Butyrate Reprograms Expression of Specific Interferon-Stimulated Genes
- 1 August 2020
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 94 (16)
- https://doi.org/10.1128/JVI.00326-20
Abstract
Butyrate is an abundant metabolite produced by gut microbiota. While butyrate is a known histone deacetylase inhibitor that activates expression of many genes involved in immune system pathways, its effects on virus infections and on the antiviral type I interferon (IFN) response have not been adequately investigated. We found that butyrate increases cellular infection with viruses relevant to human and animal health, including influenza virus, reovirus, HIV-1, human metapneumovirus, and vesicular stomatitis virus. Mechanistically, butyrate suppresses levels of specific antiviral IFN-stimulated gene (ISG) products, such as RIG-I and IFITM3, in human and mouse cells without inhibiting IFN-induced phosphorylation or nuclear translocation of the STAT1 and STAT2 transcription factors. Accordingly, we discovered that although butyrate globally increases baseline expression of more than 800 cellular genes, it strongly represses IFN-induced expression of 60% of ISGs and upregulates 3% of ISGs. Our findings reveal that there are differences in the IFN responsiveness of major subsets of ISGs depending on the presence of butyrate in the cell environment, and overall, they identify a new mechanism by which butyrate influences virus infection of cells. IMPORTANCE Butyrate is a lipid produced by intestinal bacteria. Here, we newly show that butyrate reprograms the innate antiviral immune response mediated by type I interferons (IFNs). Many of the antiviral genes induced by type I IFNs are repressed in the presence of butyrate, resulting in increased virus infection and replication. Our research demonstrates that metabolites produced by the gut microbiome, such as butyrate, can have complex effects on cellular physiology, including dampening of an inflammatory innate immune pathway resulting in a proviral cellular environment. Our work further suggests that butyrate could be broadly used as a tool to increase growth of virus stocks for research and for the generation of vaccines.Funding Information
- HHS | National Institutes of Health (AI130110)
- HHS | National Institutes of Health (AI142256)
- HHS | National Institutes of Health (AI25136)
- HHS | National Institutes of Health (AI112542)
- HHS | National Institutes of Health (GM068412)
- National Science Foundation (Graduate Research Fellowship Program)
This publication has 89 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Regulation of Inflammation by Short Chain Fatty AcidsNutrients, 2011
- Microbiota regulates immune defense against respiratory tract influenza A virus infectionProceedings of the National Academy of Sciences of the United States of America, 2011
- Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule InhibitorCell Chemical Biology, 2010
- The integrin α 4 β 7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1Proceedings of the National Academy of Sciences of the United States of America, 2009
- Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infectionProceedings of the National Academy of Sciences of the United States of America, 2009
- Genome-wide Mapping of HATs and HDACs Reveals Distinct Functions in Active and Inactive GenesCell, 2009
- α4+β7hiCD4+ memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infectionMucosal Immunology, 2009
- Sendai Virus Infection Induces Efficient Adaptive Immunity Independently of Type I InterferonsJournal of Virology, 2006
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001