MicroRNA-146a Deficiency Protects against Listeria monocytogenes Infection by Modulating the Gut Microbiota

Abstract

The gut microbiota and microRNAs play important roles in the defense against infection. However, the role of miR-146a in <i>L. monocytogenes</i> infection and gut microbiota remains unclear. We tried to determine whether miR-146a controlled <i>L. monocytogenes</i> infection by regulating the gut microbiota. Wild-type and miR-146a-deficient mice or macrophages were used to characterize the impact of miR-146a on animal survival, cell death, bacterial clearance, and gut microbiota following <i>L. monocytogenes</i> challenge. We found that <i>L. monocytogenes</i> infection induced miR-146a expression both in vitro and in vivo. When compared to wild-type mice, miR-146a-deficient mice were more resistant to <i>L. monocytogenes</i> infection. MiR-146a deficiency in macrophages resulted in reduced invasion and intracellular survival of <i>L. monocytogenes</i>. High-throughput sequencing of 16S rRNA revealed that the gut microbiota composition differed between miR-146a-deficient and wild-type mice. Relative to wild-type mice, miR-146a-deficient mice had decreased levels of the <i>Proteobacteria</i> phylum, <i>Prevotellaceae</i> family, and <i>Parasutterella</i> genus, and significantly increased short-chain fatty acid producing bacteria, including the genera <i>Alistipes</i>, <i>Blautia</i>, <i>Coprococcus_1,</i> and <i>Ruminococcus_1</i>. Wild-type mice co-housed with miR-146a-deficient mice had increased resistance to <i>L. monocytogenes</i>, indicating that miR-146a deficiency guides the gut microbiota to alleviate infection. Together, these results suggest that miR-146a deficiency protects against <i>L. monocytogenes</i> infection by regulating the gut microbiota.