Reconstruction characteristics of gut microbiota from patients with type 1 diabetes affect phenotypic reproducibility of glucose metabolism in mice

This study is reported by Chenhong Zhang’s group from the State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University. The human microbiota-associated (HMA) mice model has been widely used to probe the causal relationship between gut microbiota and human diseases, but only about 29% of studies confirm human donor microbiota replication in recipient animals. This is like "the elephant in the room", which greatly impacts result reliability and replicability, and hinders the diagnosis and treatment of diseases targeting microbiota. The HMA mice model is utilized to examine how the gut microbiota regulates environmental factors affecting T1D development. Nevertheless, the relationship between microbiota replication and the reproducibility of glucose metabolism phenotypes in HMA mice remains unclear. The authors explored how the microbiota from human donors with T1D reassembled in germ-free mice and further affected the glucose metabolic phenotypes in mice.

The team included five T1D patients and four healthy volunteers as human donors, and transplanted the fecal microbiota of each donor to 10 germ-free mice. A big variation was found in the phenotypic reproducibility of glucose metabolism in mice corresponding to different donors. Not all of the mice with microbiota from T1D patients successfully exhibited hyperglycemia and even displayed lower fasting blood glucose levels than mice with microbiota from healthy volunteers. The recipient mice were allocated into the T1D-S and H-S groups with successful phenotypic reproducibility, and T1D-F and H-F groups with failed phenotypic reproducibility based on seven glucose metabolism parameters.

Microbiota analysis revealed that the recipient mice with more similar microbiota diversity and structure to the corresponding donor better reproduced the donor phenotypes. The microbial community assembly of human donor microbiota corresponding to mice with more disordered glucose metabolism was dominated by stochastic processes (eg. birth, death, extrapolation, and specialization). The microbes enriched in T1D patients also exhibited a stronger colonization potential in these mice. What’s more, better replication of phenotype-related microbiota functional features was found in these mice.

The study reveals that it is important to evaluate the donor microbiota replication in HMA mice and confirm its relationship with phenotypic reproducibility.

“To utilize the HMA animal model more effectively in the future, we recommend setting standardized operation protocols first and verifying the replication of donor microbiota from multiple perspectives, especially the colonization of phenotype-related key microbiota members, with the help of the multi-omics analysis before evaluating the disease phenotypes in HMA animal model.” Chenhong Zhang, the lead author of the study, noted.

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Reconstruction characteristics of gut microbiota from patients with type 1 diabetes affect phenotypic reproducibility of glucose metabolism in mice