The Michigan State University Enterics Research Investigational Network, Cooperative Research Center (MSU ERIN CRC) is a multidisciplinary Research Center proposal to study the enteric microbiome in health and disease with the overarching objective to elucidate its relationship to one of the most important global health problems, diarrheal illness. MSU ERIN CRC is a synergistic group of scientists from multiple disciplines, including microbial ecology, microbiology, immunology, epidemiology, and engineering, with cooperation from physicians working in infectious diseases, surgery, and pediatrics. Our long term goal is to determine the role of the microbiome in enhancing susceptibility or providing resistance to enteric diseases. We will focus on relationships between factors mediating diarrheal disease: enteric bacterial pathogens, the enteric microbiome, and host responses controlling susceptibility, resistance, or autoimmunity. Our overarching hypotheses are: (1) the enteric microbiome protects the host from luminal, epithelial and invasive pathogens, (2) diversity of the microbiome controls resiliency after perturbations, (3) the community metabolome contributes to lesions during pathogen invasion, and (4) resident microbiota intensify autoimmune responses by bacterial motifs exhibiting molecular mimicry. We will address these hypotheses using (1) bioreactors and mice colonized with human microbiota in Areas 1 and 2, and (2) samples from an epidemiological study of laboratory-confirmed cases of diarrhea in Area 3. In Area 1, Microbial Ecology and Pathogenesis, our overall objectives are to determine if (1) reduced diversity of the intestinal microbial community allows enteric pathogens with different lifestyles (luminal, epithelium-associated, and invasive) to become established in human fecal microbial communities in bioreactors and humanized mice, and (2) if the general ecological principle of competitive exclusion governs this process. In Area 2, Host Response, our overall objectives are to determine if murine model(s) with a "humanized" microbiome will develop spontaneous autoimmune sequelae secondary to C. jejuni infection with class A LOS;these models will then be used to dissect mechanisms of autoimmunity and to serve as treatment and prevention surrogates for GBS/MFS patients. In Area 3, Clinical Research, our overall objectives are to determine if shifts in the intestinal microbiome that increase host susceptibility to enteric disease are associated with (1) loss or inhibition of community members that negatively impact activities of an enteric pathogen, or (2) loss or inhibition of community members that interact with the host to promote resistance to enteric pathogens.

Public Health Relevance

Diarrheal diseases remain a serious health problem and a high health priority in the US and the world. CDC FoodNet data from ten US states show that STEC 0157 E. coli, C. jejuni, and Salmonella incidence has not decreased since 2004 in spite of increased research, regulatory, and public education efforts targeting food and waterborne enteric pathogens. New evidence suggests that the enteric microbiome profoundly affects enteric health and disease ahd may be a new preventative/therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
3U19AI090872-05S1
Application #
8914871
Study Section
Special Emphasis Panel (ZAI1-BLG-M (M2))
Program Officer
Mills, Melody
Project Start
2010-08-15
Project End
2015-07-31
Budget Start
2014-08-25
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$68,024
Indirect Cost
$22,024
Name
Michigan State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Sambanthamoorthy, Karthik; Luo, Chunyuan; Pattabiraman, Nagarajan et al. (2014) Identification of small molecules inhibiting diguanylate cyclases to control bacterial biofilm development. Biofouling 30:17-28
Jensen, Hanne; Roos, Stefan; Jonsson, Hans et al. (2014) Role of Lactobacillus reuteri cell and mucus-binding protein A (CmbA) in adhesion to intestinal epithelial cells and mucus in vitro. Microbiology 160:671-81
Tseng, Marion; Fratamico, Pina M; Manning, Shannon D et al. (2014) Shiga toxin-producing Escherichia coli in swine: the public health perspective. Anim Health Res Rev 15:63-75
Koestler, Benjamin J; Waters, Christopher M (2014) Bile acids and bicarbonate inversely regulate intracellular cyclic di-GMP in Vibrio cholerae. Infect Immun 82:3002-14
Britton, Robert A; Young, Vincent B (2014) Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology 146:1547-53
Koestler, Benjamin J; Seregin, Sergey S; Rastall, David P W et al. (2014) Stimulation of innate immunity by in vivo cyclic di-GMP synthesis using adenovirus. Clin Vaccine Immunol 21:1550-9
Robinson, Catherine D; Auchtung, Jennifer M; Collins, James et al. (2014) Epidemic Clostridium difficile strains demonstrate increased competitive fitness compared to nonepidemic isolates. Infect Immun 82:2815-25
Britton, Robert A; Irwin, Regina; Quach, Darin et al. (2014) Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol 229:1822-30
Malik, A; Sharma, D; St Charles, J et al. (2014) Contrasting immune responses mediate Campylobacter jejuni-induced colitis and autoimmunity. Mucosal Immunol 7:802-17
Hunter, Jessica L; Severin, Geoffrey B; Koestler, Benjamin J et al. (2014) The Vibrio cholerae diguanylate cyclase VCA0965 has an AGDEF active site and synthesizes cyclic di-GMP. BMC Microbiol 14:22

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