The human gastrointestinal (GI) tract is home to an extremely complex bacterial community that plays essential roles for the host, including conversion and breakdown of metabolites, immune system development and protection against microbial pathogens. These communities are highly dynamic-their composition and metabolic activity can be altered dramatically by changes in their mammalian host, including diet, antibiotics, disease and aging. Significantly, changes in the GI microbiota (dysbiosis) are often associated with human inflammatory diseases, including Crohn's disease and ulcerative colitis, infectious diseases and colorectal cancer. These disorders affect millions of people and cost the US economy nearly $40 billion each year. The sheer complexity of the GI microbial community greatly complicates its study and makes it difficult to assign biological function(s) to specific bacterial genera, much less species. Consequently, there is a lack of sensitive biomarkers for early detection and monitoring of GI diseases. To address these gaps in knowledge, we propose to employ a highly simplified mouse model whose GI tract is colonized with only eight bacterial species, the altered Schaedler flora (ASF). Collectively, the ASF facilitates normal physiological function and health of the mouse GI system. In contrast to most bacteria comprising a conventional microbiota, each ASF member can be cultured in vitro. We are one of the few research teams in the US experienced in using this host-microbial community model to evaluate GI mucosal health and disease. Our central hypothesis is that perturbations mediated by host genetics and microbial provocateurs drive metabolic adaptations that are unique signatures of health and disease. We will use deep transcriptome sequencing along with quantitative PCR to profile changes in gene expression and abundance of the entire GI community to assess the metabolic states of the individual species in response to disease states. The ASF model will allow us to identify adaptations important for maintenance of the community through changes in the GI environment at a level not possible with a conventional mouse models, or by using mice colonized with a single bacterial species. The successful completion of these studies will yield a detailed """"""""documentary"""""""" of how individual members of the GI community respond to immune- (i.e., intrinsic) and bacterial-driven (i.e., extrinsic) perturbations. This research will contribute to the future of personalized medicine, including identification of new biomarkers that predict predisposition and severity of disease, as well as new strategies to mitigate the consequences of dysbiosis on the host.

Public Health Relevance

The human gastrointestinal (GI) tract is home to an extremely complex microbial community (microbiota) that is essential for maintaining a healthy host, and alterations in this community are associated with serious human diseases, ranging from colitis to cancer. To overcome the limitations inherent in studying the conventional GI microbiota, comprised of at least several hundred species, this project will utilize a simplified GI community model to understand how bacteria respond to environmental conditions that are relevant to health and disease. These findings will ultimately lead to new strategies for prevention and treatment of GI diseases. 5

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-GDB-2 (MC))
Program Officer
Sledjeski, Darren D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Iowa State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
Zip Code
Atherly, Todd; Mosher, Curtis; Wang, Chong et al. (2016) Helicobacter bilis Infection Alters Mucosal Bacteria and Modulates Colitis Development in Defined Microbiota Mice. Inflamm Bowel Dis 22:2571-2581
Lyte, Mark; Chapel, Ashley; Lyte, Joshua M et al. (2016) Resistant Starch Alters the Microbiota-Gut Brain Axis: Implications for Dietary Modulation of Behavior. PLoS One 11:e0146406
Wymore Brand, Meghan; Wannemuehler, Michael J; Phillips, Gregory J et al. (2015) The Altered Schaedler Flora: Continued Applications of a Defined Murine Microbial Community. ILAR J 56:169-78
Wannemuehler, Michael J; Overstreet, Ann-Marie; Ward, Doyle V et al. (2014) Draft genome sequences of the altered schaedler flora, a defined bacterial community from gnotobiotic mice. Genome Announc 2:
Rooks, Michelle G; Veiga, Patrick; Wardwell-Scott, Leslie H et al. (2014) Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission. ISME J 8:1403-17
Birt, Diane F; Phillips, Gregory J (2014) Diet, genes, and microbes: complexities of colon cancer prevention. Toxicol Pathol 42:182-8
Smith, Patrick M; Howitt, Michael R; Panikov, Nicolai et al. (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569-73
Kostic, Aleksandar D; Howitt, Michael R; Garrett, Wendy S (2013) Exploring host-microbiota interactions in animal models and humans. Genes Dev 27:701-18
Cywes-Bentley, Colette; Skurnik, David; Zaidi, Tanweer et al. (2013) Antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens. Proc Natl Acad Sci U S A 110:E2209-18