Jiejie Geng, Yumeng Zhu, Siyu Chen, Xiyu Song, Qiang Huang, Hongyan Ma, Hongjiao Liu, Xu Yang, Xiang Zhang, Jinxin Zhang, Lingjie Luo, Yanwei Wu, Shuhui Dai, Jie Cheng, Cui Zhang, Liang Chen
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.
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: Comparative metagenomic analyses across RA, AS, IBD and long covid cohorts. Long covid was established as a paradigm for postdysbiotic inflammatory diseases, single-cell RNA sequencing and functional studies in longitudinal human cohorts and co-infection mouse models (SARS-CoV-2 and Pseudomonas aeruginosa) 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.