The bacterial protein flagellin is the sole ligand of the innate immune receptor Toll-like receptor 5 (TLR5). Flagellins with strong agonism bind TLR5 at their D1 and D0 domains, while poor agonist si...

Colonic stem cell TLR5 sensing of microbes promotes macrophage recruitment and maturation to support intestinal barrier repair.

Colonic stem cell TLR5 sensing of microbes promotes macrophage recruitment and maturation to support intestinal barrier repair.

Colonic stem cell TLR5 sensing of microbes promotes macrophage recruitment and maturation to support intestinal barrier repair.

Colonic stem cell TLR5 sensing of microbes promotes macrophage recruitment and maturation to support intestinal barrier repair.

TLR5 deficiency is associated with idiopathic pulmonary fibrosis, and TLR5 activation reduces lung dysbiosis and protects against fibrosis in mice.

Flagellin, the structural protein of bacterial flagella, activates the innate immune receptor Toll-like receptor 5 (TLR5). However, the ability of different flagellins to bind and stimulate TLR5 va...

Flagellin is the protein monomer of the bacterial flagellum, which confers motility, allowing bacteria to reach their favored niches. Flagellin is highly conserved across bacterial species and thus the target of the innate immune receptor Toll-like receptor 5 (TLR5). In the gut, bacterial flagellin agonizes human TLR5, triggering a pro-inflammatory response. However, the ability to bind and activate TLR5 varies considerably between different flagellins, suggesting that the composition of an individual's flagellin repertoire - the flagellome - may mediate the inflammatory response to the microbiome, with relevance to inflammatory bowel diseases. However, to date, methods to assess the inflammatory potential of a flagellome are lacking. To address this gap, we constructed a curated database of human gut flagellins. To predict the inflammatory potential of the flagellome by sorting flagellins into either "stimulatory" (strong TLR5 agonists) or "silent" (weak TLR5 agonists), we trained a machine learning model on experimentally characterized flagellins with known binding and stimulatory activities. The FlaPro pipeline was implemented using the Snakemake workflow engine for high-throughput analysis and is available at https://github.com/leylabmpi/FlaPro. To validate our approach and explore clinical associations, we applied FlaPro to a publicly available multi-omics dataset from an inflammatory bowel disease (IBD) cohort. Our analysis demonstrates that FlaPro enables robust profiling of the human gut flagellome from metagenomic and metatranscriptomic data. Analysis of the IBD datasets revealed a depletion of flagellome diversity and a reduced silent-to-stimulatory flagellin abundance ratio in Crohn's disease and ulcerative colitis, observed at both the genomic and transcriptional levels. Multiple condition-specific alterations were identified at the level of individual flagellin clusters. These findings indicate that IBD is associated with distinct alterations in the gut flagellome, particularly in relation to TLR5 recognition. Flagellome features represent a functionally interpretable class of microbiome-derived markers with potential utility in microbiome-wide association studies in the context of human health and disease. ### Competing Interest Statement The authors have declared no competing interest. Max Planck Society and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme Grant agreement

Silent flagellins, produced by human gut bacteria, were found to be recognized by TLR5 but elicit a weak signal.

Colonic stem cell TLR5 sensing of microbes promotes macrophage recruitment and maturation to support intestinal barrier repair.

TLR5 deficiency is associated with idiopathic pulmonary fibrosis, and TLR5 activation reduces lung dysbiosis and protects against fibrosis in mice.

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 ...

The therapy activates a protein that could stop pulmonary fibrosis from progressing.