Environmental enrichment preserves intestinal endocannabinoid signaling under LPS-inflammatory conditions.

Environmental factors critically influence intestinal homeostasis, yet the molecular mechanisms underlying these effects remain incompletely understood. The endocannabinoid system (ECS), a key regulator of immune, metabolic, and epithelial functions, has emerged as a promising pharmacological target in inflammatory disorders. However, whether environmental context influences intestinal ECS signaling and the coordinated mechanisms underlying intestinal homeostasis during inflammation remains unclear. This study investigated the impact of environmental enrichment (EE) on intestinal ECS regulation in the context of impaired intestinal homeostasis during lipopolysaccharide (LPS)-induced systemic inflammation. Adult male mice were housed under standard or enriched conditions for four weeks before LPS challenge (830 μg/kg, i.p., 24 h). ECS receptors (Cnr1, Cnr2), ECS-related targets (Trpv1, Pparγ), metabolic enzymes (Nape-pld, Dagl-β, Faah, Magl), inflammatory mediators (Tlr4, Tnf-α, Il-6), epithelial barrier markers (Ocln, Zo-1), endocannabinoid levels (AEA and 2-AG), selected bacterial taxa, and microbiota-derived metabolites were evaluated in the proximal colon. LPS induced coordinated changes in the intestinal ECS-related measures, endocannabinoid levels, inflammatory signaling, barrier-associated markers, and the selected microbial-metabolic profile. EE mitigated several of these changes, including ECS-related transcriptional and protein alterations and local inflammatory responses, while modulating tight-junction proteins, selected fecal bacterial taxa, microbiota-derived metabolites, and the integrated multivariate profile. Overall, EE modulates intestinal response profile consistent with greater resilience to inflammatory stress across ECS, inflammatory, barrier-associated, and microbial-metabolic measures. These findings suggest that ECS regulation may represent a context-dependent determinant of responsiveness to ECS-targeting pharmacological interventions.