Chronic activity-based anorexia triggers a glial response in the hippocampus independent of intestinal epithelial toll-like receptor 4

Anorexia nervosa is characterized by maladaptive eating behavior and psychiatric comorbidities, which could be explained by a neuroinflammation. A gut dysbiosis could link gastrointestinal alterations to central dysfunctions, particularly via the toll-like receptor 4 (TLR4), which has been shown to play a key role in the activity-based anorexia (ABA) model. We aimed to evaluate the neuroinflammation and its behavioral consequences in the ABA model, and to decipher the role of the microbiota-gut-brain axis, and more specifically of TLR4, in these alterations of the central nervous system. We show that chronic restriction is more strongly associated with gut inflammation, cecal microbiota alteration and neuroinflammatory processes in the hippocampus than acute restriction. The hippocampal glial response is characterized by a loss of astrocyte density, and an increased number of deramified microglia. We further demonstrate that these alterations are independent of TLR4 expressed by intestinal epithelial cells. In conclusion, our results highlight that the chronicity of ABA-associated undernutrition alters the response of glial cells in the hippocampus that is linked with changes in microbiota composition, highlighting the importance of faster diagnosis and treatment of AN.