The major findings were as follows: (1) Epac‐2 improved CD‐like colitis by upregulating the expression of TJ proteins; (2) Epac‐2 protected the function of the intestinal barrier by inhibiting the inflammatory response in macrophages; and (3) the phosphorylation of NF‐κB/MAPK signalling components was attenuated by activation of Epac‐2/Rap‐1 signalling in macrophages in the bowel of Il‐10−/− mice. This evidence concerns the gene NFKB1 and Cowden disease.