Intestinal flagellin drives multisystem inflammation through TLR5-IL-15-ARA axis, 2026, Geng et al.

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-naive 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.

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we hypothesised that intestinal flagellin perpetuates systemic inflammation through a defined cellular and metabolic axis, with long covid serving as an optimal model for mechanistic dissection due to its temporal precision, pathophysiological clarity and treatment-naïve patient population.

We would like to know more about this pathophysiological clarity.