The influence of microbiota-derived metabolites on viral infections
Introduction
Gut microbiota are a vast population of microorganisms residing in the gastrointestinal tract that play a central role in maintaining metabolic and immune homeostasis. In recent years, it has become widely appreciated that these microbial communities enhance enteric viral infections through a multitude of direct and indirect mechanisms [1]. For example, bacterial surface glycans bound by an enteric virus can promote virion stabilization [2], host cell attachment and receptor binding [2,3], immune skewing in a proviral manner [4,5], and viral recombination [6]. Yet recent work in the murine norovirus (MNV) model system reveals a more nuanced situation where gut microbiota have opposing regional effects on an enteric virus, inhibiting proximal gut infection while simultaneously promoting distal gut infection [7•]. Moreover, gut microbiota also influence viral infections at extraintestinal sites where they generally have inhibitory effects instead of promoting ones [8, 9, 10, 11]. Accumulating evidence indicates that inhibition of viral infections at local and distal sites results from microbial metabolite-mediated signaling events in contrast to the stimulatory effects of microbial constituents (e.g. LPS). The focus of this review will be the mechanisms by which microbiota-derived metabolites modulate antiviral immune responses in vivo. Understanding the molecular details of these events could pave the way to developing novel rational antivirals.
Section snippets
Gut microbiota-derived metabolites
It is well-established that gut microbiota shape the development and function of the host immune system. For example, host recognition of bacterial ligands via pattern recognition receptors contributes to immune homeostasis [12]. In addition, microbiota-derived metabolites continuously interact with metabolite-specific receptors and regulate immune responses [13]. Microbial metabolites segregate into three broad categories: (1) metabolites produced from dietary components, (2) metabolites
Short-chain fatty acids
One category of dietary-derived metabolites with established effects on viral infections are SCFAs like acetate, butyrate, and propionate which are produced during bacterial fermentation of undigested carbohydrates. They are generally considered to be anti-inflammatory due to their ability to inhibit histone deacetylases (HDACs) and their activation of G protein-coupled receptors GPR41/FFAR3 and GPR43/FFAR2 [14,15]. SCFAs can regulate viruses in vitro. For example, the HDAC inhibitory activity
Flavonoids
Plant-derived polyphenol compounds, or flavonoids, can be processed by commensal bacteria to a variety of bioactive metabolites. One flavonoid degradation product, DAT, has been shown to augment the type I IFN response in the lung and protect mice from influenza virus infection [22]. Extending earlier work demonstrating that gut microbiota provide protection from severe influenza virus infections in mice [9,10], Steed et al. demonstrated that oral DAT supplementation was sufficient to protect
Bile acids
The mammalian host converts cholesterol to the primary bile acids chenodeoxycholic acid (CDCA) and cholic acid (CA) in the liver where they are conjugated with taurine or glycine. Primary conjugated bile acids are stored in the gall bladder until ingestion of a meal, at which time they are released into the gut lumen to aid in digestion. Here they encounter commensal bacteria which deconjugate and dehydroxylate them to the secondary bile acids lithocholic acid (LCA) and deoxycholic acid (DCA)
Conclusions
Over the past decade it has been clearly established that intestinal microbiota have profound effects on viral infections, both locally along the intestinal tract and systemically. While commensal bacteria in the gut lumen can directly influence enteric virus infections in a multitude of ways, 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,
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
Acknowledgement
This work was funded by N.I.H.1R01AI116892.
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Cited by (13)
Microbiota regulation of viral infections through interferon signaling
2022, Trends in MicrobiologyCitation Excerpt :More studies are needed to further clarify the roles of different BA receptors in the IFN response. DAT is a product of commensal bacteria degradation of plant-derived polyphenol compounds (flavonoids) [63]. Administration of DAT into mice infected with influenza A virus protected mice from infection-associated mortality and morbidity but did not reduce viral titers [52].