Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice
Crohn'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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2018-02-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/11/2/dmm031070 |
| _version_ | 1819076842312695808 |
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| author | Allison R. Rogala Alexi A. Schoenborn Brian E. Fee Viviana A. Cantillana Maria J. Joyce Raad Z. Gharaibeh Sayanty Roy Anthony A. Fodor R. Balfour Sartor Gregory A. Taylor Ajay S. Gulati |
| author_facet | Allison R. Rogala Alexi A. Schoenborn Brian E. Fee Viviana A. Cantillana Maria J. Joyce Raad Z. Gharaibeh Sayanty Roy Anthony A. Fodor R. Balfour Sartor Gregory A. Taylor Ajay S. Gulati |
| author_sort | Allison R. Rogala |
| collection | DOAJ |
| description | Crohn'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. |
| first_indexed | 2024-12-21T18:47:44Z |
| format | Article |
| id | doaj.art-2015fd711c414025973890eb9e992121 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-21T18:47:44Z |
| publishDate | 2018-02-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-2015fd711c414025973890eb9e9921212022-12-21T18:53:50ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-02-0111210.1242/dmm.031070031070Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient miceAllison R. Rogala0Alexi A. Schoenborn1Brian E. Fee2Viviana A. Cantillana3Maria J. Joyce4Raad Z. Gharaibeh5Sayanty Roy6Anthony A. Fodor7R. Balfour Sartor8Gregory A. Taylor9Ajay S. Gulati10 Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Geriatric Research, Education, and Clinical Center, VA Medical Center, Durham, NC 27705, USA Departments of Medicine; Molecular Genetics and Microbiology; and Immunology; Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC 27710, USA Department of Medicine, Division of Infectious Disease, Duke University Medical Center, Durham, NC 27710, USA Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC 28223, USA Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Geriatric Research, Education, and Clinical Center, VA Medical Center, Durham, NC 27705, USA Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Crohn'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.http://dmm.biologists.org/content/11/2/dmm031070Immunity-related GTPasesExperimental colitisInflammatory bowel diseases |
| spellingShingle | Allison R. Rogala Alexi A. Schoenborn Brian E. Fee Viviana A. Cantillana Maria J. Joyce Raad Z. Gharaibeh Sayanty Roy Anthony A. Fodor R. Balfour Sartor Gregory A. Taylor Ajay S. Gulati Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice Disease Models & Mechanisms Immunity-related GTPases Experimental colitis Inflammatory bowel diseases |
| title | Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice |
| title_full | Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice |
| title_fullStr | Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice |
| title_full_unstemmed | Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice |
| title_short | Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice |
| title_sort | environmental factors regulate paneth cell phenotype and host susceptibility to intestinal inflammation in irgm1 deficient mice |
| topic | Immunity-related GTPases Experimental colitis Inflammatory bowel diseases |
| url | http://dmm.biologists.org/content/11/2/dmm031070 |
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