Intestinal microbes and their metabolites affect development of colorectal cancer (CRC). Short-chain fatty acids are metabolites generated by intestinal microbes from dietary fiber. We investigated the mechanisms by which free fatty acid receptor 2 (FFAR2), a receptor for short-chain fatty acids that affects the composition of the intestinal microbiome, contributes to the pathogenesis of CRC.We performed studies with Apc mice, ApcFfar2 mice, mice with conditional disruption of Ffar2 in dendritic cells (DCs) (Ffar2CD11c-Cre mice), ApcFfar2CD11c-Cre mice, and Ffar2 mice (controls); some mice were given dextran sodium sulfate to induce colitis, with or without a FFAR2 agonist or an antibody against interleukin 27 (IL27). Colon and tumor tissues were analyzed by histology, quantitative PCR, and 16S rRNA gene sequencing; lamina propria and mesenteric lymph node tissues were analyzed by RNA sequencing and flow cytometry. Intestinal permeability was measured following gavage with fluorescently labeled dextran. We collected data on colorectal tumors from the Cancer Genome Atlas.ApcFfar2 mice developed significantly more spontaneous colon tumors than Apc mice and had increased gut permeability before tumor development, associated with reduced expression of E-cadherin. Colon tumors from ApcFfar2 mice had a higher number of bacteria than tumors from Apc mice, as well as higher frequencies of CD39CD8 T cells and exhausted or dying T cells. DCs from ApcFfar2 mice had an altered state of activation, increased death, and higher production of IL27. Administration of an antibody against IL27 reduced the numbers of colon tumors in Apc mice with colitis. Frequencies of CD39CD8 T cells and IL27 DCs were increased in colon lamina propria from Ffar2CD11c-Cre mice with colitis compared with control mice or mice without colitis. ApcFfar2CD11c-Cre mice developed even more tumors than ApcFfar2 mice, and their tumors had even higher numbers of IL27 DCs. Apc mice with colitis given the FFAR2 agonist developed fewer colon tumors, with fewer IL27 DCs, than mice not given the agonist. DCs incubated with FFAR2 agonist no longer had gene expression patterns associated with activation or IL27 production.Loss of FFAR2 promotes colon tumorigenesis in mice by reducing gut barrier integrity, increasing tumor bacterial load, promoting exhaustion of CD8 T cells, and over-activating DCs, leading to their death. Antibodies against IL27 and agonists of FFAR2 reduce tumorigenesis in mice and might be developed for treatment of CRC.