An acidic microenvironment is not merely a sequelae of disease but affects the progression and resolution of inflammation.16 As one special subset of metabolite GPCRs, proton-sensing GPCRs consisting of GPR4, GPR65, GPR68 and GPR132 act as sensors of acidification and play an essential role in regulating physiological and pathophysiological processes.17 Several IBD-associated variants around GPR65 locus have been identified in previous genome-wide association studies (GWAS),18,19 including one missense variant encoding an isoleucine-to-leucine substitution at codon 231 (I231L). This evidence concerns the gene GPR65 and inflammatory bowel disease.