The influence of microbiota-derived metabolites on viral infections

Abstract

Intestinal microbiota have profound effects on viral infections locally and systemically. While they can directly influence enteric virus infections, there is also an increasing appreciation for the role of microbiota-derived metabolites in regulating virus infections. Because metabolites diffuse across the intestinal epithelium and enter circulation, they can influence host response to pathogens at extraintestinal sites. In this review, we summarize the effects of three types of microbiota-derived metabolites on virus infections. While short-chain fatty acids serve to regulate the extent of inflammation associated with viral infections, the flavonoid desaminotyrosine and bile acids generally regulate interferon responses. A common theme that emerges is that microbiota-derived metabolites can have proviral and antiviral effects depending on the virus in question. Understanding the molecular mechanisms by which microbiota-derived metabolites impact viral infections and the highly conditional nature of these responses should pave the way to developing novel rational antivirals.

Figure 1

The SCFA butyrate has opposing effects on inflammatory disease associated with influenza virus infection of the lung and CHIKV infection of joints. (1) Gut microbes produce SCFAs including butyrate through fermentation of undigested carbohydrates in the intestinal lumen. (2) SCFAs enter circulation, reaching a wide range of peripheral tissues including bone and joints. (3) Butyrate promotes differentiation of bone marrow cells into monocytes predisposed to become tissue repair AAMs in a FFAR3-dependent process. (4) During influenza virus infection of the lung, mice fed a high fiber diet or supplemented with butyrate contain a higher proportion of AAMs in the lung macrophage population, resulting in reduced levels of the neutrophil chemoattractant CXCL1 and hence reduced tissue damage resulting from neutrophilia. (5) Conversely, mice fed a high fiber diet or supplemented with butyrate develop more severe inflammatory arthropathy during CHIKV infection, correlating with a reduced signature of resolution phase macrophages (Mfs) which function to prevent neutrophil infiltration and initiate tissue repair. Created with BioRender.com.

Figure 2

Bile acids have opposing effects on virus infections in local and systemic sites. Numerous studies have reported a role for bile acids in promoting and inhibiting viral infections, as summarized here. In general, bile acids regulate viral infections by either promoting or inhibiting IFN responses. Yet additional mechanisms are emerging, including enhancement of virus-receptor binding (e.g. murine norovirus) and increased ceramide-rich microdomains in host membranes which could cause clustering of the viral receptor (e.g. human norovirus). Created with BioRender.com.