From youth to old age: therapeutic potential of microbiota interventions in the gut-brain-axis

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Minuto, Chiara
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University College Cork
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There is a growing recognition of the involvement of the gut microbiota in the regulation of certain physiological and metabolic parameters across the life cycle of animals. A greater understanding of the microbiota changes throughout the life cycle may provide a novel therapeutic target for treating various age-related disorders from autism in childhood to dementia in old age. The increase in the elderly population with a rapid rise in dementia, cardiovascular and metabolic disease, leads to the growing demand for new interventions to decelerate the senescent decline. However, if the microbiota is to become a therapeutic target a far greater understanding of the structural changes which take place throughout the lifespan is required. In this thesis, we focus attention on microbiota-targeted interventions in young, middle age and old animals. The studies examine behaviour, physiology, and metabolism, exploring effects both in the periphery and in the brain, across a range of treatments from prebiotics to polyphenols. We highlight the physiological differences between the various age groups. Intestinal permeability and neuronal plasticity were the only modifiable parameters in the elderly. In younger animal prebiotics impact metabolism and inflammation. Polyphenols rich diets (grape pomace and rafuma) significantly alter intestinal permeability reversing the damage to the intestinal barrier due to ageing. The effect was not directly linked to changes in microbial diversity of the gut and did not significantly ameliorate the impaired immune system of the aged animals’ intestine or hippocampus. Only a significant increase in the number of dendritic cells emerged in conjunction with a reduced level of TNF-α in the blood. Neither did the polyphenols reverse some of the behavioural deficits associated with ageing. Cumulatively, these data show the specific effect of polyphenols in the elderly. We next investigated whether inulin, the most widely studied prebiotics, could improve host metabolism in middle-aged mice. We tested 52 metabolic markers involved in hypothalamic-pituitary-adrenal (HPA) axis regulation, cholesterol and glucose homeostasis and immune regulation. Interestingly, the liver, the brain and the mesenteric fat did not show any modification in middle-age animals. Inulin had a greater impact in young animals and stimulated the lipid and glucose metabolism, increasing the level of Sirtuin1, a fundamental metabolic sensor, without impacting transcriptional factor changes in the liver. The study also uncovered a range of changes in the HPA. In fact, inulin decreased the level of the glucocorticoids receptors (Nr3c1) and corticotropin-releasing hormone (Crhr1) receptors in the amygdala of young mice. In an attempt to understand the mechanisms through which microbiota-targeted interventions exert the anti-aging effects, we used a model of premature ageing (ApoE deficient mice). The effect of two different strains of lactobacillus (L.reuteri and L.mucosae) and two prebiotics derived from plants (plant sterol esters and oat b- glucan) were examined. Neural plasticity was restored in the Prefrontal cortex after 24 weeks of prebiotic administration and the level of claudin 5 increased in the hippocampus following consumption of L. mucosae. Overall, these results provide novel insights regarding the impact of a portfolio of microbiota-targeted interventions on age-related alterations in physiology and brain function and suggest the importance of using target-specific therapeutic options during particular time windows for maximum gain.
Microbiota , Probiotic , Prebiotic , Aging
Minuto, C. 2022 From youth to old age: therapeutic potential of microbiota interventions in the gut-brain-axis. PhD Thesis, University College Cork.