# Leveraging early-life microbes to prevent type 1 diabetes

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $707,748

## Abstract

PROJECT SUMMARY
Type 1 diabetes (T1D) is an autoimmune disease that affects millions of people worldwide. The incidence of
T1D is rising, especially in young children. Although significant progress has been made to predict who is at risk
for developing T1D, there are no effective therapies to prevent this disease. Both genetic and environmental
factors contribute to the risk of developing T1D. Certain major histocompatibility complex/human leukocyte
antigen (MHC/HLA) class II haplotypes dominantly protect against the development of T1D, and we recently
discovered that protective MHCII molecules shape early-life microbial communities which in turn impact immune
system development to prevent T1D. Modeling microbial protection from T1D in NOD mice may provide critical
insights to support our long-term goal of developing microbiota-based therapies to prevent T1D in humans. Due
to the complexity and high levels of variability of the intestinal microbiome, determining the specific microbial
strains that drive immune system development and function is problematic. The development of gnotobiotic mice
with defined adult microbial communities has been an important advance in the field because they simplify the
complexity and variability of the system and allow for well-controlled, mechanistic studies. However, a gnotobiotic
mouse model to study pediatric disease is lacking. We developed a new gnotobiotic mouse model of the early-
life microbiome which we call Pediatric Community or “PedsCom”. PedsCom is a consortium of 9 bacterial
strains isolated from the intestine of pre-weaning diabetes-protected Eα16/NOD mice. Remarkably, this 9-
microbe community robustly induces regulatory T cells (Tregs) and confers protection from T1D to diabetes-
susceptible NOD mice. We hypothesize that specific PedsCom microbes work in concert to prevent T1D
by providing microbial antigens and metabolites that induce peripheral regulatory T cells (pTregs) during
a critical early life window of immune system development. Aim 1 examines the timing, localization, and
metabolites produced by specific PedsCom members which drive pTreg cell development and prevent
autoimmunity. Aim 2 examines the mechanisms by which pTregs are induced by PedsCom microbes and their
protein antigens and whether pTregs whose TCRs recognize specific microbial antigens mediate protection from
T1D. Successful completion of these aims will provide critical information on which early-life microbes induce
pTregs, and the degree to which microbial antigens and metabolites work together to generate a diabetes-
protective immune system. In addition, PedsCom mice are an innovative tool for investigating early-life host-
microbiota interactions.

## Key facts

- **NIH application ID:** 10817840
- **Project number:** 5R01DK133453-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Michael A Silverman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $707,748
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817840

## Citation

> US National Institutes of Health, RePORTER application 10817840, Leveraging early-life microbes to prevent type 1 diabetes (5R01DK133453-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10817840. Licensed CC0.

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