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G-protein-coupled receptors (GPRs), including pro-inflammatory ovarian cancer GPR1 (OGR1/GPR68) and anti-inflammatory T cell death-associated gene 8 (TDAG8/GPR65), are involved in pH sensing and linked to inflammatory bowel disease (IBD). OGR1 and TDAG8 show opposite effects. To determine which effect is predominant or physiologically more relevant, we deleted both receptors in models of intestinal inflammation. Combined <i>Ogr1</i> and <i>Tdag8</i> deficiency was assessed in spontaneous and acute murine colitis models. Disease severity was assessed using clinical scores. Colon samples were analyzed using quantitative polymerase chain reaction (qPCR) and flow cytometry (FACS). In acute colitis, <i>Ogr1</i>-deficient mice showed significantly decreased clinical scores compared with wildtype (WT) mice, while <i>Tdag8</i>-deficient mice and double knockout (KO) mice presented similar scores to WT. In <i>Il-10-</i>spontaneous colitis, <i>Ogr1</i>-deficient mice presented significantly decreased, and <i>Tdag8</i>-deficient mice had increased inflammation. In the <i>Il10</i>^−/− ×<i> Ogr1</i>^−/− × <i>Tdag8</i>^−/− triple KO mice, inflammation was significantly decreased compared with <i>Tdag8</i>^−/−. Absence of <i>Ogr1</i> reduced pro-inflammatory cytokines in <i>Tdag8</i>-deficient mice. <i>Tdag8</i>^−/− had significantly more IFNγ⁺ T-lymphocytes and IL-23 T-helper cells in the colon compared with WT. The absence of OGR1 significantly alleviates the intestinal damage mediated by the lack of functional TDAG8. Both OGR1 and TDAG8 represent potential new targets for therapeutic intervention.