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

Susan Westfall, Umar Iqbal, Maria Sebastian, Giulio Maria Pasinetti

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

28 Scopus citations


The amyloid hypothesis of Alzheimer's disease (AD) has become outdated as researchers and clinicians recognize that lifestyle factors and environmental stressors have a greater impact on the etiology of AD than genetic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.

Original languageEnglish
Title of host publicationMolecular Biology of Neurodegenerative Diseases
Subtitle of host publicationVisions for the Future, Part A
EditorsDavid B. Teplow
PublisherElsevier B.V.
Number of pages35
ISBN (Print)9780128178744
StatePublished - 2019

Publication series

NameProgress in Molecular Biology and Translational Science
ISSN (Print)1877-1173
ISSN (Electronic)1878-0814


  • Allostasis
  • Alzheimer's disease
  • Gut-brain-axis
  • HPA axis
  • Inflammasome
  • Microglia
  • Neuroinflammation
  • Stress
  • Synbiotic


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