Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
J Autoimmun. 2022 Feb;127:102795. doi: 10.1016/j.jaut.2022.102795. Epub 2022 Jan 31.
Experimental and clinical data suggest that a gluten-free diet attenuates the development of type 1 diabetes. A gluten-free diet changes the gut microbiota composition, and such microbial changes are expected to reduce the autoimmune responses. However, in experiments with laboratory mice, a gluten-free diet changes the gut microbiota differently under varying experimental settings, questioning the specific role of the gut microbes. Here we show that a maternal gluten-free diet until weaning of their pups, delayed type 1 diabetes in both dams (parent generation) and offspring (F1 generation) of untreated non-obese diabetic (NOD) mice and in mice treated with a full cocktail of antibiotics that eradicates most of the existing microbiota. Breeding a second (F2) generation of NOD mice, never exposed to the gluten-free diet or the associated microbial changes, also demonstrated a preventative effect on type 1 diabetes even though their parents (the F1 generation) had only been on a gluten-free diet very early in life. Collectively, the experimental data, thus, points towards microbiota-independent dietary protection. Furthermore, both the perinatal gluten-free diet and antibiotic treatment reduced inflammation in the salivary glands and improved glucose challenged beta cell function in the F1 offspring. However, in contrast to the autoimmune response in the pancreas, those changes appeared to be microbiota dependent, as they were missing in the antibiotic treated mice, and do, therefore, not seem to be related to the preventative effect on type 1 diabetes. Interestingly, adoptive transfer of splenocytes from gluten-free fed mice protected NOD.SCID mice from developing diabetes, demonstrating that the anti-diabetic effect of a gluten-free diet was based on early life changes in the evolving immune system. In particular, genes involved in regulation of lymphocyte activation, proliferation, and cell adhesion were highly expressed in the spleen in gluten-free fed mice at weaning compared to control fed mice of the F1 generation, which suggested that gluten promotes autoimmunity by inhibiting immune regulation, though the involvement of the specific genes needs further investigation. In conclusion, gluten-free diet reduces autoimmune inflammation in salivary glands and pancreas in NOD mice in a microbiota-dependent and -independent manner respectively, and has preventative effect on type 1 diabetes by modulating the systemic immune system.
实验和临床数据表明，无麸质饮食可减轻 1 型糖尿病的发展。无麸质饮食会改变肠道微生物群落的组成，而这种微生物变化预计会减少自身免疫反应。然而，在实验室小鼠的实验中，在不同的实验环境下，无麸质饮食会改变肠道微生物群落，这使得肠道微生物的具体作用受到质疑。在这里，我们表明，母鼠在断奶前接受无麸质饮食，可延迟未经处理的非肥胖型糖尿病（NOD）小鼠及其后代（F1 代）和接受全抗生素鸡尾酒治疗的小鼠（该治疗根除了大部分现有微生物群）的 1 型糖尿病的发生。繁殖第二代（F2）NOD 小鼠，它们从未接触过无麸质饮食或相关的微生物变化，也证明了即使它们的父母（F1 代）在生命早期仅接受过无麸质饮食，也能预防 1 型糖尿病。总的来说，实验数据表明，这种饮食保护作用是独立于微生物的。此外，围产期无麸质饮食和抗生素治疗均降低了 F1 后代唾液腺的炎症，并改善了葡萄糖刺激的β细胞功能。然而，与胰腺中的自身免疫反应相反，这些变化似乎依赖于微生物群，因为在接受抗生素治疗的小鼠中这些变化缺失，因此似乎与预防 1 型糖尿病无关。有趣的是，从接受无麸质饮食的小鼠中转移的脾细胞可保护 NOD.SCID 小鼠免于发生糖尿病，这表明无麸质饮食的抗糖尿病作用是基于免疫系统发育过程中的早期生活变化。特别是，与对照喂养的 F1 代小鼠相比，在断奶时，无麸质喂养的小鼠的脾脏中高度表达了参与淋巴细胞激活、增殖和细胞黏附调节的基因，这表明麸质通过抑制免疫调节促进自身免疫，尽管具体基因的参与需要进一步研究。总之，无麸质饮食以依赖于微生物群和独立于微生物群的方式降低 NOD 小鼠唾液腺和胰腺中的自身免疫性炎症，并且通过调节全身免疫系统对 1 型糖尿病具有预防作用。
