Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation

Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.

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Publication Details

Journal
Cell Reports
Published
2024-09-01
DOI
https://doi.org/10.1016/j.celrep.2024.114736
Citations
65
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
15.20

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article

Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation

Antonia Wagener, Fraser Duthie, Eicke Latz, Susanne V. Schmidt et al.
65 citations
Cell Reports
Inflammasome and immune disorders
15.20
article

Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation

Antonia Wagener, Fraser Duthie, Eicke Latz, Susanne V. Schmidt, Andreas Jaensch, Rebecca C. Coll, Rainer Stahl, Theresa Wagner, Matthew Mangan, Sergi Cuartero, Neil Stair, Bianca Martin, Felix Meissner, Kshiti Phulphagar, Harald Färber, Christina F. Budden, Alesja Dernst, Wei Wang, Maria Cadefau-Fabregat, Lucia Lorenzi
article en
65 citations

Abstract

Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.

Cell ReportsVol. 43(9)
Queen's University Belfast (GB), University of Bonn (DE), University Hospital Bonn (DE), German Center for Neurodegenerative Diseases (DE), Josep Carreras Leukaemia Research Institute (ES), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
“la Caixa” Foundation, European Commission, Helmholtz-Gemeinschaft, Deutsche Forschungsgemeinschaft, Ministerio de Ciencia e Innovación, Directorate for Biological Sciences, HORIZON EUROPE Framework Programme, Biotechnology and Biological Sciences Research Council
Zero hunger
Openalex Percentile: Top 0%
Inflammasome and immune disorders
15.20
DOIOpen Access PDFOpenAlex
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