LACTIPLANTIBACILLUS PLANTARUM STRENGTHENS THE INTESTINAL BARRIER: INVOLVEMENT OF THE ENDOCANNABINOIDOME

Probiotics have been suggested to ameliorate the function of the intestinal epithelial barrier and so have several mediators and receptors of the expanded endocannabinoid system, the endocannabinoidome (eCBome). Here we cocultured three live strains of Lactiplantibacillus plantarum with intestinal epithelial organoids to study their effects on the gut barrier function and the possible involvement of the eCBome in this effect. All three L.plantarum strains variously reduced the trans-epithelial permeability of intestinal organoids and promoted increased mRNA expression of several tight junction proteins and intestinal barrier proteins. Concomitantly, the three strains upregulated the expression of genes encoding biosynthetic enzymes (i.e., NapePLD, Abdh4, Gde1, Daglb) and receptors (i.e., Cnr1, Cnr2, Gpr55, and Ppara), while concurrently downregulating the expression of two essential catabolic enzymes (i.e. Faah and Naaa), involved in the signaling of several eCBome mediators known for their role in regulating the intestinal epithelial barrier. Selective inhibitors of eCBome mediator degrading enzymes FAAH and MAGL, i.e., URB597 and JZL184, increased N-acyl-ethanolamine (NAE) and 2-monoacylglycerol (2-MAG) levels, respectively, enhanced the expression of intestinal epithelial barrier genes and reduced the trans-epithelial permeability of organoids, as for L. plantarum strains. Interestingly, inflammation-induced trans-epithelial permeability in organoids was also reversed by both FAAH and MAGL inhibitors. We surmise that elevated endogenous levels of either NAEs or 2-MAGs promote improvement in small intestine trans-epithelial permeability and that L. plantarum strains may exploit this mechanism to promote these beneficial effects.