Human gut microbiota transferred to germ-free NOD mice slow the progression of T1D regardless of the pace of beta cell function loss in human donor

Background: The remission of T1D is a clinically valuable period whose extension would greatly benefit the patients. We investigated whether the ability of newly diagnosed T1D patients to conserve beta-cell capacity is transmissible through the gut microbiome to germ-free (GF) non-obese diabetic (NOD) mice.

Methods: Children with T1D, aged 9 to 15 years, were followed up for the loss of their C-peptide area under the curve in paired mixed meal tolerance tests performed at 1 month and again at 12 months after T1D onset. Five children were chosen for microbiota transfer, 2 with rapid loss of beta cell function (>75% over 1 year) and 3 with slow progression of the beta cell destruction (<27% over 1 year). Their filtered stool was transferred each into one colony of 15-25 GF NOD mice. An additional colony of GF NOD mice was kept sterile to serve as a control. The mice colonies were followed for T1D incidence weekly and their stools were analysed for bacterial composition in 2 weeks intervals.

Results: Mice reproduced the bacterial composition of the donor stool suboptimally, with a significantly decreased alpha diversity (p<10-5), and with a massive increase in the phylum Bacteroidetes to the detriment of the Firmicutes phylum. T1D incidence was significantly decreased in all mice colonies with humanized microbiota as compared to the germ-free control colony. Mouse colonies with microbiota from patients with rapid or slow loss of beta cell capacity did not differ in the progression towards T1D but their microbiomes profoundly differed in certain species (Akkermansia muciniphila, Dysgonomonas sp., Bacteroides vulgatus/dorei).

Conclusions: The phenotype of beta cell capacity preservation after T1D onset is not likely to be transferrable by stool microbiota to the NOD mouse model. This result may have implications for design of novel human intervention studies.