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Nat. Rev. Endocrinol. doi:10.1038/nrendo.2015.211 Figure 2 Targeting gut microorganisms and the endocannabinoid system to improve gut-barrier function and host metabolism Figure 2 | Targeting gut microorganisms and the endocannabinoid system to improve gut-barrier function and host metabolism. Changing the composition of the gut microbiota through the use of agents such as prebiotics or specific bacteria (such as Akkermansia muciniphila) reinforces gut-barrier function by restoring the functionality of tight-junction proteins. Specific 'gate keepers' have been identified, such as an increase in the intestinal abundance of PEA, 2-AG, 2-OG, 2-PG and PGD2-G, that contribute to locking of the barrier and to reduced intestinal inflammation. Moreover, changes in gut microorganisms that are caused by prebiotics, Akkermansia muciniphila or deletion of MyD88 in intestinal epithelial cells (affecting the host innate immune response) are associated with decreased levels of AEA (a 'gate opener') and increased levels of 2-AG and 2-PG (anti-inflammatory mediators) as well as of 2-OG, which binds to GPR119 expressed on enteroendocrine cells and thereby trigger the secretion of GLP-1 and GLP-2 (involved in glucose homeostasis and gut-barrier function, respectively). Altogether, reinforcing the gut barrier and either increasing the endogenous production or reducing the degradation of specific bioactive lipids contributes to increased fat oxidation (thermogenesis/browning), reduced inflammation and the maintenance of adequate adipogenesis and insulin sensitivity. AEA, N-arachidonoylethanolamide; 2-AG, 2-arachidonoylglycerol; GLP-1, glucagon-like peptide 1; GLP-2, glucagon-like peptide 2; GPR119, G-protein coupled receptor 119; MyD88, myeloid differentiation primary response protein MyD88; NAPE-PLD, N-acylphosphatidylethanolamine-hydrolysing phospholipase D; OEA, N-oleoylethanolamine; 2-OG, 2-oleoylglycerol; PEA, N-palmitoylethanolamine; 2-PG, 2- palmitoylglycerol; PGD2-G, glycerol ester of prostaglandin D2; SEA, N-stearoylethanolamine; TLR, Toll-like receptor. Cani, P. D. et al. (2015) Endocannabinoids — at the crossroads between the gut microbiota and host metabolism Nat. Rev. Endocrinol. doi:10.1038/nrendo.2015.211