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- ItemMicrobial regulation of barrier function in the gut-brain axis(University College Cork, 2023) Sánchez Díaz, Paula; Clarke, Gerard; Cryan, John; Leigh, Sarah-Jane; Advancement in Neurosciences (Geneva, Switzerland)The gut microbiome plays a critical role in host health through modulation of gut and blood-brain barrier integrity, responding to factors such as diet, stress, and medication. A key pathway by which the gut microbiota affects gut and bloodbrain barrier integrity is through the production of bioactive metabolites. This thesis explores the role of barriers in the microbiota-gut-brain axis, which are essential for the proper functioning of body systems and homeostasis. Chapter 2 investigates how fermenting infant nutrient formulations with different bifidobacteria strains isolated from infant gut microbiome can influence the integrity of gut and blood-brain barriers in vitro. The study found that the presence of bifidobacteria strains, in some cases, had protective effects on the barriers, and these effects sometimes differed depending on the barrier studied. Chapter 3 explores the effects of indole and two of its derivates, indole-3-acetate and indole- 3-propionate, on gut barrier function in vitro. The results indicate that indole has a protective effect on barrier function, particularly at higher concentrations, and indole-3-acetate has a protective effect at the lowest concentrations tested. Surprisingly, indole-3-propionate was not protective and at higher concentrations exacerbated the effects of LPS-induced disruption. Finally, Chapter 4 focuses on the effect of cancer therapy, specifically cisplatin, on gut and blood-brain barrier structure in mice, to further explore the role of gut microbiome in cancer-related cognitive impairment. The study used mice treated with cisplatin to investigate the expression of genes involved in the structural function of barriers and inflammation, as well as gene expression of receptors activated by microbial ligands in the ileum, colon, and hippocampus. The results showed that cisplatin affected gene expression in a region- and dose-dependent manner, leading to changes in anxiety-like and fatigue behaviours in mice. Overall, this research highlights the critical role of the gut microbiome in gut barrier and blood-brain barrier function. Microbial metabolite supplementation may present a useful therapeutic option for disease processes involving disruption of the gut and/or blood-brain barriers.