UC Riverside

The endocannabinoid (eCB) system is a lipid-derived signaling pathway that regulates food intake, energy homeostasis, and reward, and is expressed throughout the gastrointestinal tract. In diet-induced obesity (DIO), the eCB system becomes dysregulated and may contribute to impaired gut barrier function; however, it remains unclear whether activation of this system by cannabis is protective or detrimental. Previous studies suggest that intestinal epithelial CB1 receptors (CB1Rs) regulate gut barrier integrity and inflammation, yet conflicting evidence exists regarding the effects of cannabinoid signaling on intestinal permeability.To address this, we examined the impact of Δ9-tetrahydrocannabinol (THC) and whole cannabis extracts on gut barrier function in male and female mice with conditional deletion of CB1Rs in the intestinal epithelium (intCB1R-/-) and control mice (intCB1R+/+). Mice were maintained on either a low-fat standard diet or a Western diet (WD) for 60 days. Intestinal permeability was assessed using 4 kDa FITC-dextran, and mice were subsequently treated with pure Δ9-THC or whole cannabis extract for 14 days. Intestinal tissues were collected for gene expression and lipidomic analyses. WD-fed male mice developed obesity, whereas this effect was absent in female intCB1R-/- mice. Gut barrier dysfunction was exacerbated in male knockout mice and accompanied by increased circulating lipopolysaccharide (LPS), indicating enhanced endotoxemia. The eCB system was dysregulated in a sex- and region-specific manner. Cannabinoid treatment normalized intestinal permeability independent of epithelial CB1Rs, suggesting that CB1-independent mechanisms may contribute to barrier restoration. In male DIO mice, cannabinoids restored jejunal expression of occludin, tumor necrosis factor alpha (TNFα), and interleukin-1 beta (IL-1β). Similarly, female DIO intCB1R+/+ mice exhibited reduced expression of occludin and IL-1β, which was restored following cannabinoid treatment. Furthermore, in males, the Western diet increased jejunal CNR2 expression, an effect reversed by exposure to cannabinoids. These findings demonstrate that intestinal CB1Rs play a protective role in maintaining gut barrier integrity during DIO in a sex-dependent manner. Moreover, cannabis exposure can restore barrier function and inflammatory balance through both CB1-dependent and independent mechanisms, highlighting the therapeutic potential of cannabinoid signaling in metabolic disease.