Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
Inflamm Bowel Dis. 2024 Mar 1;30(3):429-440. doi: 10.1093/ibd/izad158.
Exclusive enteral nutrition (EEN) with a liquid diet is the only established dietary treatment for Crohn's' disease (CD). However, the mechanism of action of EEN in CD is unclear. T helper 17 (Th17) immune response plays a critical role in CD. We hypothesized that EEN alleviates Th17 response by eliminating mechanical stress-induced expression of Th17-polarizing cytokines.
A rat model of Crohn's-like colitis was established by intracolonic instillation of TNBS (65 mg/kg in 250 µL of 40% ethanol). Control rats were treated with saline. We characterized immunophenotypes and molecular changes of the colon in control and colitis rats with and without EEN treatment. Th17 differentiation was determined using coculture assays.
TNBS instillation induced transmural inflammation with stenosis in the inflammation site and a marked increase of Th17-polarizing cytokines interleukin (IL)-6 and osteopontin and the Th17 cell population in the mechanically distended preinflammation site (P-site). EEN treatment eliminated mechanical distention and the increase of IL-6, osteopontin, and Th17 response in the P-site. IL-6 and osteopontin expression was found mainly in the muscularis externa. Mechanical stretch of colonic smooth muscle cells in vitro induced a robust increase of IL-6 and osteopontin. When naïve T cells were cultured with conditioned media from the P-site tissue or stretched cells, Th17 differentiation was significantly increased. Inhibition of IL-6, but not deletion of osteopontin, blocked the increase of Th17 differentiation.
Mechanical stress induces Th17-polarizing cytokines in the colon. EEN attenuates Th17 immune response by eliminating mechanical stress-induced IL-6 in Crohn's-like colitis.
肠内营养（EEN）是唯一确立的治疗克罗恩病（CD）的饮食治疗方法。然而，EEN 在 CD 中的作用机制尚不清楚。辅助性 T 细胞 17（Th17）免疫反应在 CD 中起着关键作用。我们假设 EEN 通过消除机械应激诱导的 Th17 极化细胞因子的表达来缓解 Th17 反应。
通过结肠内滴注 TNBS（250µL 40%乙醇中的 65mg/kg）建立大鼠克罗恩样结肠炎模型。对照组大鼠给予生理盐水处理。我们通过 EEN 治疗对对照组和结肠炎大鼠的结肠免疫表型和分子变化进行了特征描述。使用共培养测定法确定 Th17 分化。
TNBS 滴注诱导了炎症部位的壁层炎症伴狭窄，并导致机械扩张前炎症部位（P 部位）中 Th17 极化细胞因子白细胞介素（IL）-6 和骨桥蛋白以及 Th17 细胞群显著增加。EEN 治疗消除了机械扩张以及 P 部位中 IL-6、骨桥蛋白和 Th17 反应的增加。IL-6 和骨桥蛋白表达主要存在于外肌层。体外结肠平滑肌细胞的机械拉伸导致 IL-6 和骨桥蛋白的大量增加。当幼稚 T 细胞与 P 部位组织的条件培养基或拉伸细胞共培养时，Th17 分化明显增加。抑制 IL-6，但不是骨桥蛋白的缺失，阻断了 Th17 分化的增加。
机械应激诱导结肠中的 Th17 极化细胞因子。EEN 通过消除克罗恩样结肠炎中机械应激诱导的 IL-6 来减轻 Th17 免疫反应。
