Neuroimmune dysregulation in the activity-based anorexia model

Anorexia nervosa (AN) is a life-threatening psychiatric disorder that mainly affects young females. Despite its clear symptomatology, knowledge about its etiology is limited and treatments are ineffective. Severe dietary restrictions and physical activity, i.e. AN core symptom, lead to multiorgan dysfunction involving also the immune system. Indeed, AN patients, in the first phases of the disease, are characterized by a strong ability to counteract sickness and infections while in the advanced phases they show increased recurrency and severity of infections. Our hypothesis is that AN-derived alterations of the peripheral immune system might induce central dysfunctions through the activation of an aberrant microglia response. To test this hypothesis, we took advantage of the activity-based anorexia (ABA) rat model: female rats were exposed to the combination of food restriction and wheel access during adolescence (from postnatal day (P) 38 to P42. Animals were sacrificed at P42, at the acute phase, or at P49, after a 7-day recovery period. Flow cytometry analyses performed on trunk blood and bone marrow highlighted a persistent reduction of circulating CD45+ cells and a shift between granulocytes and B cells in the pool of total immune cells in the bone marrow of ABA rats, resulting in an imbalance of innate and adaptive immunity. Gene expression analyses in ventral hippocampus revealed that the acute manifestation of AN induced neuroinflammation, as shown by increased TNF-a levels, resulting in a change of microglial transcriptional profile including an increase in Trem2, Iba1, Cd11b and Cd68 expression levels after the recovery period. These results suggest that AN-induced alterations in the peripheral immune response might cause endurable central dysfunctions throughout the activation of a late pro-phagocytic microglial response in the ventral hippocampus. These persistent effects may play a key role in long-lasting vulnerability of AN patients to develop other psychiatric comorbid symptoms. Sponsored by: Cariplo foundation 2023-1003