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

Rigillo G.; Benatti C.; Rivi V.; Ciani M.; Martusciello I.; Imbeni F.; Blom J.; Pani L.; Alboni S.; Tascedda F. · European journal of pharmacology · 2026

**Background & Methods** This review study examined how environmental enrichment (EE) affects intestinal endocannabinoid system (ECS) signaling during lipopolysaccharide (LPS)-induced inflammation in adult male mice. Adult mice were housed under either standard or enriched environmental conditions for four weeks before LPS challenge, with comprehensive assessment of ECS receptors, metabolic enzymes, inflammatory mediators, epithelial barrier function, endocannabinoid levels, and microbiota composition in the proximal colon. **Key Findings** - LPS challenge induced coordinated dysregulation across multiple intestinal systems, including altered ECS gene expression (Cnr1, Cnr2), reduced endocannabinoid levels (AEA and 2-AG), elevated inflammatory signaling (Tlr4, Tnf-α, Il-6), impaired tight-junction proteins (Ocln, Zo-1), and adverse changes in selected bacterial taxa and microbiota-derived metabolites. - Environmental enrichment significantly mitigated LPS-induced inflammatory responses by preserving ECS-related transcriptional and protein alterations, maintaining intestinal barrier integrity through modulation of tight-junction proteins, and restoring selected bacterial taxa and microbiota-derived metabolites compared to standard housing conditions. - EE demonstrated protective effects across an integrated multivariate profile, suggesting enhanced resilience to inflammatory stress through coordinated preservation of ECS, inflammatory, epithelial barrier, and microbial-metabolic homeostasis. **Dosage & Administration** LPS administered at 830 μg/kg via intraperitoneal injection; tissue harvesting performed 24 hours post-LPS challenge. Environmental enrichment duration: 4 weeks prior to inflammatory challenge. **Safety & Adverse Effects** Not reported. **Evidence Quality** This is a preclinical review-type study using animal models (mice), limiting direct human applicability. Key limitations include use of a single LPS dose, restriction to male subjects, and focus on one anatomical region (proximal colon). The study provides valuable mechanistic insights into ECS-inflammation interactions but lacks human clinical validation. The comprehensive multivariate analysis and integrated assessment of ECS, immune, barrier, and microbial parameters represents a methodological strength. Findings suggest that environmental context may influence pharmacological responsiveness to ECS-targeting interventions, highlighting the importance of considering psychosocial and environmental factors in future clinical trials of cannabinoid therapeutics for inflammatory conditions.

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