Investigation of microbial-derived metabolites as risk factors and key mediators of the microbiota-gut-brain axis in early cognitive decline and dementia.

Connell, Emily (2025) Investigation of microbial-derived metabolites as risk factors and key mediators of the microbiota-gut-brain axis in early cognitive decline and dementia. Doctoral thesis, University of East Anglia.

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Abstract

Emerging evidence suggests that the microbiota-gut-brain axis, a bidirectional communication system between the gut, its microbiota, and the central nervous system (CNS), may influence cognitive health and disease. Microbial-derived metabolites are key mediators of this communication, triggering physiological responses directly and indirectly influencing CNS function. Dysregulation of this system can promote cytotoxic metabolite production, neuroinflammation and cognitive decline. However, the exact mechanisms remain undefined. Here, we investigate the role of microbial-derived metabolites as potential risk factors and modulators of early cognitive decline. Using a targeted metabolomics approach, we identified six circulatory metabolites as composite predictors of prodromal Alzheimer’s disease (AD), significantly distinguishing healthy individuals from patients with subjective or mild cognitive impairment. Multi-omics approaches further assessed the influence of dietary patterns on metabolite-mediated communication. Mice consuming a refined low-fat diet (rLFD), low in fibre and high in sucrose and processed carbohydrates, displayed significant gut microbial dysbiosis and colonic and neuronal bile acid dysmetabolism. Neuronal TCA concentrations inversely correlated with neuroinflammatory gene expression (NFκB1), suggesting a rLFD may promote detrimental neuronal processes. Conversely, we evaluated the protective benefits of a (poly)phenol-rich extract (Memophenol™) in a mouse model of chronic low-grade inflammation. Memophenol™ prevented LPS-induced increases in uremic toxins, indoxyl sulfate and TMAO, which coincided with shifts in Romboutsia and Desulfovibrio, respectively, and the expression of neuronal tight junction protein ZO-1, indicating a novel protective role. Finally, we assessed the efficacy of Neurosyn240, a Mediterranean diet-inspired supplement, as an early intervention against prodromal AD progression in 5xFAD mice. Neurosyn240 increased peripheral serotonin concentrations, which positively correlated with Bifidobacterium abundance, and negatively with hippocampal Iba-1+ microglia density. Neurosyn240 decreased LCA concentrations, which inversely correlated with Parvibacter, and was associated with reduced hippocampal amyloid deposits, highlighting novel microbiota-gut-brain axis connections. These results support a significant role for microbial-derived metabolites in early AD progression.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	08 May 2025 08:04
Last Modified:	08 May 2025 08:04
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99207
DOI:

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