SLC5A8 is a conditional tumor suppressor in colon linked to dietary fiber content

 描述(申请人提供)：LC5A8首先在结肠中被确定为候选肿瘤抑制因子。我们证明了它是短链脂肪酸(SCFA)的钠偶联转运体，它能使短链脂肪酸丁酸盐(一种膳食纤维的细菌发酵产物和组蛋白脱乙酰酶抑制剂)进入细胞内，这是其在结肠中抑制肿瘤功能的基础。然而，对SLC5A8-/-小鼠的体内研究未能支持这种功能。现在我们发现SLC5A8预防结肠炎和结肠癌的能力是由膳食纤维含量决定的。运输人对受益者负有义务。 仅当单链脂肪酸的腔内浓度较低(低纤维摄入量)时，单链脂肪酸对结肠上皮细胞的影响。相比之下，转运蛋白在粘膜免疫细胞中的强制性作用 不依赖于膳食纤维的含量。我们推测SLC5A8在结肠中是一种条件性肿瘤抑制因子，对维持粘膜免疫系统的耐受性表型是必不可少的，但其在结肠上皮细胞和LP免疫细胞中的作用受到膳食纤维含量的不同影响。此外，我们假设SLC5A8和最佳膳食纤维可以防止肠道内的细菌失调，后者已知会导致结肠炎和癌症。我们将通过完成以下特定目标来验证这些假设：(1)通过定性和定量地增加结肠中抗炎树突状细胞和免疫抑制树突状细胞的数量，证明SLC5A8对于粘膜免疫系统的免疫耐受表型是必不可少的，并确定膳食纤维含量与这一过程的相关性；(1B)描绘在低纤维和高纤维条件下野生型和SLC5A8-/-小鼠的肠道微生物区系的系统发育概况，以确定SLC5A8缺失和/或低膳食纤维是否导致肠道细菌失调，从而导致低纤维饮食条件下SLC5A8-/-小鼠结肠炎和结肠癌加重；(2A)使用选择性删除上皮细胞或髓系细胞中SLC5A8的条件基因敲除小鼠，询问结肠上皮细胞中SLC5A8与髓系细胞中SLC5A8在保护实验性结肠炎中的作用；(2B)询问结肠上皮细胞中SLC5A8与髓系细胞中SLC5A8在保护作用中的作用 利用选择性缺失SLC5A8的条件基因敲除小鼠，在低纤维和高纤维饮食条件下抗实验性结肠癌；(3)剖析在低纤维和高纤维饮食条件下，SLC5A8在结肠上皮细胞和脂蛋白树突状细胞中组蛋白乙酰化和随后的转录组图谱的变化，这些变化导致SLC5A8能够预防结肠炎和结肠癌。

 DESCRIPTION (provided by applicant): LC5A8 was first identified as a candidate tumor suppressor in colon. We showed that it is a Na+-coupled transporter for short-chain fatty acids (SCFAs) and that its ability to energize the cellular entry of the SCFA butyrate, a bacterial fermentation product of dietary fiber and an inhibitor of histone deacetylases, underlies its tumor-suppressive function in colon. However, in vivo studies with Slc5a8-/- mice failed to support such a function. Now we found that the ability of Slc5a8 to protect against colitis and colon cancer is dictated by dietary fiber content. The transporter is obligatory for the beneficial effects of SCFAs in colonic epithelial cells only when the luminal concentrations of SCFAs are low (low fiber intake). In contrast, the obligatory role of the transporter in mucosal immune cells is not dependent on dietary fiber content. We hypothesize that SLC5A8 is a conditional tumor suppressor in colon and is essential for the maintenance of the tolerogenic phenotype of the mucosal immune system, but the obligation of its role in colonic epithelial cells and LP immune cells is differentially influenced by the dietary fiber content. In addition, we hypothesize that SLC5A8 and optimal dietary fiber protect against bacterial dysbiosis in the gut, which is known to drive inflammation and cancer in colon. We will test these hypotheses by completing the following specific aims: (1A) Show that Slc5a8 is essential for the immunotolerant phenotype of the mucosal immune system by qualitatively and quantitatively increasing the number of anti- inflammatory dendritic cells and immunosuppressive Tregs in colon, and determine the relevance of dietary fiber content to this process; (1B) Delineate the phylogenetic profile of gut microbiota in wild type and Slc5a8-/- mice under low-fiber & high-fiber conditions to determine if bacterial dysbiosis occurs in the gut as a consequence of Slc5a8 deletion and/or low dietary fiber, thus driving the increased severity of colitis and enhanced colon cancer observed in Slc5a8-/- mice under low-fiber dietary conditions; (2A) Interrogate the contribution of Slc5a8 in colonic epithelial cells versus Slc5a8 in myeloid cells to the protection against experimental colitis under low-fiber & high-fiber dietary conditions using conditional knockout mice with selective deletion of Slc5a8 either in epithelial cells or in myeloid cells; (2B) Interrogate the contribution of Slc5a8 in colonic epithelial cells versus Slc5a8 in myeloid cells to the protection against experimental colon cancer under low-fiber & high-fiber dietary conditions using conditional knockout mice with selective deletion of Slc5a8 either in epithelial cells or in myeloi cells; (3) Dissect the changes in histone acetylation and consequent transcriptome landscape in colonic epithelial cells and LP dendritic cells that are responsible for the ability of Slc5a8 to protect against colitis and colon cancer under low-fiber & high-fiber dietary conditions.