PT - JOURNAL ARTICLE AU - Bruno Lamas AU - Marie-Laure Michel AU - Nadine Waldschmitt AU - Hang-Phuong Pham AU - Vassiliki Zacharioudaki AU - Louise Dupraz AU - Myriam Delacre AU - Jane M Natividad AU - Gregory Da Costa AU - Julien Planchais AU - Bruno Sovran AU - Chantal Bridonneau AU - Adrien Six AU - Philippe Langella AU - Mathias L Richard AU - Mathias Chamaillard AU - Harry Sokol TI - Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence AID - 10.1136/gutjnl-2017-314195 DP - 2018 Oct 01 TA - Gut PG - 1836--1844 VI - 67 IP - 10 4099 - http://gut.bmj.com/content/67/10/1836.short 4100 - http://gut.bmj.com/content/67/10/1836.full SO - Gut2018 Oct 01; 67 AB - Objective In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 (CARD9), a key innate immunity gene, is required to shape a normal gut microbiota. Card9 –/– mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohaemorrhagic Escherichia coli. Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and microbiota-independent mechanisms.Design C. rodentium infection was assessed in conventional and germ-free (GF) wild-type (WT) and Card9 –/– mice. To explore the impact of Card9 –/–microbiota in infection susceptibility, GF WT mice were colonised with WT (WT→GF) or Card9 –/– (Card9–/– →GF) microbiota before C. rodentium infection. Microbiota composition was determined by 16S rDNA gene sequencing. Inflammation severity was determined by histology score and lipocalin level. Microbiota–host immune system interactions were assessed by quantitative PCR analysis.Results CARD9 controls pathogen virulence in a microbiota-independent manner by supporting a specific humoral response. Higher susceptibility to C. rodentium-induced colitis was observed in Card9–/– →GF mice. The microbiota of Card9 –/– mice failed to outcompete the monosaccharide-consuming C. rodentium, worsening the infection severity. A polysaccharide-enriched diet counteracted the ecological advantage of C. rodentium and the defective pathogen-specific antibody response in Card9 –/– mice.Conclusions CARD9 modulates the susceptibility to intestinal infection by controlling the pathogen virulence in a microbiota-dependent and microbiota-independent manner. Genetic susceptibility to intestinal pathogens can be overridden by diet intervention that restores humoural immunity and a competing microbiota.