# Modulation of Th17 plasticity by intestinal paleobiomic fauna

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2021 · —

## Abstract

Our microbiome influences how our immune system functions. Our microbiome has changed as a
result of living in highly hygienic industrialized countries. A major change in our microbiome is loss of exposure
to helminths (parasitic worms). Prior to the 1940's, helminth colonization was nearly universal and there is
strong evidence that this exposure helped to shape our genome. Loss of these previously ubiquitous members
of our paleobiome, can have far ranging immunologic effect. Inflammatory bowel disease (IBD) currently
afflicts more than one million Americans and many thousands of veterans. The incidence of IBD and other
immune-mediated diseases increased dramatically after the 1940's in North America and Europe. These
diseases are rare in less developed tropical countries. Veterans that served in Vietnam or were prisoners of
war are at lower risk of developing IBD than are other veterans. Moreover, as countries develop economically
the incidence of IBD and other immune-mediated diseases increase. Now, IBD is a globally emerging
disorder. Although specific genes predispose to IBD, there is strong evidence that a change in environment
concurrent with socioeconomic improvement confers risk for developing the disorder. We propose that a
change from our historic paleobiome, i.e. the lack of helminth exposure, in developed countries is an
important risk factor for developing IBD and other immune-mediated diseases. We and others have
shown that colonization with helminths protects mice from immune-mediated colitis, encephalitis, diabetes, and
airway disease. These are models of diseases that have emerged within highly industrialized countries.
Understanding how helminth exposure decreases immune mediated diseases will guide development of
targeted therapy to prevent or treat those diseases. Th17 cells control pro-inflammatory pathological
responses, like that of IBD. Recently it has become clear that Th17 cells are heterogeneous. In addition to
making IL17, highly pro-inflammatory Th17 cells make IFNγ. Other Th17 cells with a regulatory phenotype
express FoxP3 or make IL10. Immune mediated disease likely results from dysregulated Th17 plasticity. We
discovered that mucosal IL17 production is inhibited by exposure to helminths and that this exposure
decreases Th17IFN+ and increases Th17IL10+ percentages in lamina propria and mesenteric lymph node
cell populations. Moreover, we find that helminth exposure alters Treg plasticity and in the absence of T cell
Stat6-signaling massively induces a novel Foxp3+IFN+ population. Our hypothesis is that helminth
exposure protects against colitis by altering Th17 and Treg heterogeneity/plasticity. This project will test
this hypothesis with 3 specific aims. Our first aim will explore the mechanisms enabled by helminth exposure
that alter Th17 plasticity. Our second aim will explore the mechanisms enabled by helminth exposure that
augment Treg plasticity and the role of newly discovered musculin and TIGIT circuity ...

## Key facts

- **NIH application ID:** 10162301
- **Project number:** 5I01BX002715-06
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** DAVID E ELLIOTT
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-10-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162301

## Citation

> US National Institutes of Health, RePORTER application 10162301, Modulation of Th17 plasticity by intestinal paleobiomic fauna (5I01BX002715-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10162301. Licensed CC0.

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