CB1 Deficiency Protects From LPS-Induced Preterm Birth: The Role of the Decidual Endocannabinoid System

The endocannabinoid system (ECS) plays a crucial role in various physiological processes, including reproduction. Canonical cannabinoid receptors CB1 and CB2 are activated by 2-acyl glycerol (2-AG) and Anandamide (AEA), members of a broader ECB lipidome. This study investigated the role of CB1 receptor signaling on inflammatory mediators and ECS regulation in late pregnancy and its contribution to inflammation-induced preterm birth (PTB) using a murine model. CB1-knock-out (KO) and wild-type (WT) pregnant mice were treated with lipopolysaccharide (LPS) to induce PTB. CB1-KO mice exhibited significantly lower PTB rates compared to WT, suggesting a protective effect of CB1 deficiency. We also analyzed ECS components in decidual tissue and found that CB1-KO displayed lower basal FAAH activity than WT. LPS treatment reduced decidual CB2 protein levels only in CB1-KO mice. The pattern of ECBs and related lipids was similar in WT and CB1-KO decidua and serum with a few key exceptions. Free fatty acids significantly increased in WT decidua with LPS but were unchanged in CB1-KO. Inflammatory markers such as PGE2, PGF2α, and MMP-9 activity were also elevated in WT but not in CB1-KO after LPS administration. These findings suggest that CB1 deficiency modulates endogenous lipids and inflammatory responses during late pregnancy, decreasing the risk of LPS-induced PTB. This study provides new insights into the role of CB1 in pregnancy and its potential as a therapeutic target for PTB prevention.