State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai, 200031, China.
Microbiome. 2023 Mar 29;11(1):62. doi: 10.1186/s40168-023-01507-z.
Dysbiotic gut microbiome, genetically predisposed or chemically disrupted, has been linked with insulin-dependent diabetes (IDD) including autoimmune type 1 diabetes (T1D) in both humans and animal models. However, specific IDD-inducing gut bacteria remain to be identified and their casual role in disease development demonstrated via experiments that can fulfill Koch's postulates.
Here, we show that novel gut pathobionts in the Muribaculaceae family, enriched by a low-dose dextran sulfate sodium (DSS) treatment, translocated to the pancreas and caused local inflammation, beta cell destruction and IDD in C57BL/6 mice. Antibiotic removal and transplantation of gut microbiota showed that this low DSS disrupted gut microbiota was both necessary and sufficient to induce IDD. Reduced butyrate content in the gut and decreased gene expression levels of an antimicrobial peptide in the pancreas allowed for the enrichment of selective members in the Muribaculaceae family in the gut and their translocation to the pancreas. Pure isolate of one such members induced IDD in wildtype germ-free mice on normal diet either alone or in combination with normal gut microbiome after gavaged into stomach and translocated to pancreas. Potential human relevance of this finding was shown by the induction of pancreatic inflammation, beta cell destruction and IDD development in antibiotic-treated wildtype mice via transplantation of gut microbiome from patients with IDD including autoimmune T1D.
The pathobionts that are chemically enriched in dysbiotic gut microbiota are sufficient to induce insulin-dependent diabetes after translocation to the pancreas. This indicates that IDD can be mainly a microbiome-dependent disease, inspiring the need to search for novel pathobionts for IDD development in humans. Video Abstract.
肠道微生物群落失调，无论是遗传易感性还是化学物质干扰，都与胰岛素依赖型糖尿病（IDDM）有关，包括人类和动物模型中的自身免疫性 1 型糖尿病（T1D）。然而，特定的 IDDM 诱导肠道细菌仍有待确定，其在疾病发展中的因果作用需要通过能够满足科赫假设的实验来证明。
在这里，我们表明，在 Muribaculaceae 科中存在新的肠道共生菌，通过低剂量的葡聚糖硫酸钠（DSS）处理而富集，这些共生菌易位到胰腺并引起局部炎症、β细胞破坏和 C57BL/6 小鼠的 IDDM。抗生素去除和肠道微生物群移植表明，这种低 DSS 破坏的肠道微生物群既是必要的，也是充分的，足以诱导 IDDM。肠道中丁酸含量降低和胰腺中抗菌肽基因表达水平降低，允许 Muribaculaceae 科中选择性成员的富集，并使其易位到胰腺。此类成员之一的纯分离株，无论是单独使用还是与正常肠道微生物群一起在无菌小鼠上使用正常饮食，通过灌胃进入胃后易位到胰腺，均可诱导 IDDM。通过将 IDDM 患者（包括自身免疫性 T1D）的肠道微生物群移植到抗生素处理的野生型小鼠中，诱导胰腺炎症、β细胞破坏和 IDDM 发展，证明了这一发现的潜在人类相关性。
化学上在失调肠道微生物群落中富集的条件致病菌足以在易位到胰腺后诱导胰岛素依赖型糖尿病。这表明 IDDM 主要可以是一种依赖微生物组的疾病，这激发了人们寻找人类 IDDM 发展的新型条件致病菌的必要性。
