Abstract：
The main cause of inflammatory bowel disease (IBD) is abnormal intestinal permeability due to the disruption of the tight junction of the intestinal barrier through a pathogen-mediated inflammatory mechanism and an imbalance of the gut microbiota. This study aimed to evaluate whether 2-ketoglutaric acid alleviated permeability dysfunction with tight junction localization, activated the transforming growth factor beta-activated kinase 1 (TAK1) inflammation pathway, and regulated the homeostasis of the intestinal microbiome in vitro and in vivo IBD model. Our findings revealed that 2-ketoglutaric acid significantly suppressed abnormal intestinal permeability, delocalization of tight junction proteins from the intestinal cell, expression of inflammatory cytokines, such as TNF-α, both in vitro and in vivo. 2-Ketoglutaric acid was found to directly bind to TAK1 and inhibit the TNF receptor-associated factor 6 (TRAF6)-TAK1 interaction, which is related to the activation of nuclear factor kappa B (NF-κB) pathways, thereby regulating the expression of mitogen-activated protein kinase. Dietary 2-ketoglutaric acid also alleviated gut microbiota dysbiosis and IBD symptoms, as demonstrated by improvements in the intestine length and the abundance of Ligilactobacillus, Coriobacteriaceae_UCG_002, and Ruminococcaceae_unclassified in mice with colitis. This study indicated that 2-ketoglutaric acid binds to TAK1 for activity inhibition which is related to the NF-κB pathway and alleviates abnormal permeability by regulating tight junction localization and gut microbiome homeostasis. Therefore, 2-ketoglutaric acid is an effective nutraceutical agent and prebiotic for the treatment of IBD.
摘要：
炎症性肠病（IBD）的主要原因是肠道通透性异常，这是由于通过病原体介导的炎症机制破坏了肠道屏障的紧密连接以及肠道微生物群的失衡。本研究旨在评估2-酮戊二酸是否通过紧密连接定位缓解了渗透性功能障碍，激活转化生长因子β激活激酶1（TAK1）炎症途径，并在体外和体内IBD模型中调节肠道微生物组的稳态。我们的发现表明，2-酮戊二酸显着抑制异常肠通透性，肠细胞紧密连接蛋白的离域，炎性细胞因子的表达，如TNF-α，在体外和体内。发现2-酮戊二酸直接与TAK1结合并抑制TNF受体相关因子6（TRAF6）-TAK1相互作用，与核因子κB（NF-κB）途径的激活有关，从而调节丝裂原活化蛋白激酶的表达。膳食2-酮戊二酸还可以缓解肠道微生物群失调和IBD症状，如肠道长度的改善和双鞭毛杆菌的丰度所证明的那样，在结肠炎小鼠中未分类的Coriobacteriaceae_UCG_002和Ruminococaceae_。这项研究表明，2-酮戊二酸与TAK1结合以抑制与NF-κB途径相关的活性，并通过调节紧密连接定位和肠道微生物组稳态来减轻异常通透性。因此,2-酮戊二酸是用于治疗IBD的有效营养制剂和益生元。
