AUTHOR=Lengfelder Isabella , Sava Irina G. , Hansen Jonathan J. , Kleigrewe Karin , Herzog Jeremy , Neuhaus Klaus , Hofmann Thomas , Sartor R. Balfour , Haller Dirk 

TITLE=Complex Bacterial Consortia Reprogram the Colitogenic Activity of Enterococcus faecalis in a Gnotobiotic Mouse Model of Chronic, Immune-Mediated Colitis

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01420

DOI=10.3389/fimmu.2019.01420

ISSN=1664-3224

ABSTRACT=<p>Inflammatory bowel diseases (IBD) are associated with compositional and functional changes of the intestinal microbiota, but specific contributions of individual bacteria to chronic intestinal inflammation remain unclear. <italic>Enterococcus faecalis</italic> is a resident member of the human intestinal core microbiota that has been linked to the pathogenesis of IBD and induces chronic colitis in susceptible monoassociated IL-10-deficient (IL-10<sup>−/−</sup>) mice. In this study, we characterized the colitogenic activity of <italic>E. faecalis</italic> as part of a simplified human microbial consortium based on seven enteric bacterial strains (SIHUMI). RNA sequencing analysis of <italic>E. faecalis</italic> isolated from monoassociated wild type and IL-10<sup>−/−</sup> mice identified 408 genes including 14 genes of the ethanolamine utilization (<italic>eut</italic>) locus that were significantly up-regulated in response to inflammation. Despite considerable up-regulation of <italic>eut</italic> genes, deletion of ethanolamine utilization (Δ<italic>eutVW</italic>) had no impact on <italic>E. faecalis</italic> colitogenic activity in monoassociated IL-10<sup>−/−</sup> mice. However, replacement of the <italic>E. faecalis</italic> wild type bacteria by a Δ<italic>eutVW</italic> mutant in SIHUMI-colonized IL-10<sup>−/−</sup> mice resulted in exacerbated colitis, suggesting protective functions of <italic>E. faecalis</italic> ethanolamine utilization in complex bacterial communities. To better understand <italic>E. faecalis</italic> gene response in the presence of other microbes, we purified wild type <italic>E. faecalis</italic> cells from the colon content of SIHUMI-colonized wild type and IL-10<sup>−/−</sup> mice using immuno-magnetic separation and performed RNA sequencing. Transcriptional profiling revealed that the bacterial environment reprograms <italic>E. faecalis</italic> gene expression in response to inflammation, with the majority of differentially expressed genes not being shared between monocolonized and SIHUMI conditions. While in <italic>E. faecalis</italic> monoassociation a general bacterial stress response could be observed, expression of <italic>E. faecalis</italic> genes in SIHUMI-colonized mice was characterized by up-regulation of genes involved in growth and replication. Interestingly, in mice colonized with SIHUMI lacking <italic>E. faecalis</italic> enhanced inflammation was observed in comparison to SIHUMI-colonized mice, supporting the hypothesis that <italic>E. faecalis</italic> ethanolamine metabolism protects against colitis in complex consortia. In conclusion, this study demonstrates that complex bacterial consortia interactions reprogram the gene expression profile and colitogenic activity of the opportunistic pathogen <italic>E. faecalis</italic> toward a protective function.</p>