Gut microbiota mediated allostasis prevents stress-induced neuroinflammatory risk factors of Alzheimer's disease

The amyloid hypothesis of Alzheimer's disease (AD) has become outdated as researchers and clinicians recognize that lifestyle factors and environmental stressors have a greater impact on the etiology of AD than genetic predispositions. When persistent over decades, chronic psychological and physical stressors disrupt the body's natural adaptions to stress (allostasis) resulting in a general "wear and tear" on the body termed allostatic overload. Allostatic overload results in hypercortisolemia, disrupted hypothalamic-pituitary-adrenal (HPA) axis regulation, elevated proinflammatory cytokines and chemokines, reduced synaptic plasticity, persistently activated microglia, and importantly, a dysbiotic gut microbiota. This plethora of physiological maladaptations precedes the canonical symptoms of AD, including amyloid-beta plaque accumulation and tau hyperphosphorylation, indicating that a successful therapeutic approach to AD must first alleviate these risk factors. In this chapter, the use of gut microbiota modifying synbiotics, a combination of probiotics and prebiotics, to simultaneously and sustainably alleviate stress-induced AD risk factors is proposed. Synbiotic-derived bioactive metabolites can increase the integrity of the gut epithelial barrier preventing the infiltration of bacterial peptides and other immune-activating substances. These metabolites can also alter the balance of peripheral immune cells toward an anti-inflammatory state, protecting the body against stress-induced inflammatory challenges. These peripheral adaptations ultimately promote cognitive resilience to stress-induced AD by preventing microglia inflammasome activation, reinstating HPA axis negative feedback loops and allowing healthy neurogenic and neuroplasticity processes to ensue. Overall, synbiotics provide a novel treatment paradigm for AD that promote a sustainable allostasis to chronic stress, protecting the brain from the neuropathologies driving AD.