# the Gut Microbiome as a Disease Modifier of Heterotopic Ossification

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $640,847

## Abstract

Fibrodysplasia ossificans progressiva (FOP) is a currently untreatable genetic disease in which skeletal muscle
repair is redirected to endochondral bone formation (heterotopic ossification, HO) causing pain, muscle
destruction, and joint fusion, leading to progressive immobilization and eventually premature death. This project
will explore the role of microbiota in inflammation and HO in FOP. Aim 1: Identify the modulatory roles of the gut
microbiome in disease progression in FOP mice. Advanced gnotobiotic methods and germ-free FOP mice
colonized with defined pro- or anti-inflammatory microbiota. We will also test whether dietary supplementation with
probiotic bacteria or compounds that tighten gut barrier integrity will reduce FOP progression. Aim 2: Identify the
role of the microbiome in chemokine-dependent polarization and migration of MCYs and macrophages that
enhance EHO in FOP. These studies will determine whether the gut microbiome exacerbates EHO in FOP by
sensitizing bone marrow MCYs/MΦs to chemokine-induced chemotaxis and increasing the expression of
proinflammatory chemokines during flares, which together increase infiltration and inflammatory polarization of
MCYs and MΦs. Aim 3: Establish the relationship between gut microbiota, monocyte/macrophage
activation, and severity of FOP flares in humans and mice. These studies will determine if the gut microbial
community in patients with FOP modulates disease progression by increasing systemic inflammatory tone, thus
priming MCY/MΦ activation. Stool samples will be collected from patients with FOP, microbiota analyzed and
correlated with FOP disease outcomes. We will also colonize germ-free FOP mice with the microbiome of human
FOP patients by fecal transplant in a human microbiome-association (HMA) approach. Finally, we will use a new
microfluidic culture system to determine the responses of human iPSC derived M1- and M2-like MΦs from control
and FOP patients to defined microbiome antigens.These studies will provide novel mechanistic understanding of
how the gut microbiome affects HO and provide a basis for testing how gut microbiome manipulation may augment
treatment of FOP and non-genetic HO.

## Key facts

- **NIH application ID:** 10837014
- **Project number:** 5R01AR080750-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** EDWARD C HSIAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $640,847
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837014

## Citation

> US National Institutes of Health, RePORTER application 10837014, the Gut Microbiome as a Disease Modifier of Heterotopic Ossification (5R01AR080750-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10837014. Licensed CC0.

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