Division of Microbiology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
PLoS One. 2011 Apr 12;6(4):e18648. doi: 10.1371/journal.pone.0018648.
A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta).
Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes.
When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories--cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function--this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes.
CONCLUSIONS/SIGNIFICANCE: A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research.
本研究采用非人灵长类动物（NHP）的麸质敏感性模型，研究与饮食麸质变化相关的基因扰动，这些变化发生在来自麸质敏感恒河猴（Macaca mulatta）的小肠组织中。
通过给予无麸质（GFD）和含麸质（GD）饮食，在先前描述的麸质敏感动物中实现缓解和复发阶段。在 GFD 或 GD 期间，通过儿科内窥镜从十二指肠获得针状大小的活检，用于准备总 RNA 和基因谱，使用商业恒河猴微阵列（Agilent Technologies），靶向 20000 多个基因的表达。
与正常健康对照相比，麸质敏感的猴子显示由 GD 诱导的差异基因表达。虽然观察到的基因扰动被分类为 12 个重叠类别之一——癌症、代谢、消化道功能、免疫反应、细胞生长、信号转导、自身免疫、外源性毒物解毒、细胞凋亡、肌动蛋白-胶原沉积、神经元和未知功能——但本研究侧重于癌症相关的基因网络，如细胞色素 P450 家族（解毒功能）和肌动蛋白-胶原-基质金属蛋白酶（MMP）基因。
结论/意义：在 GD 时，麸质敏感动物中显示出解毒功能丧失，同时需要代谢致癌物。观察到癌症促进因子增加，同时与肌动蛋白-胶原-MMP 基因网络表达改变相关的癌症预防因子减少。此外，在停止饮食麸质后，麸质敏感的猴子表现出差异表达基因数量减少，包括与癌症相关的基因。综上所述，这些发现表明，麸质敏感的恒河猴在癌症研究中具有潜在的扩展用途。
