# Uncovering pathogenic anti-bacterial defense mechanisms to identify novel targets for prevention of T1D

> **NIH NIH U01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $587,404

## Abstract

Abstract
While contemporary research has shown Type 1 diabetes (T1D) is associated with intestinal
dysbacteriosis and leakage, it is not known whether these factors cause the disease.
Establishing a causative link between the onset and progression of T1D and dysbacteriosis is
critical for developing effective prevention strategies. The overarching hypothesis of this
application is that T1D is preceded by pancreatic bacterial exposure, which promotes an anti-
bacterial response, pancreatic inflammation, insulitis, and autoimmunity. This hypothesis was
formulated based on our preliminary data demonstrating: 1) heightened anti-bacterial
responses in juvenile T1D; 2) pathologic responses by islets to bacteria overrepresented in the
T1D microbiome; 3) pancreatic inflammation and insulitis in a mouse model of experimental
leakage of bacteria into the pancreas; and 4) blockade of the anti-bacterial response protects
islets from insulitis. In aim 1 we will determine whether human T1D development is
preceded by a cellular and humoral anti-bacterial response and establish an association
with the duodenal microbiome. We will test whether bacteria-responsive MAIT cells are
activated before clinical disease develops and determine if they are differentially activated by
overrepresented bacteria. Next, we will discover whether the increased anti-bacterial IgA
response in T1D is directed at overrepresented bacteria. We will profile the duodenal
microbiome and determine if it is associated with these defense mechanisms. In aim 2 we will
ascertain whether pancreatic exposure to bacteria leads to immune activation, insulitis,
and hyperglycemia. We will determine whether pancreatic islets show distinct responses to
specific T1D-associated bacteria including R. gnavus, B. Dorei, and S. infantarius. Lastly, we
will interrogate the mediators of inflammation and insulitis following pancreatic exposure to
overrepresented bacterial species and test strategies to block the response. To accomplish this
task, we have established a novel mouse animal of intestinal dysbiosis and leakage to
test therapeutic interventions. The proposed experiments will identify pathogenic
mechanisms that link intestinal dysbiosis and leakage to T1D uncovering new targets for
prevention. These targets will undergo preclinical testing in this application. This submission is
responsive to the U01 Cooperative Study Group for Autoimmune Disease Prevention
(CSGADP) RFA. Broad area of interest: Pathways, mechanisms, and means best suited to
practical preventive interventions. Specific research topic: Identification and elucidation of
cellular and immune pathways that may provide targets for preventive interventions.

## Key facts

- **NIH application ID:** 9972883
- **Project number:** 5U01AI130841-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Nora E Sarvetnick
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $587,404
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972883

## Citation

> US National Institutes of Health, RePORTER application 9972883, Uncovering pathogenic anti-bacterial defense mechanisms to identify novel targets for prevention of T1D (5U01AI130841-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9972883. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*