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Gut microbiota (GM) dysregulation, known as dysbiosis, has been proposed as a crucial driver of obesity associated with “Western” diet (WD) consumption. Gut dysbiosis is associated with increased gut permeability, inflammation, and insulin resistance. However, host metabolic pathways implicated in the pathophysiology of gut dysbiosis are still elusive. Exchange protein directly activated by cAMP (Epac) plays a critical role in cell-cell junction formation and insulin secretion. Here, we used homozygous Epac1-knockout (Epac1^–/–), Epac2-knockout (Epac2^–/–), and wild-type (WT) mice to investigate the role of Epac proteins in mediating gut dysbiosis, gut permeability, and inflammation after WD feeding.

The 16S rRNA gene sequencing of fecal DNA showed that the baseline GM of Epac2^–/–, but not Epac1^–/–, mice was represented by a significantly higher Firmicutes to Bacteroidetes ratio and …