Prenatal THC Exposure Differentially Alters Gut Physiology and Microbiota in Stress-Resilient and Vulnerable Mice

Background/Objectives: Prenatal environmental exposures can shape neurodevelopmental outcomes through the gut-brain axis. The endocannabinoid system contributes to both neurodevelopment and gastrointestinal homeostasis and may, therefore, be vulnerable to disruption by exogenous cannabinoids such as Δ⁹-tetrahydrocannabinol (THC). Using established dominant (Dom; stress-resilient) and submissive (Sub; stress-vulnerable) mouse lines, this study examined whether prenatal THC exposure (PTE) produces phenotype-dependent alterations in gut physiology, colonic endocannabinoid- and inflammation-related gene expression, and gut microbiota composition. Methods: Pregnant Dom and Sub mice received vehicle or THC during gestation. Maternal stool samples were analyzed after exposure, and offspring were assessed at postnatal day 30. Gut and colon lengths were measured; colonic mRNA expression of selected endocannabinoid-, barrier-, and inflammation-related genes was quantified by qRT-PCR; and gut microbiota composition was analyzed using 16S rRNA sequencing with diversity and differential-abundance analyses. Results: PTE induced phenotype-dependent alterations in maternal gut microbiota. Sub dams exhibited enrichment of taxa associated with inflammatory states and depletion of Bacteroides and Parabacteroides, whereas Dom dams showed no significant taxonomic shifts. In offspring, Sub mice showed shorter baseline gut and colon lengths than Dom mice. PTE reduced gut and colon length in Dom offspring but not in Sub offspring. PTE also increased colonic CB1R expression in Dom offspring and reduced PPARγ expression in Sub offspring. Microbiota analysis revealed bidirectional phenotype-dependent remodeling, including increased Lachnospiraceae-related taxa and reduced Ligilactobacillus in Dom offspring, with an opposite pattern in Sub offspring. Conclusions: PTE produces phenotype-dependent effects on gut physiology, colonic gene expression, and microbiota composition. These findings identify the host stress-coping phenotype as a potential modifier of developmental responses to prenatal THC but do not establish causal relationships among microbiota, intestinal outcomes, and previously reported behavioral effects.