Mouse gut microbiome of azaleic acid treated mouse

Background: Olfactory receptor 544 (Olfr544) is ectopically expressed in extra-nasal tissues, and the activation of Olfr544 by its ligand, azelaic acid (AzA), reduces adiposity. This study investigated the antiobesogenic mechanism of Olfr544 in the gut. Results: Olfr544 is expressed in the small intestine and colon of mice and the GLUTag L cell line. AzA induces the cAMP-PKA-CREB singling axis and increases GLP-1 secretion in GLUTag cells and in mice administered AzA orally. However, the induction of GLP-1 secretion by AzA was negated in cells with Olfr544 knock down and in Olfr544-KO mice. These results indicate that GLP-1 secretion by AzA is Olfr544-dependent. Gut microbiome analysis revealed that AzA did not dramatically change gut microbiota structure but rather affected the prevalence of specific family and species of microorganisms. Particularly, AzA induced the prevalence of Bacteroides acidifaciens, a gut microorganism prevalent in lean individuals. In fecal metabolomic analysis, metabolites in glutathione, trehalose, sphingolipid synthesis and pentose phosphate pathway intermediates were increased by AzA. These metabolomic profile may be responsible for selective survival of gut microorganisms by Olfr544 activation and the increased synthesis of glutathione, trehalose, and sphingolipids, which induce antioxidative and anti-inflammatory effects in the gut. AzA suppressed LPS-induced proinflammatory cytokines in cultured cells and in mice and thus improved intestinal permeability in mice. Conclusion: These results highlight that Olfr544 has profound effects in the gut in the regulation of adiposity by secreting the antiobesogenic hormone GLP-1 and modulating gut microbiome, fecal metabolites, and colonal inflammation.