# Microbial and Host Factors in the Progression to Celiac Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $792,071

## Abstract

PROJECT SUMMARY
Celiac disease (CeD) is an immune-mediated enteropathy that occurs when genetically susceptible individuals
consume gluten. CeD affects >1% of the US population, and its prevalence is rising. HLA-DQ2 and/or DQ8
haplotypes are necessary for the development of CeD. However, only ~3% of individuals with these risk alleles
develop CeD, suggesting a role for environmental factors and gene-by-environment interactions in the initiation
and pathogenesis of this disease. Diagnosis of this lifelong disease obligates strict adherence to a restrictive
diet, which markedly reduces quality of life. Potential celiac disease (PCeD) is used to describe individuals with
HLA-DQ2/HLA-DQ8 risk alleles and circulating antibodies to tissue transglutaminase and endomysium, and yet
normal duodenal villous architecture. PCeD can progress to CeD (PCeD-P), revert to seronegativity, or remain
persistently seropositive without abnormal small bowel histology (PCeD that is static (PCeD-S)). The PCeD
population provides a unique ability to define the cascade of microbial and host factors culminating in CeD.
Insight into the mechanisms that lead to the loss of gluten tolerance and resulting tissue injury will provide reliable
markers of disease progression, aid in case management, and offer an opportunity to prevent the progression
to mucosal injury. To do this, we will recruit children with suspected CeD based on positive serology and children
with negative celiac serology undergoing upper endoscopy at Washington University and University of Alabama.
This will allow us to compare paired plasma, stool, duodenal biopsies, duodenal fluid aspirates, and clinical
metadata from four gluten consuming groups (newly diagnosed treatment naïve CeD, PCeD-P, PCeD-S, and
non-CeD controls). To determine if there are transcriptomic signatures in children with PCeD who subsequently
develop histologically proven CeD (PCeD-P), we will perform spatial transcriptomics on biopsies from PCeD
participants and sex, age, and race matched CeD and non-CeD controls. Previously, we demonstrated that a
subset of CD8+ T cells expressing killer cell immunoglobulin-like receptors (KIR) are increased in frequency in
the blood and duodenum of adults with CeD and suppress pathogenic gliadin specific CD4+ T cells. We will
determine the frequency of KIR+CD8+ T cells, gliadin specific CD4+ T cells, and the ratio of these cells among
CeD, PCeD, and non-CeD controls. Additionally, we will determine the transcriptomic and TCR clonality shifts
within KIR+CD8+ T cells and associate these to CeD progression. Understanding the interplay between CD4+
T cells and CD8+ T cells will help in assessing the contribution of adaptive immune system in CeD progression
in children. We do not know if microbial differences drive small bowel CeD inflammation, or vice-versa. By
systematically comparing the gut (small bowel and stool) bacterial microbiome and virome of children with biopsy
confirmed CeD, PCeD-P, PCeD-S, and n...

## Key facts

- **NIH application ID:** 10872801
- **Project number:** 1R01AI183261-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Lori R Holtz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $792,071
- **Award type:** 1
- **Project period:** 2024-06-12 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872801

## Citation

> US National Institutes of Health, RePORTER application 10872801, Microbial and Host Factors in the Progression to Celiac Disease (1R01AI183261-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10872801. Licensed CC0.

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