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Cecum gene expression signatures in germ-free WT mice colonized with microbiota from WT or Card9-/- mice and infected with Citrobacter rodentium induced colitis

ABSTRACT: It is crucial to decipher the host-microbiota interactions as they are involved in intestinal homeostasis and diseases. Caspase Recruitment Domain 9 (Card9) is an inflammatory bowel disease (IBD) susceptibility gene coding for an adapter protein for innate immunity toward many microorganisms. Card9-/- mice are more susceptible to colitis induced by Citrobacter rodentium as a result of impaired of the IL-22 pathway. C. rodentium is a natural mouse pathogen widely used to model human infections with Enteropathogenic Escherichia coli and Enterohaemorrhagic E. coli. To explore the role of the gut microbiota in the susceptibility of Card9-/- mice to C. rodentium infection, we colonized WT germ-free (GF) mice with the microbiota of WT (WT-->GF) or Card9-/- (Card9-/- -->GF) mice and challenged them with C. rodentium. Card9-/- -->GF mice were more susceptible than WT-->GF mice to C. rodentium. To examine the mechanisms responsible for this defect, we compared the cecum transcriptomes of WT -->GF and Card9-/- -->GF mice before and during C. rodentium-induced colitis. The number of down-regulated and up-regulated genes on day 12 after C. rodentium infection was lower in Card9-/- -->GF mice than WT-->GF mice. Card9-/- -->GF mice showed a significant down-regulation of gut morphogenesis and wound healing pathways suggesting that recovery is impaired in Card9-/- -->GF mice after C. rodentium infection. Immune response and cell division pathways were up-regulated in WT-->GF mice but not in Card9-/- -->GF confirming the defect of global response to infection when only the Card9-/- microbiota was transferred. The most induced and differentially expressed genes between Card9-/- -->GF and WT-->GF mice on day 4 after C. rodentium infection were Reg3g (encoding REGIIIγ) and Reg3b (encoding REGIIIβ).

ORGANISM(S): Mus musculus

PROVIDER: GSE90577 | GEO | 2017/11/25

SECONDARY ACCESSION(S): PRJNA355113

REPOSITORIES: GEO

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Project description:Background: The etiology of Inflammatory Bowel Disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3 and Reg3 independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that five weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype. Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or healthy microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for the host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders.

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Cecum gene expression signatures in germ-free WT mice colonized with microbiota from WT or Card9-/- mice and infected with Citrobacter rodentium induced colitis

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