Bile acid signaling as a therapeutically tractable pathway linking early caregiving adversity to social behavior

Adverse early caregiving produces lasting changes in social behavior and increases vulnerability to psychiatric illness, yet the biological pathways through which these experiences become embedded during development remain poorly understood. Using two complementary rat models of early-life adversity (ELA), we combined behavioral phenotyping with serum metabolomics and basolateral amygdala (BLA) transcriptomics to identify bile acid biology as a candidate pathway associated with disrupted social development. In the Deconstructed Adversity Model (DAM), which dissociates adverse social experience from non-social stress, social adversity produced distinct behavioral alterations accompanied by sex-, age-, and adversity-dependent changes in peripheral bile acid and tryptophan metabolism together with sex-specific BLA gene co-expression networks associated with social behavior. These coordinated peripheral and central alterations converged on bile acid biology as a candidate pathway for pharmacological intervention. We next tested this prediction in the Scarcity Adversity Model via Limited Bedding (SAM-LB), where oral supplementation with chenodeoxycholic acid (CDCA), but not the related primary bile acid cholic acid (CA), during the adversity period rescued the infant affiliative social deficit produced by adverse caregiving. Together, these findings identify bile acid biology as a pharmacologically tractable pathway associated with the developmental consequences of adverse early caregiving and support further investigation of CDCA, an FDA-approved bile acid, as a candidate intervention for mitigating early social behavioral deficits.