Role of gut microbiota components-induced neuroinflammation on food reward alterations during obesity

In recent years, the increase in obesity rates has been linked to overconsumption of energy-dense foods. Food intake is regulated by two systems: the homeostatic system mainly in the hypothalamus and the food reward system, influenced by the hedonic value of foods. The palatable foods (rich in fat and/or sugar) trigger responses in the brain reward system, mainly involving dopaminergic neurons in the mesocorticolimbic pathways. Studies indicate alterations of food reward behaviors in rodents and individuals suffering from obesity, associated with an hypofunctioning of the dopaminergic pathway. The gut microbiota has emerged as a crucial regulator of metabolism, influencing food intake through the gut-brain axis. Our team demonstrated a causal role of the gut microbiota in these food reward dysregulations in the context of obesity. Changes in the gut microbiota composition and increased gut permeability, observed during obesity, are associated with the release of bacterial components such as lipopolysaccharides (LPS) into the bloodstream. This leakage triggers a condition known as metabolic endotoxemia and initiates inflammation by activating toll-like receptors 4 (TLR4), including in the brain, which results in neuroinflammation. Thus, this thesis aims to investigate how neuroinflammation-induced by gut microbiota components contributes to the dysregulations of food reward during obesity. In the first chapter, we observed the food reward alterations and the hypofunctioning of the dopaminergic system in high-fat diet-induced obese mice through a series of behavioral paradigms related to food reward events and the use of pharmacological agents targeting the dopamine circuit. Furthermore, our observations revealed that only one day of HFD feeding, induced impairments in food reward-like functions in mice. These rapid changes underscore the immediate impact of dietary modifications on behaviors and brain functions. Therefore, we demonstrated that obese mice showed inflammatory processes and impaired blood-brain barrier integrity in reward-related brain regions compared to lean mice. Our study fills gaps in existing literature by highlighting the detrimental effects of an HFD on brain health, emphasizing the food behavioral implications. Then, we showed that TLR4 deletion, using total knockout mice, partially abolishes the impairments of the food reward system in the context of obesity. We also observed that TLR4 deletion in obese mice can protect against impaired dopamine receptor 2 postsynaptic signalling and activation of glial cells in the brain. Then, we demonstrated that low concentration of LPS directly in the brain, mimicking obese conditions, play a partial causal role in these dysregulations via the activation of TLR4. These results collectively reveal previously unrecognized mechanisms, indicating that neuroinflammation triggered by gut microbiota components such as LPS through TLR4 could contribute to the imbalances of the food reward system and dopamine signalling, paving the way for future treatment approaches. In the second chapter, as a complementary approach, we investigated if gut microbiota modulation can alleviate food reward alterations in the context of obesity. An imbalance in gut microbiota associated with obesity often involves decreased levels of Akkermansia muciniphila. Daily supplementation of this bacterium, by oral daily gavage in mice, has been shown to regulate inflammation and decrease metabolic endotoxemia in obese mice. In this thesis, we demonstrated that the administration of Akkermansia muciniphila allows to improve the food reward imbalances in obese mice, potentially through a previously unexplored pathway that decreases neuroinflammation. Altogether, this PhD work provides a new potential mechanism by which the gut microbiota can induce food reward dysregulations in the context of obesity and a new possible beneficial bacterium candidate to alleviate these impairments, paving the way for future therapeutic approaches.