Hu Youjia, Jin Ping, Peng Jian, Zhang Xiaojun, Wong F Susan, Wen Li
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
J Autoimmun. 2016 Aug;72:47-56. doi: 10.1016/j.jaut.2016.05.001. Epub 2016 May 10.
Environmental factors clearly influence the pathogenesis of Type 1 diabetes, an autoimmune disease. We have studied gut microbiota as important environmental agents that could affect the initiation or progression of type 1 diabetes especially in the prenatal period. We used neomycin, targeting mainly Gram negative or vancomycin, targeting mainly Gram positive bacteria, to treat pregnant NOD mothers and to study autoimmune diabetes development in their offspring. Neomycin-treated offspring were protected from diabetes, while vancomycin-treated offspring had accelerated diabetes development, and both antibiotics caused distinctly different shifts in gut microbiota composition compared with the offspring from untreated control mice. Our study demonstrated that neomycin treatment of pregnant mothers leads to generation of immune-tolerogenic antigen-presenting cells (APCs) in the offspring and these APCs had reduced specific autoantigen-presenting function both in vitro and in vivo. Moreover, the protection from diabetes mediated by tolerogenic APCs was vertically transmissible to the second generation. In contrast, more diabetogenic inflammatory T cells were found in the lymphoid organs of the offspring from the vancomycin-treated pregnant mothers. This change however was not transmitted to the second generation. Our results suggested that prenatal exposure to antibiotic influenced gut bacterial composition at the earliest time point in life and is critical for consequent education of the immune system. As different bacteria can induce different immune responses, understanding these differences and how to generate self-tolerogenic APCs could be important for developing new therapy for type 1 diabetes.
环境因素显然会影响1型糖尿病（一种自身免疫性疾病）的发病机制。我们研究了肠道微生物群，它们作为重要的环境因素，可能会影响1型糖尿病的发病或进展，尤其是在产前阶段。我们使用主要针对革兰氏阴性菌的新霉素或主要针对革兰氏阳性菌的万古霉素来治疗怀孕的非肥胖糖尿病（NOD）小鼠母亲，并研究其后代自身免疫性糖尿病的发展情况。用新霉素治疗的后代可预防糖尿病，而用万古霉素治疗的后代糖尿病发展加速，与未治疗的对照小鼠的后代相比，这两种抗生素都导致肠道微生物群组成发生明显不同的变化。我们的研究表明，对怀孕母亲进行新霉素治疗会导致其后代产生免疫耐受性抗原呈递细胞（APC），并且这些APC在体外和体内的特异性自身抗原呈递功能均降低。此外，由耐受性APC介导的对糖尿病的保护作用可垂直传递给第二代。相比之下，在接受万古霉素治疗的怀孕母亲的后代的淋巴器官中发现了更多促糖尿病的炎性T细胞。然而，这种变化并未传递给第二代。我们的结果表明，产前接触抗生素会在生命的最早时间点影响肠道细菌组成，并且对随后的免疫系统发育至关重要。由于不同的细菌可诱导不同的免疫反应，了解这些差异以及如何产生自身耐受性APC可能对开发1型糖尿病的新疗法很重要。
