Sergio Velez
Research Mentor: Priyanka Verma
Mentor Department: Division of Rheumatology, Department of Internal Medicine, Medicine
Author(s): Sergio Vélez Catalá, Priyanka Verma
Session: Session 6 (3:00 PM – 3:50 PM)
Presentation Type: Poster 97
Abstract
Systemic sclerosis (SSc) is a complex autoimmune disease characterized by immune dysregulation and progressive fibrosis of the skin and internal organs. Intestinal dysbiosis is a prominent feature of SSc; however, its contribution to disease pathogenesis remains poorly understood. Gut microbial metabolism of dietary nutrients generates trimethylamine (TMA), which is converted to trimethylamine N-oxide (TMAO) by flavin-containing monooxygenase 3 (FMO3). We previously reported elevated circulating TMAO levels and increased extrahepatic FMO3 expression in skin biopsies from patients with SSc, and demonstrated that FMO3- deficient mice are protected from bleomycin-induced skin and lung fibrosis. In the present study, we validated the pathogenic role of the TMAO–FMO3 axis using an ex vivo murine skin explant culture model. Six-millimeter dorsal skin punch biopsies from wild-type and FMO3 knockout mice were cultured at an air–liquid interface and treated with transforming growth factor-ß1 (TGF-ß1) and TMAO for up to 7 days. Fibrotic responses were assessed by histology and immunofluorescence analysis of myofibroblast markers (a-smooth muscle actin and procollagen I), TGF-ß signaling activation (phosphorylated SMAD), and endoplasmic reticulum stress signaling (phosphorylated PERK). Our findings demonstrate that loss of FMO3 confers protection against fibrosis-associated molecular and cellular changes. These results identify the gut microbiota–derived TMAO–FMO3 axis as a critical mediator of skin fibrosis and a potential therapeutic target in systemic sclerosis.
