The active flares of colitis (collectively referred to as inflammatory bowel disease [IBD]) are characterized by migration of neutrophils to the intestinal lumen forming an intestinal crypt abscess. Such neutrophil movement is directed via polarized chemokine secretion by the epithelial cells that line the intestine. As I transitioned from trainee to faculty, I elucidated the mechanism by which such epithelial chemokine secretion is regulated. Briefly, I found that epithelial Ca++ mobilization is a key signal regulating such chemokine secretion. Further, such chemokine secretion is activated via the protein flagellin that is secreted by bacteria. Flagellin is secreted by commensal and pathogenic bacteria. However, only flagellin that crosses epithelia to the basolateral membrane domain activates epithelial chemokine secretion. Such translocation of flagellin is mediated by pathogens, but not commensal bacteria, explaining why, normally, only pathogenic bacteria induce epithelia to orchestrate inflammation. However, aberrant translocation of, and/or responses to, flagellin may occur in IBD and thus may underlie the inappropriate chemokine secretion that occurs in IBD. For my first independent award application, I propose to expand on the above studies while investigating the hypothesis that bacterial-epithelial interactions regulate the neutrophil infiltration (i.e., active inflammation) associated with both innate immunity and IBD. Consequently, pharmacologic manipulation of these interactions can be therapeutic for IBD. This hypothesis will be studied in vitro and in vivo via three specific aims, all of which are supported by substantial preliminary data. Specifically, I will characterize bacterial translocation of flagellin across intestinal epithelia, investigate how flagellin activates epithelial chemokine secretion, and further define the activation of anti-inflammatory signaling pathways by lipoxins. In vitro and in vivo models will be utilized.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK061417-01A1
Application #
6577688
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (01))
Program Officer
May, Michael K
Project Start
2003-03-15
Project End
2008-02-29
Budget Start
2003-03-15
Budget End
2004-02-29
Support Year
1
Fiscal Year
2003
Total Cost
$243,200
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Singh, Vishal; Yeoh, Beng San; Chassaing, Benoit et al. (2018) Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. Cell 175:679-694.e22
Zou, Jun; Chassaing, Benoit; Singh, Vishal et al. (2018) Fiber-Mediated Nourishment of Gut Microbiota Protects against Diet-Induced Obesity by Restoring IL-22-Mediated Colonic Health. Cell Host Microbe 23:41-53.e4
Chassaing, Benoit; Vijay-Kumar, Matam; Gewirtz, Andrew T (2017) How diet can impact gut microbiota to promote or endanger health. Curr Opin Gastroenterol 33:417-421
Chassaing, Benoit; Raja, Shreya M; Lewis, James D et al. (2017) Colonic Microbiota Encroachment Correlates With Dysglycemia in Humans. Cell Mol Gastroenterol Hepatol 4:205-221
Singh, Vishal; Yeoh, Beng San; Chassaing, Benoit et al. (2016) Microbiota-inducible Innate Immune, Siderophore Binding Protein Lipocalin 2 is Critical for Intestinal Homeostasis. Cell Mol Gastroenterol Hepatol 2:482-498.e6
Singh, Vishal; Chassaing, Benoit; Zhang, Limin et al. (2015) Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice. Cell Metab 22:983-96
Zhang, Benyue; Chassaing, Benoit; Shi, Zhenda et al. (2014) Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science 346:861-5
Chassaing, Benoit; Koren, Omry; Carvalho, Frederic A et al. (2014) AIEC pathobiont instigates chronic colitis in susceptible hosts by altering microbiota composition. Gut 63:1069-80
Chassaing, Benoit; Srinivasan, Gayathri; Delgado, Maria A et al. (2012) Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation. PLoS One 7:e44328
Carvalho, Frederic A; Koren, Omry; Goodrich, Julia K et al. (2012) Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12:139-52

Showing the most recent 10 out of 43 publications