Microbial metabolites calibrate innate immunity upon systemic viral infection

ABSTRACT:

Gut microbiome dysbiosis is often associated with immune-mediated diseases. Here, we used germ-free (GF) mice, the synthetic minimal consortium OMM12, and specific pathogen-free (SPF) mice to dissect the causal influence of the microbiome on anti-viral immunity. The lack of microbial diversity affected innate immune cells in their responsiveness upon Lymphocytic choriomeningitis virus (LCMV) infection. Single-cell RNA sequencing of myeloid cells from the small intestinal lamina propria revealed a strong impact of the microbial composition on activation of monocytes and other myeloid cell populations defined by an elevated response signature to type 1 interferons in GF and OMM12 mice. To link compositional changes in microbes to the divergent immune regulation upon LCMV infection, metabolomics analysis of the gut luminal content and serum at steady state and after infection was performed and revealed differences in the abundance of bile acids and tryptophan derivatives. LCMV infection itself only impacted on the intestinal metabolic composition of OMM12 and germfree mice, whereas SPF mice were largely resilient to infection-induced metabolic alterations. The metabolic composition of gnotobiotic mice leads to a reduced capacity of AhR activation. Among those alterations, tryptophan derivatives like indoline-2-carboxylic acid, indol-3-carbinol, 1,3-dihydro-(2H)-indol-2-one, indoxyl sulfate, indole-3-acrylic acid, and 5-methoxytryptamine are potential candidates with immunomodulatory capacities through AhR activation. Collectively, this study reveals a major impact of microbiota-induced, altered metabolism on innate immunity of myeloid cells after viral infection. Thereby, myeloid cell functionality can be dramatically shaped by the gut microbial composition and availability of certain metabolites, especially AhR ligands, which is of high relevance to further understand the host-microbiota interactions and to sharpen immune-modulating therapeutic strategies.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase

PROVIDER: MTBLS7382 | MetaboLights | 2026-08-01

REPOSITORIES: MetaboLights