The gut-brain connection: probiotic supplementation to alleviate cognitive decline and inflammation in rodent models of pretangle tau and stress

Flynn, Cassandra M. (2025) The gut-brain connection: probiotic supplementation to alleviate cognitive decline and inflammation in rodent models of pretangle tau and stress. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

The microbiota-gut-brain axis is a crucial link to peripheral and central nervous systems, with gut health implicated in health and disease, including Alzheimer’s disease (AD) and stress. The objective of this dissertation is to explore the role of strengthening the gut microbiota in brain health and early-AD pathologies. First, I will investigate the effects of probiotic supplementation on cognitive function, brain inflammation, and gut microbiota composition. We employed a locus coeruleus hyperphosphorylated pretangle tau rat model, which closely resembles preclinical AD. Rats with pseudophosphorylated human tau in the LC showed deficits in spatial and olfactory learning, increased microglia and astrocyte activity, blood-brain barrier (BBB) leakage, and elevated peripheral inflammation. Probiotic supplementation increased gut microbiome diversity, optimized bacterial composition, and ameliorated cognitive deficits. A reduction in inflammation and glycogen synthase kinase 3 beta (GSK-3β) activity in the hippocampus of female rats was observed, suggesting gut health modulation as a potential therapeutic strategy in preclinical AD, and providing a possible mechanism underlying AD sex differences. Second, I examined the effects of probiotics prior to chronic stress or enrichment on cognitive function and brain health. Probiotics prevented stress-induced spatial memory impairments and enhanced learning under enrichment conditions. We propose this is linked to increased gut microbiome diversity and eubiosis, which was observed in our animals. Probiotics prevented increased levels of the microglia marker ionized calcium-binding adaptor molecule 1 (Iba-1) found in stressed rats and showed differences in BBB integrity and tyrosine hydroxylase (TH) levels in the hippocampus between stress and enrichment groups, with beneficial effects observed in enriched animals. These findings highlight the potential of probiotics to enhance cognitive function and brain health through modulation of the gut microbiota, offering a non-invasive therapeutic approach for AD and stress-related cognitive decline.

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