Bacterial indole-3-propionic acid inhibits macrophage IL-1β production through targeting methionine metabolism.

Summary

Indole-3-propionic acid (IPA), a microbial tryptophan metabolite, binds MAT2A to boost SAM synthesis, promoting DNA methylation of USP16, enhancing TLR4 ubiquitination, and inhibiting NF-κB signaling. This epigenetic reprogramming suppresses IL-1β in M1 macrophages and attenuates LPS-induced sepsis in mice, revealing a metabolite–immunometabolism pathway.

Key Findings

• IPA downregulates IL-1β production in M1 macrophages by inhibiting NF-κB signaling.
• Mechanistically, IPA binds MAT2A to increase SAM, drives DNA methylation of USP16, promotes TLR4 ubiquitination, and suppresses NF-κB activation.
• IPA administration attenuates LPS-induced sepsis in mice, demonstrating in vivo relevance of this metabolite–immune pathway.

Clinical Implications

Suggests potential adjunctive strategies leveraging microbiome-derived metabolites or MAT2A/SAM axis modulation to dampen macrophage IL-1β and inflammation in sepsis.

Limitations

• Relies on LPS-induced sepsis models that may not capture polymicrobial or clinical sepsis complexity
• Human translational validation and safety data are lacking

Future Directions

Evaluate MAT2A targeting and IPA analogs in polymicrobial sepsis models and explore translational biomarkers of SAM/USP16/TLR4 axis in patients.