Inflammatory status along the brain-liver axis in animals vulnerable to prenatal stress: sex-related implications for stress-induced comorbidities

The prevalence of mood disorders is constantly increasing, with exposure to stress early in life (ELS) as one of the major risk factors. Recent studies reported that ELS can increase the risk for mental disorders, but also for several cardiometabolic conditions, often in comorbidity. However, biological processes underlying these negative outcomes with a sex dependent effect are still poorly understood. Here, we used the preclinical model of prenatal stress (PNS) mimicking early in life adversities to investigate the presence of an abnormal inflammatory response as a possible mechanism leading to the onset of a vulnerable phenotype for mental and metabolic disorders in the offspring. We showed that adolescent male rats, classified as vulnerable to PNS by a two-step cluster analysis, based on three different behavioral tests, have brain microglia hyperactivation in the dorsal hippocampus. We then focused on liver, as a key organ involved in the development of several metabolic disorders and strictly communicating with the brain via immune-inflammatory pathways. We found that rats showing a vulnerable behavioral phenotype also showed abnormal inflammatory response in the liver. Moreover, liver inflammation is correlated with an increased expression of leptin receptor, an important adipokine involved in several metabolic processes. Overall, this study suggests that male but not female rats exposed to PNS and showing a vulnerable phenotype are characterized by brain and liver pro-inflammatory status, pointing out the need to target the inflammatory system via pharmacological or non-pharmacological strategies to reduce the risk for both mental and physical disorders in individuals exposed to ELS.