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

Authors

Medina, C., Deme, P., Win, V., Nikitah, I., McKie, I. S., Song, M., Raudales, M., Regier, E., Amsden, E., Bendale, P., Haughey, N., Opendak, M.

Abstract

Background: Adverse early caregiving produces lasting changes in social behavior and increases vulnerability to psychiatric illness, yet the biological pathways through which early social experience becomes embedded remain poorly understood, and few are therapeutically accessible during development. We tested whether peripheral bile acid signaling links adverse caregiving to disrupted social development and can be pharmacologically targeted. Methods: Using two complementary rat models of early-life adversity, one dissociating adverse social experience from non-social stress, the other degrading caregiving quality via limited bedding, we combined social behavioral testing in both sexes with serum metabolomics and basolateral amygdala transcriptomics across infancy and adolescence, and tested oral supplementation with the primary bile acids chenodeoxycholic acid (CDCA) or cholic acid (CA) during the adversity period. Results: Social, but not non-social, adversity produced sex-, age-, and adversity-specific changes in peripheral bile acid and tryptophan metabolism alongside remodeling of behavior-associated amygdala gene networks. Supplementation with CDCA, but not the related bile acid CA, rescued the infant affiliative social deficit produced by adverse caregiving, without altering approach in control-reared animals. Conclusions: Bile acid signaling is a mechanistically informative and pharmacologically tractable pathway linking adverse early caregiving to disrupted social behavior. Because CDCA is FDA-approved, these findings support bile acid-based interventions as a candidate strategy for mitigating the developmental consequences of early-life adversity and highlight biological sex as a determinant of vulnerability.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 20 Aug 2026.

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