Prebiotics mitigate the detrimental effects of High-Fat diet on Memory, anxiety and microglia functionality in ageing mice.

ABSTRACT

Ageing is characterised by a progressive increase in systemic inflammation and especially neuroinflammation. Neuroinflammation is associated with altered brain states that affect behaviour, such as an increased level of anxiety with a concomitant decline in cognitive abilities. Although multiple factors play a role in the development of neuroinflammation, microglia have emerged as a crucial target. Microglia are the only macrophage population in the CNS parenchyma that plays a crucial role in maintaining homeostasis and in the immune response, which depends on the activation and subsequent deactivation of microglia. Therefore, microglial dysfunction has a major impact on neuroinflammation. The gut microbiota has been shown to significantly influence microglia from birth to adulthood in terms of development, proliferation, and function. Diet is a key modulating factor that influences the composition of the gut microbiota, along with prebiotics that support the growth of beneficial gut bacteria. Although the role of diet in neuroinflammation and behaviour has been well established, its relationship with microglia functionality is less explored. This article establishes a link between diet, animal behaviour and the functionality of microglia. The results of this research stem from experiments on mouse behaviour, i.e., memory, anxiety, and studies on microglia functionality, i.e., cytochemistry (phagocytosis, cellular senescence, and ROS assays), gene expression and protein quantification. In addition, shotgun sequencing was performed to identify specific bacterial families that may play a crucial role in the brain function. The results showed negative effects of long-term consumption of a high fat diet on ageing mice, epitomised by increased body weight, glucose intolerance, anxiety, cognitive impairment and microglia dysfunction compared to ageing mice on a control diet. These effects were a consequence of the changes in gut microbiota modulated by the diet. However, by adding the prebiotics fructo- and galacto-oligosaccharides, we were able to mitigate the deleterious effects of a long-term high-fat diet.