Exposure to a Single Early Life Antibiotic Pulse Accelerated Type 1 Diabetes Development in NOD Mice

Presentation Number: SUN 599
Date of Presentation: April 2nd, 2017

Xue-Song Zhang*1, Alexandra Livanos1, Victoria E Ruiz1, Jackie Li1, Thomas Battaglia1, Sandy Ng1, Rachel Sibley1, Anthony Williamson2, Marcus Rauch2 and Martin J Blaser1
1New York University Langone Medical Center, New York, NY, 2Janssen Prevention Center, London, United Kingdom


Type 1 Diabetes (T1D), an autoimmune disease, is rising in incidence around the world with a decreasing average age of onset and changed environmental triggers may account for this rise. Our recent studies of exposing non-obese diabetic (NOD) mice to 3 pulses of antibiotic (tylosin) treatment (3PAT) during D10-40 of life provided evidence that early-life antibiotic exposure alters the gut microbiota, significantly affecting immune system development and promoting T1D development (1). We now have developed a model to test the hypothesis that a single PAT (tylosin) exposure earlier in life (D5-10) (1PAT) is sufficient to perturb gut microbiome development and increases T1D development. NOD mice were bred and litters exposed to either 1PAT or 3PAT (non-acidified water alone as control). T1D development was monitored by measuring blood glucose and pancreatic islet histology. The gut microbiota was evaluated by high-throughput 16S rRNA Illumina sequencing followed by QIIME and LEfSe analyses. PAT-exposed or control NOD mice were sequentially sacrificed and the host ileal immune-response gene expression profiles were analyzed by NanoString and potentially involved pathways were further evaluated by RT-qPCR. Both 1PAT and 3PAT significantly and similarly accelerated T1D development in male NOD mice. Sequence analysis revealed that 1PAT dramatically decreased gut bacterial diversity over the long-term. Several specific taxa were identified that were irreversibly decreased in early life by 1PAT, which could potentially be protective against T1D onset. ELISA analysis indicated that fecal IgA was decreased by 1PAT for at least 6 weeks. NanoString and follow-up RT-qPCR revealed that 1PAT significantly repressed expression of multiple components in pathways involved in innate and adaptive immunity. In summary, our results provide evidence that early life gut microbiome perturbation by single pulse antibiotic treatment at levels that are therapeutically given to human children affects both adaptive and innate immunity and accelerates T1D onset, possibly through effects on particular taxa.


Disclosure: AW: Principal Investigator, Johnson &Johnson. MR: Principal Investigator, Johnson &Johnson. Nothing to Disclose: XSZ, AL, VER, JL, TB, SN, RS, MJB