In summary, our study has demonstrated that GPR65 functions as a critical contributor to the pathogenesis of IBD and that that blocking GPR65 in CD4+ T cells appears to downregulate the immune response of Th1 and Th17 cell via the cAMP‐PKA‐C‐Raf‐ERK1/2‐LKB1‐NUAK2 signalling pathway, leading to alleviating intestinal mucosal inflammation. Here, CD4 is linked to inflammatory bowel disease.