# Exploring the role of microbiota and inflammation in tic fluctuations

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $243,625

## Abstract

ABSTRACT
Chronic tic disorders (CTD), including Tourette’s disorder and persistent tic disorders, are a significant
source of disability for children and adolescents, yet pharmacological therapies remain highly unsatisfactory
due to serious adverse events. An ideal direction to develop safer treatments for CTD would be to target the
same biological processes whereby tics spontaneously wax and wane over time; however, the mechanisms
underlying these fluctuations remain poorly understood.
A novel opportunity to solve this problem may come from recent evidence documenting that tic severity is
influenced by the gut microbiota. Understanding whether changes in the composition of the gut microbiota
may account for tic exacerbations - and through which molecular mechanisms - may lead to therapeutic
breakthroughs in CTD; this issue, however, remains unexplored. The goal of the studies proposed in this R21
application is to explore whether and how variations in the gut microbiota contribute to tic exacerbations.
The gut microbiota may influence tic severity through multiple mechanisms, including the synthesis of
inflammatory cytokines. Ample correlational evidence points to tumor necrosis factor-α (TNF) as the
inflammatory cytokine best associated with tic exacerbations. Thus, to test whether this cytokine increases tic
severity, we evaluated its effects in a mouse model of CTD. These preliminary studies showed that low TNF
doses that do not elicit sickness behavior significantly increase tic-like stereotypies in these mice.
Based on these findings, we hypothesize that, in CTD patients, gut microbiota alterations lead to increased
production of TNF or other inflammatory cytokines, which exacerbate tics. To test this hypothesis, the
exploratory studies proposed in this R21 application will use a translational platform, combining clinical
analyses in CTD patients and mechanistic experiments in mouse models. Specifically:
- In Aim 1, we will assess the alterations of gut microbiota associated with CTD and test whether tic
 exacerbations are associated with alterations of the gut microbiota and inflammatory responses by testing
 fecal and blood samples from forty CTD patients and forty non-affected controls.
- In Aim 2, we will test the causal link between gut microbiota alterations and tic exacerbations by
 transplanting fecal specimens from CTD-affected individuals into our mouse models of Tourette’s disorder;
 we will also test whether TNF or other inflammatory cytokines contribute to potential changes in tic severity.
The translational studies proposed in this R21 application will be the first systematic analyses of the role of gut
microbiota in tic fluctuations. If our hypothesis is verified, future R01-funded studies will test whether fecal
material transplant from non-affected individuals and/or probiotic treatments can reduce tic severity. We will
also study the downstream mechanisms whereby inflammation increases tic severity. Thus, our results may
l...

## Key facts

- **NIH application ID:** 10431544
- **Project number:** 1R21NS127009-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Marco Bortolato
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,625
- **Award type:** 1
- **Project period:** 2022-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10431544

## Citation

> US National Institutes of Health, RePORTER application 10431544, Exploring the role of microbiota and inflammation in tic fluctuations (1R21NS127009-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10431544. Licensed CC0.

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