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Subsequently, pH-sensing mechanisms are of interest for the understanding of IBD pathophysiology. Tissue hypoxia and acidosis\u2014two contributing factors to disease pathophysiology\u2014are linked to IBD, and understanding their interplay is highly relevant for the development of new therapeutic options. One member of the proton-sensing G protein-coupled receptor (GPCR) family, GPR65 (T-cell death-associated gene 8, TDAG8), was identified as a susceptibility gene for IBD in a large genome-wide association study. In response to acidic extracellular pH, GPR65 induces an anti-inflammatory response, whereas the two other proton-sensing receptors, GPR4 and GPR68 (ovarian cancer G protein-coupled receptor 1, OGR1), mediate pro-inflammatory responses. Here, we review the current knowledge on the role of these proton-sensing receptors in IBD and IBD-associated fibrosis and cancer, as well as colitis-associated cancer (CAC). We also describe emerging small molecule modulators of these receptors as therapeutic opportunities for the treatment of IBD.<\/jats:p>","DOI":"10.1007\/s00424-024-02943-y","type":"journal-article","created":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T00:06:10Z","timestamp":1711065970000},"page":"611-622","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Role of pH-sensing receptors in colitis"],"prefix":"10.1007","volume":"476","author":[{"given":"Martin","family":"Hausmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Seuwen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl","family":"de Valli\u00e8re","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moana","family":"Busch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro A.","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Rogler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,22]]},"reference":[{"issue":"12","key":"2943_CR1","doi-asserted-by":"publisher","first-page":"7556","DOI":"10.4049\/jimmunol.166.12.7556","volume":"166","author":"R Abe","year":"2001","unstructured":"Abe R, Donnelly SC, Peng T, Bucala R, Metz CN (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. 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