Short chain fatty acid butyrate promotes virus infection by repressing interferon stimulated genes

Abstract

Butyrate is an abundant metabolite produced by the gut microbiota and is known to modulate multiple immune system pathways and inflammatory diseases. However, studies of its effects on virus infection of cells are limited and enigmatic. We found that butyrate increases cellular infection and virus replication in influenza virus, reovirus, and human immunodeficiency virus infections. Further exploring this phenomenon, we found that addition of butyrate to cells deficient in type I interferon (IFN) signaling did not increase susceptibility to virus infection. Accordingly, we discovered that butyrate suppressed levels of specific IFN stimulated gene (ISG) products in human and mouse cells. Butyrate did not inhibit IFN-induced phosphorylation of transcription factors STAT1 and STAT2 or their translocation to the nucleus, indicating that IFN signaling was not disrupted. Rather, our data are suggestive of a role for inhibition of histone deacetylase activity by butyrate in limiting ISG induction. Global transcript analysis revealed that butyrate increases expression of more than 800 cellular genes, but represses IFN-induced expression of 60% of ISGs. Overall, we identify a new mechanism by which butyrate promotes virus infection via repression of ISGs. Our findings also add to the growing body of evidence showing that individual ISGs respond differently to type I IFN induction depending on the cellular environment, including the presence of butyrate. ImportanceButyrate is a lipid produced by intestinal bacteria that can regulate inflammation throughout the body. Here we show for the first time that butyrate influences the innate antiviral immune response mediated by type I IFNs. A majority of antiviral genes induced

Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2

“…Another important finding of this study is the involvement of butanoate metabolism. As already demonstrated by Chemudupatiet et al [ 52 ], high levels of the short chain fatty acid butyrate increase cellular infection and promote virus replication. The upregulation of butyric acid and derivatives in the plasma of COVID-19 patients could explain this correlation.…”

Influence of Sodium Butyrate on Provoke of Immune Response in Vaccinated Broilers With Avian Influenza (H9N2) Vaccines

“…The relative agreement of results occurred with Astill et al [22] that mentioned an elevation of IFN-γ expression in the vaccinated group with inactivated beta propiolactone H9N2 vaccine. Although no significant differences in IFN-γ level between vaccinated groups, sodium butyrate decreased this level in treated groups, these results explain the mechanism of action of butyrate by suppression of specific Anti-viral IFN-stimulated gene products, butyrate generally boost the expression of many cellular genes, but it powerfully inhibits 60% of interferon stimulating genes [23]. Another study referred to the role of Microcin C7 (antimicrobial peptide) as a significant peptide by reducing gene expression of pro-inflammatory including IFN-γ [24].…”

Gut Microbiota of Obese Children Influences Inflammatory Mucosal Immune Pathways in the Respiratory Tract to Influenza Virus Infection: Optimization of an Ideal Duration of Microbial Colonization in a Gnotobiotic Pig Model

“…A reduced production of SCFA was shown to significantly affect the functions of alveolar macrophages thus increasing lung pathology ( 37 ). On the other hand, the role of SCFA during influenza infections is inconsistently reported between studies ( 37 , 67 , 69 , 70 ). Other bacteria such as Lactococcus , Megasphaera , Streptococcus have been showed to produce other SCFA (formate, acetate, and valerate), lactic acids and vitamin B-1 with beneficial impact on the gut homeostasis and host immune system ( 71 – 73 ).…”