Herzog, H. M.; Fang, C.; Lam, L.; Jin, K.; Zamarioli, A.; Dinh, E.; Gupta, C. L.; Sharma, A.; Moody, T.; Pierce, J. L.; Hohl, M. S.; Takimoto, S. W.; Lyalina, S.; Wentworth, K. L.; Yu, K.; Lu, V. F.; Isadora Mamikunian, I.; Hunt, N. K.; Lynch, S.; Pollard, K. S.; Hernandez, C. J.; Perrien, D. S.; Hsiao, E. C.

Inflammatory diseases cause significant morbidity and mortality, but their pathobiology is often difficult to dissect due to complex genetic-environmental interactions. Genetic forms of heterotopic ossification, such as fibrodysplasia ossificans progressiva (FOP), reduce genetic variability, allowing careful dissection of non-genetic drivers of inflammation. While >95% of FOP patients harbor the ACVR1R206H mutation, patients exhibit significant variability in disease progression, suggesting a role of environmental drivers. Here, we identify the gut microbiome as a regulator of inflammation-driven HO in FOP. Metagenomic profiling of cohabitating FOP/unaffected sibling pairs revealed a pathogenic gut microbiome profile in FOP patients (Bray-Curtis, p < 0.05). In Pdgfr-Cre/Acvr1R206H (FOP) mice, gut microbiome ablation by antibiotics reduced spontaneous HO formation (47.4% reduction, p < 0.05) and reduced plasma IL-1 pathway activity. IL-1{beta} blockade in FOP mice suppressed trauma-induced HO formation. These findings identify a gut microbiome-IL-1-HO axis with modifiable targets for developing treatments for HO and related inflammatory conditions.