The microbial metabolite desaminotyrosine protects from influenza through type I interferon

Abstract

The microbiota is known to modulate the host response to influenza infection through as-yet-unclear mechanisms. We hypothesized that components of the microbiota exert effects through type I interferon (IFN), a hypothesis supported by analysis of influenza in a gain-of-function genetic mouse model. Here we show that a microbially associated metabolite, desaminotyrosine (DAT), protects from influenza through augmentation of type I IFN signaling and diminution of lung immunopathology. A specific human-associated gut microbe, Clostridium orbiscindens, produced DAT and rescued antibiotic-treated influenza-infected mice. DAT protected the host by priming the amplification loop of type I IFN signaling. These findings show that specific components of the enteric microbiota have distal effects on responses to lethal infections through modulation of type I IFN.

Impact of gut colonization with butyrate producing microbiota on respiratory viral infection following allo-HCT

“…In recent years, it has been shown that some of the bacterial species constituting the intestinal microbiota contribute to protection against infections through a variety of direct and indirect (immunomodulatory) mechanisms. [5][6][7][8][9] In addition, the health benefits of microbiota-associated SCFA are increasingly appreciated, and several butyrate-specific mechanisms have recently been identified that suggest their association with protection from LRTI in our patient cohort. A recent study of mice showed that intraperitoneal butyrate administration reduced persistent lung inflammation during Klebsiella pneumoniae infection, leading to the suggestion that butyrate restores interleukin-10 (IL-10) levels in the lung by inhibiting histone deacetylase.…”

“…5,6 For example, commensalderived signals are thought to establish the activation threshold of the innate immune system required for optimal antiviral immunity 7 and are associated with augmenting adaptive immune responses to respiratory influenza virus infection in mice. 8,9 Butyrate, a microbiotaassociated SCFA, serves as an important immunomodulatory compound. This product of microbial fermentation by anaerobic gut bacteria enhances the integrity of the intestinal epithelium 10 and modulates enteric tolerance against microbial communities.…”

Temporal Regulation of the Bacterial Metabolite Deoxycholate during Colonic Repair Is Critical for Crypt Regeneration

“…Clostridium scindens and Clostridium clostridioforme were obtained from ATCC. Individual strains of bacteria were grown in chopped media broth and orally administered at ~7×10 8 bacteria per mouse (Buffie et al, 2015; Steed et al, 2017). …”

“…Metabolite libraries from the intestinal contents of mice and other hosts can now be determined by untargeted mass-spectroscopy approaches (Matsumoto et al, 2012). Such libraries are a powerful source of material for screens of host cell responses relevant to intestinal repair (Kaiko et al, 2016; Steed et al, 2017). Here, through a metabolite screen and in vivo validation using the biopsy injury model, we discovered that the temporal presence of a bacterial metabolite, deoxycholate (DCA), regulates the transition between phases of intestinal healing by controlling local PGE2 production.…”

Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome

“…Besides the ability of the microbiota to modulate the IFN response through as yet unclear mechanisms, specific components of the enteric microbiota (i.e. microbial metabolite desaminotyrosine) have been shown to exert distal effects on responses to lethal viral infections through modulation of type I IFN [157]. Thus, bacterial products can modulate different components of the innate immune system to potentially facilitate responses to microbial pathogens.…”