Gender disparity has been recently reported for the severity of inflammatory bowel disease (IBD), with female patients with Crohn's disease (CD), one of the idiopathic IBDs, likely to experience more severe disease manifestations compared to males, and with symptom activity associated with hormonal surges during puberty, pregnancy and the post-partum period. Although the precise etiology is currently unknown, it is well accepted that IBD results from a dysregulated immune response to environmental factors (e.g., gut microflora) in genetically-predisposed individuals. However, the mechanism(s) underlying sex differences in IBD is an understudied area of investigation and little is known regarding how the orchestration of genetics, host immunity, as well as the gut microenvironment leads to gender disparity, specifically in Crohn's patients. Based on our extensive preliminary data, the central hypothesis of the present proposal is that gut microbial ligands signaling through TLR9 promote phenotypic and functional diversity in mucosal Treg populations that contribute to sex differences in experimental CD, such as that observed in SAMP mice, a spontaneous model of CD-like ileitis, and in patients with CD. This hypothesis will be tested by performing two specific aims: 1) Determine the impact of the gut microbiota on sex differences in the phenotypic and functional properties of the mucosal Treg population/subpopulations, and 2) Determine the mechanism(s) as to how TLR9 activation specifically results in sex-associated gut inflammation. The proposed studies are designed to elucidate potential mechanism(s) underlying sex differences in spontaneous, experimental Crohn's-like ileitis, and identify potential, early diseas pathways that can lead to the development of novel, gender-targeted strategies to improve treatment of patients suffering from this devastating disease.

Public Health Relevance

Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases (IBD)s, is characterized by a chronic, relapsing inflammation of the GI tract that is generally thought to result from uncontrolled immune responses to environmental factors in genetically predisposed individuals. Recent evidence shows that clear gender disparity in CD exists, with females displaying more severe disease manifestations than males that is associated with hormonal surges during puberty, pregnancy and the post-partum period;however, sex differences in mucosal immunity, in general, and IBD, in particular, is an understudied area of investigation. The present proposal will investigate one potential mechanism that gut microbial ligands promote phenotypic and functional diversity in mucosal Treg populations that contribute to sex differences in the pathogenesis of chronic intestinal inflammation, such as that observed in IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI102269-02
Application #
8517580
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Rothermel, Annette L
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$184,475
Indirect Cost
$66,975
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Goodman, W A; Garg, R R; Reuter, B K et al. (2014) Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis. Mucosal Immunol 7:1255-65
Goodman, Wendy A; Pizarro, Theresa T (2013) Regulatory cell populations in the intestinal mucosa. Curr Opin Gastroenterol 29:614-20
Pastorelli, Luca; De Salvo, Carlo; Vecchi, Maurizio et al. (2013) The role of IL-33 in gut mucosal inflammation. Mediators Inflamm 2013:608187