Burden of negative energy balance in anorexia nervosa: Role of circadian rhythm, mitochondrial dynamics, microbiota–gut–brain axis and their interactions

Anorexia nervosa (AN) is a chronic eating disorder that often requires prolonged hospitalisation for effective treatment. As a multifactorial disease, many environmental, psychiatric, and biological factors impede recovery, creating a vicious circle of anorexia, gastrointestinal disorders, and anxiety-depressive disorders. Individuals with AN often exhibit inappropriate physical activity, sleep disturbances, alterations in circadian hormonal profiles, disruption of the gut barrier, dysbiosis of the gut microbiota, oxidative stress, and alterations in brain function. The aim of this review is to provide a non-exhaustive overview of the biological factors involved to gain a deeper understanding of the pathophysiology of AN and to identify potential targets for clinical cure. We have chosen to describe the interconnected factors of gut microbiota, circadian rhythm, mitochondria, and brain alterations. Indeed, clinical and experimental data allow the establishment of relationships between these altered factors. Sleep disorders and brain changes have been linked to cognitive alterations, mood disorders, and disrupted feeding behaviour. Compulsive exercise behaviour has been associated with a negative energy balance, but adapted physical activity may confer protection against certain comorbidities. Circadian rhythm may be associated with mitochondrial dysfunction, sleep disorders, and physical activity. Mitochondrial dysfunction could lead to putative neuroinflammation, causing a reduction in grey matter volume. The gut microbiota, which exhibits circadian variations, interacts with both homeostatic and hedonic food intake regulation, and is associated with mitochondrial function and physical activity. Better understand all this relationship in anorectic conditions is an important issue to open new therapeutic strategies.