Bile acids are cholesterol-derived, natural surfactants, produced in the liver. They are critical to lipid digestion, antibacterial defense, and cholesterol synthesis, as well as other aspects of human biology. Importantly, bile acid dysregulation has been linked to intestinal bowel disease. Intestinal inflammation is modulated through a fine balance between the intestinal microbiota and the mucosal immune system. Imbalance can activate immune signaling pathways, leading to uncontrolled, pathological immune responses. Gut-residing bacteria in both the small and large intestines are exposed to a significant amount of bile acids and are known to convert host- derived bile acids into more hydrophobic, and thus, more bioavailable derivatives. We hypothesize that bacteria-produced secondary bile acids directly regulate the differentiation and/or function of key immune cells under inflammatory conditions, providing a communications link between commensal bacteria and mucosal immunity. We propose 1) to dissect the mechanisms of bile acid-mediated immune modulation and identify bile acid immune cell targets, 2) to identify bacteria and their enzymes that generate immune-modulatory bile acids and 3) to identify the novel metabolites of bile acids that regulate mucosal inflammation in vivo, at physiological concentrations. Elucidation of these mechanisms will not only provide novel therapeutic options for inflammatory diseases, but also open exciting avenues to study unique regulatory interactions between gut-residing microorganisms, small molecule metabolites and host immune cells.

Public Health Relevance

Microbial dysbiosis and deregulated immune responses have been centrally implicated in the development of inflammatory bowel disease (IBD). Bile acids, which are critical for lipid digestion, are subject to metabolism by the intestinal microbiota. The resulting bile acid metabolites are thought to modulate many biological processes. I hypothesize that microbiota- generated bile acids may be protective in IBD by directly regulating immune cell function and differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK110559-01
Application #
9160596
Study Section
Special Emphasis Panel (ZRG1-DKUS-P (55))
Program Officer
Perrin, Peter J
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$505,773
Indirect Cost
$183,219
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Kim, Sangdoo; Kim, Hyunju; Yim, Yeong Shin et al. (2017) Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549:528-532