The Gut Microbial Metabolite Trimethylamine N-Oxide is Linked to Specific Complications of Systemic Sclerosis

BACKGROUND: Systemic sclerosis (SSc) is a rare immune-mediated connective tissue disease characterized by fibrosis of the skin and internal organs, whose pathogenesis is not fully understood. Recent studies have revealed dysbiosis in patients with systemic sclerosis and have indicated the possible role of the microbiota and its metabolites in the pathogenesis of the disease. Trimethylamine N-oxide (TMAO) is a compound produced by dysbiotic microbiota observed at higher concentrations in several autoimmune diseases. OBJECTIVE: To determine concentrations of the bacteria-derived metabolite TMAO in patients with systemic sclerosis and to assess possible correlation between TMAO and a specific manifestation of the disease. PATIENTS AND METHODS: The study included 63 patients with SSc and 47 matched control subjects. The concentration of TMAO was measured with high-performance liquid chromatography. RESULTS: Plasma TMAO level was significantly increased in patients with SSc (283.0 [188.5–367.5] ng/mL versus 205.5 [101.0–318.0] ng/mL; p < 0.01). An increased concentration of TMAO was observed in patients with concomitant interstitial lung disease (ILD) (302.0 ng/mL [212.0–385.5] ng/mL versus 204.0 [135.5–292.0] ng/mL; p < 0.01) and esophageal dysmotility (289.75 [213.75–387.5] ng/mL versus 209.5 ng/mL [141.5–315.0] ng/mL; p < 0.05) compared to patients without these complications. Furthermore, TMAO concentration exhibited significant correlation with markers of heart involvement (left ventricle ejection fraction, NT-proBNP), marker of ILD severity and Scleroderma Clinical Trials Consortium Damage Index. CONCLUSION: The concentration of TMAO, gut microbiota-associated metabolite, is increased in systemic sclerosis, particularly in patients with advanced organ involvement. This is the first study evaluating plasma TMAO in systemic sclerosis. Bacterial metabolites may be a link between dysbiosis and organ involvement in the course of the disease. Modulation of gut bacterial-derived metabolites may represent a new therapeutic approach in the management of systemic sclerosis.