Intestinal flagellin drives multisystem inflammation through TLR5-IL-15-ARA axis

BACKGROUND: Systemic inflammatory diseases including rheumatoid arthritis (RA), ankylosing spondylitis (AS), IBD and long covid share convergent multi-organ phenotypes. Long covid provides a tractable model for dissecting gut-driven mechanisms of systemic inflammation, given its defined temporal onset and treatment-naïve postinfectious context. OBJECTIVE: To characterise a gut-driven mechanism of systemic inflammation in long covid and assess its cross-disease correlates in RA, AS and IBD. DESIGN: ) were employed to dissect cellular and molecular mechanisms. Genetic and pharmacological interventions targeting the interleukin (IL)-15-arachidonic acid (ARA) axis were validated for therapeutic efficacy. RESULTS: Flagellated bacterial expansion defined a shared intestinal signature across all four diseases. Mechanistic studies in long covid demonstrated that flagellated bacteria activated toll-like receptor 5 (TLR5) on neutrophils, triggering the formation of neutrophil extracellular trap (NET) and IL-15 release. IL-15 subsequently stimulated macrophage ARA production. The co-infection murine model recapitulated multi-organ pathophysiology of long Covid, including pulmonary fibrosis and intestinal lymphoid aggregates. Genetic ablation of macrophage ARA synthesis or neutrophil IL-15 attenuated lung pathology, whereas gut microbiome clearance with gentamicin uniquely suppressed systemic inflammation. CONCLUSIONS: We delineate a flagellin-TLR5-IL-15-ARA axis as a candidate mechanism driving systemic inflammation in long covid. These findings position intestinal flagellin as a candidate therapeutic target and ARA as a potential biomarker for long covid, warranting prospective validation across inflammatory disease boundaries.