A Seed and Soil Model for Gut Microbiome Aging to Contribute to Alzheimer's Disease

It is becoming clear that characteristic age-related changes in the composition of the gut microbiome accompany specific age-related diseases, and may well be contributing meaningfully to the development of those conditions. At the very least, the aged gut microbiome creates chronic inflammation, and that unresolved inflammatory signaling is disruptive to cell and tissue function throughout the body. There may be many other meaningfully involved mechanisms, however, such as changes in metabolite production. Many microbial metabolites have a beneficial effect on cell function, such as butyrate, and are known to decline with age.

The gut microbiota is critical for host protection against pathogens, immune development, and metabolism of dietary nutrients and drugs. In healthy individuals, the gut microbial composition is established early in life and remains relatively stable over time. Nevertheless, this ecosystem may become destabilized as a result of aging, environmental factors, and lifestyle habits such as diet. Shifts in gut microbial composition and diversity (i.e., gut dysbiosis) have been reported to influence neuroimmune and neuroendocrine functions through a bottom-up fashion resulting in neuroinflammation, microglial dysregulation, and aberrant protein aggregation in the Alzheimer's disease (AD) brain. Accordingly, this dysbiotic condition may set the stage for a toxic brain environment that stimulates AD neuropathophysiology, including the deposition of amyloid-beta (Aβ) plaques and neurofibrillary tangles.

The relationship between disruptions in the microbiota-gut-brain axis and AD can be explained by the Seed and Soil Model of Neurocognitive Disorders. Based on this model, the "seed" represents a predisposition to a neurocognitive disorder (e.g., genetic profile) and the "soil" refers to factors that moderate the expression of that seed. Together, the seed and the soil ultimately determine whether a person will develop the disorder. This model was created to explain why some people who are predisposed to develop neurocognitive disorders do not develop them. Although this model did not originally apply to the microbiota-gut-brain axis, the concept is general enough that it can be applied to many new contexts as ideas evolve.

In the case of AD and the microbiota-gut-brain axis, the seed could represent a polygenic risk score or family history of AD, whereas the soil could be represented by certain dysbiotic taxa. Dysbiotic taxa can contribute to many consequences including altered intestinal permeability that leads to a leaky gut and fosters the activation of local and distant immune cells. Given that the metabolites of gut leakiness are linked to increased permeability of the blood-brain barrier, these dysfunctions promote the translocation of bacterial endotoxins from the gut to the brain and increase inflammation within the system. According to the Seed and Soil Model of Neurocognitive Disorders, this translocation would create a toxic microenvironment in the brain vulnerable to pathogenesis, especially for those with a genetic predisposition to AD.

Consistent with this notion, a recent systematic meta-analysis showed that individuals with AD exhibited less gut microbial diversity than those with mild cognitive impairment (MCI) or healthy controls. Likewise, the gradient changes of abundance from normal cognition to MCI and AD stage were observed in several strains of gut microbiota (i.e., phylum Proteobacteria, family Clostridiaceae, and genus Phascolarctobacterium). Prior evidence also has revealed that gut-derived lipopolysaccharide (endotoxin) acts as an Aβ fibrillogenesis promoter, potentially leading to neuroinflammation and neurodegeneration.

Link: https://doi.org/10.18632/aging.204840