Early-life antibiotic exposure perturbs the microbiome, dysregulates intestinal immune gene expression, and accelerates and amplifies type 1 diabetes (T1D) development in NOD mice. We have previously shown that cecal microbiota transfer (CMT) from healthy donors rescues antibiotic-induced T1D development via restoration of intestinal microbiota and baseline immune parameters. To better understand the role of specific members of the gut microbiome in T1D development, we conventionalized germ-free (GF) recipients with cecal microbiota from three donor mouse groups that had been treated as follows: 1) [Control] received PBS only; 2) [Antibiotic] (tylosin) -disrupted microbiome; and 3) given tylosin as in 2) , followed by cecal microbiota gavage [CMT-restored microbiome]. In the now-conventionalized mice, those that received the CMT-restored microbiome had a lower rate of T1D development than those that received the antibiotic-perturbed microbiota. This showed that the disease phenotypes in one generation can be transferred into the next. Conventionalization with the CMT-restored microbiota led to the most diverse microbiomes and lowest expression of antimicrobial, immune and mucin genes. Surprisingly, gavage with the Control inoculum failed to protect the conventionalized recipients against T1D development compared with the antibiotic group, led to low diversity microbiomes, low abundance of taxa S24-7 and Oscillospira, and increased expression of antimicrobial, immune, and mucin synthesis genes. We conclude that: 1) The CMT protective effect is transferrable to the next generation, and 2) the very low density of S24-7 and Oscillospira in the GF recipients conventionalized with the Control inoculum led to decreased microbiome richness and evenness, increased gene expression, and loss of T1D protection. The effects of these two taxa on T1D development in NOD mice should be further studied.

Disclosure

S.Pan: None. X.Zhang: None. M.J.Blaser: None.

Funding

National Institutes of Health (UAI22285) ; Fondation LeDucq (TransAtlantic Program 17CVD01)

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