# A Pediatric Microbial Community to Dissect Host-Commensal Interactions in Type 1 Diabetes

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $220,000

## 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 human leukocyte antigen (HLA)
haplotypes dominantly protect against the development of T1D, yet the mechanism of this remarkable
protection from autoimmunity is not well-understood. NOD mice, the most widely used model of T1D, do not
express a major histocompatibility complex (MHC) class II E molecule. Transgenic expression of the MHCII E
molecule in NOD mice (Eα16/NOD) completely prevents T1D, mirroring dominant HLA protection from T1D in
humans. Using these Eα16/NOD mice as a model of dominant genetic protection from T1D, we recently
demonstrated that protection from autoimmunity operates by the immune system shaping the early-life
commensal microbiota. Modeling of HLA class II dominant protection from T1D in murine models 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 are modulated by the immune system 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 have leveraged the Eα16/NOD
mouse model of genetic protection from T1D to generate a new gnotobiotic mouse model of the early-life
microbiome which we call Pediatric Community or “PedsCom-A”. PedsCom-A is a consortium of 9 bacterial
strains isolated from the intestine of pre-weaning diabetes-protected Eα16/NOD mice. We hypothesize that
MHCII molecules play a major role in shaping the intestinal microbiome early in development, and
these microbes in turn impact the development of the immune system to prevent T1D. Aim 1 examines
the mechanisms of interaction and colonization dynamics of these 9 bacteria in PedsCom-A colonized NOD
mice and NOD mice expressing the MHCII E molecule (Eα16/NOD). Aim 2 examines whether PedsCom-A
microbes prevents T1D in NOD and Eα16/NOD mice. Successful completion of these aims will provide critical
information on which early-life microbes are influenced by expression of the MHCII E molecule to generate a
diabetes-protective microbiome, and whether these 9 microbes that constitute PedsCom are sufficient to
prevents T1D in diabetes-prone NOD mice. In addition, PedsCom-A mice are an innovative tool for
investigating early-life host-microbiota interactions.

## Key facts

- **NIH application ID:** 10109980
- **Project number:** 5R21AI146629-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Michael A Silverman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $220,000
- **Award type:** 5
- **Project period:** 2020-02-19 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109980

## Citation

> US National Institutes of Health, RePORTER application 10109980, A Pediatric Microbial Community to Dissect Host-Commensal Interactions in Type 1 Diabetes (5R21AI146629-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10109980. Licensed CC0.

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