Pathobionts from chemically disrupted gut microbiota induce insulin-dependent diabetes in mice
Xin Yang,
Zhiyi Wang,
Junling Niu,
Rui Zhai,
Xinhe Xue,
Guojun Wu,
Yuanyuan Fang,
Guangxun Meng,
Huijuan Yuan,
Liping Zhao,
Chenhong Zhang
Affiliations
Xin Yang
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
Zhiyi Wang
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
Junling Niu
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
Rui Zhai
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
Xinhe Xue
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
Guojun Wu
Department of Biochemistry and Microbiology and New Jersey Institute for Food, Nutrition, and Health, School of Environmental and Biological Sciences, Rutgers University
Yuanyuan Fang
Department of Endocrinology of Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University
Guangxun Meng
The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, University of Chinese Academy of Sciences
Huijuan Yuan
Department of Endocrinology of Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University
Liping Zhao
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
Chenhong Zhang
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
Abstract Background 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. Results 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. Conclusion 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
