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Bacterial indole-3-propionic acid inhibits macrophage IL-1β production through targeting methionine metabolism
Ziyi Han1,2, Jian Fu1, Aiyan Gong3
1State Key Laboratory of Livestock and Poultry Breeding, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
Abstract:
The gut microbiota plays key roles in host health by shaping the host immune responses through their metabolites, like indole derivatives from tryptophan. However, the direct role of these indole derivatives in macrophage fate decision and the underlying mechanism remains unknown. Here, we found that bacterial indole-3-propionic acid (IPA) downregulates interleukin-1beta (IL-1β) production in M1 macrophages through inhibition of nuclear factor-kappa B (NF-κB) signaling. Mechanistically, IPA binds specifically with methionine adenosyl-transferase 2A (MAT2A) to promote S-adenosylmethionine (SAM) synthesis, which facilitates the DNA methylation of ubiquitin-specific peptidase 16 (USP16, a deubiquitinase), and in turn promotes Toll-like receptor 4 (TLR4) ubiquitination and NF-κB inhibition. Furthermore, IPA administration attenuates sepsis in mouse models induced by lipopolysaccharides (LPS), showcasing its potential as a microbial-derived adjunct in alleviating inflammation. Collectively, our findings reveal a newly found microbial metabolite-immune system regulatory pathway mediated by IPA.
Insights
Bacterial indole-3-propionic acid (IPA) reduces inflammation by inhibiting key immune signaling pathways in macrophages. This microbial metabolite shows potential for treating inflammatory conditions like sepsis.
Area of Science:
- Microbiome-Immune System Interactions
- Metabolomics
- Immunology
Background:
- Gut microbiota metabolites, such as indole derivatives, modulate host immune responses.
- The specific mechanisms by which indole derivatives influence macrophage function remain largely unexplored.
Purpose of the Study:
- To investigate the direct role of bacterial indole-3-propionic acid (IPA) in macrophage fate determination.
- To elucidate the molecular mechanisms underlying IPA's immunomodulatory effects.
Main Methods:
- Investigated IPA's effect on interleukin-1beta (IL-1β) production in M1 macrophages.
- Utilized molecular assays to explore the inhibition of nuclear factor-kappa B (NF-κB) signaling.
- Examined IPA's interaction with methionine adenosyl-transferase 2A (MAT2A) and its downstream effects on S-adenosylmethionine (SAM) synthesis, DNA methylation of USP16, and Toll-like receptor 4 (TLR4) ubiquitination.
- Assessed IPA's efficacy in a lipopolysaccharide (LPS)-induced mouse model of sepsis.
Main Results:
- Bacterial IPA was found to downregulate IL-1β production in M1 macrophages by inhibiting NF-κB signaling.
- IPA specifically binds to MAT2A, enhancing SAM synthesis, which promotes DNA methylation of USP16.
- This process leads to increased TLR4 ubiquitination and subsequent NF-κB inhibition.
- IPA administration effectively attenuated sepsis in mouse models.
Conclusions:
- IPA represents a novel microbial metabolite that regulates immune responses by modulating macrophage activation.
- The identified pathway involves IPA-MAT2A-SAM-mediated epigenetic modification of USP16, leading to NF-κB suppression.
- IPA demonstrates therapeutic potential as an adjunct therapy for inflammatory diseases, including sepsis.
