Gut Microbe-Derived Metabolite Trimethylamine N-Oxide Activates PERK to Drive Mesenchymal Differentiation and Fibrosis

Abstract

Intestinal dysbiosis is prominent in systemic sclerosis (SSc), but it remains unknown if and how it contributes to synchronous microvascular injury and fibrosis that characterize this disease. Trimethylamine (TMA) is generated in the gut and converted by flavin-containing monooxygenase (FMO3) to trimethylamine N-oxide (TMAO), which has been implicated in chronic cardiovascular diseases. We now show that TMAO reprograms skin fibroblasts, vascular endothelial cells and adipocytic progenitor cells to myofibroblasts in a process mediated via R-like endoplasmic reticulum kinase (PERK), a TMAO-binding protein. Remarkably, FMO3, principally expressed in the liver, was found also to be present in both isolated skin fibroblasts and in skin explants, and its expression was elevated in pericytes and fibroblasts in SSc skin biopsies and explanted dermal fibroblasts. A TMAO meta-organismal pathway in SSc thus potentially links the gut microbiome to vasculopathy and fibrosis via stromal cell reprogramming, implicating this pathway in pathogenesis, and as a target for therapy.