Foodborne infections are estimated to cause >76 million illnesses, 300,000 hospitalizations and 5,000 deaths in the U.S. each year. Salmonella, Campylobacter, Shigella, and enterohemmorhagic Escherichia coli (EHEC) cause most infections, particularly in children <5 years of age. These four pathogens contribute to a wide range of illnesses including both bloody and non-bloody diarrhea, but also cause kidney failure, neurological disorders and death in some cases. For most enteric bacterial pathogens, the disease process is initiated by transmission to a susceptible host, passage through the gut, and attachment to host epithelial cells lining the gastrointestinal tract Most pathogens have evolved a variety of specialized mechanisms that enhance this process, and in several cases, specific genotypes have been shown to cause more severe disease than others. While bacterial characteristics are clearly important, the role of the host in disease pathogenesis should not be overlooked, as the interplay between different pathogens and host microbial communities is likely to be important for disease development. Here, we propose to use pyrosequencing combined with metagenomics to investigate the impact that these four common diarrheal pathogens have on the composition and function of the intestinal microbiome. We will analyze stool DNAs from 200 healthy individuals without diarrhea and make comparisons to 800 individuals with diarrhea caused by EHEC, Salmonella, Campylobacter, and Shigella.
The specific aims are: (1) Demonstrate that the composition, diversity and structure of the intestinal microbial community and the presence and expression of key virulence and antibiotic resistance genes impacts diarrheal disease caused by different enteric bacterial pathogens;(2) Determine that enteric disease profoundly affects the abundance of community members, the production and expression of microbiota by-products, and the distribution and diversity of functional marker genes (e.g., short chain fatty acids);and (3) Demonstrate that specific genetic and phenotypic characteristics of different enteric pathogens will more frequently and drastically alter the microbiome in patients with enteric disease. The proposed study will enhance our understanding of how the microbiome is impacted by infection with common enteric pathogens while controlling for gender, age, microbiota compositional and functional profiles, host immune responses, and bacterial characterisfics. Beneficial microbial communities, microbes and microbial products important for preventing enteric disease will be identified, which in turn, could guide future prevention and treatment strategies.

Public Health Relevance

By examining differences in the composition, diversity and functionality of the intestinal microbiome in 800 patients with enteric disease relafive to 200 healthy individuals, we will identify microbial communifies, microbes and by-products important for disease. Moreover, we will determine how different enteric pathogens affect the host microbiota while controlling for factors such as the genetic and phenotypic characteristics of infecting strains, age, gender, secretory IgA levels, antibiotic use, and diet.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090872-04
Application #
8516447
Study Section
Special Emphasis Panel (ZAI1-BLG-M)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$416,342
Indirect Cost
$137,471
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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