Cross-Fostering with control dams rescues Gut Dysbiosis and Chromatin-associated Transcriptional Changes in Offspring of Opioid-Exposed Dams

Abstract Prenatal opioid exposure disrupts gut homeostasis and causes gastrointestinal complications in offspring, but the mechanisms remain unclear. Here using a murine model of prenatal hydromorphone exposure, we examined gut microbiota, intestinal injury, transcriptomic signatures, and chromatin accessibility. Exposed pups displayed marked dysbiosis, epithelial damage, and upregulation of inflammatory gene programs accompanied by relaxed ileal chromatin. Cross-fostering to opioid-naïve dams restored microbial diversity, reestablished metabolite-producing taxa, and reversed injury-associated transcriptional and chromatin changes. Fecal microbiota transplantation from exposed dams recapitulated intestinal injury, indicating a microbiome-driven mechanism. These findings reveal a novel gut-microbiome-epigenome axis underlying opioid-induced injury and highlight early microbial intervention as a potential strategy to mitigate developmental harm. Competing Interest Statement The authors have declared no competing interest. List of abbreviations - HP_HM - hydromorphone pups nursed by hydromorphone mothers - HP_CM - hydromorphone pups nursed by control mothers - CP_HM - control pups nursed by hydromorphone mothers - CP_CM - control pups nursed by control mothers - ATAC-seq - Assay for Transposase-Accessible Chromatin sequencing