The Germ-free and Gut Microbiology Core C is an essential component of this PPG competitive renewal application that will control for and quantify the modulating role of the gut flora in innate immunity during experimental IBD. The core will provide PPG investigators with: 1) germ-free (GF) ileitis-prone and ileitis-free mice, and 2) sequencing and culture-based analysis of the gut microbiota. Developing a core infrastructure to study the role of the gut flora in modulating experimental CD using a common centralized facility is crucial to the success of the Program, and represents a cost-effective alternative to guarantee proper and reproducible results. The core will provide a highly-controlled environment to differentiate strain-specific and strain-independent mechanisms of CD-associated innate immunity that may be modulated by the gut microbiota. To support the research strategies proposed in this PPG project and the research benefits of the unique pattern of intestinal disease present in the SAMP1/YitFc mouse model of CD-like ileitis, the Specific Aims of the Germ-free and Gut Microbiome Core C will be to:
Aim 1). Conduct mechanistic microbiota studies in which human or mouse gut flora will be transplanted into GF mouse models of CD (SAMP or AKR) to quantify the modulatory role of the gut microbiome on innate immunity. This core will expand on our current knowledge and logistic infrastructure to provide mouse and human gut microbiota transplantation services into GF mice in order to test the hypotheses proposed in this PPG, while implementing new methods to accurately study the gut microbiota.
Aim 2). Provide a culture-based microbiological service approach to identify microbial determinants of intestinal disease severity. This core will provide consultation and services to effectively identify cultivable microorganisms that could modulate intestinal disease severity. Beneficial/anti-inflammatory microbes will ultimately have the potential to become commercial probiotics.
Aim 3). Provide cost-effective gut microbiome DNA and RNA-based sequencing analyses of samples from mice with or without genetic mutations as proposed in this grant. This core will centralize current in site and remote sequencing and analytical capabilities and unify protocols that we have validated with our collaborators to provide 16S rRNA microbiome analysis to the PPG projects. Established collaborations at CWRU and the Argonne National Laboratory at the University of Chicago will facilitate and standardize study design, sampling, and sequencing/data analysis protocols for microbiome and metatranscriptomic analysis.

Public Health Relevance

Crohn's disease (CD) affects almost a million individuals in the US and incurs significant costs to society. Understanding the precise mechanisms of innate immune disturbances that cause the disease, by using germ- free mice and state-of-the-art culture and microbial community genomic sequencing technologies will allow us to develop better strategies to modify the gut microbiota and prevent this severe intestinal disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
United States
Zip Code
Kumar, Anand; Davenport, Karen Walston; Vuyisich, Grace et al. (2018) Complete Genome Sequences of Historic Clostridioides difficile Food-Dwelling Ribotype 078 Strains in Canada Identical to That of the Historic Human Clinical Strain M120 in the United Kingdom. Microbiol Resour Announc 7:
Rathkey, Joseph K; Zhao, Junjie; Liu, Zhonghua et al. (2018) Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci Immunol 3:
Mehta, Kathan; Jaiswal, Palashkumar; Briggs, Farren et al. (2018) In-patient outcomes of Hematopoietic Stem Cell Transplantation in Patients with Immune Mediated Inflammatory Diseases: A Nationwide Study. Sci Rep 8:6825
Yang, Jie; Liu, Zhonghua; Wang, Chuanping et al. (2018) Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor. Proc Natl Acad Sci U S A 115:6792-6797
Liu, Zhonghua; Wang, Chuanping; Rathkey, Joseph K et al. (2018) Structures of the Gasdermin D C-Terminal Domains Reveal Mechanisms of Autoinhibition. Structure 26:778-784.e3
Perez, Jessica M; Chen, Yinghua; Xiao, Tsan S et al. (2018) Phosphorylation of the E3 ubiquitin protein ligase ITCH diminishes binding to its cognate E2 ubiquitin ligase. J Biol Chem 293:1100-1105
Rodriguez-Palacios, Alexander; Aladyshkina, Natalia; Ezeji, Jessica C et al. (2018) 'Cyclical Bias' in Microbiome Research Revealed by A Portable Germ-Free Housing System Using Nested Isolation. Sci Rep 8:3801
Chirieleison, Steven M; Rathkey, Joseph K; Abbott, Derek W (2018) Unique BIR domain sets determine inhibitor of apoptosis protein-driven cell death and NOD2 complex signal specificity. Sci Signal 11:
Goodman, Wendy A; Havran, Hannah L; Quereshy, Humzah A et al. (2018) Estrogen Receptor ? Loss-of-Function Protects Female Mice From DSS-Induced Experimental Colitis. Cell Mol Gastroenterol Hepatol 5:630-633.e1
Li, Zhaodong; Buttó, Ludovica F; Buela, Kristine-Anne et al. (2018) Death Receptor 3 Signaling Controls the Balance between Regulatory and Effector Lymphocytes in SAMP1/YitFc Mice with Crohn's Disease-Like Ileitis. Front Immunol 9:362

Showing the most recent 10 out of 90 publications