Metaorganismal TMAO pathway driving scleroderma pathogenesis: novel gene-environment interaction paradigm and therapeutic target

New approaches for developing disease-modifying therapy in scleroderma (systemic sclerosis, SSc) are urgently needed. This application seeks to generate data for an entirely novel paradigm for the elusive gene-environment interaction in SSc that ties the diet and gut dysbiosis to vascular injury and fibrosis underlying SSc pathogenesis. Our high risk, high reward approach is fundamentally different from traditional reductionist strategies and seeks to integrate environmental dietary factors (via gut microbial TMA generation from nutrient in the western diet) with enhanced host TMA metabolism (via genetic variant of FMO3) in a metaorganismal pathway that drives disease and to develop novel approaches for pharmacological disease-modifying therapy.