Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is development of autoantibodies and T-cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these, one peptide, found in the normal human gut commensal Parabacteroides distasonis, activated both human T cell clones from T1D patients and T-cell hybridomas from non-obese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with P. distasonis insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells and destructive CD8+ T-cells, while decreasing FoxP3+ regulatory T-cells. Western blot analysis identified P. distasonis reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human infant gut microbiome data revealed that exposure of infants to P. distasonis may modulate disease pathogenesis. Taken together, these data demonstrate the potential role for an insB:9-23-mimimetic peptide from gut microbiota as a molecular trigger or modifier of T1D pathogenesis.

中文翻译：

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1 型糖尿病发病机制中的肠道微生物肽和分子模拟

1型糖尿病（T1D）是一种以胰腺β细胞破坏为特征的自身免疫性疾病。这一过程的最早方面之一是针对胰岛素 B 链中表位的自身抗体和 T 细胞的开发 (insB:9-23)。对与 insB:9-23 序列具有同源性的微生物蛋白质序列的分析揭示了 17 个肽，其与 insB:9-23 具有 >50% 的同一性。其中，一种存在于正常人类肠道共生Parabacteroides distasonis中的肽激活了来自 T1D 患者的人类 T 细胞克隆和来自非肥胖糖尿病 (NOD) 小鼠的对 insB:9-23 具有特异性的 T 细胞杂交瘤。用P. distasonis insB:9-23 肽模拟物或 insB:9-23 肽对 NOD 小鼠进行免疫验证了免疫交叉反应性。雌性 NOD 小鼠的定植P. distasonis加速了 T1D 的发展，增加了巨噬细胞、树突状细胞和破坏性 CD8+ T 细胞，同时减少了 FoxP3+ 调节性 T 细胞。蛋白质印迹分析鉴定了 P. distasonis定殖的 NOD 小鼠和人类 T1D 患者血清中的P. distasonis反应抗体。此外，将脾细胞从P. distasonis处理的小鼠过继转移到 NOD/SCID 小鼠会增强受体的疾病表型。最后，对人类婴儿肠道微生物组数据的分析表明，婴儿接触P. distasonis可以调节疾病的发病机制。总之，这些数据证明了来自肠道微生物群的 insB:9-23-模拟肽作为 T1D 发病机制的分子触发或调节剂的潜在作用。