Contributions of the gut microbiota and intestinal gluconeogenesis to metabolic adaptations in a mouse model of anorexia nervosa.

Abstract

Anorexia nervosa is a metabolic-psychiatric disorder characterized by severe food restriction, often accompanied by hyperactivity, associated with high mortality and the lack of specific pharmacological treatment. Despite a marked energy deficit, patients paradoxically maintain euglycemia, suggesting adaptations in energy homeostasis. This study aims to characterize the interactions between food restriction, the gut microbiota and peripheral organs in a mouse model mimicking anorexia nervosa. Our results show that food-restricted mice exhibit improved glucose tolerance and increased expression of the gluconeogenic genes G6pc and Pck1 in the intestine, suggesting an adaptation in endogenous glucose production. Gut microbiota analysis reveals a marked shift in composition in food-restricted mice, with an increase in the Lachnospiraceae and Marinifilaceae families and a decrease in Lactobacillaceae. These changes are associated with metabolic parameters such as glycemia, body weight, and GLP-1 levels. Transfer of microbiota from food-restricted mice into control mice improves glucose tolerance and increases the gluconeogenic gene expression. Furthermore, the improvement in glucose tolerance is abolished in mice lacking intestinal gluconeogenesis, suggesting that intestinal gluconeogenesis is required for the effects of the FR microbiota on glucose homeostasis. Overall, these findings highlight a complex metabolic adaptation in a mouse model of anorexia nervosa, involving interactions between the gut microbiota, intestinal gluconeogenesis and maintenance of energy homeostasis.