Mucosal healing is the single greatest indicator of long-term outcomes in inflammatory bowel diseases (IBD), radiation enteritis, and other inflammatory diseases of the bowel, including likelihood and length of remission and risk of complications. Yet few therapies in current use for these diseases are designed to target this important aspect of patient care in large part because so little is known about the mediators and mechanisms underlying intestinal epithelial restitution following injury. We recently discovered through a gene-target deletion model that the small molecular weight heat shock protein, Hsp25 (human form is Hsp27), is essential to the mucosal wound response by controlling a check point where microbial and host factors converge to activate the STAT3 pathway. Without or with reduced levels of Hsp25, which is often the case in inflamed mucosa, host reparative factors like IL-22 and IL-6 simply do not work. This puts into perspective the uniqueness and importance of Hsp25/27 in the hierarchy of factors and mechanisms involved in mucosal healing responses. Our studies further reveal a previously unreported function of Hsp25/27 as an innate immune modulator of the gut microbiome that selects certain flagellin-expressing microbes that reinforce its own mucosal expression and function. In essence, this forms a self- perpetuating, reinforcing loop that insures vigorous wound healing responses driven by host and microbe signals. This proposal will therefore test the hypothesis that mucosal healing is dependent on a dynamic relationship between host and microbial factors, and when severely disturbed in inflammatory diseases of the bowel, will lead to impaired wound healing responses and chronic disease. Using the lens of the mutualistic interaction between intestinal epithelial Hsp25/27 and TLR5-activating gut microbes, we will focus on two components of this relationship to better understand the mediators and mechanisms that underlie it.
Aim 1 will determine the role and mechanisms of flagellin-induced intestinal epithelial cell (IEC) Hsp25/27 in checkpoint regulation for host- and microbe-mediated mucosal healing. As part of this aim, the capacity for FliC (flagellin- deficient) mutant and wild type E. coli and indigenous flagellated microbial strains to induce Hsp25 and permit Stat3-mediated mucosal healing following injury will be tested. The mechanisms by which Hsp25/27 accomplish it regulation of Stat3 will be defined.
Aim 2 will examine another aspect of Hsp25/27 ? as an innate immune modulator of the gut microbiome that promotes flagellin-expressing microbes that sustain its own expression and function in the gut mucosa. We will determine if IEC Hsp25/27 is secreted into the colonic mucus and lumen and how it selects, yet separates wound-promoting gut microbiota from the mucosa surface. The goal will be to examine these mechanisms and mediators in the context of human and experimental colitis to understand where these relationships breakdown, resulting in delayed or impaired mucosal healing. This knowledge can be leveraged to develop novel interventions to promote mucosal healing.

Public Health Relevance

This proposal is focused on defining the dynamic interactions between host and microbes essential for mucosal healing which is the single greatest indicator of long-term outcomes in inflammatory and injurious diseases of the bowel. The studies will investigate the mutually reinforcing relationships between the uniquely different stress protein, Hsp25/27, and Hsp25/27-activating flagellated microbes under conditions of mucosal injury and health using both experimental and human subject-based approaches. These studies will provide transformative insights into a previously unknown, yet essential network for wound responses that can be leveraged to develop novel interventions to promote mucosal healing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK047722-24A1
Application #
9686896
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
1993-09-30
Project End
2021-08-31
Budget Start
2018-09-20
Budget End
2019-08-31
Support Year
24
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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