The intestinal epithelium is comprised of a single epithelial layer with both absorptive and secretory functions and is responsible for nutrient absorption. Additionally it is in constant contact with the abundant and diverse indigenous microbiota that inhabits the intestinal lumen. The epithelium and the microbiota exists in a remarkably stable, bal- anced symbiosis. This symbiosis is responsible for homeostasis of the intestinal ecosystem, and disturbances in this relationship has been associated with a wide variety of disease states. While animal models and the use of germ-free and gnotobiotic mice have led to remarkable advances in our understanding of host-microbial interac- tions, species-specific differences have made it difficult to study many human enteric pathogens, and suitable in vitro cell culture models that accurately represent human physiology are severely lacking. We have recently de- scribed an in vitro system that accurately reflects both the complex cellular makeup and the topological organization of the human intestine. Using human pluripotent stem cells (hPSCs), we have generated 3-dimensional (3D) intes- tinal units called Human Intestinal Organoids (HIOs). HIOs contain both intestinal epithelium and mesenchyme and are comprised of all of the different cell types found in the small intestine. HIOs have already proven to be a powerful system to study human intestinal development. Our preliminary results demonstrate that HIOs are also an excellent system to study how enteric pathogens affect the host epithelium. Therefore, the overarching goal of this project is to determine how specific enteric pathogens and normal microbiota affect the host HIO epithelium at the cellular and molecular level, and to determine how complex host-microbiota-pathogen relationships are estab- lished and maintained within the HIO. We propose to 1) investigate how interaction between commensal microbes and the HIO epithelium affects each partner in this symbiosis, 2) determine how contact pathogens affects the physiology of the HIO epithelium and 3) determine if contact with commensal microbes will alter the patho- gen/epithelium interaction. To accomplish these specific aims, we have established a multidisciplinary team that will examine the complex relationship between the HIO epithelium, the indigenous microbiota and viral and bacterial enteric pathogens.

Public Health Relevance

This project will investigate the use of human intestinal organoids (HIOs), which are complex, 3-dimensional intestinal tissues, as a model to study how bacteria and viruses can cause human disease. The interaction of the intestinal organoid epithelium with normal bacteria from the gut as well as disease-causing microbes will be studied. This work will lead to a new, high throughput human model system to study enteric infections, screen for novel therapies and test therapeutics prior to clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI116482-04
Application #
9631943
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Alexander, William A
Project Start
Project End
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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