Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
Gastroenterology. 2019 Jun;156(8):2266-2280. doi: 10.1053/j.gastro.2019.02.028. Epub 2019 Feb 22.
BACKGROUND & AIMS: Wheat-related disorders, a spectrum of conditions induced by the ingestion of gluten-containing cereals, have been increasing in prevalence. Patients with celiac disease have gluten-specific immune responses, but the contribution of non-gluten proteins to symptoms in patients with celiac disease or other wheat-related disorders is controversial.
C57BL/6 (control), Myd88, Ticam1, and Il15 mice were placed on diets that lacked wheat or gluten, with or without wheat amylase trypsin inhibitors (ATIs), for 1 week. Small intestine tissues were collected and intestinal intraepithelial lymphocytes (IELs) were measured; we also investigated gut permeability and intestinal transit. Control mice fed ATIs for 1 week were gavaged daily with Lactobacillus strains that had high or low ATI-degrading capacity. Nonobese diabetic/DQ8 mice were sensitized to gluten and fed an ATI diet, a gluten-containing diet or a diet with ATIs and gluten for 2 weeks. Mice were also treated with Lactobacillus strains that had high or low ATI-degrading capacity. Intestinal tissues were collected and IELs, gene expression, gut permeability and intestinal microbiota profiles were measured.
In intestinal tissues from control mice, ATIs induced an innate immune response by activation of Toll-like receptor 4 signaling to MD2 and CD14, and caused barrier dysfunction in the absence of mucosal damage. Administration of ATIs to gluten-sensitized mice expressing HLA-DQ8 increased intestinal inflammation in response to gluten in the diet. We found ATIs to be degraded by Lactobacillus, which reduced the inflammatory effects of ATIs.
ATIs mediate wheat-induced intestinal dysfunction in wild-type mice and exacerbate inflammation to gluten in susceptible mice. Microbiome-modulating strategies, such as administration of bacteria with ATI-degrading capacity, may be effective in patients with wheat-sensitive disorders.
由摄入含麸质谷物引起的一系列与小麦相关的疾病，其发病率正在上升。乳糜泻患者存在针对麸质的免疫反应，但非麸质蛋白对乳糜泻或其他与小麦相关疾病患者症状的贡献仍存在争议。
将 C57BL/6（对照）、Myd88、Ticam1 和 Il15 小鼠分别置于不含小麦或麸质的饮食中，同时给予或不给予小麦淀粉酶胰蛋白酶抑制剂（ATIs），为期 1 周。收集小肠组织并测量肠道上皮内淋巴细胞（IEL）；我们还研究了肠道通透性和肠道转运。将 ATIs 喂养 1 周的对照小鼠每日用具有高或低 ATI 降解能力的乳酸菌灌胃。非肥胖型糖尿病/DQ8 小鼠对麸质致敏并喂食 ATI 饮食、含麸质饮食或含 ATIs 和麸质的饮食 2 周。还使用具有高或低 ATI 降解能力的乳酸菌对小鼠进行处理。收集肠道组织，测量 IEL、基因表达、肠道通透性和肠道微生物组谱。
在对照小鼠的肠道组织中，ATIs 通过激活 Toll 样受体 4 信号转导至 MD2 和 CD14 诱导先天免疫反应，并在没有粘膜损伤的情况下引起屏障功能障碍。向表达 HLA-DQ8 的麸质致敏小鼠给予 ATIs 会增加饮食中麸质引起的肠道炎症。我们发现 ATIs 可被乳酸菌降解，从而降低 ATIs 的炎症作用。
ATIs 介导野生型小鼠的小麦诱导性肠道功能障碍，并加重易感小鼠对麸质的炎症反应。调节微生物组的策略，如给予具有 ATI 降解能力的细菌，可能对小麦敏感障碍患者有效。
