# Role of gut protists in celiac disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $621,342

## Abstract

Project Summary
Celiac disease (CeD) is mediated by abnormal immune responses to gluten antigens found in wheat, barley,
and rye and has an estimated prevalence of 1% in the general US population. Normally, tolerogenic dendritic
cells (DCs) sample dietary antigens from the intestinal lumen and are central in establishing and maintaining oral
tolerance. In persons with CeD the suppression of gluten-specific immune responses is impaired (loss of oral
tolerance (LOT)). LOT is characterized by dampened regulatory T cell (Treg) responses, resulting in
inflammatory T helper 1 (Th1) immune responses against gluten in genetically susceptible individuals expressing
the human leukocyte antigen (HLA) DQ2 or DQ8 alleles. The Th1 response against gluten is central to CeD
pathogenesis and precedes the development of villous atrophy, the pathological hallmark of CeD. HLA DQ2 or
DQ8 increases the risk of CeD and is required for CeD development, but neither is sufficient. Epidemiological
and immunological observations support a role for additional genetic and environmental factors in CeD
pathogenesis. In line with this hypothesis, we and others have discovered that both, interleukin-15 (IL-15)
overexpression in the intestine and enteric virus infections promote LOT to gluten by inducing a proinflammatory
program in otherwise tolerogenic DCs, which in turn triggers adverse inflammatory Th1 responses to gluten in
CeD-relevant mouse models. One promising strategy to promote oral tolerance and to prevent or revert LOT in
CeD is to use the immunoregulatory potential of commensal gut microbes. The planned research is based on a
novel phenomenon that we just learned from host-protist interactions: commensal gut colonizing protists of the
order Parabasalia promote tolerogenic mucosal immune responses to dietary antigens, resulting in the
prevention of virus-induced LOT. We hypothesize that gut Parabasalia promote oral tolerance to dietary gluten,
prevent LOT and revert LOT to gluten in CeD mouse models by directly modulating dietary-antigen presenting
CD103+ DCs. We further posit that individuals colonized with Parabasalia have decreased risk of developing
CeD. These are all original concepts in the field of CeD. The technical innovation in this proposal stems from:
well-defined and highly relevant humanized CeD mouse models, new approaches to study human gut colonizing
Parabasalia in oral tolerance, and cutting-edge next-generation sequencing tools to determine Parabasalia-
induced functional changes in CD103+ DCs to delineate the mechanism of how Parabasalia promote oral
tolerance and protect from LOT to gluten in CeD. Taken together, we will use conceptually and technically
innovative studies to gain novel insights into how gut Parabasalia promote oral tolerance and prevent/revert LOT
to gluten in CeD. Furthermore, this study will motivate the design of novel Parabasalia-based therapies to prevent
LOT to gluten in individuals at-risk for developing CeD and to re-estab...

## Key facts

- **NIH application ID:** 10782548
- **Project number:** 5R01AI168478-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Reinhard Hinterleitner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $621,342
- **Award type:** 5
- **Project period:** 2023-02-08 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10782548

## Citation

> US National Institutes of Health, RePORTER application 10782548, Role of gut protists in celiac disease (5R01AI168478-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10782548. Licensed CC0.

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