptic activity.
Disease-specific metabolic signatures have been identified for AD and could be used as biomarkers for disease diagnosis. In the current study, the authors gathered evidence supporting the bidirectional relationship between the gut microbiome and AD. To this end, the gut microbiome was shown to cause cognitive impairment and AD pathology progression through several mechanisms, including neuroinflammation, immune dysregulation, as well as amyloid and tau aggregation.
The human gut contains many Gram-positive bacteria such as Lactobacillus, Clostridium and Eubacterium, as well as Gram-negative bacteria such as Bacteroides and Prevotella. Gut dysbiosis leads to abnormal aggregation of brain proteins, immune dysregulation and inflammation. The composition of the gut microbiome can change due to diet, exercise, medication use, or infection.
The drosophila AD model showed that infection with enterobacteria ameliorates AD pathology, as bacterial infection promotes inflammation and immune hemocyte recruitment to the brain, as well as increases tumor necrosis factor (TNF) and c-jun N-terminal kinase (JNK). mediated neurodegeneration.
Several studies have shown that the gut microbiome is associated with the trafficking of interleukin 17 (IL-17)-producing γδ-T cells from the gut to the meninges. This phenomenon stimulates astrocytic release of IL-17, chemokine receptor 6 (CCR6)-mediated neuroinflammation, and synaptic dysfunction.
A previous in vivo mouse study reported intestinal dysbiosis after one month of exposure to ampicillin. This resulted in reduced hippocampal N-methyl-D-aspartic acid (NMDA) receptor expression, impaired spatial memory, and elevated aggression. It should be noted that these pathologies were altered following the introduction of Lactobacillus fermentum to the animal diet.
The use of probiotics such as Bifidobacterium longum has improved the cognitive function of male BALB/c mice. Another study revealed that transplants of fecal microbiota from healthy mice into an AD mouse model led to a reduction in amyloid and tau pathologies and improved cognitive abilities.
Most of the evidence supporting the bidirectional relationship between gut microbiota and AD was obtained from studies with AD transgenic animals. These studies indicated that alterations in the gut microbiome with aging also enhanced the expression of intestinal amyloid precursor protein (APP).
Future perspectives
Underlying cellular mechanisms arising from altered gut microbiota that may subsequently influence AD prognosis include neuroinflammation, gut and blood-brain barrier disturbances, dysregulated immune responses, amyloid and tau aggregation, dysregulation of synaptic function and oxidative stress.
Although several gut modulation modalities in preclinical studies showed the potential to decrease AD pathology or improve cognitive abilities, more research is required before these results can be translated into human studies. This is because undesirable changes in the composition of the gut microbiome could improve several neurological outcomes. Furthermore, the effect of gut microbial alterations on AD pathologies may vary significantly between animals and humans.
Many studies identified several confounding factors that are not adequately accounted for, such as age, diet, sex, and comorbidities that limit the translation of preclinical data into human studies. There is also a lack of longitudinal analyzes on the role of the gut microbiome in AD.
Another aspect that limits the translation of these preclinical data to human clinical studies is the relatively low reproducibility of findings between studies. This is due to differences in methodologies and difficulties in controlling environmental factors that influence gut microbial composition and metabolic activity.
In the future, scientists must consider genetic factors that affect the composition and function of the gut microbiome. Further studies are also needed to ensure the safety of gut microbial alterations in humans.
Journal reference:
- Tarawneh, R. and Penhos, E. (2022) The gut microbiome and Alzheimer’s disease: complex, bidirectional interactions. Neuroscience and Biobehavior Reviews. doi:10.1016/j.neubiorev.2022.104814