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Decoding the interplay between the microbiota-gut-brain axis and the hypothalamic regulation of eating behaviour
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Date
2024
Authors
Cuesta-Marti, Cristina
Journal Title
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Publisher
University College Cork
Published Version
Abstract
Unhealthy eating and choices from an early age have been associated with increases in childhood overweight and obesity, which have risen significantly in recent years. In 2022, 390 million aged 5–19 (20% of children worldwide), were overweight with 8% of these children and adolescents going on to live with metabolic disorders such as obesity and/or diabetes. The prevalence of obesity has quadrupled among this age group since 1990. Also, startling is when exposure to unhealthy diets occurs during early-life period, neurodevelopment can also be impacted which results in consequences on metabolic health and eating behaviours.
In this thesis, we identify key molecular signalling pathways involved in the regulation of appetite and eating behaviour underlying the enduring detrimental consequences of an early-life high-fat-high-sugar (HFHS) diet exposure (Chapter 2). From a novelty perspective we postulate a key role for the gut microbiota and its metabolites in the “priming” effects of this exposure. Increased food manipulation, or food crumbling behaviour was observed in a sex-specific manner (Chapter 2). The exposure to a HFHS diet during early-life had specific molecular effects in brain regions involved in the regulation of eating behaviour, including the striatum and the hypothalamus, in both sexes (Chapter 2). We also observed that microbiota-targeted interventions, via a prebiotic or putative probiotic, restored the alterations induced by the exposure to this unhealthy diet during early-life in an intervention- and sex- dependent manner (Chapter 2). This highlights the promising potential of microbiota-targeted strategies to ameliorate these metabolic effects, exacerbated hedonic food intake behaviours, and molecular changes.
To further understand the molecular impact of diet-host-microbe interactions on the central regulation of appetite, we investigated bacteria-derived metabolites produced in cell-free supernatants of single bacteria for gene expression alterations in hypothalamic cell lines (Chapter 3 and 4). We identified that bacterial-derived metabolites were able to modulate the hypothalamic expression of ghrelin receptor and glucagon-like peptide 1, genes involved in appetite regulation (Chapter 3). Additionally, we showed that metabolite-containing cell-free bacterial supernatants, as well as the microbiota-derived metabolite lactate, were able to upregulate the hypothalamic gene expression of oxytocin and its receptor, which are involved in the regulation of social behaviour, reproduction as well as eating behaviour (Chapter 4).
These findings enhance our understanding of the potential molecular mechanisms by which the gut microbiota and bacterial-derived metabolites and compounds may play a role in the central regulation of appetite and oxytocinergic system.
Overall, these findings contribute to our understanding of how early-life exposure to an unhealthy diet can shape long-term eating behaviours, the role of the gut microbiota and their metabolites on the regulation of feeding and appetite. Our findings on the molecular and behavioural mechanisms underlying these the long-term effects and the impact of microbiota-targeted interventions, particularly in a sex-specific manner, may contribute to the knowledge for potential strategies to prevent or mitigate the global burden of obesity, metabolic disorders, and eating disorders.
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Keywords
Eating behaviour , Gut microbiota , Microbiota-gut-brain axis , Early life , High-fat/high-sugar diet , Microbiota-targeted interventions , Microbiota-derived metabolites , Bacterial supernatants
Citation
Cuesta-Marti, C. 2024. Decoding the interplay between the microbiota-gut-brain axis and the hypothalamic regulation of eating behaviour. PhD Thesis, University College Cork.