Butyrate Reprograms Expression of Specific Interferon-Stimulated Genes

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 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 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 pro-viral 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.

Microbiota-derived short-chain fatty acids do not interfere with SARS-CoV-2 infection of human colonic samples

“…This effect was associated with suppression of specific antiviral interferon-stimulated genes. 23 Another study reported an exacerbation of arthropathy-induced by Chikungunya virus in mice after treatment with high-fiber diet or butyrate. 24 …”

“…Thus, one of the main investigations that has been carried out around the world is to dissect how the infection occurs in each tissue and systems and how that tissue reacts to the presence of this infection, especially in patients who already have an inflammatory condition, such as obesity. 23 , 28 , 29 A study with intestinal and pulmonary epithelial cell lines showed that SARS-CoV-2 infection alters the expression of inflammatory cytokines and anti-viral molecules such as IFNα and IFNβ in lung cells. Their findings suggested the pre-activation of IFN-I signaling pathway as a potential therapeutic and prophylactic management for COVID-19 30 .…”

“…This effect was associated with suppression of specific antiviral interferon-stimulated genes. 23 Another study reported an exacerbation of arthropathy-induced by Chikungunya virus in mice after treatment with high-fiber diet or butyrate. 24 Using colon biopsies from patients who were diagnosed with SARS-CoV-2 a few days after colonoscopy, it was possible to observe that intestinal cells are infected with the new coronavirus.…”

Targeted Metabolomics Identifies High Performing Diagnostic and Prognostic Biomarkers for COVID-19

“…In particular, increased serum levels of these metabolites have been found in patients with this condition and it is notable that diarrhea is one of the symptoms that is common to both COVID and IBS 29 . In addition, high levels of butyric acid have been thought to promote viral replication and interfere with the interferon response 30 . Therefore, the dysregulation of gut microbiota, expressed by various gastrointestinal symptoms and an altered pro le of microbial metabolites, underscores the potential relevance of dietary interventions to prevent the progression of COVID-19 severity.…”

Polymicrobial Interactions Operative during Pathogen Transmission

“…Immunomodulatory signals by the gut microbial community can also alter susceptibility to nonenteric infections. Production of the short-chain fatty acid butyrate by enteric commensals can lead to a systemic suppression of IFN production and interferon responsive gene expression and increase susceptibility to influenza virus, reovirus, HIV-1, human metapneumovirus, and vesicular stomatitis virus (126). Alteration of the gut microbial community during an IAV infection can alter the production of another short-chain fatty acid, acetate, reducing bactericidal activity of alveolar macrophages and enhances susceptibility to bacterial pneumonia (127).…”