BACKGROUND & AIMS Intestinal microbes and their metabolites affect the 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 can affect the composition of the intestinal microbiome, contributes to the pathogenesis of CRC. METHODS We performed studies with ApcMin/+ mice, ApcMin/+Ffar2-/- mice, mice with conditional disruption of Ffar2 in dendritic cells (DCs) (Ffar2fl/flCD11c-Cre mice), ApcMin/+Ffar2fl/flCD11c-Cre mice, and Ffar2fl/fl 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 polymerase chain reaction, and 16S ribosomal RNA gene sequencing; lamina propria and mesenteric lymph node tissues were analyzed by RNA sequencing and flow cytometry. Intestinal permeability was measured after gavage with fluorescently labeled dextran. We collected data on colorectal tumors from The Cancer Genome Atlas. RESULTS ApcMin/+Ffar2-/- mice developed significantly more spontaneous colon tumors than ApcMin/+ mice and had increased gut permeability before tumor development, associated with reduced expression of E-cadherin. Colon tumors from ApcMin/+Ffar2-/- mice had a higher number of bacteria than tumors from ApcMin/+ mice, as well as higher frequencies of CD39+CD8+ T cells and exhausted or dying T cells. DCs from ApcMin/+Ffar2-/- 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 ApcMin/+ mice with colitis. Frequencies of CD39+CD8+ T cells and IL27+ DCs were increased in colon lamina propria from Ffar2fl/flCD11c-Cre mice with colitis compared with control mice or mice without colitis. ApcMin/+Ffar2fl/flCD11c-Cre mice developed even more tumors than ApcMin/+Ffar2fl/fl mice, and their tumors had even higher numbers of IL27+ DCs. ApcMin/+ mice with colitis given the FFAR2 agonist developed fewer colon tumors, with fewer IL27+ DCs, than mice not given the agonist. DCs incubated with the FFAR2 agonist no longer had gene expression patterns associated with activation or IL27 production. CONCLUSIONS Loss of FFAR2 promotes colon tumorigenesis in mice by reducing gut barrier integrity, increasing tumor bacterial load, promoting exhaustion of CD8+ T cells, and overactivating DCs, leading to their death. Antibodies against IL27 and an FFAR2 agonist reduce tumorigenesis in mice and might be developed for the treatment of CRC.

中文翻译：

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树突状细胞表达的游离脂肪酸受体2阻止了其白介素27的表达，并且是维持黏膜屏障和抵抗小鼠结肠直肠肿瘤免疫反应所必需的。

背景与目的肠道微生物及其代谢产物影响结直肠癌（CRC）的发展。短链脂肪酸是由肠道微生物从膳食纤维产生的代谢产物。我们调查了游离脂肪酸受体2（FFAR2）（一种可影响肠道微生物组组成的短链脂肪酸受体）促成CRC发病机理的机制。方法我们对ApcMin / +小鼠，ApcMin / + Ffar2-/-小鼠，在树突状细胞（DC）中有条件破坏Ffar2的小鼠（Ffar2fl / flCD11c-Cre小鼠），ApcMin / + Ffar2fl / flCD11c-Cre小鼠，和Ffar2fl / fl小鼠（对照）；一些小鼠接受或不使用FFAR2激动剂或抗白介素27（IL27）抗体的右旋糖酐硫酸钠诱导结肠炎。通过组织学分析结肠和肿瘤组织，定量聚合酶链反应和16S核糖体RNA基因测序；通过RNA测序和流式细胞仪分析固有层和肠系膜淋巴结组织。用荧光标记的右旋糖酐管饲后测量肠通透性。我们从The Cancer Genome Atlas收集了有关结直肠肿瘤的数据。结果与ApcMin / +小鼠相比，ApcMin / + Ffar2-/-小鼠自发的结肠肿瘤明显增多，并且在肿瘤发展之前肠道通透性增加，这与E-钙粘蛋白的表达降低有关。与来自ApcMin / +小鼠的肿瘤相比，来自ApcMin / + Ffar2-/-小鼠的结肠肿瘤细菌数量更高，并且CD39 + CD8 + T细胞和疲惫或垂死的T细胞的频率更高。来自ApcMin / + Ffar2-/-小鼠的DC的活化状态发生改变，死亡增加，IL27的产生更高。给予抗IL27抗体可减少患有结肠炎的ApcMin / +小鼠的结肠肿瘤数量。与对照组或无结肠炎的小鼠相比，患有结肠炎的Ffar2fl / flCD11c-Cre小鼠的结肠固有层中CD39 + CD8 + T细胞和IL27 + DC的频率增加。ApcMin / + Ffar2fl / flCD11c-Cre小鼠比ApcMin / + Ffar2fl / fl小鼠出现更多的肿瘤，并且它们的肿瘤中IL27 + DC的数量甚至更高。与未给予激动剂的小鼠相比，给予FFAR2激动剂的ApcMin / +结肠炎小鼠出现更少的结肠肿瘤，具有更少的IL27 + DC。与FFAR2激动剂一起孵育的DC不再具有与激活或IL27产生相关的基因表达模式。结论FFAR2的缺失可通过降低肠道屏障完整性，增加肿瘤细菌负荷来促进小鼠结肠癌的发生，促进CD8 + T细胞衰竭，并激活DC，导致其死亡。针对IL27和FFAR2激动剂的抗体可减少小鼠的肿瘤发生，可能会开发用于治疗CRC。