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Title

Bacteriophage communities as drivers of microbiota mediated dysbiosis during colitis

Project Description

The intestine is home to a dense community of bacteria that are integral to human health. The dysregulation of bacterial communities in the intestine is associated with inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. In addition to bacteria, the intestine harbors numerous bacterial viruses known as bacteriophage (phage). Intestinal phages exist as lysogenic prophages stably integrated into bacterial chromosomes or as replicating lytic particles capable of infecting and killing their bacterial host. Prophages undergo lytic induction to produce infectious phage particles when bacterial cells experience stress. Phage particle numbers are elevated at the intestinal mucosal surface during IBD and specific phage species increase in abundance in both Crohn’s disease and ulcerative colitis patients. This suggests that phages play an unidentified role in IBD and may be relevant biomarkers for the detection of IBD in humans. Using a mouse model of intestinal colitis coupled with metagenomic analysis of phage communities during dysbiosis, we have discovered that colitis significantly alters select members of the intestinal phage population. Specifically we see a decrease in phages associated with beneficial intestinal commensal bacteria, whereas the phages of overt intestinal pathogenic bacteria become more abundant. These preliminary studies indicate that the immune system imposes pressure on the microbiota resulting in altered phage community composition. This project will expand on these observations by exploring two specific aims. We will first determine the mechanisms by which the immune system alters phage abundances in the intestine to uncover whether intestinal inflammation alters phage community composition and promotes prophage induction from bacterial chromosomes. We will then test whether colitic phage populations are sufficient to promote intestinal inflammation and contribute to the development of IBD. In such a scenario phages may directly alter the composition of the intestinal bacterial community resulting in dysbiosis or liberate antigens from bacteria during phage-mediated host cell lysis leading to heightened inflammation. This project will provide novel insight into how phages contribute to microbiota-dependent disease etiology of IBD. It will delineate a relationship between host immunity and phages, providing critical information needed toward understanding the utility of phages as therapeutic tools to manipulate the microbiota and as potential biomarkers of human IBD.

Area of Study

Microbiology and Infectious Diseases

Populations

 

Method

Animal Models; Cell Biology, Molecular Biology, and Genetics

Disease or Symptom

Gastrointestinal Disease; Immune Related Disease; Infection

Department

Immunology and Microbiology

Mentor Location

Anschutz RC1

Mentor Contact Number

3037248670

Mentor Email

breck.duerkop@ucdenver.edu

Website

http://www.ucdenver.edu/academics/colleges/medicalschool/departments/ImmunologyMicrobiology/faculty/departmental/Pages/DUERKOP.aspx

Mentor Name

Duerkop, Breck

Funding Department/Program

Immunology and Microbiology; Medicine

Status

Current

Display on public listing?

Yes

Upload Date

 

Attachments

Created at 8/5/2018 2:02 PM by Hom, Patrick H
Last modified at 8/5/2018 2:02 PM by Hom, Patrick H