Abstract
ABSTRACTCrohn's disease (CD) represents a chronic inflammatory disorder of the intestinal tract. Several susceptibility genes have been linked to CD, though their precise role in the pathogenesis of this disorder remains unclear. Immunity-related GTPase M (IRGM) is an established risk allele in CD. We have shown previously that conventionally raised (CV) mice lacking the IRGM ortholog, Irgm1 exhibit abnormal Paneth cells (PCs) and increased susceptibility to intestinal injury. In the present study, we sought to utilize this model system to determine if environmental conditions impact these phenotypes, as is thought to be the case in human CD. To accomplish this, wild-type and Irgm1−/− mice were rederived into specific pathogen-free (SPF) and germ-free (GF) conditions. We next assessed how these differential housing environments influenced intestinal injury patterns, and epithelial cell morphology and function in wild-type and Irgm1−/− mice. Remarkably, in contrast to CV mice, SPF Irgm1−/− mice showed only a slight increase in susceptibility to dextran sodium sulfate-induced inflammation. SPF Irgm1−/− mice also displayed minimal abnormalities in PC number and morphology, and in antimicrobial peptide expression. Goblet cell numbers and epithelial proliferation were also unaffected by Irgm1 in SPF conditions. No microbial differences were observed between wild-type and Irgm1−/− mice, but gut bacterial communities differed profoundly between CV and SPF mice. Specifically, Helicobacter sequences were significantly increased in CV mice; however, inoculating SPF Irgm1−/− mice with Helicobacter hepaticus was not sufficient to transmit a pro-inflammatory phenotype. In summary, our findings suggest the impact of Irgm1-deficiency on susceptibility to intestinal inflammation and epithelial function is critically dependent on environmental influences. This work establishes the importance of Irgm1−/− mice as a model to elucidate host-environment interactions that regulate mucosal homeostasis and intestinal inflammatory responses. Defining such interactions will be essential for developing novel preventative and therapeutic strategies for human CD.
Highlights
Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to occur as a result of dysregulated host immune responses to the enteric microbiota within a genetically susceptible host (Abraham and Cho, 2009; Leone et al, 2013)
Increased susceptibility to dextran sodium sulfate (DSS)-induced intestinal injury is attenuated in Irgm1-deficient mice housed in specific pathogen-free (SPF) conditions To determine whether Irgm1−/− mice housed in SPF conditions exhibit the increased susceptibility to intestinal inflammation previously observed in conventionally raised (CV) KO animals, SPF KO and WT littermate mice were subject to acute DSS injury as described (Liu et al, 2013)
In contrast to our previous findings when applying CV housing conditions, in which DSS-treated Irgm1 KO mice lost more weight than their WT counterparts, no differences in weight loss were detected between WT and KO groups when mice were housed in an SPF environment (Fig. 1A)
Summary
Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to occur as a result of dysregulated host immune responses to the enteric microbiota within a genetically susceptible host (Abraham and Cho, 2009; Leone et al, 2013). Genome wide association studies have identified a multitude of genes associated with development of CD, many of which encode factors involved in the regulation of the autophagy pathway (Baskaran et al, 2014; Cleynen et al, 2013; Hoefkens et al, 2013; Li et al, 2014; Liu et al, 2015; Khor et al, 2011) Among these is the immunity-related GTPase M (IRGM), which has recently been shown to play an integral role in the initiation of autophagy during microbial clearance (Chauhan et al, 2015). Irgm1−/− mice showed an overall increased susceptibility to dextran sodium sulfate (DSS)-induced colonic injury. The PCs of Irgm1-deficient mice expressed decreased mRNA levels of the AMPs α-defensin 20 (Defa20) and lysozyme (Lyz) (Liu et al, 2013)
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