A Gut Microbial Metabolite Alleviates Stress-Induced Neurobehavioral Dysfunction in an Alzheimer's Disease Model

Chronic psychological stress is a known risk factor for neurodegenerative disorders like Alzheimer's disease (AD), but its role in AD neuropathology remains unclear. Using the water-avoidance stress model in the APP/PS1 preclinical mouse model of AD, we investigate how chronic stress exacerbates neurobehavioral dysfunction and cognitive impairment and explore the neuroprotective potential of indole-3-propionate (IPA), a microbiome-derived metabolite, in mitigating these effects. Our findings show that psychological stress leads to depression- and anxiety-like behaviors, as indicated by reduced grooming and exploration behaviors; however, these effects are ameliorated by IPA supplementation. Stress also disrupts the gut microbiome and promotes intestinal inflammation. While IPA does not significantly alter microbiome composition, it mitigates inflammation by normalizing IL-17a and TGF-β gene expression and reducing TNF-⍺ and IL-6 protein levels. Although stress has a limited effect on hippocampal inflammation, IPA suppresses low-grade neuroinflammation by downregulating IL-1β, TNF-⍺, IL-6, and MCP-1 protein levels. Additionally, IPA treatment tends to reduce hippocampal amyloid-β plaques. These findings highlight the detrimental effects of chronic psychosocial stress on AD pathology and suggest that IPA may confer neuroprotection through the gut-immune-brain axis, supporting the therapeutic potential of microbial metabolites in mitigating cognitive decline.